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WO2025083600A1 - Prédiction de la réponse au traitement néoadjuvant dans le cancer du poumon non à petites cellules - Google Patents

Prédiction de la réponse au traitement néoadjuvant dans le cancer du poumon non à petites cellules Download PDF

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WO2025083600A1
WO2025083600A1 PCT/IB2024/060194 IB2024060194W WO2025083600A1 WO 2025083600 A1 WO2025083600 A1 WO 2025083600A1 IB 2024060194 W IB2024060194 W IB 2024060194W WO 2025083600 A1 WO2025083600 A1 WO 2025083600A1
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treatment
ctdna
patient
durvalumab
nsclc
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Davina GALE
Zhou Zhu
Zhongwu LAI
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AstraZeneca AB
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AstraZeneca AB
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • the present disclosure relates to methods of assessing the success of treatment with durvalumab and chemotherapy for resectable non-small cell lung cancer (R-NSCLC) in patients based on circulating tumor DNA (ctDNA) detection, ctDNA clearance and/or ctDNA partial clearance and/or variant allele fraction (VAF) before and after such treatment.
  • R-NSCLC circulating tumor DNA
  • VAF variant allele fraction
  • the present disclosure also relates to methods for treating patients with R-NSCLC based on ctDNA detection, ctDNA clearance and/or ctDNA partial clearance and/or VAF before and after such treatment.
  • SEQUENCE LISTING This application contains a sequence listing which is submitted electronically and is hereby incorporated by reference in its entirety.
  • Non-small cell lung cancer represents 80% to 85% of all lung cancers (Pisters and Le Chevalier, “Adjuvant chemotherapy in completely resected non-small-cell lung cancer: J Clin Oncol.2005 May 10; 23(14):3270-8).
  • OS 5-year overall survival
  • circulating tumor DNA (ctDNA) clearance can be used to predict success of a R- NSCLC treatment comprising durvalumab and chemotherapy.
  • ctDNA circulating tumor DNA
  • VAF variant allele frequency
  • the disclosure provides a method of assessing the success of a treatment comprising durvalumab and a chemotherapy for resectable non-small cell lung cancer (R- NSCLC) in a patient, the method comprising: (a) optionally, determining the ctDNA level in a pre-treatment sample obtained from the patient prior to administration of the treatment; (b) administering the treatment to the patient; and (c) determining the ctDNA level in a post- treatment sample obtained from the patient after administration of the treatment; wherein a decrease in the ctDNA level in the post-treatment sample compared to the ctDNA level in the pre-treatment sample is indicative that the treatment is and/or will be successful, or wherein no change in the ctDNA level or an increase in the ctDNA level in the post-treatment sample compared to the ctDNA level in the pre-treatment sample is indicative that the treatment is not and/or will not be successful.
  • R- NSCLC resectable non-small cell lung cancer
  • the disclosure provides a method of treating a patient having resectable non-small cell lung cancer (R-NSCLC), the method comprising: (a) optionally, determining ctDNA level in a pre-treatment sample obtained from the patient prior to administration of a treatment comprising durvalumab and a chemotherapy to the patient; (b) administering the treatment to the patient; (c) determining the ctDNA level in a post- treatment sample obtained from the patient after administration of the treatment; (d) administering the treatment to the patient or resecting the R-NSCLC if there is a decrease in the ctDNA level in the post-treatment sample compared to the ctDNA level in the pre- treatment sample, or administering an alternative treatment to the patient if there is no change or an increase in the ctDNA level in the post-treatment sample compared to the ctDNA level in the pre-treatment sample.
  • R-NSCLC resectable non-small cell lung cancer
  • the disclosure relates to methods of assessing the success of a treatment comprising durvalumab and a chemotherapy for R-NSCLC in a patient, or methods of treating a patient having R-NSCLC, wherein the method comprises, in part, determining a variant allele fraction (VAF) in the pre-treatment sample and a VAF in the post-treatment sample; wherein a decrease in the VAF in the post-treatment sample compared to the VAF in the pre-treatment sample is indicative that the treatment is and/or will be successful; and Reference Nos: B7H1-550-PCT administering the treatment to the patient if there is a decrease in the VAF in the post- treatment sample compared to the VAF in the pre-treatment sample.
  • VAF variant allele fraction
  • the disclosure relates to a method of assessing the success of a treatment comprising durvalumab and a chemotherapy for resectable non-small cell lung cancer (R-NSCLC) in a patient, the method comprising: (a) administering a treatment comprising durvalumab and chemotherapy to the patient; and (b) determining the ctDNA level in a post-treatment sample obtained from the patient after administration of the treatment; wherein detecting ctDNA in the post-treatment sample is indicative that the treatment is not and/or will not be successful.
  • R-NSCLC resectable non-small cell lung cancer
  • the disclosure relates to a method of treating a patient having resectable non-small cell lung cancer (R-NSCLC), the method comprising: (a) administering a treatment comprising durvalumab and chemotherapy to the patient; (b) determining the ctDNA level in a post-treatment sample obtained from the patient after administration of the treatment; and (c) administering an alternative treatment to the patient if ctDNA is detected in the post-treatment sample.
  • R-NSCLC resectable non-small cell lung cancer
  • FIG.1 shows the design of the AEGEAN study, a phase 3 global, randomised, double blind, placebo-controlled study of perioperative Durvalumab + neoadjuvant chemotherapy (D arm) versus Placebo and chemotherapy (PBO arm). Plasma samples were collected at protocol-specified timepoints, including prior to each neoadjuvant treatment cycle, before surgery, and adjuvant treatment cycle.
  • ⁇ Ventana SP263 immunohistochemistry assay Choice of CT regimen determined by histology and at the investigator’s discretion.
  • cisplatin + pemetrexed or carboplatin + pemetrexed For non-squamous: carboplatin + paclitaxel or cisplatin + gemcitabine (or carboplatin + gemcitabine for patients who have comorbidities or who are unable to tolerate cisplatin per the investigator’s judgment).
  • ⁇ Post-operative radiotherapy was permitted where indicated per local guidance. ⁇ Not all patients had samples available at all timepoints.
  • FIG.2 shows the distribution and median VAFs (variant allele fractions) quantifying the amount of circulating tumor DNA (ctDNA) at longitudinal timepoints in patients in the Durvalumab + chemotherapy (D arm) versus the Placebo + chemotherapy (PBO arm).
  • Plasma samples analysed were collected pre-dose at cycle 1 day 1 (C1D1), cycle 2 day 1 (C2D1), cycle 3 day 1 (C3D1), cycle 4 day 1 (C4D1) and pre-surgery prior to treatment.
  • ctDNA was considered detected if the signal to noise exceeded a threshold of P ⁇ 0.01.
  • FIG.3 shows the baseline characteristics and pathological response (pCR, pathological complete response; MPR, major pathological response) rates of ctDNA- evaluable patients compared to those for the overall mITT (modified Intention to Treat) population in the Durvalumab + chemotherapy (D arm) vs the Placebo + chemotherapy (PBO arm).
  • pCR pathological complete response
  • MPR major pathological response
  • C1D1 168 adjuvant
  • FIG.4 shows longitudinal ctDNA VAFs (variant allele fractions) quantifying the amount of ctDNA in patients with (Y) or without (N) a pathological complete response (top) or major pathological response (bottom).
  • D+CT (blue): Durvalumab + chemotherapy arm; PBO+CT (red); Placebo + chemotherapy arm.
  • ctDNA was considered detected if the signal to noise exceeded a threshold of P ⁇ 0.01, as determined using the Invitae Personalized Cancer MonitoringTM assay.
  • ctDNA detected orange circles; ctDNA not detected: blue circles.
  • FIG.5 shows the amount of residual volume of tumor (RVT) in patients with (Yes, light grey) or without (No, dark grey) a pathological complete response in patients with ctDNA clearance (CL) at the timepoints specified.
  • RVT residual volume of tumor
  • -90% indicates a major pathologic response.
  • D+CT Durvalumab + chemotherapy arm
  • PBO+CT Placebo + chemotherapy arm.
  • FIG.6 shows the ctDNA clearance rate at different longitudinal timepoints at cycle 2 day 1 (C2D1); C3D1, C4D1 and pre-surgery.
  • ctDNA clearance is defined as the proportion of patients with a change from ctDNA detected at baseline C1D1 to undetected at the specified on-treatment timepoint.
  • ctDNA non-clearance is defined as ctDNA-positive at the specified on-treatment timepoint (where baseline [C1D1] can be either evaluable or non-evaluable).
  • the plot shows analysis of a variable number of patients at each timepoint. Among patients who were ctDNA-positive at baseline (C1D1), higher rates of ctDNA clearance were observed in the D arm vs the PBO arm. *The plot shows an analysis of a variable number of patients at each timepoint.
  • ctDNA clearance is defined as the proportion of patients with a change from ctDNA detected at baseline (C1D1) to undetected at the specified on-treatment timepoint.
  • ctDNA non-clearance is defined as ctDNA-positive at the specified on-treatment timepoint (where baseline [C1D1] can be either evaluable or non-evaluable).
  • FIG.7 shows the pathological complete response rate (pCR; left) or Major Pathological response rate (MPR; right) of patients who had either ctDNA clearance (CL) or non clearance (no CL) at cycle 2 day 1 (C2D1) following treatment with Durvalumab + chemotherapy (D arm) or Placebo + chemotherapy (PBO arm).
  • FIG.8 shows the pathological complete response rate (pCR; left) or Major Pathological response rate (MPR; right) in patients who had either ctDNA clearance (CL) or non clearance (no CL) at cycle 3 day 1 (C3D1) following treatment with Durvalumab + chemotherapy (D arm) or Placebo + chemotherapy (PBO arm).
  • Confidence Intervals (CIs) were calculated by Montgomeryn-Nurminen without stratification.
  • ctDNA clearance positive baseline and negative on-treatment.
  • ctDNA non-clearance positive on-treatment (includes baseline evaluable and non-evaluable).
  • FIG.9 shows the pathological complete response rate (pCR; left) or Major Pathological response rate (MPR; right) of patients who had either ctDNA clearance (CL) or non clearance (no CL) at cycle 4 day 1 (C4D1) following treatment with Durvalumab + chemotherapy (D arm) or Placebo + chemotherapy (PBO arm). Confidence Intervals (CIs) were calculated by Montgomeryn-Nurminen without stratification.
  • ctDNA clearance positive baseline and negative on-treatment.
  • ctDNA non-clearance positive on-treatment (includes baseline evaluable and non-evaluable).
  • FIG.10 shows the pathological complete response rate (pCR; left) or Major Pathological response rate (MPR; right) of patients who had either ctDNA clearance (CL) or non clearance (no CL) at pre-surgery following treatment with Durvalumab + chemotherapy (D arm) or Placebo + chemotherapy (PBO arm).
  • Confidence Intervals (CIs) were calculated by Montgomeryn-Nurminen without stratification.
  • ctDNA clearance positive baseline and negative on-treatment.
  • ctDNA non-clearance positive on-treatment (includes baseline evaluable and non-evaluable).
  • FIG.11 shows the ctDNA clearance rate in patients with a pathological complete response (pCR; left, solid line), no pCR (left, dotted line), major pathological response (MPR; right, solid line), no MPR (right, dotted line) at different longitudinal timepoints (i.e., cycle 2 day 1 [C2D1], C3D1, C4D1 and pre-surgery).
  • PBO arm (PBO) Placebo + chemotherapy.
  • pCR 25.6% vs 6.3%) and MPR (44.4% vs 18.8%) rates were higher in the D arm vs the PBO arm.
  • FIG.12 shows the ctDNA Variant Allele Fractions (VAFs) and dynamics at different longitudinal timepoints (Cycle 1 Day 1 [PreC1D1], etc.), with each line corresponding to a patient.
