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WO2025155787A1 - Polythérapie à inhibiteur double de farnésyltransférase et de géranylgéranyltransférase -1, et de sotorasib - Google Patents

Polythérapie à inhibiteur double de farnésyltransférase et de géranylgéranyltransférase -1, et de sotorasib

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Publication number
WO2025155787A1
WO2025155787A1 PCT/US2025/011976 US2025011976W WO2025155787A1 WO 2025155787 A1 WO2025155787 A1 WO 2025155787A1 US 2025011976 W US2025011976 W US 2025011976W WO 2025155787 A1 WO2025155787 A1 WO 2025155787A1
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WIPO (PCT)
Prior art keywords
sotorasib
fgti
kras
cancer
pharmaceutically acceptable
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Pending
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PCT/US2025/011976
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English (en)
Inventor
Said Sebti
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Virginia Commonwealth University
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Virginia Commonwealth University
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Publication of WO2025155787A1 publication Critical patent/WO2025155787A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole

Definitions

  • the invention is generally related to a combination of FGTI-2734, a dual FT and GGT- 1 inhibitor, and sotorasib for the treatment of cancer.
  • BACKGROUND OF THE INVENTION Lung cancer is a significant health concern in the United States with 238,340 new cases and 127,070 deaths in 2023, 1 with non-small cell lung cancer (NSCLC) comprising approximately 85% of cases.
  • NSCLC non-small cell lung cancer
  • Clinically-relevant resistance mechanisms observed in tumors from patients treated with sotorasib or adagrasib are multifaceted and include amplification/overexpression of wild- type (WT) KRAS and WT receptor tyrosine kinases (RTKs) (e.g., MET, EGFR, HER2, FGFR2), RTK mutations (e.g., EGFR-A289V and RET-M918T), acquired secondary KRAS oncogenic mutations (e.g., G12D, G12V, G12R, G12W, G13D, Q61H), and acquired secondary mutations within the sotorasib switch II binding site in KRAS (e.g., R68S, Y96D, H95D, H95Q, H95R) 14-20, 22-25 .
  • WT wild- type
  • RTKs WT receptor tyrosine kinases
  • RTKs e.g., MET, EGFR, HER2, FG
  • FGTI-2734 inhibits KRAS, HRAS and NRAS prenylation and enhances the ability of sotorasib to induce apoptosis in KRAS G12C lung cancer LU99 and Calu1 cells.
  • LU99 and B Calu1 cells were treated for 24 and 48 hours with sotorasib (3 ⁇ M) and FGTI-2734 (20 ⁇ M) individually or in combination, and processed for Western blotting.
  • P and U designate Prenylated and Un-prenylated, respectively. * designates KRAS G12C covalently modified with sotorasib.
  • C Chemical structure of FGTI-2734.
  • LU99 cells (D - vehicle) were treated (24 hours) with (E) sotorasib (3 ⁇ M) or (F) FGTI-2734 (20 ⁇ M) alone or (G) in combination and processed for Annexin V-FITC staining as a read out for apoptosis and DAPI to stain cell nuclei.
  • FGTI-2734 overcomes resistance and enhances the anti-tumor activity of sotorasib in resistant and sensitive KRAS G12C lung cancer xenografts and in a PDX derived from a KRAS G12C lung cancer patient.
  • the sotorasib and FGTI-2734 doses varied over time and were as follows: Day 0 to day 14 (sotorasib [30 mpk] and FGTI-2734 [100 mpk]); Day 15 to day 22 (sotorasib [15 mpk] and FGTI-2734 [150 mpk]); Day 23 to day 36 (mice were not treated with any drugs); Day 37 to day 47 (sotorasib [15 mpk] and FGTI-2734 [150 mpk]).
  • Figure 5 The tumors from the LU99 and H358 xenograft studies
  • Embodiments of the disclosure provide compositions and methods for a synergistic anti- cancer treatment comprising a combination of FGTI-2734 or a pharmaceutically acceptable salt thereof and sotorasib or a pharmaceutically acceptable salt thereof.
  • cancer refers to a neoplasm, cancer, or precancerous lesion.
  • the neoplasm or cancer may be benign or malignant. This includes cells or tissues that have characteristics relating to changes that may lead to malignancy or cancer, such as mutations controlling cell growth and proliferation. Examples of cancers, e.g.
