WO2023049363A1 - Sotorasib et afatinib pour le traitement du cancer comprenant une mutation kras g12c - Google Patents

Sotorasib et afatinib pour le traitement du cancer comprenant une mutation kras g12c Download PDF

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WO2023049363A1
WO2023049363A1 PCT/US2022/044557 US2022044557W WO2023049363A1 WO 2023049363 A1 WO2023049363 A1 WO 2023049363A1 US 2022044557 W US2022044557 W US 2022044557W WO 2023049363 A1 WO2023049363 A1 WO 2023049363A1
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patient
sotorasib
cancer
afatinib
administering
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Gregory Friberg
Haby HENARY
Brett E. Houk
Omar MATHER
Gataree Ngarmchamnanrith
Sandeep Dutta
Wendy J. Snyder
Neelesh Soman
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Amgen Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • 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
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, ***e
    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/08—Oxides; Hydroxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/10—Carbonates; Bicarbonates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the rat sarcoma (RAS) proto-oncogene has been identified as an oncogenic driver of tumorigenesis in cancers, such as non-small cell lung cancer (NSCLC) and colorectal cancer (CRC).
  • NSCLC non-small cell lung cancer
  • CRC colorectal cancer
  • the RAS family consists of 3 closely related genes that express guanosine triphosphate (GTP)-ases responsible for regulating cellular proliferation and survival.
  • GTP guanosine triphosphate
  • the RAS proteins, Kirsten rat sarcoma viral oncogene homolog (KRAS), Harvey rat sarcoma viral oncogene homolog (HRAS), and neuroblastoma RAS viral oncogene homolog (NRAS) can be mutationally activated at codons 12, 13, or 61 , leading to human cancers.
  • KRAS being the most frequently mutated isoform in most cancers. While the role of KRAS mutations in human cancers has been known for decades, no anti-cancer therapies specifically targeting KRAS mutations have been successfully developed, until recently, largely because the protein had been considered intractable for inhibition by small molecules.
  • the cancer is a solid tumor.
  • the cancer is non-small cell lung cancer, and in some cases, is metastatic or locally advanced.
  • the cancer is colorectal cancer.
  • the cancer is pancreatic cancer.
  • the cancer is small bowel cancer, appendiceal cancer, endometrial cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell tumor, ovarian cancer, gastrointestinal neuroendocrine tumor, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.
  • Figure 1 shows the mean plasma concentration time profile after once daily oral administration of 180, 360, 720, or 960 mg sotorasib on Day 1 , where N indicates number of observations across data points.
  • Figure 2 shows the mean plasma concentration time profile after once daily oral administration of 180, 360, 720, or 960 mg sotorasib on Day 8, where N indicates number of observations across data points.
  • compositions comprising a KRAS G12C mutation in a patient comprising administering to the patient sotorasib and afatinib in amounts effective to treat the cancer.
  • administration of two or more therapeutics e.g., sotorasib, afatinib
  • concomitant administration of the therapeutics e.g., within 1 hour, within 45 minutes, within 30 minutes, within 15 minutes, or within 10 minutes of each other
  • sequential administration e.g., administration separated by at least 1 hour, or at least two hours, or at least four hours, or at least six hours, or at least eight hours, or at least twelve hours, or at least 24 hours, or at least 2 days, or at least 3 days.
  • combination therapy of two or more therapeutics as discussed herein include both concomitant and sequential administration.
  • Sotorasib is a small molecule that irreversibly inhibits the KRAS G12C mutant protein. Sotorasib is also referred to as AMG 510 or 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1 /W)-1 -[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4- [(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1 -yl]pyrido[2,3-c/]pyrimidin-2(1 H)-one and has the following structure:
  • Sotorasib binds to the P2 pocket of KRAS adjacent to the mutant cysteine at position 12 and the nucleotide-binding pocket.
  • the inhibitor contains a thiol reactive portion which covalently modifies the cysteine residue and locks KRAS G12C in an inactive, guanosine diphosphate (GDP) bound conformation.
  • GDP guanosine diphosphate
  • RNA interference RNA interference
  • small molecule inhibition has previously demonstrated an inhibition of cell growth and induction of apoptosis in tumor cell lines and xenografts harboring KRAS mutations (including the KRAS G12C mutation) (Janes et al., 2018; McDonald et al., 2017; Xie et al., 2017; Ostrem and Shokat, 2016; Patricelli et al., 2016).
  • sotorasib have confirmed these in vitro findings and have likewise demonstrated inhibition of growth and regression of cells and tumors harboring KRAS G12C mutations (Canon et al., 2019). See also, LUMAKRAS® US Prescribing Information, Amgen Inc., Thousand Oaks, California, 91320 (revision 5/2021), which is herein incorporated by reference in its entirety.
  • Afatinib is a pan-ErbB tyrosine kinase inhibitor.
  • Afatinib covalently binds to the kinase domains of EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4) and irreversibly inhibits tyrosine kinase autophosphorylation, resulting in downregulation of ErbB signaling.
  • Afatinib (GILOTRIF®) is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have non-resistant EGFR mutations as detected by a Food and Drug Administration (FDA)-approved test.
  • NSCLC metastatic non-small cell lung cancer
  • GILOTRIF is also indicated for the treatment of patients with metastatic squamous NSCLC progressing after platinum-based chemotherapy. See also, Afatinib (GILOTRIF®), US Prescribing Information, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, 06877 (revision 10/2019), which is herein incorporated by reference in its entirety.
  • the methods comprise administering sotorasib in an amount ranging from 120 mg to 960 mg. In some embodiments, the methods comprise administering 960 mg sotorasib to the patient once daily. In some embodiments, the methods comprise administering 720 mg sotorasib to the patient once daily. In some embodiments, the methods comprise administering 480 to the patient once daily. In some embodiments, the methods comprise administering 240 mg to the patient once daily. In some embodiments, the methods comprises administering 120 mg to the patient once daily. In some embodiments, the methods comprise administering 480 mg to the patient twice daily. In some embodiments, the methods comprise administering 240 mg to the patient twice daily.
  • the methods comprise administering afatinib to the patient once daily.
  • the methods comprise administering panitumumab in an amount ranging from 20 mg to 40 mg (e.g., 20 mg, 25 mg, 30 mg, 35 mg, 40 mg) once daily.
  • the methods comprise administering 40 mg afatinib.
  • the methods further comprise administering 30 mg afatinib.
  • the methods further comprise administering 20 mg afatinib.
  • the methods described herein comprise administering to the patient (a) 960 mg sotorasib daily; and (b) 40 mg afatinib daily. In some embodiments, the methods described herein comprise administering to the patient (a) 960 mg sotorasib daily; and (b) 30 mg afatinib daily. In some embodiments, the methods described herein comprise administering to the patient (a) 960 mg sotorasib daily; and (b) 20 mg afatinib daily. In some embodiments, the methods described herein comprise administering to the patient (a) 240 mg sotorasib daily; and (b) 30 mg afatinib daily.
  • the methods described herein comprise administering to the patient (a) 240 mg sotorasib daily; and (b) 20 mg afatinib daily. In some embodiments, the methods described herein comprise administering to the patient (a) 120 mg sotorasib daily; and (b) 30 mg afatinib daily. In some embodiments, the methods described herein comprise administering to the patient (a) 120 mg sotorasib daily; and (b) 20 mg afatinib daily.
  • the methods further comprise administering an anti-diarrheal agent to the patient.
  • the anti-diarrheal agent is loperamide or atropine/diphenoxylate.
  • the methods comprise administering the sotorasib and afatinib for a treatment period of at least 21 days, at least 3 months, at least 6 months, or at least 1 year.
  • sotorasib and afatinib are administered under fasted conditions. In various embodiments, sotorasib is administered before afatinib.
  • the patient is in further need of treatment with an acid-reducing agent.
  • Acidreducing agents include, but are not limited to, a proton pump inhibitor (PPI), a H2 receptor antagonist (H2RA), and a locally acting antacid.