  • ctDNA was considered detected if the signal to noise exceeded a threshold of P ⁇ 0.01.
  • FIG.13A shows tables showing the positive predictive value (PPV) and negative predictive value (NPV) of ctDNA clearance at different neoadjuvant timepoints for pCR (pathological complete response) or MPR (major pathological response).
  • PPV positive predictive value
  • NPV negative predictive value
  • FIG.13B shows tables showing the positive predictive value (PPV) and negative predictive value (NPV) of ctDNA clearance at different neoadjuvant timepoints for pCR (pathological complete response) or MPR (major pathological response).
  • PPV positive predictive value
  • NPV negative predictive value
  • the number of patients analysed at each timepoint were as follows: C2D1 (27, 5), C3D1 (50, 6), C4D1 (51, 6) and Pre-surgery (45, 6).
  • NPV negative predictive value
  • PPV positive predictive value
  • FIG.14A – FIG.14D show the Kaplan-Meier analysis of Event Free Survival (EFS) by distinct combination groups of ctDNA and pathological responses for patients treated with Durvalumab and chemotherapy (D+CT) at the specified timepoint (cycle 2 day 1 (C2D1), FIG.14A; cycle 3 day 1 (C3D1), FIG.14B; cycle 4 day 1 (C4D1), FIG.14C; and pre- surgery, FIG.14D).
  • pCR(+); ctDNA-CL(+) Patients with ctDNA clearance who have a later pathological complete response (pCR).
  • pCR(+); ctDNA-CL(-) Patients with no ctDNA clearance who have a later pathological complete response (pCR).
  • pCR(-); ctDNA-CL(+) Patients with ctDNA clearance who do not have a later pCR.
  • pCR(-); ctDNA-CL(-) Patients without ctDNA clearance who do not have a later pCR.
  • Patients who are pCR-/ctDNA CL- have shortest EFS. From C3D1, patients who are pCR+/ctDNA CL+ have similar EFS benefits compared to patients who are pCR-/ctDNA CL+. * Note in the subset analysis, there are small N’s and large CIs.
  • FIG.15A – FIG.15D show the Kaplan-Meier analysis of Event Free Survival (EFS) by distinct combination groups of ctDNA and pathological responses for patients treated with placebo and chemotherapy (PBO+CT) at the specified timepoint (cycle 2 day 1 (C2D1), FIG. 15A; cycle 3 day 1 (C3D1), FIG.15B; cycle 4 day 1 (C4D1), FIG.15C; and pre-surgery, FIG.15D).
  • pCR(+); ctDNA-CL(+) Patients with ctDNA clearance who have a later pathological complete response (pCR).
  • pCR(+); ctDNA-CL(-) Patients with no ctDNA clearance who have a later pathological complete response (pCR).
  • pCR(-); ctDNA-CL(+) Patients with ctDNA clearance who do not have a later pCR.
  • pCR(-); ctDNA-CL(-) Patients without ctDNA clearance who do not have a later pCR.
  • Patients who are pCR-/ctDNA CL- Reference Nos: B7H1-550-PCT have shortest EFS.
  • pCR+/ctDNA CL+ marginally improved EFS compared to pCR-/ctDNA CL+. * Note in the subset analysis, there are small N’s and large CIs.
  • FIG.17 shows pCR (left) and MPR (right) by radiological response (tumor size) after neoadjuvant treatment, pre-surgery. *CIs calculated by stratified Mangatinen and Nurminen method.
  • FIG.18 shows ctDNA clearance at early neoadjuvant timepoints identified patients with improved EFS. More patients were identified by ctDNA clearance during neoadjuvant Tx than were identified by pCR (determined post-Sx) ⁇ . The number of patients in each subgroup were based on the BEP, and patients were not required to be evaluable at all visits to be included in the analysis, resulting in the differences in the number of patients at each visit (i.e., not all patients had samples at all timepoints). Medians and 95% CI were estimated using the Kaplan-Meier method. HRs were calculated using an unstratified Cox proportional hazards model.
  • *EFS was defined as time from randomisation to the earliest of: (A) progressive disease (PD) that precludes surgery; (B) PD discovered and reported by the investigator upon attempting surgery that prevents completion of surgery; (C) local/distant recurrence using BICR per RECIST v1.1; or (D) death from any cause.
  • PD progressive disease
  • C local/distant recurrence using BICR per RECIST v1.1
  • D death from any cause.
  • FIG.19 shows associations of ctDNA clearance and neoadjuvant C2D1 with EFS and OS.
  • FIG.21 shows associations of ctDNA clearance at pre-surgery with pCR and EFS. Patients with no ctDNA clearance at pre-surgery and no pCR had the poorest EFS outcomes. HRs were calculated using an unstratified Cox proportional hazard model using the Efron method to adjust for ties and Wald confidence intervals. *Data are shown for the pre-Sx timepoint for comparison of pCR; similar data were observed at earlier cycles of neoadjuvant Tx.
  • FIG.22 shows associations of MRD at the post-surgical landmark (adjuvant C1D1) with DFS.
  • the present disclosure relates to methods of assessing the success of treatment with durvalumab and chemotherapy for resectable non-small cell lung cancer (R-NSCLC) in patients based on circulating tumor DNA (ctDNA) detection, ctDNA clearance and/or ctDNA partial clearance and/or variant allele fraction (VAF), and/or radiological response (tumor size) before and after such treatment.
  • R-NSCLC circulating tumor DNA
  • VAF ctDNA clearance and/or ctDNA partial clearance and/or variant allele fraction
  • tumor size radiological response
  • the present disclosure also relates to methods for treating patients with R-NSCLC based on ctDNA detection, ctDNA clearance and/or ctDNA partial clearance and/or VAF before and after such treatment.
  • the disclosure provides a method of assessing the success of a treatment comprising durvalumab and a chemotherapy for resectable non-small cell lung cancer (R- NSCLC) in a patient, the method comprising: (a) optionally, determining the circulating tumor DNA (ctDNA) level in a pre-treatment sample obtained from the patient prior to administration of the treatment; (b) administering the treatment to the patient; and (c) determining the ctDNA level in a post-treatment sample obtained from the patient after administration of the treatment; wherein a decrease in the ctDNA level in the post-treatment sample compared to the ctDNA level in the pre-treatment sample is indicative that the treatment is and/or will be successful, or wherein no change in the ctDNA level or an increase in the ctDNA level in
  • the disclosure provides a method of treating a patient having resectable non-small cell lung cancer (R-NSCLC), the method comprising: (a) optionally, determining the circulating tumor DNA (ctDNA) level in a pre-treatment sample obtained from the patient prior to administration of a treatment comprising durvalumab and a chemotherapy to the patient; (b) administering the treatment to the patient; (c) determining the ctDNA level in a post-treatment sample obtained from the patient after administration of the treatment; (d) administering the treatment to the patient or resecting the R-NSCLC if there is a decrease in the ctDNA level in the post-treatment sample compared to the ctDNA level in the pre-treatment sample, or administering an alternative treatment to the patient if there is no change or an increase in the ctDNA level in the post-treatment sample compared to the ctDNA level in the pre-treatment sample.
  • R-NSCLC resectable non-small cell lung cancer
  • the disclosure provides a method of assessing the success of a treatment comprising durvalumab and a chemotherapy for resectable non-small cell lung cancer (R-NSCLC) in a patient, the method comprising: (a) administering a treatment comprising durvalumab and chemotherapy to the patient; and (b) determining the ctDNA level in a post-treatment sample obtained from the patient after administration of the treatment; wherein detecting ctDNA in the post-treatment sample is indicative that the treatment is not and/or will not be successful.
  • R-NSCLC resectable non-small cell lung cancer
  • the disclosure provides a method of a method of treating a patient having resectable non-small cell lung cancer (R-NSCLC), the method comprising: (a) administering a treatment comprising durvalumab and chemotherapy to the patient; (b) determining the ctDNA level in a post-treatment sample obtained from the patient after administration of the treatment; and (c) administering an alternative treatment to the patient if ctDNA is detected in the post-treatment sample.
  • R-NSCLC resectable non-small cell lung cancer
  • the disclosure relates to methods of assessing the success of a treatment comprising durvalumab and a chemotherapy for R-NSCLC in a patient, or methods of treating a patient having R-NSCLC, wherein the method comprises, in part, determining a variant allele fraction (VAF) in the pre-treatment sample and a VAF in the post-treatment sample; wherein a decrease in the VAF in the post-treatment sample compared to the VAF in the pre-treatment sample is indicative that the treatment is and/or will be successful; and administering the treatment to the patient if there is a decrease in the VAF in the post- treatment sample compared to the VAF in the pre-treatment sample.
  • VAF variant allele fraction
  • any concentration range, percentage range, ratio range or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated. Units, prefixes, and symbols are denoted in their Système International de Unites (SI) accepted form. Numeric ranges are inclusive of the numbers defining the range. Unless otherwise indicated, nucleotide sequences are written left to right in 5' to 3' orientation. Amino acid sequences are written left to right in amino to carboxy orientation.
  • x, y, and/or z can refer to “x” alone, “y” alone, “z” alone, “x, y, and z,” “(x and y) or z,” “x or (y and z),” or “x or y or z.”
  • the terms “treat,” “treatment,” or “treating” when used in the context of treating cancer refer to reducing disease pathology, reducing or eliminating disease symptoms, promoting increased survival rates, and/or reducing discomfort.
  • treating can refer to the ability of a therapy when administered to a subject, to reduce disease symptoms, signs, or causes.
  • Treating also refers to mitigating or decreasing at least one clinical symptom and/or inhibition or delay in the progression of the condition and/or prevention or delay of the onset of a disease or illness.
  • the terms "subject,” “individual,” or “patient,” refer to any subject, particularly a mammalian subject, for whom diagnosis, prognosis, or therapy is desired. Mammalian subjects include, for example, humans, non-human primates, dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, bears, and so on.
  • the term “patient” may refer to a human. This disclosure provides methods of predicting treatment outcome for R-NSCLC.
  • the methods can comprise: optionally, detecting circulating tumor DNA (ctDNA) and/or variant allele frequency (VAF) in a sample obtained from a patient at a first time point in a pre- treatment sample before the patient undergoes a R-NSCLC treatment; detecting ctDNA and/or variant allele frequency in a sample obtained from the patient at one or more additional time points in one or more additional samples after the patient undergoes the R- NSCLC treatment; determining the difference between the detected ctDNA and/or variant allele frequency in the pre-treatment sample and at least one or more additional samples, wherein a decrease in the ctDNA and/or variant allele frequency in at least one of the additional samples relative to the pre-treatment sample indicates the patient as responsive to the R-NSCLC treatment (i.e., that the treatment is successful); and continuing the R-NSCLC treatment to the patient if the patient is indicated as responsive to the R-NSCLC treatment.
  • ctDNA circulating tumor DNA
  • VAF variant allele frequency
  • This disclosure also provides methods of assessing the success of a treatment comprising durvalumab and a chemotherapy for resectable non-small cell lung cancer (R- NSCLC) in a patient, the method comprising (a) optionally, determining the circulating tumor DNA (ctDNA) level in a pre-treatment sample obtained from the patient prior to Reference Nos: B7H1-550-PCT administration of the treatment; (b) administering the treatment to the patient; and (c) determining the ctDNA level in a post-treatment sample obtained from the patient after administration of the treatment; wherein no change or an increase in the ctDNA level in the post-treatment sample is indicative that the treatment is and/or will be successful.