  • solid tumors to be treated include but are not limited to: lung cancer, including non-small cell lung cancer, colorectal cancer, pancreatic cancer, including pancreatic ductal adenocarcinoma, gall bladder cancer, thyroid cancer, bile duct cancer, breast cancer, urothelial cancer, head and neck cancer, esophagus cancer, thyroid cancer, oral cancer, cervical cancer, ovarian cancer, and liver cancer (e.g., hepatocellular carcinoma).
  • hematological malignancies e.g., cancers that affect blood, bone marrow and/or lymph nodes. Such malignancies include, but are not limited to leukemias and lymphomas.
  • the presently disclosed compounds can be used for treatment of diseases such as Acute lymphoblastic leukemia (ALL), Acute myelogenous leukemia (AML), Chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Chronic myelogenous leukemia (CML), Acute monocytic leukemia (AMoL) and/or other leukemias.
  • ALL Acute lymphoblastic leukemia
  • AML Acute myelogenous leukemia
  • CLL Chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • CML Chronic myelogenous leukemia
  • Acute monocytic leukemia Acute monocytic leukemia
  • the compounds are useful for treatment of lymphomas such as all subtypes of Hodgkins lymphoma or non-Hodgkins lymphoma.
  • Determining whether a tumor or cancer comprises a G12C KRAS, HRAS or NRAS mutation can be undertaken by assessing the nucleotide sequence encoding the KRAS, HRAS or NRAS protein, by assessing the amino acid sequence of the KRAS, HRAS or NRAS protein, or by assessing the characteristics of a putative KRAS, HRAS or NRAS mutant protein.
  • the sequence of wild-type human KRAS, HRAS or NRAS is known in the art, (e.g. Accession No. NP203524). Methods for detecting a mutation in a KRAS, HRAS or NRAS nucleotide sequence are known by those of skill in the art.
  • PCR-RFLP polymerase chain reaction-restriction fragment length polymorphism
  • PCR-SSCP polymerase chain reaction-single strand conformation polymorphism
  • MASA mutant allele-specific PCR amplification
  • direct sequencing primer extension reactions
  • electrophoresis oligonucleotide ligation assays
  • hybridization assays TaqMan assays
  • SNP genotyping assays high resolution melting assays and microarray analyses.
  • samples are evaluated for G12C KRAS, HRAS or NRAS mutations by real-time PCR.
  • fluorescent probes specific for the KRAS, HRAS or NRAS G12C mutation are used. When a mutation is present, the probe binds and fluorescence is detected.
  • the KRAS, HRAS or NRAS G12C mutation is identified using a direct sequencing method of specific regions (e.g., exon 2 and/or exon 3) in the KRAS, HRAS or NRAS gene. This technique will identify all possible mutations in the region sequenced. Methods for detecting a mutation in a KRAS, HRAS or NRAS protein are known by those of skill in the art.
  • Methods for determining whether a tumor or cancer comprises a G12C KRAS, HRAS or NRAS mutation can use a variety of samples.
  • the sample is taken from a subject having a tumor or cancer.
  • the sample is a fresh tumor/cancer sample.
  • the sample is a frozen tumor/cancer sample.
  • the sample is a formalin-fixed paraffin-embedded sample.
  • the sample is a circulating tumor cell (CTC) sample.
  • CTC circulating tumor cell
  • the sample is processed to a cell lysate.
  • the sample is processed to DNA or RNA.
  • the cancer is resistant to treatment with sotorasib (or other KRAS G12C inhibitor) treatment alone.
  • the subject has previously been administered sotorasib or another KRAS G12C inhibitor.
  • the subject has not previously been administered sotorasib or another KRAS G12C inhibitor.
  • FGTI-2734 enhances the anti-tumor activity of sotorasib in highly resistant and sensitive KRAS G12C cancer cells that have not previously been exposed to sotorasib, indicating that FGTI-2734 overcomes sotorasib intrinsic resistance. However, it is also contemplated that FGTI-2734 also overcomes sotorasib acquired resistance. Thus, FGTI- 2734 may enhance sotorasib anti-tumor efficacy in sotorasib-na ⁇ ve patients, in addition to those who progressed while on sotorasib.
  • the anti-cancer agents described herein may be administered in vivo by any suitable route (e.g. parenterally or enterally) including but not limited to: inoculation or injection (e.g.