  • PPI proton pump inhibitor
  • H2RA H2 receptor antagonist
  • the patient is further in need of treatment with a PPI or a H2RA.
  • Exemplary PPIs include, but are not limited to, omeprazole, pantoprazole, esomeprazole, lansoprazole, rabeprazole, or dexlansoprazole.
  • Exemplary H2RAs include, but are not limited to, famotidine, ranitidine, cimetidine, nizatidine, roxatidine and lafutidine.
  • Exemplary locally acting antacids include, but are not limited to, sodium bicarbonate, calcium carbonate, aluminum hydroxide, and magnesium hydroxide.
  • the patient who is in further need of treatment with an acid-reducing agent, is not administered a proton pump inhibitor or a H2 receptor antagonist in combination with sotorasib.
  • the patient who is in further need of treatment with an acid-reducing agent, is not administered a proton pump inhibitor or a H2 receptor antagonist in combination with sotorasib, but is administered a locally acting antacid in combination with sotorasib.
  • sotorasib is administered about 4 hours before or about 10 hours after a locally acting antacid.
  • the patient is in further need of treatment with a CYP3A4 inducer.
  • the patient is not administered a CYP3A4 inducer in combination with sotorasib.
  • Exemplary CYP3A4 inducers include, but are not limited to, barbiturates, brigatinib, carbamazepine, clobazam, dabrafenib, efavirenz, elagolix, enzalutamide, eslicarbazepine, glucocorticoids, letermovir, lorlatinib, modafinil, nevirapine, oritavancin, oxcarbazepine, perampanel, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, telotristat, and troglitazone.
  • the patient is not administered a strong CYP3A4 inducer in combination with sotorasib.
  • strong CYP3A4 inducers include, but are not limited to, phenytoin and rifampin. See, e.g., www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates- inhibitors-and-inducers, accessed May 2021 .
  • the patient is in further need of treatment with a CYP3A4 substrate.
  • the patient is not administered a CYP3A4 substrate in combination with sotorasib.
  • Exemplary CYP3A4 substrates include, but are not limited to, abemaciclib, abiraterone, acalabrutinib, alectinib, alfentanil, alprazolam, amitriptyline, amlodipine, apixaban, aprepitant, aripiprazole, astemizole, atorvastatin, avanafil, axitinib, boceprevir, bosutinib, brexpiprazole, brigatinib, buspirone, cafergot, caffeine, carbamazepine, cariprazine, ceritinib, cerivastatin, chlorpheniramine, cilostazol, cisapride,
  • the patient is in further need of treatment with a P-glycoprotein (P-gp) substrate.
  • P-gp substrates include, but are not limited to dabigatran etexilate, digoxin, fexofenadine, everolimus, cyclosporine, sirolimus, and vincristine. See, e.g., www.fda.gov/drugs/drug-interactions-labeling/drug- development-and-drug-interactions-table-substrates-inhibitors-and-inducers, accessed May 2021.
  • the patient is not administered a P-gp substrate in combination with sotorasib, wherein the P-gp substrate is a P-gp substrate with a narrow therapeutic index.
  • P-gp substrates with a narrow therapeutic index include, but are not limited to, digoxin, everolimus, cyclosporine, sirolimus, and vincristine.
  • the patient has a cancer that was determined to have one or more cells expressing the KRAS G12C mutant protein prior to administration of sotorasib as disclosed herein. Determination of KRAS G12C mutant protein can be assessed as described elsewhere in this disclosure.
  • the patient administered the sotorasib in the methods described herein have been previously treated with a different anti-cancer therapy, e.g., at least one - such as one, or two, or three - other systemic cancer therapy.
  • a different anti-cancer therapy e.g., at least one - such as one, or two, or three - other systemic cancer therapy.
  • the patient had previously been treated with one other systemic cancer therapy, such that the sotorasib therapy is a second line therapy.
  • the patient had previously been treated with two other systemic cancer therapy, such that the sotorasib therapy as provided herein is a third line therapy.
  • the prior systemic cancer therapy is a therapy with a KRAS G12C inhibitor.
  • the patient exhibits reduced sensitivity to a therapy with a KRAS G12C inhibitor.
  • the patient is resistant to a therapy with a KRAS G12C inhibitor.
  • KRAS G12C inhibitor is sotorasib, adagrasib, GDC-6036, D-1553, JDQ443, LY3484356, BI1823911, JAB-21822, RMC-6291, or APG-1842.
  • the KRAS G12C inhibitor is sotorasib.
  • the KRAS G12C inhibitor is adagrasib.
  • the therapy is monotherapy.
  • the therapy with a KRAS G12C inhibitor is sotorasib monotherapy.
  • the therapy with a KRAS G12C inhibitor is monotherapy with adagrasib.
  • sensitivity refers to the way a cancer reacts to a drug, e.g., sotorasib.
  • sensitivity means “responsive to treatment” and the concepts of “sensitivity” and “responsiveness” are positively associated in that a cancer or tumor that is responsive to a drug treatment is said to be sensitive to that drug.
  • Sensitivity in exemplary instances is defined according to Pelikan, Edward, Glossary of Terms and Symbols used in Pharmacology (Pharmacology and Experimental Therapeutics Department Glossary at Boston University School of Medicine), as the ability of a population, an individual or a tissue, relative to the abilities of others, to respond in a qualitatively normal fashion to a particular drug dose.
  • “Sensitivity” may be measured or described quantitatively in terms of the point of intersection of a dose-effect curve with the axis of abscissal values or a line parallel to it; such a point corresponds to the dose just required to produce a given degree of effect.
  • the “sensitivity” of a measuring system is defined as the lowest input (smallest dose) required producing a given degree of output (effect).
  • “sensitivity” is opposite to “resistance” and the concept of “resistance” is negatively associated with “sensitivity”. For example, a cancer that is resistant to a drug treatment is either not sensitive nor responsive to that drug or was initially sensitive to the drug and is no longer sensitive upon acquiring resistance; that drug is not or no longer an effective treatment for that tumor or cancer cell.
  • Prior systemic cancer therapies include, but are not limited to, chemotherapies and immunotherapies.
  • Specific contemplated prior systemic cancer therapies include, but are not limited to, anti-PD1 therapy, anti-PD L1 therapy, platinum based chemotherapy and anti-EGFR therapy.
  • anti-PD1 therapy and anti- PDL1 therapies include, but are not limited to, pembrolizumab, nivolumab, cemiplimab, tisielizumab, toripalimab, aspartalizumab, dostarlimab, retifanlimab, Heillimab, pidilizumab atezolizumab, avelumab, durvalumab, and zeluvalimab (AMG 404).
  • platinum based chemotherapies include, but are not limited to, carboplatin, oxaliplatin, cisplatin, nedaplatin, satraplatin, lobaplatin, triplatin tetranitrate, picoplatin, ProLindac, and aroplatin.
  • anti-EGFR therapy include, but are not limited to, cetuximab and panitumumab.
  • the patient has previously been administered a systemic cancer therapy that is a targeted therapy if the cancer was identified to have an actionable oncogenic driver mutation in the epidermal growth factor receptor gene EGFR), anaplastic lymphoma kinase gene (ALA), and/or ROS proto-oncogene 1 (ROS1).
  • Targeted therapies for EGFR mutations include, but are not limited to, erlotinib, gefitinib, and afatinib.
  • Targeted therapies for ALK mutations include, but are not limited to, crizotinib, entrectinib, lorlatinib, repotrecti nib, brigatinib, alkotinib, alectinib, ensartinib, and ceritinib.
  • Targeted therapies for ROS1 mutations include, but are not limited to, crizotinib, entrecetinib, ensartinib, alkotinib, brigatinib, taletrectinib, cabozantinib, repotrecti nib, lorlatinib, and ceritinib.
  • the patient exhibits an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 (see, e.g., Zubrod et al., 1960).
  • Status 0 indicates fully active and able to carry on all pre-disease performance without restriction.