  • This disclosure also provides methods of treating a patient having resectable non-small cell lung cancer (R-NSCLC), the method comprising (a) optionally, determining the circulating tumor DNA (ctDNA) level in a pre-treatment sample obtained from the patient prior to administration of a treatment comprising durvalumab and
  • detecting ctDNA in the post- treatment sample is indicative that the treatment is not and/or will not be successful. In certain embodiments, there is an increase or no change in the ctDNA and/or variant allele frequency in at least one of the additional samples relative to the pre-treatment sample.
  • an increase or no change in the ctDNA and/or variant allele frequency in at least one of the additional samples relative to the pre-treatment sample indicates the patient as non-responsive to the R-NSCLC treatment (i.e., that the treatment is not successful), and discontinuing the R-NSCLC treatment to the patient and/or starting a different R-NSCLC treatment to the patient if the patient is indicated as non-responsive to the R-NSCLC treatment.
  • the R-NSCLC treatment refers to neoadjuvant treatment.
  • R-NSCLC treatment comprises administering durvalumab and a chemotherapy to the patient about every 21 days (Q3W) for about 4 cycles.
  • neoadjuvant treatment R-NSCLC treatment is administration of durvalumab and a chemotherapy to the patient about every 21 days (Q3W) for about 4 cycles.
  • the presence of ctDNA is detected in a post-treatment sample.
  • the detection of ctDNA in a post-treatment sample indicates the patient as non-responsive to the R-NSCLC treatment (i.e., that the treatment is not successful and/or will not be successful), and discontinuing the R-NSCLC treatment to the patient and/or starting a different or alternative R-NSCLC treatment to the patient if the patient is indicated as non-responsive to the R-NSCLC treatment.
  • the R-NSCLC treatment refers to neoadjuvant treatment.
  • Reference Nos: B7H1-550-PCT This disclosure also provides methods of predicting treatment outcome for R-NSCLC that further comprise determining tumor size of the R-NSCLC in the patient prior to administration of a treatment comprising durvalumab and a chemotherapy to the patient, administering the treatment to the patient; and determining tumor size of the R-NSCLC in the patient after administration of the treatment; wherein a decrease in tumor size after administration of the treatment is indicative that the treatment is and/or will be successful.
  • tumor size is determined prior to resecting the R-NSCLC.
  • tumor size is determined using magnetic resonance imaging (MRI), computed tomography (CT), or both MRI and CT.
  • MRI magnetic resonance imaging
  • CT computed tomography
  • a reduction in tumor size following treatment and prior to surgery can be an early indicator of pathological response to identify patients who may benefit most from treatment with durvalumab plus chemotherapy before surgery.
  • patients with radiological CR/PR have a higher rate of pCR and MPR as compared to patients with radiological stable disease. Also disclosed herein are methods of treating R-NSCLC.
  • the methods can comprise administering a R-NSCLC treatment to a subject in need thereof and determining a decrease in ctDNA and/or variant allele frequency in a post-treatment sample from the patient when compared to a pre-treatment sample from the patient, and continuing with the R-NSCLC treatment.
  • the methods also comprise administering a R-NSCLC treatment to a subject in need thereof and determining an increase or no change in ctDNA and/or variant allele frequency in a post-treatment sample from the patient when compared to a pre-treatment sample from the patient, and discontinuing with the R-NSCLC treatment, and optionally, starting a different or an alternative R-NSCLC treatment.
  • This disclosure also provides methods of assessing the success of a treatment comprising durvalumab and a chemotherapy for resectable non-small cell lung cancer (R- NSCLC) in a patient, the method comprising administering the treatment to the patient and determining the ctDNA level in a post-treatment sample obtained from the patient after administration of the treatment; wherein detecting ctDNA in the post-treatment sample and/or detecting an increase in the ctDNA level in the post-treatment sample is indicative that the treatment is not successful and/or will not be successful.
  • the first time point can be, for example, prior or immediately prior to the R-NSCLC treatment.
  • ctDNA is determined in a sample obtained from the patient at one or more additional time points (a skilled person would appreciate that a first sample can refer to a pre-treatment sample and a second sample can refer to a post-treatment sample).
  • the at least one of the one or more additional time points Reference Nos: B7H1-550-PCT can be, for example, at the end of or after at least a cycle of the R-NSCLC treatment.
  • the cycle of the R-NSCLC treatment is the first cycle of the R-NSCLC treatment.
  • the first time point is prior or immediately prior to a first cycle of the R-NSCLC treatment
  • the one or more additional time points are at the end of or after a second cycle of the R-NSCLC treatment.
  • the first cycle of the R-NSCLC treatment is immediately prior to the second cycle of the R-NSCLC treatment, which is immediately prior to the third cycle of the R-NSCLC treatment, which is immediately prior to the fourth cycle of the R-NSCLC treatment.
  • the R-NSCLC treatment may comprise up to 4 cycles of durvalumab and a chemotherapy before taking a post-treatment sample.
  • circulating-tumor DNA or "ctDNA” has its general meaning in the art and refers to DNA that comes from tumor cells.
  • ctDNA is detected in a blood sample from a patient.
  • ctDNA is detected in a blood sample that has been obtained from a patient.
  • the methods disclosed herein do not involve a surgical steps to obtain a patient sample.
  • the methods described herein may not encompass taking the sample.
  • ctDNA can carry one or more types of mutations, for example, germline mutations, somatic mutations, or both.
  • Germline mutations refer to mutations existing in germline DNA of a subject.
  • ctDNA from a patient can carry one or more mutations in one or more genes, for example, known cancer-associated genes (e.g., genes known to be associated NSCLC).
  • Somatic mutations refer to mutations originating in somatic cells of a subject, e.g., cancer cells.
  • the mutation can be cancer-associated mutations (e.g., cancer- associated somatic mutations).
  • Various assays can be used to detect and determine ctDNA levels.
  • ctDNA levels are detected using a ctDNA assay.
  • the methods provided herein can comprise isolation of cell-free DNA from the blood (e.g., plasma) of a patient of interest (e.g., a patient with R-NSCLC, or a subject is in remission of R-NSCLC, or a subject suspected to have R-NSCLC) and analysis of ctDNA in the cell-free DNA, employing the use of molecular barcoding and sequencing as a readout.
  • the method can comprise isolating plasma and ctDNA from intact cell-depleted blood.
  • the method can comprise centrifugation to generate plasma and extraction of nucleic acids from plasma, followed by library preparation with barcoding, sequencing, and then analysis.
  • the ctDNA for example, can be obtained from a whole blood and/or plasma sample by known methods.
  • the whole blood and/or plasma sample can be Reference Nos: B7H1-550-PCT analyzed by methods including, but not limited to, polymerase chain reaction (PCR) and next generation sequencing (NGS).
  • PCR polymerase chain reaction
  • NGS next generation sequencing
  • the ctDNA is detected using droplet digital PCR (ddPCR).
  • ddPCR droplet digital PCR
  • ctDNA levels can be determined using, for example, polymerase chain reaction (PCR), next generation sequencing (NGS), whole genome sequencing, whole exome sequencing, and/or droplet digital PCR (ddPCR).
  • the ctDNA is detected using a tumor na ⁇ ve assay (not requiring tissue or a germline sample).
  • the ctDNA is detected using a methylation-based assay or a methylation-based tumor-na ⁇ ve assay.
  • the ctDNA is detected using assays targeting SNVs, SVs or copy number variants or assays using fragmentomics to assess size differences of ctDNA and cell-free DNA. For example, whole exome sequencing as well as whole genome sequencing of tumor and or germline samples can be used to identify patient-specific mutations in the tumor, which are used to design an assay to track ctDNA in the plasma, using next generation sequencing, multiplex PCR, hybrid capture or droplet digital PCR.
  • tumor-specific mutations can be identified directly from whole genome sequencing of the plasma sample from the patient, without the need for a specific assay design, and ctDNA levels assessed by bioinformatic analysis.
  • determining ctDNA levels can comprise using a tumour- informed assay (e.g., a tumour-informed assay that uses whole genome sequencing analysis, or multiplex PCR, or hybrid capture); or a tumor na ⁇ ve/uninformed assay (e.g., a tumour na ⁇ ve/uninformed assay does not require next generation sequencing of the tumor and germline blood to identify patient-specific mutations for assay design).
  • determining ctDNA levels can comprise using a personalized ctDNA assay.
  • determining ctDNA levels can comprise using a generic ctDNA assay. In another example, determining ctDNA levels can comprise using a personalized tumour-informed ctDNA assay. In another example, determining ctDNA levels can comprise using a personalized tumour-uninformed ctDNA assay. In another example, determining ctDNA levels can comprise using a generic tumour-informed ctDNA assay. In another example, determining ctDNA levels can comprise using a generic tumour-uninformed ctDNA assay.
  • ctDNA is detected using INVITAE Personalized Cancer Monitoring (PCMTM), which is a patient-specific, tumor-informed liquid biopsy assay that uses next-generation sequencing and Anchored Multiplex PCR (AMPTM) to monitor molecular residual disease with high sensitivity at low variant allele fractions
  • PCMTM INVITAE Personalized Cancer Monitoring
  • AMPTM Anchored Multiplex PCR
  • the INVITAE assay is a tumour-informed assay that uses whole exome sequencing analysis of the tumor Reference Nos: B7H1-550-PCT and germline to identify tumor-specific mutations, which has a LoD95 of 80ppm (parts per million).
  • the assays used for determining ctDNA levels can have a detection limit of about 80 ppm (parts per million), which is 0.008% variant allele fraction (VAF), or 80 ppm to about 0.3 ppm (0.00003%).
  • the approximate range for a tumor-informed assay can be about 0.01% - 0.0001% VAF
  • the approximate range for tumor-uniformed assay can be about 0.1% - 0.3% VAF, or about 0.05% - 0.3% VAF, or about 0.02% - 0.3% VAF.
  • Exemplary amounts of ctDNA in a biological sample can range from about 1 ng per 4 mL of plasma to about 200 ng per 4 mL of plasma. In certain embodiments, ctDNA in a sample can range from about 5 ng per 4 mL of plasma to about 50 ng per 4 mL of plasma. Exemplary amounts of ctDNA in a biological sample (e.g., plasma) can range, for example, from about 1 ng/mL to about 50 ng/mL. In certain embodiments, ctDNA levels in a biological sample (e.g., plasma) can range, from about 5 ng/mL to about 10 ng/mL.
  • the ctDNA can have an exemplary size distribution of about 100-500 nucleotides, with a size of about 145 nucleotides (base pairs) for ctDNA and about a size of about 166 nucleotides (base pairs for cell-free DNA).
  • the method comprises determining ctDNA levels of the subject before the treatment.
  • the treatment comprises one or more cycles, and the ctDNA is determined before, during and after each cycle of the treatment.
  • the ctDNA can be determined before, during and after two or more cycles of the treatment, three or more cycles of the treatment, or each cycle of the treatment.
  • Each cycle of treatment can be at least 21 days, for example, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, or more, or a range between any two of these values.
  • 'C2D1' refers to day 1 of cycle 2
  • 'C3D1' refers to day 1 of cycle 3
  • 'C4D1' refers to day 1 of cycle 4.
  • the method comprises determining the ctDNA level or determining the VAF in a post-treatment sample.
  • the method comprises determining the ctDNA level or determining the VAF in a post-treatment sample after C1D1, C2D1, C3D1, or C4D1.
  • each cycle of treatment is from about 21 days to about 28 days. In some embodiments, each cycle of treatment is about 21 days. In some embodiments, each cycle of treatment is about 28 days.
  • the first time point or pre-treatment sample is prior or immediately prior to the Reference Nos: B7H1-550-PCT R-NSCLC treatment, and at least one of the one or more additional time points or post- treatment samples are at the end of or after at least a cycle of the R-NSCLC treatment. In some embodiments, the first time point or pre-treatment sample is prior or immediately prior to a first cycle of the R-NSCLC treatment, and the one or more additional time points or post-treatment samples are at the end of or after a second cycle of the R- NSCLC treatment.