  • epithelial or mucocutaneous linings e.g., nasal, oral, vaginal, rectal, gastrointestinal mucosa, and the like.
  • suitable means include but are not limited to: inhalation (e.g. as a mist or spray), orally (e.g. as a pill, capsule, liquid, etc.), intravaginally, intranasally, rectally, by ingestion of a food or probiotic product containing the compound, as eye drops, etc.
  • the mode of administration is oral or by injection.
  • the anti-cancer agents described herein may be administered simultaneously or sequentially.
  • the present disclosure also provides a method of treatment comprising administering to a subject a formulation as described herein, with or without an additional biological active agent or anti-cancer agent, e.g. an immunotherapy agent, chemotherapeutic agent, anti-angiogenesis agent, signal transduction inhibitor, antiproliferative agent, glycolysis inhibitor, or autophagy inhibitor.
  • the additional therapeutic agent is selected from an anti-PD-1 antibody, a chemotherapeutic agent, a MEK inhibitor, an EGFR inhibitor, a TOR inhibitor, a SHP2 inhibitor, PI3K inhibitor, and an AKT inhibitor.
  • the treatment described herein is administered with or without radiation therapy.
  • a patient or subject to be treated by any of the compositions or methods of the present disclosure can mean either a human or a non-human animal including, but not limited to mammals, dogs, horses, cats, rabbits, gerbils, hamsters, rodents, birds, aquatic mammals, cattle, pigs, camelids, and other zoological animals.
  • the formulation or active agent is administered to the subject in a therapeutically effective amount.
  • a therapeutically effective amount or an “effective amount” is meant a sufficient amount to treat the disease or disorder at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood that the total daily usage of the compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific active agent employed; and like factors well known in the medical arts.
  • the effective amount of the drug or composition may: (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow to some extent and preferably stop cancer cell infiltration into peripheral organs; (iv) inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay occurrence and/or recurrence of tumor; and/or (vii) relieve to some extent one or more of the symptoms associated with the cancer. It is well within the skill of the art to start doses of the compound at levels or frequencies lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage or frequency until the desired effect is achieved.
  • Such doses may be administered in a single dose or it may be divided into multiple doses.
  • Further embodiments provide a method of inhibiting the viability of or inducing apoptosis in sotorasib-resistant or sotorasib-sensitive lung cancer cells in vitro or in vivo comprising the step of exposing the lung cancer cells to a combination therapy as described herein.
  • Embodiments of the disclosure also provide compositions comprising the anti-cancer agents described herein.
  • kits comprises two separate pharmaceutical compositions: FGTI- 2734 (or other FGTI) and sotorasib (or other KRAS G12C inhibitor).
  • the kit comprises a container for containing the separate compositions such as a divided bottle or a divided foil packet. Additional examples of containers include syringes, boxes, and bags.
  • the kit comprises directions for the use of the separate components.
  • the kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing health care professional.
  • An example of such a kit is a so-called blister pack.
  • Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil.
  • the recesses have the size and shape of the tablets or capsules to be packed.
  • the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed.
  • the tablets or capsules are sealed in the recesses between the plastic foil and the sheet.
  • the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
  • the pharmaceutical compositions can be formulated according to known methods for preparing pharmaceutically useful compositions.
  • Examples include, but are not limited to, phosphate buffered saline, physiological saline, water, and emulsions, such as oil/water emulsions.
  • the carrier can be a solvent or dispersing medium containing, for example, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • Formulations are described in a number of sources that are well known and readily available to those skilled in the art. For example, Remington's Pharmaceutical Sciences (Martin E W [1995] Easton Pa., Mack Publishing Company, 19 th ed.) describes formulations which can be used in connection with the subject invention. The final amount of the compounds in the formulations may vary.
  • the cells were treated for 24 hours either with 0.1% DMSO vehicle control, sotorasib, FGTI-2734 or the combination of sotorasib and FGTI-2734.
  • the sotorasib concentration used for the sotorasib-sensitive H2122 and H358 cells was 0.1 ⁇ M and for the sotorasib-resistant LU99 and Calu1 cells was 3 ⁇ M sotorasib.
  • the FGTI-2734 concentration used was 20 ⁇ M for all 4 cell lines.