  • Status 1 indicates restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature.
  • Status 2 indicates ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours.
  • Status 3 indicates capable of only limited selfcare, confined to bed or chair more than 50% of waking hours.
  • Status 4 indicates completely disabled, cannot carry on any selfcare and totally confined to bed or chair.
  • Status 5 indicates death.
  • the methods comprise administering a reduced total daily dose of sotorasib when the patient experiences an adverse event to the initial total daily dose.
  • the initial daily dose is 960 mg sotorasib and the reduced total daily dose is 480 mg sotorasib.
  • the initial daily dose is 480 mg sotorasib and the reduced total daily dose is 240 mg sotorasib.
  • the methods further comprise administering a second reduced total daily dose of sotorasib when the patient experiences an adverse event to the reduced total daily dose.
  • AE reverse event
  • the adverse event is hepatotoxicity (e.g., elevation of liver enzymes), interstitial lung disease (ILD)Zpneumonitis, diarrhea, and/or nausea/vomiting.
  • hepatotoxicity e.g., elevation of liver enzymes
  • ILD interstitial lung disease
  • the adverse event is hepatotoxicity.
  • hepatotoxicity refers to a patient having abnormal laboratory values of liver biomarkers (e.g., alkaline phosphatase (ALP), aspartate amino transferase (AST), alanine aminotransferase (ALT), and/or total bilirubin (TBL)), when the patient had baseline levels of the liver biomarker(s) prior to sotorasib administration that were not abnormal laboratory values or were lower than those measured after administration of sotorasib.
  • ALP alkaline phosphatase
  • AST aspartate amino transferase
  • ALT alanine aminotransferase
  • TBL total bilirubin
  • ALT Alanine transaminase
  • SGPT serum glutamic pyruvate transaminase
  • ALAT alanine aminotransferase
  • AST Aspartate transaminase
  • SGOT serum glutamic oxaloacetic transaminase
  • ASAT aspartate aminotransferase
  • AST can increase in response to liver damage. Elevated AST also can result from damage to other sources, including red blood cells, cardiac muscle, skeletal muscle, kidney tissue, and brain tissue. The ratio of AST to ALT can be used as a biomarker of liver damage.
  • Bilirubin is a catabolite of heme that is cleared from the body by the liver. Conjugation of bilirubin to glucuronic acid by hepatocytes produces direct bilirubin, a water-soluble product that is readily cleared from the body. Indirect bilirubin is unconjugated, and the sum of direct and indirect bilirubin constitutes total bilirubin. Elevated total bilirubin can be indicative of liver impairment.
  • Alkaline phosphatase hydrolyzes phosphate groups from various molecules and is present in the cells lining the biliary ducts of the liver. ALP levels in plasma can rise in response to liver damage and are higher in growing children and elderly patients with Paget's disease. However, elevated ALP levels usually reflect biliary tree disease. [0042] In some embodiments, the patient is not suffering from a disorder that results in elevated liver biomarkers.
  • disorders associated with elevated liver biomarkers include, but are not limited to, hepatobiliary tract disease; viral hepatitis (e.g., hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, herpes simplex virus, varicella, toxoplasmosis, and parvovirus); right sided heart failure, hypotension or any cause of hypoxia to the liver causing ischemia; exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary supplements, plants and mushrooms; heritable disorders causing impaired glucuronidation (e.g., Gilbert’s syndrome, Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (e.g., indinavir, atazanavir); alpha-one antitrypsin deficiency; alcoholic hepatitis; autoimmune hepatitis; Wilson
  • the baseline liver function of the patient can be assessed by various means known in the art, such as blood chemistry tests measuring biomarkers of liver function.
  • the methods described herein comprise monitoring liver biomarkers in the patient and withholding sotorasib administration in patients having > Grade 2 abnormal liver function, as assessed by levels of AST and/or ALT.
  • sotorasib administration is paused until the AST and/or ALT levels in the patient improve(s) to Grade 1 or better (baseline).
  • Adverse effect Grades for abnormal liver function are defined herein by the modified Common Toxicity Criteria (CTC) provided in Table 1 . See the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 (NCI CTCAE) published Nov. 27, 2017 by the National Cancer Institute, incorporated herein by reference in its entirety.
  • CTC Common Toxicity Criteria
  • ALP alkaline phosphatase
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • ULN upper limit of normal
  • WNL within normal limits
  • Grade 0 levels are characterized by biomarker levels within normal limits (WNL).
  • Normal refers to Grade 0 adverse effects.
  • Abnormal liver function, as used herein, refers to Grade 1 and above adverse effects.
  • Grade 1 liver function abnormalities include elevations in ALT or AST greater than the ULN and less than or equal to 3-times the ULN if baseline was normal; 1 .5 - 3.0 x baseline if baseline was abnormal. Grade 1 liver function abnormalities also include elevations of bilirubin levels greater than the ULN and less than or equal to 1.5-times the ULN if baseline was normal; > 1.0 - 1.5 x baseline if baseline was abnormal. Grade 1 liver function abnormalities also include elevations of ALP greater than the ULN and less than or equal to 2.5-times the ULN if baseline was normal; > 2.0 - 2.5 x baseline if baseline was abnormal.
  • Grade 2 liver function abnormalities include elevations in ALT or AST greater than 3-times and less than or equal to 5-times the upper limit of normal (ULN) if baseline was normal; >3.0 - 5.0 x baseline if baseline was abnormal. Grade 2 liver function abnormalities also include elevations of bilirubin levels greater than 1 .5- times and less than or equal to 3-times the ULN if baseline was normal; > 1.5 - 3. O x baseline if baseline was abnormal. Grade 2 liver function abnormalities also include elevations of ALP greater than 2.5-times and less than or equal to 5-times the ULN if baseline was normal; > 2.5 - 5.0 x baseline if baseline was abnormal.
  • Grade 3 liver function abnormalities include elevations in ALT, AST, or ALP greater than 5-times and less than or equal to 20-times the ULN if baseline was normal; >5.0 - 20.0 x baseline if baseline was abnormal.
  • Grade 3 liver function abnormalities also include elevations of bilirubin levels greater than 3-times and less than or equal to 10-times the ULN if baseline was normal; > 3.0 - 10 x baseline if baseline was abnormal.
  • Grade 4 liver function abnormalities include elevations in ALT, AST, or ALP greater than 20-times the ULN if baseline was normal; > 20 x baseline if baseline was abnormal. Grade 4 liver function abnormalities also include elevations of bilirubin levels greater than 10 times the ULN if baseline was normal; > 10.0 x baseline if baseline was abnormal.
  • the ULN for various indicators of liver function depends on the assay used, the patient population, and each laboratory's normal range of values for the specified biomarker, but can readily be determined by the skilled practitioner. Exemplary values for normal ranges for a healthy adult population are set forth in Table 2 below. See Cecil Textbook of Medicine, pp. 2317-2341, W.B. Saunders & Co. (1985).
  • the total daily dose of sotorasib is reduced (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) when the AST and/or ALT level(s) in the patient is/are elevated, e.g. to a Grade 2 or Grade 3 level, where the baseline AST and/or ALT levels of the patient were below Grade 2 or Grade 3 levels.
  • the total daily dose of sotorasib is reduced (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg), when the AST and/or ALT level(s) in the patient is/are elevated is to a Grade 1 level, wherein the baseline AST and/or ALT levels of the patient were below Grade 1 levels.
  • the total daily dose of sotorasib is reduced (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) when (1) AST and bilirubin levels in the patient are elevated, or (2) when AST or ALP levels in the patient are elevated, or (3) when ALT and bilirubin levels in the patient are elevated, or (4) when ALT and ALP levels in the patient are elevated, or (5) when bilirubin and ALP levels in the patient are elevated, e.g., to a Grade 1 , Grade 2, Grade 3 or Grade 4 level, wherein the baseline AST, bilirubin, ALP, and/or ALT levels of the patient were below Grade 1 , Grade 2, Grade 3 or Grade 4 levels, respectively.