  • the first cycle of the R-NSCLC treatment is immediately prior to the second cycle of the R-NSCLC treatment.
  • a decrease in the ctDNA and/or variant allele frequency in at least one of the additional samples relative to the pre-treatment sample indicates the patient as responsive to the R-NSCLC treatment (i.e., that the treatment is successful).
  • the method comprises continuing the R-NSCLC treatment to the patient when the patient is indicated as responsive to the R-NSCLC treatment.
  • the patient completes the total number of pre-surgery/neoadjuvant cycles (about 3 to 6 cycles about every 14 – 28 days (Q2W to Q4W) of durvalumab and chemotherapy, or 4 cycles about every 21 days (Q3W) of durvalumab and chemotherapy), or if all of the neoadjvant cycles are completed, then the patient progresses to surgery (resecting the R-NSCLC), optionally followed by adjuvant durvalumab.
  • pre-surgery/neoadjuvant cycles about 3 to 6 cycles about every 14 – 28 days (Q2W to Q4W) of durvalumab and chemotherapy, or 4 cycles about every 21 days (Q3W) of durvalumab and chemotherapy
  • the method comprises discontinuing the R-NSCLC treatment to the patient and/or starting a different R-NSCLC treatment to the patient when the patient is not indicated as responsive to the R-NSCLC treatment.
  • ctDNA is detected in at least one post-treatment sample, which indicates that the patient is non-responsive to the R-NSCLC treatment (i.e., that the treatment is not successful or will not be successful).
  • ctDNA levels Reference Nos: B7H1-550-PCT can have a detection limit of about 80ppm to about 0.3 ppm.
  • a baseline value from a pre-treatment sample can be the ctDNA level before administration of a R-NSCLC treatment.
  • the methods as disclosed herein would not be used, and such a patient would continue with the R-NSCLC treatment.
  • ctDNA clearance can be used to predict the success of the R- NSCLC treatment.
  • ctDNA clearance refers to undetectable levels of ctDNA in a sample obtained from the patient. For example, achieving ctDNA clearance in at least one of the additional samples relative to the pre-treatment sample indicates the patient as responsive to the R-NSCLC treatment (i.e., that the treatment is successful). In some embodiments, detecting the presence of ctDNA in at least one post-treatment sample indicates that the patient as non-responsive to the R-NSCLC treatment (i.e., that the treatment is not successful or will not be successful). In some embodiments, the method comprises continuing the R-NSCLC treatment to the patient when the R-NSCLC treatment results in ctDNA clearance.
  • the method comprises discontinuing the R-NSCLC treatment to the patient and/or starting a different R-NSCLC treatment to the patient when ctDNA clearance and/or partial clearance does not occur and thus the patient is not indicated as responsive to the R-NSCLC treatment.
  • a decreased ctDNA level in the post-treatment sample, or at least one of the additional samples, relative to the pre-treatment sample can comprise a decrease of at least 50% ctDNA from the ctDNA level in the pre-treatment sample, a decrease of at least 60% ctDNA from the ctDNA level in the pre-treatment sample, a decrease of at least 70% ctDNA from the ctDNA level in the pre-treatment sample, a decrease of at least 80% ctDNA from the ctDNA level in the pre-treatment sample, a decrease of at least 90% ctDNA from the ctDNA level in the pre-treatment sample, at least 95% ctDNA from the ctDNA level in the pre-treatment sample, a decrease of at least 98% ctDNA from the ctDNA level in the pre- treatment sample, a decrease of at least 99% ctDNA from the ctDNA level in the pre-treatment sample, or a decrease of 100% ctDNA from the ctDNA level in the pre-treatment
  • ctDNA clearance refers to 100% clearance of ctDNA, wherein 100% clearance of ctDNA (or simply ctDNA clearance) refers to a ctDNA level below (undetected ctDNA) the lower limit of detection of the assay used to detect ctDNA.
  • a ctDNA clearance indicates a successful treatment, and can predict an Reference Nos: B7H1-550-PCT improvement in pCR, MPR, DFS, OS, and/or EFS compared to standard of care or platinum- based chemotherapy.
  • a ctDNA clearance indicates a successful treatment, and can predict an improvement in pCR and/or EFS compared to standard of care or platinum-based chemotherapy.
  • a partial response or a partial molecular response refers to ctDNA clearance of greater than or equal to 50% clearance compared to the ctDNA level in the pre-treatment sample to less than 100% clearance.
  • a partial response indicates a successful treatment, and can predict an improvement in pCR, MPR, DFS, OS, and/or EFS compared to standard of care or platinum based chemotherapy.
  • the term "responsive" refers to a patient that achieves a response, i.e., a patient where the cancer is eradicated, reduced or improved, and thus an indication that the treatment is successful.
  • a successful treatment can refer to an improvement in pCR, MPR, DFS, OS, and/or EFS compared to standard of care or platinum based chemotherapy.
  • a patient with ctDNA clearance in a post-treatment sample is considered a "responder” and shows an improvement in pCR, MPR, DFS, OS, and/or EFS compared to standard of care or platinum based chemotherapy.
  • a "non- responder” or “refractory" patient includes patients for whom the cancer does not show reduction or improvement after the preoperative adjuvant therapy.
  • a patient with less than 50% ctDNA clearance in a post-treatment sample is considered a "non- responder" and does not have an improvement in pCR, MPR, DFS, OS, and/or EFS compared to standard of care or platinum based chemotherapy.
  • a patient having ctDNA detected in a post-treatment sample is considered a "non-responder” and does not have an improvement in pCR, MPR, DFS, OS, and/or EFS compared to standard of care or platinum based chemotherapy.
  • variant allele frequency VAF is also determined and can be used to predict treatment success.
  • determining ctDNA levels also comprises detecting variant allele frequency in the ctDNA.
  • the method further comprises detecting the variant allele frequency of ctDNA in a subject at a first time point in a pre-treatment sample, detecting variant allele frequency from the subject at one or more additional time points in one or more additional samples, and determining the difference of the variant allele frequency between the first and at least one of the one or more additional samples, wherein a decrease in the variant allele frequency at the additional sample(s) relative to the pre-treatment sample indicates that the treatment is successful (an Reference Nos: B7H1-550-PCT increase in the variant allele frequency at the additional sample(s) relative to the pre- treatment sample indicates that the patient is at risk of relapse).
  • the variant allele frequency (VAF) in ctDNA can be determined, for example, by determining the levels of ctDNA using a tumor-informed or tumor-uninformed assay in each of the pre-treatment sample and one or more additional samples, and/or by the mean or median variant allele frequency in each of the pre-treatment sample and one or more additional samples.
  • the ctDNA level can be used to determine the VAF in a sample.
  • VAF is ctDNA as a percentage of cell-free DNA present in a sample (e.g., blood or tumor).
  • the methods as disclosed herein can comprise detecting variant allele frequency in the ctDNA in a pre-treatment sample obtained from the patient at a first time point, detecting variant allele frequency in the ctDNA obtained from the patient at one or more additional time points in one or more additional samples, and determining the difference of the variant allele frequency in ctDNA between the first and at least one of the one or more additional samples, wherein a decrease in the variant allele frequency in at least one of the additional samples relative to the pre-treatment sample indicates the patient as responsive to the treatment.
  • a decreased VAF in the post-treatment sample, or at least one of the additional samples, relative to the pre-treatment sample can comprise a decrease of at least 50% VAF from baseline, a decrease of at least 60% VAF from baseline, a decrease of at least 70% VAF from baseline, a decrease of at least 80% VAF from baseline, a decrease of at least 90% VAF from baseline, a decrease of at least 95% VAF from baseline, a decrease of at least 98% VAF from baseline, or a decrease of at least 99% ctDNA from baseline.
  • the variant allele frequency can be determined, for example, by determining the levels of ctDNA using a tumor-informed or tumor-uninformed assay in each of the pre-treatment sample and one or more additional samples, or by the mean or median variant allele frequency in each of the pre-treatment sample and one or more additional samples.
  • the variant allele frequency is mutant allelic frequency for a driver mutation of lung cancer.
  • the methods are indicative that the treatment is and/or will be successful if the patient has and/or will have an improvement in one or more of EFS, OS, PCR, mPR and DFS.
  • the methods disclosed herein are indicative that the treatment is and/or will be unsuccessful if the Reference Nos: B7H1-550-PCT patient does not have and/or will not have an improvement in one or more of EFS, OS, PCR, mPR and DFS.
  • this disclosure provides methods of treating a patient identified as having resectable non-small cell lung cancer (R-NSCLC).
  • the methods can comprise administering a R-NSCLC treatment to a subject in need thereof and determining a decrease in ctDNA and/or variant allele frequency in a pre-treatment sample of the patient obtained at a first time point before the patient receives the R-NSCLC treatment when compared to a post-treatment sample of the patient obtained at a second time point after the patient receives the R-NSCLC treatment; and continuing with the R-NSCLC treatment.
  • the presence of ctDNA is detected in a post-treatment sample.
  • the detection of ctDNA in a post-treatment sample indicates the patient as non-responsive to the R-NSCLC treatment (i.e., that the treatment is not successful and/or will not be successful), and discontinuing the R-NSCLC treatment to the patient and/or starting a different R-NSCLC treatment to the patient.
  • the patient having R-NSCLC is newly diagnosed.
  • the patient having R-NSCLC is previously untreated.
  • the patient having R-NSCLC is histologically or cytologically documented as having stage II or stage III cancer (according to the American Joint Committee on Cancer [AJCC] Cancer Staging Manual, version 8).
  • the patient having R-NSCLC is histologically or cytologically documented as having stage IIA to select [N2] stage IIIB cancer (according to the American Joint Committee on Cancer [AJCC] Cancer Staging Manual, version 8).
  • the patient having R-NSCLC is newly diagnosed, previously untreated, and histologically or cytologically documented, resectable NSCLC (stage IIA to select [N2] stage IIIB according to the American Joint Committee on Cancer [AJCC] Cancer Staging Manual, version 8).
  • the patient having R- NSCLC is has resectable Stage IIA to select [i.e., N2] Stage IIIB) disease (according to Version 8 of the IASLC Staging Manual in Thoracic Oncology 2016).
  • the patient having R-NSCLC is a candidate for lobectomy, sleeve resection, or bilobectomy as planned surgery at the time of enrollment.
  • the patient's tumor PD-L1 status of the R-NSCLC is determined prior to treatment.
  • the R-NSCLC of the patients has a PD- L1 tumor cell expression ⁇ 1%.
  • the R-NSCLC of the patients has a PD-L1 tumor cell expression 1–49%. In some embodiments, the R-NSCLC of the patients has a PD-L1 tumor cell expression ⁇ 50%.
  • a patient's tumor PD-L1 Reference Nos: B7H1-550-PCT status is determined using an immunohistochemistry (IHC) assay. In certain embodiments, a patient's tumor PD-L1 status is determined using Ventana PD-L1 (SP263) immunohistochemistry (IHC) assay applied to formalin fixed paraffin embedded tissue sample. In some embodiments, the R-NSCLC is a squamous cell carcinoma.
  • the R-NSCLC is a non-squamous cell carcinoma. In some embodiments, the R-NSCLC is an adenocarcinoma. In some embodiments, the patient's tumor EGFR and ALK status of the R-NSCLC is determined prior to treatment. In some embodiments, the patient does not have an EGFR mutation and/or an ALK translocation. In some embodiments, patients with Kirsten rat sarcoma (KRAS) mutations in their tumors were not required to be tested for EGFR/ALK and patients with squamous cell carcinoma were not required to be tested for ALK.