  • mice Six-week-old female athymic nude mice (Crl:NU(NCr)-Foxn1nu) were purchased from Charles River Laboratories, Wilmington, MA, USA and were maintained and treated in accordance with VCU’s Institutional Animal Care and Use Committee procedures and guidelines (IACUC Protocol Number AD10002149).
  • the animals were randomized to the following treatment groups: (1) vehicle control, (2) FGTI-2734, (3) sotorasib, and (4) FGTI-2734 and sotorasib combination.
  • the vehicle group received 30% PEG400 (Sigma-Aldrich (Millipore), USA, Cat#P3265) +10% Kolliphor® EL (Sigma- Aldrich (Millipore), USA, Cat# C5135) + 60% MilliQ water;
  • FGTI-2734 was dissolved in the above vehicle, and sotorasib was dissolved in 40% PEG300 (Sigma-Aldrich (Millipore), USA, Cat# 202371) + 10% DMSO (Sigma-Aldrich (Millipore), USA, Cat# 472301) + 1% Tween®- 80 (Sigma-Aldrich (Millipore), USA, Cat# P1754) + 49% sterile saline (0.9% NaCl).
  • mice All mice were treated orally once daily via 100 ⁇ L with the doses as described herein. For all 4 groups, animals showed no evidence of gross toxicity (weight loss, decreased activity, decreased food intake). Per the IACUC Protocol (# AD10002149) criteria, mice with tumors that reached 2000 mm 3 were euthanized.
  • Anti-tumor efficacy studies of a PDX of from a patient with KRAS G12C lung cancer Fresh tumor biopsies were obtained from a KRAS G12C lung cancer patient (VCU, IRB protocol HM20021072) with written consent from the patient. The research was conducted according to International Ethical Guidelines for Biomedical Research Involving Human Subjects.
  • mice Fresh 2-mm tumor pieces were obtained from lung cancer resection and transported on ice to the animal surgery suite for subcutaneous implantation into NOD.Cg- Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice.
  • the mice were housed, maintained, and treated in accordance with VCU’s Institutional Animal Care and Use Committee procedures and guidelines (Animal IACUC protocol AD10002523).
  • a viable tumor piece was then implanted s.c. on the right flanks of anesthetized NSG mice (generation 1) and passaged for 2 more generations as described previously. 28, 44, 54 When the tumors of generation 3 mice reached approximately 100-200 mm 3 , the mice were randomized into 4 groups as described above for the xenograft models.
  • results FGTI-2734 inhibits KRAS, NRAS, and HRAS membrane localization and interacts synergistically with sotorasib to inhibit the viability and induce apoptosis of KRAS G12C lung cancer cell lines.
  • sotorasib sensitivity/resistance of 8 human KRAS G12C NSCLC cell lines H358, H2122, H2030, HOP62, HCC1171, LU65, LU99, Calu1
  • CCG CellTiter-Glo®
  • H358, HCC1171, LU65, and H2122 cells to be sensitive to sotorasib (IC50s of 0.016, 0.019 0.030, and 0.048 ⁇ M, respectively), and LU99, H2030, HOP62, and Calu1 cells to be highly resistant (IC50s of 25.23, 33.8, 49.2, and 54.20 ⁇ M, respectively) (Fig. 1A-1D and data not shown).
  • sotorasib IC50s of 0.016, 0.019 0.030, and 0.048 ⁇ M, respectively
  • LU99, H2030, HOP62, and Calu1 cells to be highly resistant (IC50s of 25.23, 33.8, 49.2, and 54.20 ⁇ M, respectively) (Fig. 1A-1D and data not shown).
  • sotorasib To determine whether FGTI-2734 can inhibit KRAS, HRAS and NRAS prenylation and membrane localization and enhance the ability of sotorasib to induce apoptosis, we exposed the cells for 24 and 48 hours to sotorasib (3 ⁇ M for LU99, Calu-1, HOP62, and H2030 cells and 0.1 ⁇ M for H358, LU65, HCC1171, and H2122 cells) and FGTI-2734 (20 ⁇ M for all cell lines) individually or in combination, and processed the cells for Western blotting.
  • FGTI-2734 enhances the in vivo anti-tumor activity of sotorasib in KRAS G12C lung cancer xenografts.
  • sotorasib we subcutaneously implanted nude mice with LU99, H358, H2122 and Calu- 1 cells, and after the tumors were palpable, mice were orally treated daily with vehicle, sotorasib, FGTI-2734, or the combination.