  • sotorasib is reduced (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) when (1) AST and bilirubin levels in the patient are elevated, or (2) when AST or ALP levels in the patient are elevated, or (3) when
  • three biomarkers of liver function may be elevated in the patient (e.g., ALT and AST and bilirubin, or ALT and AST and ALP) to a Grade 1, Grade 2, Grade 3 or Grade 4 level, wherein the baseline biomarker levels of the patient were below Grade 1 , Grade 2, Grade 3 or Grade 4 levels, respectively.
  • the total daily dose of sotorasib is reduced (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) when the level of ALT and/or AST is greater than about 3 times compared to the upper limit of normal (ULN).
  • the abnormal level of ALT and/or AST is greater than about 3- to about 5-fold increase compared to the upper limit of normal (ULN), i.e. a "Grade 2 abnormality".
  • the Grade 2 abnormality is an abnormal level of ALT and/or AST greater than about 3-fold to about 5-fold increase compared to baseline.
  • the abnormal level of ALP is greater than about 2.5- to about 5-fold increase compared to the upper limit of normal (ULN), i.e., a "Grade 2 abnormality".
  • the Grade 2 abnormality is an abnormal level of ALP greater than about 2.5-fold to about 5-fold increase compared to baseline.
  • the abnormal level of bilirubin is greater than about 1 .5- to about 3-fold increase compared to the upper limit of normal (ULN), i.e., a "Grade 2 abnormality”.
  • the Grade 2 abnormality is an abnormal level of bilirubin greater than about 1 .5-fold to about 3-fold increase compared to baseline.
  • the total daily dose of sotorasib is reduced (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) when the level of ALT and/or AST is greater than about 5 times compared to the upper limit of normal (ULN).
  • the total daily dose is reduced when the level of ALT, AST, or ALP is greater than about 5- to about 20-fold increase compared to the upper limit of normal (ULN), i.e. a "Grade 3 abnormality".
  • the Grade 3 abnormality is an abnormal level of ALT and/or AST greater than about 5-fold to about 20-fold increase compared to baseline.
  • the abnormal level of ALP is greater than about 5- to about 20-fold increase compared to the upper limit of normal (U LN), i.e., a "Grade 3 abnormality".
  • U LN upper limit of normal
  • the Grade 3 abnormality is an abnormal level of ALP greater than about 5-fold to about 20- fold increase compared to baseline.
  • the total daily dose is reduced when the level of bilirubin is greater than about 3- to about 10-fold increase compared to the upper limit of normal (ULN), i.e., a "Grade 3 abnormality".
  • the Grade 3 abnormality is an abnormal level of bilirubin greater than about 3-fold to about 10-fold increase compared to baseline.
  • the total daily dose of sotorasib is reduced (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) when the level of ALT and/or AST is greater than about 20 times compared to the upper limit of normal (ULN) (i.e., a “Grade 4 abnormality”).
  • the Grade 4 abnormality is an abnormal level of ALT and/or AST greater than about 20-fold increase compared to baseline.
  • the abnormal level of ALP is greater than about 20-fold increase compared to the upper limit of normal (ULN), i.e., a "Grade 4 abnormality".
  • the Grade 4 abnormality is an abnormal level of ALP greater than about 20- fold increase compared to baseline.
  • the total daily dose is reduced when the level of bilirubin is greater than about 10-fold increase compared to the upper limit of normal (ULN), i.e., a "Grade 4 abnormality".
  • the Grade 4 abnormality is an abnormal level of bilirubin greater than about 10-fold increase compared to baseline.
  • the methods described herein further comprise increasing the total dose of sotorasib (e.g., from 240 mg to 480 mg, or from 480 mg to 960 mg) when liver biomarker(s) in the patient has improved to a Grade 1 or better (e.g., baseline).
  • sotorasib e.g., from 240 mg to 480 mg, or from 480 mg to 960 mg
  • the adverse event is nausea or vomiting.
  • the nausea/vomiting is present despite appropriate supportive care (e.g., anti-emetic therapy).
  • “Nausea” as used herein refers to a disorder characterized by a queasy sensation and/or the urge to vomit.
  • the methods described herein comprise withholding sotorasib administration in a patient having a Grade 3 nausea until the patient has improved to s Grade 1 or baseline.
  • the methods comprise administering a reduced total daily dose of sotorasib (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) to the patient.
  • the methods described herein comprise withholding sotorasib administration in a patient having a Grade 3 vomiting until the vomiting improves to s Grade 1 or baseline.
  • the methods comprise administering a reduced total daily dose of sotorasib (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) to the patient.
  • the methods described herein further comprise increasing the total dose of sotorasib (e.g., from 240 mg to 480mg, or from 480 mg to 960 mg) when nausea in the patient has improved to a Grade 1 or better (e.g., baseline).
  • sotorasib e.g., from 240 mg to 480mg, or from 480 mg to 960 mg
  • the adverse event is diarrhea.
  • the diarrhea is present despite appropriate supportive care (e.g., anti-diarrheal therapy).
  • An anti-diarrheal therapy can be administration of an anti-diarrheal agent, such as loperamide or atropine/diphenoxylate.
  • Adverse effect Grades for diarrhea are defined herein by the modified Common Toxicity Criteria (CTC) provided in Table 4. See the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 (NCI CTCAE) published Nov. 27, 2017 by the National Cancer Institute, incorporated herein by reference in its entirety.
  • CTC Common Toxicity Criteria
  • the methods described herein comprise withholding sotorasib administration in a patient having a Grade 3 diarrhea until the patient has improved to s Grade 1 or baseline. In some embodiments, once the patient has improved to s Grade 1 or baseline, the methods comprise administering a reduced total daily dose of sotorasib (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) to the patient. In some embodiments, the methods described herein comprise administering an anti-diarrheal agent to the patient. In some embodiments, the anti-diarrheal agent is loperamide or atropine/diphenoxylate.
  • the methods described herein further comprise increasing the total dose of sotorasib (e.g., from 240 mg to 480mg, or from 480 mg to 960 mg) when diarrhea in the patient has improved to a Grade 1 or better (e.g., baseline).
  • sotorasib e.g., from 240 mg to 480mg, or from 480 mg to 960 mg
  • the adverse event is interstitial lung disease (ILD) or pneumonitis.
  • ILD interstitial lung disease
  • pneumonitis In cases where ILD or pneumonitis is suspected at any grade level, sotorasib is withheld. In cases where ILD or pneumonitis is confirmed, and no other causes of the ILD or pneumonitis is identified, sotorasib is permanently discontinued.
  • a patient is administered the therapy for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 15 months, at least 18 months, at least 21 months, or at least 23 months, e.g., for 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 21 months, or 24 months.
  • the patient is administered the therapy for at least 1 month.
  • the patient is administered the therapy for at least 3 months.
  • the patient is administered the patient is administered the
  • the patient can respond to the therapy as measured by at least a stable disease (SD), as determined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 protocol (Eisenhauer, et al., 2009).
  • SD stable disease
  • the stable disease is neither sufficient shrinkage to qualify for partial response (PR) nor sufficient increase to qualify for progressive disease (PD).
  • Response can be measured by one or more of decrease in tumor size, suppression or decrease of tumor growth, decrease in target or tumor lesions, delayed time to progression, no new tumor or lesion, a decrease in new tumor formation, an increase in survival or progression-free survival (PFS), and no metastases.
  • the progression of a patient’s disease can be assessed by measuring tumor size, tumor lesions, or formation of new tumors or lesions, by assessing the patient using a computerized tomography (CT) scan, a positron emission tomography (PET) scan, a magnetic resonance imaging (MRI) scan, an X-ray, ultrasound, or some combination thereof.
  • CT computerized tomography
  • PET positron emission tomography
  • MRI magnetic resonance imaging
  • Progression free survival can be assessed as described in the RECIST 1.1 protocol.
  • the patient exhibits a PFS of at least 1 month.