  • KRAS Kirsten rat sarcoma
  • durvalumab refers to an antibody that selectively binds PD-L1 and blocks the binding of PD-L1 to the PD-1 and CD80 receptors.
  • the durvalumab antibody is disclosed in U.S. Patent No.9,493,565 (referred to as "2.14H9OPT”), which is incorporated by reference herein in its entirety.
  • the fragment crystallizable (Fc) domain of durvalumab contains a triple mutation in the constant domain of the IgG1 heavy chain that reduces binding to the complement component C1q and the Fc ⁇ receptors responsible for mediating antibody-dependent cell-mediated cytotoxicity ("ADCC").
  • the triple mutation refers to the IgG1 Fc region comprising a L234F/L235E/P331S triple mutation (EU numbering; see also US 9,493,565).
  • Durvalumab can relieve PD-L1-mediated suppression of human T-cell activation in vitro and inhibits tumor growth in a xenograft model via a T-cell dependent mechanism.
  • Durvalumab sequences MEDI4736 VL EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGIPDRFSGSGSG TDFTLTISRLEPEDFAVYYCQQYGSLPWTFGQGTKVEIK (SEQ ID NO. 1) MEDI4736 VL CDR1 RASQRVSSSYLA (SEQ ID NO. 2) MEDI4736 VL CDR2 DASSRAT (SEQ ID NO. 3) MEDI4736 VL CDR3 QQYGSLPWT (SEQ ID NO.
  • MEDI4736 VH EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFT ISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDYWGQGTLVTVSS (SEQ ID NO. 5)
  • MEDI4736 VH CDR1 GFTFSRYWMS (SEQ ID NO. 6)
  • Reference Nos: B7H1-550-PCT MEDI4736 VH CDR2 NIKQDGSEKYYVDSVKG (SEQ ID NO. 7)
  • MEDI4736 VH CDR3 EGGWFGELAFDY SEQ ID NO.
  • chemotherapy refers to one or more chemotherapeutic agents that can be used to treat a patient diagnosed with a non-small cell lung cancer.
  • chemotherapeutic agent refers to a chemical compound that is selectively destructive or selectively toxic to malignant cells and tissues.
  • platinum-based chemotherapy refers to chemotherapy drugs that contain the element platinum. Platinum-based chemotherapy has been used to treat many different types of cancer.
  • a platinum-based chemotherapy refers to chemotherapy treatment comprising comprises at least one of one or more of carboplatin, cisplatin, nedaplatin, and oxaliplatin.
  • a platinum-based chemotherapy can also refer to chemotherapy treatment comprising at least one or more of triplatin tetranitrate, phenanthriplatin, picoplatin, and satraplatin.
  • a platinum- based chemotherapy further comprises one or more of afatinib, cetuximab, bevacizumab, erlotinib, gemcitabine, paclitaxel, pemetrexed, and vemurafenib.
  • a platinum-based chemotherapy further comprises one or more of cisplatin, gemcitabine, paclitaxel, and pemetrexed.
  • a platinum-based chemotherapy comprises carboplatin and paclitaxel.
  • a platinum-based chemotherapy comprises cisplatin and gemcitabine. In certain embodiments, a platinum-based chemotherapy comprises carboplatin and gemcitabine. In certain embodiments, a platinum-based chemotherapy comprises carboplatin and pemetrexed. In certain embodiments, a platinum-based chemotherapy comprises cisplatin and pemetrexed. In certain embodiments, a platinum-based chemotherapy comprises a carboplatin area under the serum drug concentration-time curve (AUC) dose of about 5 to 6 mg/mL/min. In certain embodiments, a platinum-based chemotherapy comprises a cisplatin dose of about 75 mg/m 2 .
  • AUC serum drug concentration-time curve
  • a platinum-based chemotherapy comprises a paclitaxel dose of about 200 mg/m 2 . In certain embodiments, a platinum-based chemotherapy comprises a pemetrexed dose of about 500 mg/m 2 . In certain embodiments, a platinum-based chemotherapy comprises a gemcitabine dose of about 1250 mg/m 2 .
  • adjuvant therapy refers to any type of therapy of cancer given as additional treatment, usually after surgical resection of the primary tumor, in a patient affected with a cancer that is at risk of metastasizing and/or at risk of recurrence.
  • Adjuvant therapies can comprise immunotherapy, monoclonal antibody therapy, radiotherapy, hormone therapy, chemotherapy.
  • adjuvant therapy is durvalumab.
  • adjuvant therapy is radiotherapy.
  • adjuvant therapy comprises durvalumab and radiotherapy.
  • the term "neoadjuvant therapy” refers to any type of therapy of cancer given as additional treatment, usually before surgical resection of the primary tumor, in a patient affected with a cancer that is at risk of metastasizing and/or likely to recur.
  • Neoadjuvant therapies can comprise immunotherapy, monoclonal antibody therapy, radiotherapy, hormone therapy, chemotherapy.
  • neoadjuvant therapy is durvalumab.
  • neoadjuvant therapy is chemotherapy.
  • neoadjuvant therapy comprises both durvalumab and chemotherapy (for example, a platinum-based chemotherapy).
  • the R-NSCLC treatment refers to a combination therapy comprising durvalumab and chemotherapy.
  • the combination therapy may be neoadjuvant durvalumab and neoadjuvant chemotherapy.
  • the combination therapy may be perioperative durvalumab and neoadjuvant chemotherapy.
  • the combination therapy may comprise neoadjuvant durvalumab, neoadjuvant chemotherapy and adjuvant durvalumab.
  • the R-NSCLC treatment comprises administering about 1000 mg to about 2000 mg durvalumab once about every 14 to 28 days for up to about 3 to 6 total cycles prior to surgery to remove the resectable NSCLC and then about 1000 mg to about 2000 mg durvalumab once about every 14 to 28 days for up to about 12 cycles following the surgery.
  • the R-NSCLC treatment comprises administering about 1500 mg durvalumab once about every three weeks (q3w) for up to a maximum of about 4 cycles prior to surgery to remove the resectable NSCLC and then about 1500 mg durvalumab once about every four weeks (q4w) for about 12 cycles following the surgery.
  • durvalumab can be provided as a 500-mg vial solution for infusion after dilution.
  • the solution contains 50 mg/mL durvalumab, 26 mM histidine/histidine-hydrochloride, 275 mM trehalose dihydrate, and 0.02% w/v polysorbate 80; it has a pH of 6.0 and density of 1.054 g/mL.
  • a dose Reference Nos: B7H1-550-PCT of about 1500 mg (for patients >30 kg in WT) can be administered using an IV bag containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab concentration ranging from 1 to 15 mg/mL and delivered through an IV administration set with a 0.2- or 0.22- ⁇ m filter.
  • WT-based dosing at 20 mg/kg can be administered using an IV bag selected such that the final concentration is within 1 to 15 mg/mL.
  • a standard infusion time is 1 hour ( ⁇ 10 mins); however, if there are interruptions, the total allowed time must not exceed 8 hours at room temperature.
  • this disclosure provides methods of treating a patient identified as having resectable non-small cell lung cancer (R-NSCLC), comprising (i) administering to the patient about 1000 - 2000 mg of durvalumab and a platinum-based chemotherapy about every 14 – 28 days for about 3 to 6 cycles; (ii) removing the R-NSCLC by surgery; and then (iii) administering to the patient about 1000 – 2000 mg of durvalumab about every 14 to 28 days for at least about 12 weeks.
  • the presence of ctDNA is detected in a post-treatment sample.
  • the detection of ctDNA in a post-treatment sample indicates the patient as non-responsive to the R-NSCLC treatment (i.e., that the treatment is not successful and/or will not be successful), and discontinuing the R-NSCLC treatment to the patient and/or starting a different R-NSCLC treatment to the patient if the patient is indicated as non-responsive to the R-NSCLC treatment.
  • a different R-NSCLC treatment or an alternative treatment refers to an entirely new therapy effect for treating R- NSCLC.
  • a different R-NSCLC treatment or an alternative treatment refers to durvalumab in combination with an alternative chemotherapy.
  • a different R-NSCLC treatment or an alternative treatment refers chemotherapy as disclosed herein but with an alternative to durvalumab.
  • a different R-NSCLC treatment or an alternative treatment refers durvalumab and chemotherapy as disclosed herein and an additional treatment.
  • patients after the surgery to remove the resectable NSCLC, patients should start durvalumab administration as soon as clinically feasible and within about 10 weeks from the surgery to remove the resectable NSCLC. A minimum of about 3 weeks is recommended between surgery to remove the resectable NSCLC and the start of durvalumab treatment (first post-surgical scan must be performed prior to starting adjuvant treatment and post-operative radiotherapy, if required).
  • surgery to remove the resectable NSCLC should happen within about 40 days from the last administration of durvalumab.
  • surgery to remove the resectable NSCLC comprises anatomic pulmonary resection of the NSCLC.
  • either open thoracotomy or video-assisted thoracoscopic surgery access can be carried out as appropriate to the expertise of the surgeon.
  • lung-sparing anatomic resection is preferred over pneumonectomy, if anatomically appropriate and margin-negative resection is achieved.
  • T3 (invasion) and T4 local extension tumors may require en-bloc resection of the involved structure with negative margins.
  • patients can receive post-operative radiotherapy (PORT) following surgery to remove the resectable NSCLC.
  • Post-operative radiotherapy (PORT) can be given within about 8 weeks after surgery.
  • adjuvant durvalumab starts no longer than about 3 weeks after the end of PORT.
  • adjuvant durvalumab starts no more than about 10 weeks after surgery.
  • post- operative radiotherapy (PORT) is allowed for patients in which it is indicated according to local guidance.
  • PORT can include, but is not limited to, doses ranging from 50 to 60 Gy, 1.8 to 2 Gy per fraction, 5 fractions a week; for patients with positive margins of disease (R1). In some embodiments, PORT can include, but is not limited to, doses ranging from 60 to 66 Gy, 1.8 to 2 Gy per fraction, 5 fractions a week. In some embodiments, intensity-modulated radiation therapy (IMRT) or 3D-conformal radiotherapy (3D-CRT) is allowed. In some embodiments of the methods disclosed herein, the methods result in improvement in one or more of EFS, pCR, DFS, OS, and mPR compared to a standard of care.
  • IMRT intensity-modulated radiation therapy
  • 3D-CRT 3D-conformal radiotherapy
  • the methods results in improvement in one or more of EFS, pCR, DFS, OS, and mPR compared to a platinum-based chemotherapy.
  • the success of the method of treatment is determined by an improvement in pathological complete response (pCR) as compared to standard of care, e.g., neoadjuvant chemotherapy, such as neoadjuvant platinum-based chemotherapy.
  • the success of the method of treatment is determined by an improvement in major pathological response (mPR) as compared to standard of care, e.g., neoadjuvant chemotherapy, such as neoadjuvant platinum-based chemotherapy.
  • the success of the method of treatment is determined by an improvement event free survival (EFS) as compared to standard of care, e.g., neoadjuvant chemotherapy, such as neoadjuvant platinum-based chemotherapy.
  • EFS improvement event free survival
  • neoadjuvant chemotherapy such as neoadjuvant platinum-based chemotherapy.
  • DFS improvement in disease free survival
  • the success of the method of treatment is determined by an improvement in overall survival (OS) as compared to standard of care, e.g., neoadjuvant chemotherapy, such as neoadjuvant platinum-based chemotherapy.
  • OS overall survival
  • neoadjuvant chemotherapy such as neoadjuvant platinum-based chemotherapy.