  • H358 xenografts In H358 xenografts, FGTI- 2734 (100 mpk) alone inhibited tumor growth partially, but in combination with sotorasib (5 mpk), the 2 drugs caused significant tumor regression as early as day 2 and continued throughout the treatment period decreasing the average tumor volume from 187 +/- 22 mm 3 at day 0 to 24 +/- 3 mm 3 at day 29, corresponding to 87% tumor regression on day 29 (Fig. 3B). In H2122 xenografts, low- dose sotorasib (5 mpk) inhibited tumor growth partially (Fig. 3C).
  • FGTI-2734 enhances the in vivo anti-tumor activity of sotorasib in a KRAS G12C lung cancer patient- derived xenograft (PDX).
  • PDX KRAS G12C lung cancer patient- derived xenograft
  • tumors treated with FGTI-2734 alone continued to grow whereas those treated with sotorasib alone started to regress but significantly less than the regression caused by the combination treatment (Fig. 3D).
  • tumors from mice treated with sotorasib (15 mpk) alone and FGTI- 2734 (150 mpk) alone grew whereas those from mice treated with the combination regressed significantly.
  • the treatment was re-started on day 37 with sotorasib at 15 mpk and FGTI-2734 at 150 mpk.
  • the tumors treated with single-agent FGTI-2734 or sotorasib continued to grow whereas those treated with the combination continued to significantly regress throughout the treatment period (Fig. 3D).
  • the average tumor volume from the mice treated with vehicle, FGTI-2734, and sotorasib alone grew from 118 ⁇ 27, 129 ⁇ 26, and 113 ⁇ 27 at day 0 to 1573 ⁇ 440, 726 ⁇ 200, and 339 ⁇ 142 at day 47, respectively (Fig. 3D), corresponding to 1333%, 563%, and 300% increase in tumor growth.
  • the average tumor volume from the mice treated with the combination decreased from 110 ⁇ 28 mm 3 at day 0 to 41 ⁇ 12 mm 3 at day 47 (Fig.3D), corresponding to -62% tumor regression on day 47.
  • FGTI-2734 blocks sotorasib-induced ERK adaptive reactivation in KRAS G12C lung cancer cells in vitro and in xenografts in vivo.
  • FGTI-2734 Block sotorasib-induced ERK adaptive reactivation in KRAS G12C lung cancer cells in vitro and in xenografts in vivo.
  • FGTI-2734 could also enhance the anti-tumor activity of sotorasib in the context of other clinically-relevant resistance mechanisms that are dependent on RAS membrane localization including those involving patients whose tumors acquired RTK mutations such as EGFR-A289V and RET-M918T, fusions involving ALK, RET and FGFR3, mutations in NRAS, and loss-of-function mutations in NF1 while on KRAS G12C inhibitors.
  • KRAS(G12C) inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients. Cancer Discov 2020;10:54-71. 15. Canon J, Rex K, Saiki AY, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature 2019;575:217-223. 16. Skoulidis F, Li BT, Dy GK, et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med 2021;384:2371-2381. 17.
  • Klomp JA Klomp JE, Stalnecker CA, et al. Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers. Science 2024;384:eadk0775.
  • Berndt N Hamilton AD, Sebti SM. Targeting protein prenylation for cancer therapy. Nat Rev Cancer 2011;11:775-791.
  • Kazi A Xiang S, Yang H, et al.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une méthode de traitement d'un cancer chez un patient qui en a besoin. La méthode comprend l'administration au sujet d'une quantité thérapeutiquement efficace de sotorasib ou d'un sel pharmaceutiquement acceptable de celui-ci et d'une quantité thérapeutiquement efficace de FGTI-2734 ou d'un sel pharmaceutiquement acceptable de celui-ci. L'invention concerne également des compositions de formes posologiques et des kits comprenant du sotorasib et du FGTI-2734 ou des sels pharmaceutiquement acceptables de ceux-ci.
PCT/US2025/011976 2024-01-19 2025-01-17 Polythérapie à inhibiteur double de farnésyltransférase et de géranylgéranyltransférase -1, et de sotorasib Pending WO2025155787A1 (fr)

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Citations (1)

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US11439645B2 (en) * 2018-11-19 2022-09-13 Amgen Inc. Combination therapy including a KRASG12C inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers

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