  • the patient exhibits a PFS of at least 3 months.
  • the patient exhibits a PFS of at least 6 months.
  • sotorasib is a small molecule that specifically and irreversibly inhibits KRAS G12C (Hong et al., 2020). Hong et al.
  • Sotorasib was evaluated in a Phase 1 dose escalation and expansion trial with 129 patients having histologically confirmed, locally advanced or metastatic cancer with the KRAS p.G12C mutation identified by local molecular testing on tumor tissues, including 59 patients with non-small cell lung cancer, 42 patients with colorectal cancer, and 28 patients with other tumor types (Hong et al., 2020, at page 1208-1209). Hong et al. report a disease control rate (95% Cl) of 88.1 % for non-small cell lung cancer, 73.8% for colorectal cancer and 75.0% for other tumor types (Hong et al., 2020, at page 1213, Table 3).
  • the cancer types showing either stable disease (SD) or partial response (PR) as reported by Hong et al. were non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, or melanoma (Hong et al., 2020, at page 1212 ( Figure A), and Supplementary Appendix (page 59 ( Figure S5) and page 63 ( Figure S6)).
  • SD stable disease
  • PR partial response
  • KRAS G12C mutations occur with the alteration frequencies shown in the table below (Gerami et al., 2012; Gao et al., 2013). For example, the table shows that 11.6% of patients with non-small cell lung cancer have a cancer, wherein one or more cells express KRAS G12C mutant protein. Accordingly, sotorasib, which specifically and irreversibly bind to KRAS G12C is useful for treatment of patients having a cancer, including, but not limited to the cancers listed in Table 5 below.
  • the cancer is a solid tumor.
  • the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.
  • the cancer is small bowel cancer, appendiceal cancer, endometrial cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell tumor, ovarian cancer, gastrointestinal neuroendocrine tumor, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.
  • the cancer is non- small cell lung cancer, and in some specific embodiments, metastatic or locally advanced non-small cell lung cancer.
  • the cancer is colorectal cancer.
  • the cancer is pancreatic cancer.
  • the presence or absence of G12C, STK11, KEAP1, EGFR, ALK and/or ROS1 mutations in a cancer as described herein can be determined using methods known in the art. Determining whether a tumor or cancer comprises a mutation can be undertaken, for example, by assessing the nucleotide sequence encoding the protein, by assessing the amino acid sequence of the protein, or by assessing the characteristics of a putative mutant protein or any other suitable method known in the art.
  • the nucleotide and amino acid sequence of wildtype human KRAS (nucleotide sequence set forth in Genbank Accession No. BC010502; amino acid sequence set forth in Genbank Accession No.
  • AGC09594 STK11 (Gene ID: 6794; available at www.ncbi.nlm.nih.gov/gene/6794; accessed January 2020), KEAP1 (Gene ID: 9817; available at www.ncbi.nlm.nih.gov/gene/9817; accessed January 2020), EGFR (Gene ID: 1956; available at www.ncbi.nlm.nih.gov/gene/1956; accessed March 2021), ALK (Gene ID: 238; available at www.ncbi.nlm.nih.gov/gene/238; accessed March 2021), and ROS1 (Gene ID: 6098; available at www.ncbi.nlm. nih.gov/gene/6098; accessed March 2021) are known in the art.
  • Methods for detecting a mutation include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) assays, real-time PGR assays, PGR sequencing, mutant allele-specific PGR amplification (MASA) assays, direct and/or next generation-based sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high resolution melting assays and microarray analyses.
  • PCR-RFLP polymerase chain reaction-restriction fragment length polymorphism
  • PCR-SSCP polymerase chain reaction-single strand conformation polymorphism
  • MASA mutant allele-specific PGR amplification
  • samples are evaluated for mutations, such as the KRAS G12C mutation, by real-time PGR.
  • fluorescent probes specific for a certain mutation such as the KRAS G12C mutation
  • the probe binds and fluorescence is detected.
  • the mutation is identified using a direct sequencing method of specific regions in the gene. This technique identifies all possible mutations in the region sequenced.
  • gel electrophoresis, capillary electrophoresis, size exclusion chromatography, sequencing, and/or arrays can be used to detect the presence or absence of insertion mutations.
  • the methods include, but are not limited to, detection of a mutant using a binding agent (e.g., an antibody) specific for the mutant protein, protein electrophoresis and Western blotting, and direct peptide sequencing.
  • a binding agent e.g., an antibody
  • multiplex PCR-based sequencing is used for mutation detection and can include a number of amplicons that provides improved sensitivity of detection of one or more genetic biomarkers.
  • multiplex PCR-based sequencing can include about 60 amplicons (e.g., 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, or 70 amplicons).
  • multiplex PCR-based sequencing can include 61 amplicons.
  • Amplicons produced using multiplex PCR-based sequencing can include nucleic acids having a length from about 15 bp to about 1000 bp (e.g., from about 25 bp to about 1000 bp, from about 35 bp to about 1000 bp, from about 50 bp to about 1000 bp, from about 100 bp to about 1000 bp, from about 250 bp to about 1000 bp, from about 500 bp to about 1000 bp, from about 750 bp to about 1000 bp, from about 15 bp to about 750 bp, from about 15 bp to about 500 bp, from about 15 bp to about 300 bp, from about 15 bp to about 200 bp, from about 15 bp to about 100 bp, from about 15 bp to about 80 bp, from about 15 bp to about 75 bp, from about 15 bp to about 50 bp, from about 15 bp to about 40 bp, from about 15
  • amplicons produced using multiplex PCR-based sequencing can include nucleic acids having a length of about 33 bp.
  • the presence of one or more mutations present in a sample obtained from a patient is detected using sequencing technology (e.g., a next-generation sequencing technology).
  • sequencing technology e.g., a next-generation sequencing technology.
  • a variety of sequencing technologies are known in the art. For example, methods for detection and characterization of circulating tumor DNA in cell-free DNA can be described elsewhere (see, e.g., Haber and Velculescu, 2014).
  • Non-limiting examples of such techniques include SafeSeqs (see, e.g., Kinde et al., 2011), OnTarget (see, e.g., Forshew et al., 2012), and TamSeq (see, e.g., Thompson et al., 2012).
  • the presence of one or more mutations present in a sample obtained from a patient is detected using droplet digital PGR (ddPCR), a method that is known to be highly sensitive for mutation detection.
  • ddPCR droplet digital PGR
  • the presence of one or more mutations present in a sample obtained from a patient is detected using other sequencing technologies, including but not limited to, chain-termination techniques, shotgun techniques, sequencing-by-synthesis methods, methods that utilize microfluidics, other capture technologies, or any of the other sequencing techniques known in the art that are useful for detection of small amounts of DNA in a sample (e.g., ctDNA in a cell-free DNA sample).
  • the presence of one or more mutations present in a sample obtained from a patient is detected using array-based methods.
  • the step of detecting a genetic alteration (e.g., one or more genetic alterations) in cell-free DNA is performed using a DNA microarray.
  • a DNA microarray can detect one more of a plurality of cancer cell mutations.
  • cell-free DNA is amplified prior to detecting the genetic alteration.
  • array-based methods that can be used in any of the methods described herein, include: a complementary DNA (cDNA) microarray (see, e.g., Kumar et al. 2012; Laere et al.
  • oligonucleotide microarray see, e.g., Kim et al. 2006; Lodes et al. 2009
  • BAG bacterial artificial chromosome
  • SNP single-nucleotide polymorphism
  • the cDNA microarray is an Affymetrix microarray (see, e.g., Irizarry 2003; Dalma-Weiszhausz et al. 2006), a NimbleGen microarray (see, e.g., Wei et al. 2008; Albert et al.
  • the oligonucleotide microarray is a DNA tiling array (see, e.g., Mockler and Ecker, 2005; Bertone et al. 2006).
  • Other suitable array-based methods are known in the art.
  • Methods for determining whether a tumor or cancer comprises a mutation can use a variety of samples.