  • success of treatment may be defined as an increase in EFS, pCR, DFS, OS, and/or mPR in patients treated with (i) neoadjuvant durvalumab and neoadjuvant chemotherapy compared to patients treated with neoadjuvant chemotherapy only; or (ii) perioperative durvalumab and neoadjuvant chemotherapy compared to patients treated with neoadjuvant chemotherapy only; or (iii) neoadjuvant durvalumab, neoadjuvant chemotherapy and adjuvant durvalumab compared to patients treated with neoa
  • carboplatin AUC 5 (mg/mL/min) can be administered from cycle 1. 3) Pemetrexed + cisplatin: pemetrexed 500 mg/m 2 and cisplatin 75 mg/m 2 via IV infusion on Day 1 of each 3-week cycle, for 4 cycles (for non-squamous tumor histology).
  • carboplatin AUC 5 (mg/mL/min) can be administered from cycle 1. 4) Pemetrexed + carboplatin: pemetrexed 500 mg/m 2 and carboplatin AUC 5 (mg/mL/min) via IV infusion on Day 1 of each 3-week cycle, for 4 cycles (for non-squamous tumor histology).
  • standard of care may further include resection of the non-small cell lung cancer tumor.
  • Event-free survival refers to the time from randomization to the first of the following: a) local or distant recurrence as determined by BICR using RECIST 1.1 assessments; b) death due to any cause (event date is the date of death); c) PD that precludes surgery (event date is the date of this determination) or PD discovered and reported by the Investigator upon attempting surgery that prevents completion of surgery (event date is the date of the first attempt at surgery).
  • Event-free survival can be analyzed using the log-rank test based on blinded independent central review (BICR) assessment using RECIST v1.1 and pathology review stratified by disease stage (Stage II versus Stage III) and by PD-L1 expression status ( ⁇ 1% versus ⁇ 1%) on the mITT.
  • the p- value can be obtained from the stratified log-rank test using the Efron (Hertz-Picciotto and Rockhill “Validity and efficiency of approximation methods for tied survival times in Cox regression.” Biometrics 1997; 53(3):1151-6.).
  • pathological complete response or "pathological CR” or “pCR” refer to the proportion of patients who have 0% residual viable tumor cells within all resected tissue (including primary lung lesion and lymph nodes) following neoadjuvant treatment as assessed by central pathology laboratory. Patients who are not evaluable per central pathology assessment (this includes patients with R2 margins) or who do not have a surgical specimen can be considered as non-pCR (e.g., pathology assessments captured as "non-evaluable” or "missing,” as appropriate). Central pathology assessment of pCR will be performed according to the recommended methods and definitions described by IASLC 2020 (Travis et al.
  • Disease-free survival and “DFS” refer to the time from the date of surgery until the first date of disease recurrence as determined by BICR using RECIST 1.1 assessments (local or distant), or date of death due to any cause, whichever occurs first.
  • Pathological confirmation from biopsied lesions can also be taken into consideration (as applicable). A new primary malignancy, confirmed by pathology, is not considered a DFS event.
  • Disease-free survival can be analyzed using the log-rank test based on BICR assessment using RECIST 1.1 and pathology review stratified by disease stage Reference Nos: B7H1-550-PCT (Stage II versus Stage III) and by PD-L1 expression status ( ⁇ 1% versus ⁇ 1%) on the modified resected analysis set.
  • the p-value can be obtained from the stratified log-rank test using the Efron (Hertz-Picciotto and Rockhill 1997) approach for handling ties.
  • MPR major pathological response
  • mPR mPR
  • patients who are not evaluable per central pathology assessment (including patients with R2 margins) or who do not have a surgical specimen can be considered as having non-mPR (e.g., response captured as "non-evaluable” or "missing,” as appropriate).
  • the analysis can be performed using a CMH test, stratified by disease stage (Stage II versus Stage III) and PDL1 expression status ( ⁇ 1% versus ⁇ 1%).
  • the effect of treatment can be estimated by the difference in proportions between treatment groups, together with their corresponding CI and p-value.
  • all survival and OS refer to the time from the date of randomization until death due to any cause regardless of whether the subject withdraws from randomized therapy or receives another anticancer therapy. Any patient not known to have died at the time of analysis will be censored based on the last recorded date on which the patient was known to be alive.
  • Overall survival can be analyzed in the mITT population using the same methodology as described for EFS.
  • the effect of treatment can be estimated by the HR together with its corresponding CI. Kaplan-Meier plots can be presented by treatment arm.
  • ITT Intent-to-treat
  • mITT Modified Intent-to-treat
  • Resected population set The resected set can consist of all patients in the ITT who had surgical resection following the neoadjuvant period, who do not have R2 margins, and Reference Nos: B7H1-550-PCT whose first scan following surgery shows no evaluable disease (defined as no post-surgery R2 margins and no RECIST evidence of disease).
  • Modified Resected population set The modified resected set can consist of all patients in the resected set, excluding those whose tumors have EGFRm/ALK translocation. Unless otherwise specified, this analysis set is used for DFS only.
  • Embodiment 1 A method of assessing the success of a treatment comprising durvalumab and a chemotherapy for resectable non-small cell lung cancer (R-NSCLC) in a patient, the method comprising: (a) optionally, determining the circulating tumor DNA (ctDNA) level in a pre- treatment sample obtained from the patient prior to administration of the treatment; (b) administering the treatment to the patient; and (c) determining the ctDNA level in a post-treatment sample obtained from the patient after administration of the treatment; wherein a decrease in the ctDNA level in the post-treatment sample compared to the ctDNA level in the pre-treatment sample is indicative that the treatment is and/or will be successful, or Reference Nos: B7H1-550-PCT wherein no change in the ctDNA level or an increase in the ctDNA level in the post- treatment sample compared to the ctDNA level in the pre-treatment sample is indicative that the treatment is not and/or will not be successful.
  • Embodiment 2 A method of treating a patient having resectable non-small cell lung cancer (R-NSCLC), the method comprising: (a) optionally, determining the circulating tumor DNA (ctDNA) level in a pre- treatment sample obtained from the patient prior to administration of a treatment comprising durvalumab and a chemotherapy to the patient; (b) administering the treatment to the patient; (c) determining the ctDNA level in a post-treatment sample obtained from the patient after administration of the treatment; and (d) administering the treatment to the patient or resecting the R-NSCLC if there is a decrease in the ctDNA level in the post-treatment sample compared to the ctDNA level in the pre-treatment sample, or administering an alternative treatment to the patient if there is no change or an increase in the ctDNA level in the post-treatment sample compared to the ctDNA level in the pre-treatment sample.
  • R-NSCLC resectable non-small cell lung cancer
  • Embodiment 3 The method of either embodiment 1 or embodiment 2, wherein the decrease in the ctDNA level in the post-treatment sample is a decrease of at least 50% from the ctDNA level in the pre-treatment sample, at least 60% from the ctDNA level in the pre-treatment sample, at least 70% from the ctDNA level in the pre-treatment sample, at least 80% from the ctDNA level in the pre-treatment sample, at least 90% from the ctDNA level in the pre- treatment sample, at least 95% from the ctDNA level in the pre-treatment sample, at least 98% from the ctDNA level in the pre-treatment sample, at least 99% from the ctDNA level in the pre-treatment sample, or a decrease of 100% from the ctDNA level in the pre-treatment sample.
  • Embodiment 4 The method of any one of embodiments 1 to 3, wherein the ctDNA level in the post-treatment sample is undetectable.
  • Embodiment 5 The method of any one of embodiments 1 to 4, wherein the method is indicative that treatment is and/or will be successful.
  • Embodiment 6 The method of any one of embodiments 1 to 5, wherein detecting ctDNA in the post-treatment sample is indicative that the treatment is not and/or will not be successful.
  • Embodiment 7 A method of assessing the success of a treatment comprising durvalumab and a chemotherapy for resectable non-small cell lung cancer (R-NSCLC) in a patient, the method comprising: (a) administering a treatment comprising durvalumab and chemotherapy to the patient; and (b) determining the ctDNA level in a post-treatment sample obtained from the patient after administration of the treatment; wherein detecting ctDNA in the post-treatment sample is indicative that the treatment is not and/or will not be successful.
  • R-NSCLC resectable non-small cell lung cancer
  • Embodiment 8 A method of treating a patient having resectable non-small cell lung cancer (R-NSCLC), the method comprising: (a) administering a treatment comprising durvalumab and chemotherapy to the patient; (b) determining the ctDNA level in a post-treatment sample obtained from the patient after administration of the treatment; and (c) administering an alternative treatment to the patient if ctDNA is detected in the post-treatment sample.
  • R-NSCLC resectable non-small cell lung cancer
  • Embodiment 9 The method of any one of embodiments 1 to 8, wherein the method further comprises: determining a variant allele fraction (VAF) in the pre-treatment sample and a VAF in the post-treatment sample; wherein a decrease in the VAF in the post-treatment sample compared to the VAF in the pre-treatment sample is indicative that the treatment is and/or will be successful; and administering the treatment to the patient if there is a decrease in the VAF in the post- treatment sample compared to the VAF in the pre-treatment sample.
  • VAF variant allele fraction
  • Embodiment 10 The method of any one of embodiments 1 to 8, wherein the decrease in the VAF in the post-treatment sample is a decrease of at least 50% from the VAF in the pre- treatment sample, at least 60% from the VAF in the pre-treatment sample, at least 70% from Reference Nos: B7H1-550-PCT the VAF in the pre-treatment sample, at least 80% from the VAF in the pre-treatment sample, at least 90% from the VAF in the pre-treatment sample, at least 95% from the VAF in the pre-treatment sample, at least 98% from the VAF in the pre-treatment sample, at least 99% from the VAF in the pre-treatment sample, or a decrease of 100% from the VAF in the pre-treatment sample.
  • Embodiment 11 The method of either embodiment 9 or embodiment 10, wherein the VAF in the post-treatment sample is undetectable and/or below a limit of detection.
  • Embodiment 12 The method of any one of embodiments 9 to 11, wherein the method is indicative that treatment is and/or will be successful.
  • Embodiment 13 The method of any one of embodiments 9 to 12, wherein detecting VAF in the post-treatment sample is indicative that the treatment is not and/or will not be successful.
  • Embodiment 14 The method of any one of embodiments 1 to 13, wherein determining the ctDNA level or determining the VAF in the post-treatment sample occurs after about 21 days of the treatment, after about 42 days of the treatment, after about 63 days of the treatment, or after about 84 days of the treatment.
  • Embodiment 15 The method of any one of embodiments 1 to 14, wherein determining the ctDNA level or determining the VAF in the post-treatment sample occurs after about 1 cycle of the treatment, after about 2 cycles of the treatment, after about 3 cycles of the treatment, or after about 4 cycles of the treatment.
  • Embodiment 16 The method of any one of embodiments 1 to 14, wherein the ctDNA level is detected by a sequencing reaction.
  • Embodiment 17 The method of any one of embodiments 1 to 16 further comprising: (a) determining tumor size of the R-NSCLC in the patient prior to administration of a treatment comprising durvalumab and a chemotherapy to the patient; (b) administering the treatment to the patient; (c) determining tumor size of the R-NSCLC in the patient after administration of the treatment; Reference Nos: B7H1-550-PCT wherein a decrease in tumor size after administration of the treatment is indicative that the treatment is and/or will be successful.
  • Embodiment 18 The method of embodiment 17, wherein tumor size is determined prior to resecting the R-NSCLC.
  • Embodiment 19 The method of either embodiment 17 or embodiment 18, wherein tumor size is determined using magnetic resonance imaging (MRI), computed tomography (CT), or both MRI and CT.
  • Embodiment 20 The method of any one of embodiments 1 to19, wherein the treatment comprises administering durvalumab and a chemotherapy to the patient about every 21 days (Q3W) for about 4 cycles.