  • the sample is taken from a patient 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 (FFPE) sample.
  • the sample is a circulating cell-free DNA and/or circulating tumor cell (CTC) sample.
  • the sample is processed to a cell lysate.
  • the sample is processed to DNA or RNA.
  • the sample is acquired by resection, core needle biopsy (CNB), fine needle aspiration (FNA), collection of urine, or collection of hair follicles.
  • CNB core needle biopsy
  • FNA fine needle aspiration
  • collection of urine or collection of hair follicles.
  • a liquid biopsy test using whole blood or cerebral spinal fluid may be used to assess mutation status.
  • a test approved by a regulatory authority such as the US Food and Drug Administration (FDA) is used to determine whether the patient has a mutation, e.g., a KRAS G12C mutated cancer, or whether the tumor or tissue sample obtained from such patient contains cells with a mutation.
  • a regulatory authority such as the US Food and Drug Administration (FDA)
  • FDA US Food and Drug Administration
  • the test for a KRAS mutation used is therascreen® KRAS RGQ PCR Kit (Qiagen).
  • the therascreen® KRAS RGQ PCR Kit is a real-time qualitative PCR assay for the detection of 7 somatic mutations in codons 12 and 13 of the human KRAS oncogene (G12A, G12D, G12R, G12C, G12S, G12V, and G13D) using the Rotor-Gene Q MDx 5plex HRM instrument.
  • the kit is intended for use with DNA extracted from FFPE samples of NSCLC or CRC acquired by resection, CNB, or FNA.
  • Mutation testing for STK11, KEAP1, EGFR, ALK and/or ROS1 can be conducted with commercially available tests, such as the Resolution Bioscience Resolution ctDx LungTM assay that includes 24 genes (including those actionable in NSCLC). Tissue samples may be tested using Tempus xT 648 panel.
  • the cancer has been identified as having a KRAS G12C mutation. In some embodiments, the cancer has been identified as having a mutation of STK11, e.g., a loss-of-function mutation. In some embodiments, the cancer has been identified as having a mutation of KEAP1, e.g., a loss-of-function mutation. In some embodiments, the cancer has been identified as having wild-type STK11. In some embodiments, the cancer has been identified as having wild-type KEAP1.
  • the cancer has been identified as having a loss-of-function mutation of STK11 and wild-type KEAP1. In some embodiments, the cancer has been identified as having a loss-of-function mutation of STK11 and a loss-of-function mutation of KEAP1. In some embodiments, the cancer has been identified as having wild-type of STK11 and wild-type KEAP1. In some embodiments, the cancer has been identified as having wild-type of STK11 and a loss-of-function mutation of KEAP1.
  • loss-of-function mutation refers to a mutation (e.g., a substitution, deletion, truncation, or frameshift mutation) that results in expression of a mutant protein that no longer exhibits wild-type activity (e.g., reduced or eliminated wild-type biological activity or enzymatic activity), results in expression of only a fragment of the protein that no longer exhibits wild-type activity, or results in no expression of the wild-type protein.
  • a mutation e.g., a substitution, deletion, truncation, or frameshift mutation
  • a loss-of-function mutation affecting the STK11 gene in a cell may result in the loss of expression of the STK11 protein, expression of only a fragment of the STK11 protein, or expression of the STK11 protein that exhibits diminished or no enzymatic activity (e.g., no serine/threonine kinase enzymatic activity) in the cancerous cell.
  • enzymatic activity e.g., no serine/threonine kinase enzymatic activity
  • a loss-of-function mutation affecting the KEAP1 gene in a cell may result in the loss of expression of the KEAP1 protein, expression of only a fragment of the KEAP1 protein, or expression of a KEAP1 protein that exhibits diminished or no activity (e.g., inability to interact with or activate Nuclear factor erythroid 2-related factor 2 (NRF2)) in the cell.
  • NEF2 Nuclear factor erythroid 2-related factor 2
  • PD-L1 expression can be determined by methods known in the art.
  • PD-L1 expression can be detected using PD-L1 IHC 22C3 pharmDx, an FDA-approved in vitro diagnostic immunohistochemistry (IHC) test developed by Dako and Merck as a companion test for treatment with pembrolizumab.
  • IHC in vitro diagnostic immunohistochemistry
  • This is qualitative assay using Monoclonal Mouse Anti-PD-L1, Clone 22C3 PD-L1 and EnVision FLEX visualization system on Autostainer Lin 48 to detect PD-L1 in FFPE samples, such as human non-small cell lung cancer tissue.
  • Expression levels can be measured using the tumor proportion score (TPS), which measures the percentage of viable tumor cells showing partial or complete membrane staining at any intensity. Staining can show PD-L1 expression from 0% to 100%.
  • TPS tumor proportion score
  • PD-L1 expression can also be detected using PD-L1 IHC 28-8 pharmDx, the FDA- approved in vitro diagnostic immunohistochemistry (IHC) test developed by Dako and Bristol-Meyers Squibb as a companion test for treatment with nivolumab.
  • IHC in vitro diagnostic immunohistochemistry
  • This qualitative assay uses the Monoclonal rabbit anti-PD-L1, Clone 28-8 and EnVision FLEX visualization system on Autostainer Lin 48 to detect PD-L1 in formalin-fixed, paraffin-embedded (FFPE) human cancer tissue.
  • FFPE paraffin-embedded
  • Ventana SP263 assay developed by Ventana in collaboration with AstraZeneca
  • monoclonal rabbit anti- PD-LI Clone SP263
  • Ventana SP142 Assay developed by Ventana in collaboration with Genentech/Roche
  • a test approved by a regulatory authority such as the US Food and Drug Administration (FDA) is used to determine the PD-L1 TPS of a cancer as disclosed herein.
  • the PD-L1 TPS is determined using a immunohistochemistry (IHC) test.
  • the IHC test is the PD-L1 IHC 22C3 pharmDx test.
  • the IHC test conducted with samples acquired by, for example, resection, CNB, or FNA.
  • the patient has a PD-L1 TPS of less than 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 50%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1 %.
  • the patient has a PD-L1 TPS of less than 50%, or less than 1%.
  • the patient has a PD-L1 TPS of more than or equal to 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 50%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%.
  • the patient has a PD-L1 TPS of less than or equal to 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 50%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%.
  • the patient has a PD-L1 TPS of less than or equal to 50%, or less than or equal to 1 %.
  • the patient has a PD-L1 TPS of more than 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 50%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%.
  • the patient has a PD-L1 TPS score a range bound by any of the values cited in the foregoing embodiments.
  • the patient has a PD-L1 TPS score in the range of less than 50% and more than or equal to 1 %, less than or equal to 50% and more than 1 %, less than or equal to 50% and more than or equal to 1 %, or less than 50% and more than 1%.
  • the patient has a PD-L1 TPS score in the range of less than 50% and more than or equal to 1%.
  • the patient has a PD-L1 TPS score in the range of more than or equal to 0% and less than 1 %.
  • the patient has a PD-L1 TPS score in the range of more than 50% and less than or equal to 100%.
  • the patient has a PD-L1 TPS score of less than 1 %. In some embodiments, the patient as a PD-L1 TPS score of 1-49%. In some embodiments, the patient has a PD-L1 TPS score of 50% or greater (i.e., 50%-100%).
  • a method of treating cancer comprising a KRAS G12C mutation in a patient comprising administering to the patient sotorasib and afatinib in amounts effective to treat the cancer.
  • cancer is small bowel cancer, appendiceal cancer, endometrial cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell tumor, ovarian cancer, gastrointestinal neuroendocrine tumor, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.
  • the cancer is small bowel cancer, appendiceal cancer, endometrial cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell tumor, ovarian cancer, gastrointestinal neuroendocrine tumor, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.
  • NSCLC non-small cell lung cancer
  • CYP3A4 inducer is a barbiturate, brigatinib, carbamazepine, clobazam, dabrafenib, efavirenz, elagolix, enzalutamide, eslicarbazepine, glucocorticoid, letermovir, lorlatinib, modafinil, nevirapine, oritavancin, oxcarbazepine, perampanel, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, telotristat, or troglitazone.
  • 57 The method of embodiment 55 or 56, wherein the CYP3A4 substrate is abemaciclib, abiraterone, acalabrutinib, alectinib, alfentanil, alprazolam, amitriptyline, amlodipine, apixaban, aprepitant, aripiprazole, astemizole, atorvastatin, avanafil, axitinib, boceprevir, bosutinib, brexpiprazole, brigatinib, buspirone, cafergot, caffeine, carbamazepine, cariprazine, ceritinib, cerivastatin, chlorpheniramine, cilostazol, cisapride, citalopram, clarithromycin, clobazam, clopidogrel, cobimetinib, ***e, codeine, colchicine, copanlisib, criz
  • the study will include a dose exploration phase (Part 1) and expansion phase (Part 2) and will be conducted at approximately 99 sites globally.
  • Part 1 of the study will assess the safety of the selected starting dose of afatinib in combination with sotorasib.
  • the starting dose of sotorasib is the recommended phase 2 dose (RP2D) of 960 mg orally daily.
  • the starting dose of afatinib (30 mg orally daily) is based on available safety data (GILOTRIF® Prescribing Information, 2019).
  • Subjects in Part 1 will be treated with sotorasib and afatinib.
  • the term “subject” is used throughout the Examples interchangeably with “patient.”
  • the planned dose levels are:
  • Dose Level 2 sotorasib 960 mg and afatinib 40 mg orally daily
  • Dose Level -1 sotorasib 960 mg and afatinib 20 mg orally daily
  • Dose exploration will begin with 3 to 6 subjects treated at Dose Level 1 .
  • the study DLT period is 21 days.
  • a Dose Level Review Team (DLRT) meeting will be convened.
  • the following may occur: 1) dose escalation to Dose Level 2 and initiation of enrollment in Part 2, Group A Dose Level 1, 2) additional enrollment to Dose Level 1 , 3) dose de-escalation to Dose Level -1 , or 4) initiation of enrollment in Part 2 Group B at the same dose level with loperamide primary prophylaxis.
  • Part 1 will end once any of the following events occur:
  • -Dose Level 2 is determined to be safe and tolerable (minimum of 6 evaluable subjects overall).
  • Dose Level 1 or Dose Level - 1 is determined to be safe and tolerable (minimum of 6 evaluable subjects) and the next higher dose level is determined to be unsafe and intolerable
  • dose escalation may be halted or modified by the Sponsor as deemed appropriate.
  • Part 2 will consist of Group A and Group B.
  • Subjects enrolled in Part 2 Group A and Group B will include at least 5 subjects who received prior KRAS p.G12C inhibitor therapy.
  • Part 2 Group A Based on the dose escalation/de-escalation outcome in Part 1 , selected dose levels in Part 2 Group A that are equal to or lower than the safe and tolerable dose level from Part 1 (Dose Level 1 : sotorasib 960 mg and afatanib 30 mg) will start to enroll up to 40 subjects at each dose level beginning at Dose Level -1 a.
  • Dose Level 1 sotorasib 960 mg and afatanib 30 mg
  • Dose Level 1 sotorasib 960 mg and afatinib 30 mg orally daily
  • Dose Level 1a sotorasib 240 mg and afatinib 30 mg orally daily
  • Dose Level 2 sotorasib 960 mg and afatinib 40 mg orally daily
  • Dose Level -1 sotorasib 960 mg and afatinib 20 mg orally daily
  • Dose Level 1 in Part 1 is deemed safe and tolerable, Dose Level 1 in Part 2 Group A will commence enrollment in parallel to additional dose exploration in Part 1 .
  • Part 2 Group B will be treated with sotorasib and afatinib at a Dose Level that are equal to or lower than the safe and tolerable Dose Level from Part 1 (Dose Level 1 : sotorasib 960 mg and afatinib 30 mg) with loperamide primary prophylaxis for diarrhea management with enrollment of up to 40 subjects at each dose level, starting with dose level 1 for Group B.
  • the planned dose levels for Part 2, Group B are:
  • Dose Level 1 sotorasib 960 mg and afatinib 30 mg orally daily
  • Dose Level - 1 a sotorasib 240 mg and afatinib 30 mg orally daily
  • Dose Level - 1 a sotorasib 120 mg and afatinib 30 mg orally daily
  • Interim safety analyses will be done after approximately 20 subjects have been enrolled at the same dose level and have had the opportunity to be on treatment for at least 21 days. Based on these interim safety and efficacy results and after reviewing the updated estimate of the MTD or recommended safe combination doses using all available data including data from dose exploration and expansion subjects, the DLRT may modify the dose level of treated subjects. A final estimate of the MTD or RP2D will use all data from dose exploration and dose expansion.
  • sotorasib and afatinib may continue until evidence of disease progression, intolerance to study medication, withdrawal of consent, or end of study.
  • intolerance or toxicity to afatinib the subject may continue on sotorasib alone until evidence of disease progression, withdrawal of consent, or end of study.
  • Loperamide is indicated for the control and symptomatic relief of acute nonspecific diarrhea and of chronic diarrhea associated with inflammatory bowel disease.
  • the recommended initial dose is 4 mg (2 capsules) followed by 2 mg (1 capsule) after each unformed stool.
  • loperamide is administered as needed, and the total daily dose should not exceed 16 mg.
  • loperamide is administered prophylactically in cycles 1 and 2, and as needed in cycles 3 and beyond, similar to the loperamide primary prophylaxis guidelines in the Neratinib Regional Prescribing Information (NERLYNX® Prescribing Information, 2020).
  • KRAS p.G12C mutation must be identified by an approved diagnostic device for detection of KRAS p.G12C in NSCLC or be performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory.
  • CLIA Clinical Laboratory Improvement Amendments
  • Subjects must be willing to undergo pretreatment tumor biopsy if medically feasible. If a tumor biopsy prior to treatment is not medically feasible, subjects must be willing to provide archived tumor tissue samples (formalin-fixed paraffin-embedded [FFPE] sample) collected within the past 3 years. Subjects who do not have archived tissue available can be allowed to enroll without undergoing tumor biopsy upon agreement with investigator and the Medical Monitor if a tumor biopsy is not feasible.
  • FFPE paraffin-embedded
  • QTc Corrected QT interval
  • Adequate renal laboratory assessments include measured creatinine clearance or estimated glomerular filtration rate based on Modification of Diet in Renal Disease (MDRD) calculation 60 mL/min/1.73 m 2 .
  • PT Prothrombin time
  • PTT activated partial thromboplastin time
  • INR International normalized ratio
  • Gastrointestinal (Gl) tract disease causing the inability to take oral medication, malabsorption syndrome, requirement for IV alimentation, uncontrolled inflammatory Gl disease (e.g., Crohn’s disease, ulcerative colitis).
  • HepBsAg Positive Hepatitis B Surface Antigen
  • Hepatitis C virus RNA by polymerase chain reaction (PCR) is necessary. Detectable Hepatitis C virus RNA suggests chronic hepatitis C.
  • Anti-tumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, retinoid therapy, hormonal therapy [except for subjects with breast cancer], or investigational agent) within 28 days of study day 1 ; concurrent use of hormone deprivation therapy for hormone-refractory prostate cancer or breast cancer is permitted. Exception: subjects who receive prior tyrosine kinase inhibitor monotherapy, sotorasib monotherapy or conventional chemotherapy within 14 days of study day 1 are eligible.
  • Therapeutic or palliative radiation therapy within 2 weeks of study day 1. Subjects must have recovered from all radiotherapy related toxicity.
  • cytochrome P450 (CYP) 3A4 sensitive substrates or P-glycoprotein (P-gp) substrates e.g., with a narrow therapeutic window
  • CYP3A4 or P-gp substrate or its major active metabolite whichever is longer, prior to start of therapy.