  • Embodiment 21 The method of embodiment 20 further comprising resecting the R-NSCLC after the about 4 cycles of the treatment comprising durvalumab and a chemotherapy.
  • Embodiment 22 The method of embodiment 21 further comprising administering to the patient durvalumab about every 14 to 28 days for up to about 12 cycles after resecting the R- NSCLC.
  • Embodiment 23 The method of embodiment 21 further comprising administering to the patient durvalumab about every 28 days (Q4W) for up to about 12 cycles after resecting the R-NSCLC.
  • Embodiment 24 The method of any one of embodiments 1 to 23, wherein about 1000 to 2000 mg of durvalumab is administered to the patient.
  • Embodiment 25 The method of embodiment 24, wherein about 1500 mg of durvalumab is administered to the patient.
  • Embodiment 26 The method of any one of embodiments 1 to 25, wherein the chemotherapy is a platinum-based chemotherapy.
  • Embodiment 27 The method of embodiment 26, wherein the platinum-based chemotherapy is one or more of carboplatin, cisplatin, nedaplatin, and oxaliplatin.
  • Embodiment 28 The method of embodiment 27, wherein the platinum-based chemotherapy comprises a carboplatin area under the serum drug concentration-time curve (AUC) dose of about 5 to about 6 mg/mL/min, or a cisplatin dose of about 75 mg/m 2 .
  • AUC serum drug concentration-time curve
  • Embodiment 29 The method of any one of embodiments 26 to 28, wherein the platinum- based chemotherapy further comprises one or more of afatinib, cetuximab, bevacizumab, erlotinib, gemcitabine, paclitaxel, pemetrexed, and vemurafenib.
  • Embodiment 30 The method of any one of embodiments 26 to 28, wherein the platinum- based chemotherapy further comprises one or more of cisplatin, gemcitabine, paclitaxel, and pemetrexed.
  • Embodiment 31 The method of either embodiment 29 or embodiment 30, wherein the platinum-based chemotherapy further comprises a paclitaxel dose of about 200 mg/m 2 , a pemetrexed dose of about 500 mg/m 2 , or a gemcitabine dose of about 1250 mg/m 2 .
  • Embodiment 32 The method of any one of embodiments 1 to 31, wherein the R-NSCLC is a squamous cell carcinoma.
  • Embodiment 33 The method of any one of embodiments 1 to 31, wherein the R-NSCLC is a non-squamous cell carcinoma.
  • Embodiment 34 The method of any one of embodiments 1 to 33, wherein the patient does not have an EGFR mutation and/or an ALK translocation.
  • Embodiment 35 The method of any one of embodiments 21 to 23 further comprising a post- operative radiation therapy.
  • Embodiment 36 The method of embodiment 35, wherein the post-operative radiation therapy starts within about 8 weeks after resecting the R-NSCLC.
  • Embodiment 37 The method of embodiment 36, wherein administering durvalumab starts within about 3 weeks from the end of the post-operative radiation therapy.
  • Embodiment 38 The method of any one of embodiments 1 to 37, wherein an increase in the ctDNA level in the post-treatment sample compared to the pre-treatment sample is determined, and one or more alternative treatments R-NSCLC is administered to the patient.
  • Embodiment 39 The method of any one of embodiments 1 to 38, wherein the method results in improvement in one or more of EFS, pCR, DFS, OS, and mPR compared to a standard of care.
  • Embodiment 40 The method of any one of embodiments 1 to 38, wherein the method results in improvement in one or more of EFS, pCR, DFS, OS, and mPR compared to a platinum- based chemotherapy.
  • Example 1 Neoadjuvant/Adjuvant Durvalumab for the treatment of patients with Resectable Non-Small Cell Lung Cancer (R-NSCLC)
  • the AEGEAN (NCT03800134) study described herein is a phase III, double-blind, placebo-controlled, multi-center international study of assessed perioperative (i.e., neoadjuvant and adjuvant) durvalumab plus neoadjuvant chemotherapy for the treatment of patients with resectable stage II and stage III non-small cell lung cancer (R-NSCLC).
  • NSCLC non-small cell lung cancer
  • Eligible patients had newly diagnosed, previously untreated, histologically or cytologically documented, resectable NSCLC (stage IIA to select [N2] stage IIIB according to the American Joint Committee on Cancer [AJCC] Cancer Staging Manual, version 8).
  • Patients were randomized in a 1:1 ratio to receive either durvalumab plus a platinum-based chemotherapy before surgery followed by durvalumab post-surgery (Arm 1; a platinum-based chemotherapy plus durvalumab intravenously every three weeks (four cycles) before surgery, followed by durvalumab intravenously every four weeks (12 cycles)) or placebo plus a platinum-based chemotherapy before surgery followed by placebo post- surgery (Arm 2; a platinum-based chemotherapy plus placebo intravenously every three weeks (four cycles) before surgery, followed by placebo intravenously every four weeks (12 cycles)).
  • Patients were also stratified by disease stage (Stage II versus Stage III) and by PD- L1 expression status ( ⁇ 1% versus ⁇ 1%). Patients had resectable (Stage IIA to select [i.e., N2] Stage IIIB) disease (according to Version 8 of the IASLC Staging Manual in Thoracic Oncology 2016) and were candidates for lobectomy, sleeve resection, or bilobectomy as planned surgery at the time of enrollment. At screening, complete surgical resection of the primary NSCLC was deemed achievable by performing a multidisciplinary evaluation, which included a thoracic surgeon who performs lung cancer surgery as a prominent part of his/her practice.
  • Additional inclusion criteria necessitated an age of 18 years or older; an Eastern Cooperative Oncology Group performance status of 0 or 1; an estimated life expectancy of ⁇ 12 weeks; documented tumor PD-L1 status (as assessed at a central laboratory using the VENTANA SP263 immunohistochemistry assay); and ⁇ 1 lesion, not previously irradiated, that qualified as a Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) target lesion.
  • T4 tumors were only eligible if they were defined as T4 based only on their size (more than 7 cm); any other reason for T4 (e.g., adherent to any of the following structures: Reference Nos: B7H1-550-PCT diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina) were considered ineligible. Nodal status was investigated with whole body 18F-fluoro-deoxyglucose positron emission tomography (FDG-PET), plus contrast-enhanced computed tomography (CT).
  • FDG-PET 18F-fluoro-deoxyglucose positron emission tomography
  • CT contrast-enhanced computed tomography
  • positron emission tomography (PET)/CT scan was positive in the mediastinum, or if scan was negative, but there was T>3 cm, central tumor, or clinical N1 (cN1), then it was recommended that nodal status be proven by biopsy via endobronchial ultrasound, mediastinoscopy, or thoracoscopy.
  • Mandatory brain magnetic resonance imaging was performed (MRI; preferred) with IV contrast or brain CT with IV contrast at the time of staging.
  • Patients had no prior exposure to immune-mediated therapy including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies, excluding therapeutic anticancer vaccines.
  • the modified intent-to-treat population included all patients who were randomized, excluding patients with documented EGFR/ALK aberrations. ⁇ Characteristics with missing or other responses were histology (0.3% in the durvalumab arm and 1.1% in the placebo arm had ‘other’ histology), disease stage (0.3% in the durvalumab arm had stage IV disease and 0.3% in the placebo arm had stage III [NOS] disease, as reported per the eCRF), and N2 lymph node station status (1.6% in the durvalumab arm and 3.5% in the placebo arm had N2 disease with missing data on single-station versus multi-station classification). Race was self- reported per the eCRF.
  • Demographics AEGEAN Observations Reference Nos: B7H1-550-PCT Study mITT, N 740 Age, median (range) 65.0 (30–88) • Patients with resectable NSCLC are on average Age, mean ⁇ SD 64.0 ⁇ 8.8 approximately 65 years of age across geographies. The age of patients on the AEGEAN study was representative of a real- world population. Sex • Globally NSCLC affects more men than women. The Male 71.6% gender balance in the AEGEAN study was Female 28.4% representative of a real-world population.
  • ECOG performance The majority of patients diagnosed with resectable status NSCLC have good performance status (ECOG 0 68.4% performance status of 0), a trend that was also 1 31.6% borne out in the AEGEAN study. ⁇ 2 0% Unknown/ Missing 0% Smoking Status • Lung cancer is strongly associated with smoking, with Current smoker/ former 86% approximately 80% of patients having a history smoker of smoking. This was also reflected in the Never smoker 24% AEGEAN study population. Region • The AEGEAN study enrolled patients across 28 Asia 41% countries and 3 continents. The race and Europe 38% ethnicity composition of the AEGEAN study North America 12% are indicative of a large, diverse, and global South America 9% Race clinical trial.
  • the modified intent-to-treat population included all patients who were randomized, excluding patients with documented EGFR/ALK aberrations. ⁇ Except where specified otherwise, percentages were calculated using the full modified intent-to-treat population as the denominator. As per the investigator’s assessment. Patients who ‘underwent’ surgery were those for whom curative-intent thoracic surgery was attempted regardless of whether it was completed. Patients who ‘completed’ surgery were those for whom curative-intent thoracic surgery was completed (assessed by the investigator at the time of surgery). ⁇ Includes patients who had surgery outside of the study.
  • AJCC American Joint Committee on Cancer
  • ECOG PS Eastern Cooperative Oncology Group performance status
  • eCRF electronic case report form
  • NOS not otherwise specified
  • PD-L1 programmed cell death-ligand 1
  • TC tumor cell
  • TNM tumor, [lymph] nodes, metastasis. Table 5.
  • the safety analysis set includes all randomized patients who received ⁇ 1 dose of study treatment; adverse events were graded using Common Terminology Criteria for Adverse Events version 5.0.
  • the overall study period spans from the first dose of study treatment (durvalumab/placebo/chemotherapy) until the earliest of: the last dose of study treatment or surgery + 90 days (taking the latest dose of durvalumab or placebo or chemotherapy or the date of surgery, + 90 days); the data cut-off date; or the date of the first dose of subsequent anti-cancer treatment.
  • Study Design and Treatment Approximately 800 patients with resectable NSCLC (Stage IIA to select Stage IIIB; either squamous or non-squamous) were randomized in a 1:1 ratio to receive either durvalumab plus platinum-based chemotherapy before surgery followed by durvalumab post- surgery (Arm 1) or placebo plus platinum-based chemotherapy before surgery followed by placebo post-surgery (Arm 2).
  • Patients were stratified by disease stage (Stage II versus Stage III) and by programmed cell death ligand-1 (PD-L1) expression status ( ⁇ 1% versus ⁇ 1%). Patients received 4 cycles of durvalumab or placebo plus a platinum-based chemotherapy (every 3 weeks [q3w]) followed by surgery to remove the NSCLC. Surgery consisted of lobectomy, sleeve resection, or bilobectomy, as determined by the attending surgeon based on the baseline findings. Patients whose planned surgery at enrollment includes pneumonectomy, segmentectomies, or wedge resections at eligibility assessment were not eligible for this study. All patients were staged and managed according to the National Comprehensive Cancer Network 2020 Guidelines (version 1.2021). Surgery was expected within 40 days from the dose.
  • Treatments and treatment duration Patients received 1500 mg durvalumab or placebo via intravenous (IV) infusion q3w for up to a maximum of 4 cycles prior to surgery and q4w for 12 cycles following surgery, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. If a patient's weight (WT) falls to 30 kg or below ( ⁇ 30 kg), then the patient received WT-based dosing equivalent to 20 mg/kg of durvalumab [or placebo] q3w or q4w after consultation between Investigator and Study Physician/Medical Engineer, until the WT improved to >30 kg, at which point the patient started receiving the fixed dosing of durvalumab 1500 mg [or placebo] q3w or q4w.
  • IV intravenous
  • SoC Standard of Care
  • Squamous tumor histology Carboplatin + paclitaxel: carboplatin area under the serum drug concentration-time curve (AUC) 6 (mg/mL/min) and paclitaxel 200 mg/m 2 via IV infusion on Day 1 of each 3-week cycle, for 4 cycles.
  • Squamous tumor histology Cisplatin + gemcitabine: cisplatin 75 mg/m 2 via IV infusion on Day 1 of each 3-week cycle, for 4 cycles, and gemcitabine 1250 mg/m 2 via IV infusion on Day 1 and Day 8 of each 3-week cycle, for 4 cycles.
  • EFS event-free survival
  • pCR pathological complete response
  • Other secondary endpoints included evaluation of the primary endpoints Reference Nos: B7H1-550-PCT and key secondary endpoints in patients with PD-L1 expression ⁇ 1%; pharmacokinetics and immunogenicity; patient-reported outcomes; and safety.
  • EFS was defined as the time from randomization to any of the following events: progression of disease (PD) that precludes surgery, local or distant recurrence, or death due to any cause.
  • EFS was defined as the time from randomization to the earliest of: (1) progressive disease that precludes surgery; (2) progressive disease discovered and reported by the investigator upon attempting surgery that prevents completion of surgery; (3) local or distant recurrence using blinded independent central review according to RECIST v1.1; or (4) death from any cause. Failure to undergo/complete surgery for reasons other than progressive disease was not considered an EFS event (i.e., patients remained in follow-up for RECIST- defined progression).
  • Tumors were evaluated per RECIST v1.1 using imaging collected at the following timepoints: baseline ( ⁇ 28 days before randomization); after completing neoadjuvant treatment and before surgery; 5 weeks ( ⁇ 2 weeks) after surgery and before starting adjuvant treatment; every 12 weeks ( ⁇ 1 week) until Week 48 after surgery; every 24 weeks ( ⁇ 2 weeks) until Week 192 (i.e., ⁇ 4 years post-surgery); and every 48 weeks ( ⁇ 2 weeks) thereafter until local or distant recurrence, consent withdrawal, or death. Safety was monitored throughout the study and adverse events (AEs) were graded using the National Cancer Institute Common Toxicity Criteria for AEs version 5.0.
  • EFS mITT and PD-L1 TC ⁇ 1% analysis set
  • pCR mITT and PD-L1 TC ⁇ 1% analysis set
  • mPR mITT and PD-L1 TC ⁇ 1% analysis set
  • DFS modified resected set and PD-L1 TC ⁇ 1% resected set
  • OS mITT and PD-L1 TC ⁇ 1% analysis set
  • Baseline demographics and clinical characteristics and planned neoadjuvant chemotherapy doublet regimens were largely balanced between the treatment arms in the mITT population (Table 1). Median age was 65.0 years, and most patients were male (71.6%), had a performance status of 0 (68.4%), and were current or former smokers (85.5%). Over 70% of patients had stage III disease, and half of all patients had N2 disease. Approximately equal proportions of patients had squamous and non-squamous histology. Across both treatment arms, 33.4% of patients had tumor PD-L1 expression of ⁇ 1%, and carboplatin was the planned neoadjuvant platinum agent for over 70% of patients.
  • the safety analysis set includes all randomized patients who received ⁇ 1 dose of study treatment. SoC, standard of care. Surgery Summary At the data cut-off, approximately 81% of patients in each treatment arm (Table 3; mITT population) had undergone surgery (noting that curative-intent thoracic surgery was attempted regardless of whether it was completed). In total, 77.6% of patients in the durvalumab arm and 76.7% of patients in the placebo arm had completed surgery (i.e., curative-intent thoracic surgery deemed completed as assessed by the investigator), among whom a slightly higher proportion had R0 resection in the durvalumab arm versus the placebo arm (94.7% vs.91.3%).
  • the safety analysis set includes all randomized patients who received ⁇ 1 dose of study treatment. *Reasons for surgical delay are not mutually exclusive for patients with multiple reasons per delay or subjects with multiple delays (although a patient can only be counted once per category). Table 8. Details of Surgery and Surgical Outcomes in the Modified Intent-to-treat Population.
  • CI confidence interval
  • RECIST v1.1 Response Evaluation Criteria in Solid Tumors version 1.1.
  • a trend towards pCR benefit with durvalumab was observed across all prespecified subgroups, with the results largely consistent with the overall mITT population.
  • Primary tumor pathological regression was, overall, greater in the durvalumab arm versus the placebo arm. See Table 9 for a summary of objective response prior to surgery in the mITT population.
  • AEs possibly related to any study treatment with an outcome of death were uncommon, with rates of 1.8% and 0.5% in the durvalumab and placebo arms, respectively.
  • the most common AEs of any cause largely reflected the safety profile of the chemotherapy agents used in the study (Table 10); the rates of the most common AEs were largely similar across both treatment arms. Rates of any-grade rash (14% vs.8.5%) and pruritus (11.8% vs.5.5%) were higher among patients in the durvalumab arm versus the placebo arm; however, grade 3 or 4 events were uncommon, and occurred with similar frequency in both treatment arms.
  • the safety analysis set includes all randomized patients who received ⁇ 1 dose of study treatment; adverse events were graded using Common Terminology Criteria for Adverse Events version 5.0. Included are adverse events reported with an any-grade incidence of at least 10% in the durvalumab arm during the overall study period, which spans from the first dose of study treatment (durvalumab or placebo or chemotherapy) until the earliest of: the last dose of study treatment or surgery + 90 days (taking the latest dose of durvalumab or placebo or chemotherapy or the date of surgery, + 90 days); the data cut-off date; or the date of the first dose of subsequent anti-cancer treatment. ⁇ Two patients (one in each arm) had decreased appetite with an outcome of death (max.
  • the safety analysis set includes all randomized patients who received ⁇ 1 dose of study treatment; adverse events were graded using Common Terminology Criteria for Adverse Events version 5.0. Included are adverse events assessed by the investigator as possibly related to any study treatment (durvalumab or placebo or chemotherapy) reported with an any-grade Reference Nos: B7H1-550-PCT incidence of at least 5% in the durvalumab arm during the overall study period, which spans from the first dose of study treatment until the earliest of: the last dose of study treatment or surgery + 90 days (taking the latest dose of durvalumab or placebo or chemotherapy or the date of surgery, + 90 days); the data cut-off date; or the date of the first dose of subsequent anti-cancer treatment.
  • the safety analysis set includes all randomized patients who received ⁇ 1 dose of study Tx; AEs were graded using Common Terminology Criteria for Adverse Events v5.0.
  • An immune-mediated AE was defined as an AE of special interest consistent with an immune-mediated mechanism of action, where there is no clear alternate etiology, and requiring the use of systemic corticosteroids or other immunosuppressants and/or, for specific endocrine events, endocrine therapy.
  • AE adverse event.
  • Summary Perioperative durvalumab plus neoadjuvant chemotherapy (CT) significantly improved both pCR and EFS among patients with resectable NSCLC versus neoadjuvant CT alone.
  • the improvement in pCR rate was 13.0% (95% CI: 8.7–17.6).
  • EFS and pCR benefit with durvalumab was broadly observed across all predefined subgroups and was consistent with improvements observed in the overall mITT population.
  • EFS benefit for example, was observed regardless of age, disease stage (including patients with N2 disease), histology, and PD-L1 expression, including, notably, patients with PD-L1 expression ⁇ 1% (although the magnitude of benefit was numerically better in patients with PD-L1 expression ⁇ 50%).
  • AEs possibly related to study Tx with an outcome of death were rare in both arms. Immune-mediated AEs were more common in the durvalumab arm versus the placebo arm (23.5% vs.9.8%); however, most were grade 1 or 2. Also, although differences in the populations and study designs of AEGEAN versus PACIFIC confound between-study comparisons (particularly, use of chemoradiotherapy in the latter), it is notable that the rates of any-grade and grade 3 or 4 immune AEs were similar between these studies (Antonia et al. N Engl J Med 2017; 377:1919–29; Antonia et al. N Engl J Med 2018; 379:2342–50).
  • AEGEAN was not designed to assess the individual contributions of the neoadjuvant and adjuvant components of treatment. Nonetheless, the results reported here justify a perioperative treatment strategy and substantiate other studies that have employed this approach with immunotherapy in the melanoma and NSCLC settings (Patel et al., N Engl J Med 2023; 388:813-823; Lu et al., Journal of Clinical Oncology 41, no.36_suppl (April 20, 2023) 425126-425126). Moreover, the benefit of the full course of perioperative durvalumab may only be fully realized until such time as all patients have had the opportunity to complete adjuvant study treatment.
  • Example 2 Associations of ctDNA clearance, radiological response, and pathological response with neoadjuvant treatment in patients with resectable NSCLC from the phase 3 AEGEAN trial
  • the AEGEAN (NCT03800134) study is a phase III, double-blind, placebo-controlled, multi-center international study of perioperative (i.e., neoadjuvant and adjuvant) durvalumab plus neoadjuvant chemotherapy for the treatment of patients with resectable stage II and stage III non-small cell lung cancer (R-NSCLC).
  • perioperative durvalumab (D) plus neoadjuvant chemotherapy (CT) significantly improved pathological complete response (pCR), major pathological response (MPR), and event-free survival (EFS), with manageable safety, versus neoadjuvant CT alone among patients with resectable (R) NSCLC (modified ITT [mITT] population).
  • CT pathological complete response
  • MPR major pathological response
  • EFS event-free survival
  • R-NSCLC patients (stage II–IIIB[N2]; AJCC 8th ed) were randomised (1:1) to receive neoadjuvant chemotherapy (CT) + durvalumab or placebo (PBO) intravenously (IV) (Q3W, 4 cycles) prior to surgery, followed by durvalumab or PBO IV (Q4W, 12 cycles), respectively, after surgery.
  • Plasma samples were collected at protocol-specified timepoints, including prior to each neoadjuvant treatment cycle and before surgery. Analysis was Reference Nos: B7H1-550-PCT performed using patient-specific tumour-informed assays, following identification of mutations in diagnostic tissue via whole exome sequencing.
  • ctDNA variant allele fractions VAFs
  • dynamics were assessed during neoadjuvant treatment, including ctDNA clearance and association with pCR or MPR.
  • Radiological CR/PR had a higher rate of pCR and MPR as compared to patients with radiological stable disease (SD); no patients with radiological progressive disease (PD) had pCR or MPR (Figure 17).
  • ctDNA clearance at early presurgical timepoints identified patients with improved event-free survival, which was more pronounced in patients who received durvalumab with chemotherapy before surgery and durvalumab after surgery, compared to patients who only received chemotherapy before surgery. More patients with such improvement were identified by ctDNA clearance than by pathological response.

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Abstract

L'invention concerne des procédés d'évaluation du succès du traitement avec du durvalumab et une chimiothérapie pour le cancer du poumon non à petites cellules réséquable (R-NSCLC) chez des patients sur la base de la détection d'ADN tumoral circulant (ADNtc), de la clairance d'ADNtc et/ou de la clairance partielle et/ou de la fraction d'allèle variant (VAF) avant et après un tel traitement. L'invention concerne également des méthodes de traitement de patients atteints de R-NSCLC sur la base de la détection d'ADNtc, de la clairance de l'ADNct et/ou de la clairance moléculaire partielle et/ou de VAF avant et après un tel traitement.
PCT/IB2024/060194 2023-10-17 2024-10-17 Prédiction de la réponse au traitement néoadjuvant dans le cancer du poumon non à petites cellules Pending WO2025083600A1 (fr)

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