  • CYP3A4 sensitive substrates include abemaciclib, buspirone, isavuconazole, ridaforolimus, ABT-384, capravirine, itacitinib, saquinavir, acalabrutinib, casopitant, ivabradine, sildenafil, alfentanil, cobimetinib, ivacaftor, simeprevir, alisporivir, conivaptan, L-771,688, simvastatin, almorexant, danoprevir, levomethadyl (LAAM), sirolimus, alpha dihydroergocryptine, darifenacin, lomitapide, tacrolimus, aplaviroc, darunavir, lopinavir, terfenadine, aprepitant, dasatinib, lovastatin, ticagrelor, asunaprevir, dronedarone, lumefantrine, tilidine
  • Strong inducers of CYP3A4 include rifampin, phenytoin, mitotane, carbamazepine, avasimibe, enzalutamide, rifapentine, St John's Wort extract, apalutamide, lumacaftor, ivosidenib, and phenobarbital.
  • Subject has known sensitivity to any of the products or components to be administered during dosing.
  • Female subject is pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 7 days after the last dose of sotorasib.
  • Female subject is pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 1 month after the last dose of afatinib.
  • the dose limiting toxicity (DLT) window (i.e., DLT-evaluable period) will be the first 21 days of sotorasib and afatinib treatment (starting cycle 1 , day 1).
  • the grading of adverse events (AEs) will be based on the guidelines provided in the CTCAE version 5.0.
  • a subject will be DLT evaluable if the subject has completed the DLT window as described above and received > 80% of the planned dose of sotorasib and afatinib or experienced a DLT any time during the DLT window.
  • a subject will not be DLT evaluable if he/she drops out before completion of the DLT-evaluable period for reasons other than a DLT.
  • DLT is defined as any adverse event meeting the criteria listed below occurring during the first treatment cycle and attributable to sotorasib and/or afatinib.
  • Hy’s Law case i.e., severe drug-induced liver injury [DILI]
  • DLT severe drug-induced liver injury
  • a Hy’s Law case is defined as: AST or ALT values of > 3 x ULN AND with serum total bilirubin level (TBL) of > 2 x ULN without signs of cholestasis and with no other clear alternative reason to explain the observed liver related laboratory abnormalities.
  • Sotorasib will be discontinued or dosage reduced, in the event of a toxicity that, in the opinion of the investigator, warrants the discontinuation, or dose reduction as indicated above. If day 1 of a cycle is delayed, day 1 of subsequent cycles should be adjusted accordingly to maintain the 21 -day cycle duration. However, if a within-cycle dose is held the missed dose will not be made up and day 1 of subsequent cycles should not be adjusted.
  • ALP alkaline phosphatase
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • CTCAE Common Terminology Criteria for Adverse Events
  • INR international normalized ratio
  • LFT liver function test
  • TBL total bilirubin
  • ULN upper limit of normal a If increase in AST/ALT is likely related to alternative agent, discontinue causative agent and await resolution to baseline or grade 1 prior to resuming sotorasib.
  • c Close monitoring at restart (e.g., daily LFTs x 2, then weekly x 4).
  • Sotorasib dose may be increased after discussion with Medical Monitor. d There is no limit to the number of sotorasib re-challenges for isolated alkaline phosphatase elevations that resolve to baseline or grade 1 . e If the sotorasib starting dose is 960 mg, dose decrements below 240 mg are not allowable. If the sotorasib starting dose is 240 mg or 120 mg, dose decrements below 120 mg are not allowable..
  • Hepatotoxicity Response Subjects with abnormal hepatic laboratory values (i.e., alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TBL)) and/or international normalized ratio (I NR) and/or signs/symptoms of hepatitis (as described below) may meet the criteria for withholding or permanent discontinuation of sotorasib or other protocol-required therapies, as specified in the Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009..
  • ALP alkaline phosphatase
  • AST aspartate aminotransferase
  • ALT alanine aminotransferase
  • TBL total bilirubin
  • I NR international normalized ratio
  • AST/ALT and/or TBL values include, but are not limited to: Hepatobiliary tract disease; Viral hepatitis (e.g., hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, herpes simplex virus, varicella, toxoplasmosis, and parvovirus); Right sided heart failure, hypotension or any cause of hypoxia to the liver causing ischemia; Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary supplements, plants and mushrooms; Heritable disorders causing impaired glucuronidation (e.g., Gilbert’s syndrome, Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (e.g., indina
  • Rechallenge may be considered if an alternative cause for impaired liver tests (ALT, AST, ALP) and/or elevated TBL, is discovered and/or the laboratory abnormalities resolve to normal or baseline, as described in the below.
  • ALP alkaline phosphatase
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • INR international normalized ratio
  • TBL total bilirubin
  • ULN upper limit of normal
  • Dose modification for specific adverse reactions attributed to afatinib should be made according to the Afatinib (GILOTRIF®), US Prescribing Information, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, 06877 (revision 10/2019), or regional prescribing information, as applicable.
  • GLOTRIF® Afatinib
  • US Prescribing Information Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, 06877 (revision 10/2019)
  • regional prescribing information as applicable.
  • Withhold afatinib for any adverse reactions of:
  • Subjects with Grade 3 or Grade 4 ALT or AST elevations who are deriving clinical benefit may resume treatment with afatinib when sotorasib is resumed and after discussion with the Medical Monitor.
  • the dose must be 10 mg per day less than the dose at which the adverse reaction occurred.
  • the screening scans must be performed within 28 days prior to enrollment and will be used as baseline. Imaging performed as part of standard of care that falls within the screening window given for scans may be used for the baseline scan as long as it meets the scan requirements for screening. All subsequent scans will be performed in the same manner as at screening, with the same contrast, preferably on the same scanner. Radiological assessment must include CT of the chest, and contrast-enhanced CT or MRI of the abdomen and pelvis, as well as assessment of all other known sites of disease as detailed within the Site Imaging Manual. [0275] The same imaging modality, MRI field strength and IV and oral contrast agents should be used at screening should be used for all subsequent assessments. Liver specific MRI contrast agents should not be used. To reduce potential safety concerns, macrocyclic gadolinium contrast agents are recommended per National Health Institute guidelines or follow local standards if more rigorous.
  • Radiographic response requires confirmation by a repeat, consecutive scan at least 4 weeks after the first documentation of response and may be delayed until the next scheduled scan to avoid unnecessary procedures.
  • All subjects must have MRI of the brain performed within 28 days prior to first dose of sotorasib and afatinib. Subsequently, brain scans may be performed at any time if, in the judgment of the managing physician. All brain scans on protocol are required to be MRI unless MRI is contraindicated, and then CT with contrast is acceptable.
  • Radiological imaging assessment at the end of the study or during the end of treatment (EOT) visit should be performed only for subjects that discontinue treatment for a reason other than disease progression per RECIST v1 .1 guidelines.
  • Measurable Tumor Lesions - Non-nodal lesions with clear borders that can be accurately measured in at least 1 dimension with longest diameter 10 mm in CT/MRI scan with slice thickness no greater than 5 mm. When slice thickness is greater than 5 mm, the minimum size of measurable lesion should be twice the slice thickness.
  • lymph node must be > 15 mm in short axis when assessed by CT/MRI (scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis is measured and followed. Nodal size is normally reported as two dimensions in the axial plane. The smaller of these measures is the short axis (perpendicular to the longest axis).
  • Non-measurable Lesions All other lesions, including small lesions (longest diameter ⁇ 10 mm or pathological lymph nodes with 10 mm but to ⁇ 15 mm short axis with CT scan slice thickness no greater than 5 mm) are considered non-measurable and characterized as non-target lesions.
  • non-measurable lesions include: Lesions with prior local treatment: tumor lesions situated in a previously irradiated area, or an area subject to other loco-regional therapy, should not be considered measurable unless there has been demonstrated progression in the lesion; Biopsied lesions; Categorically, clusters of small lesions, bone lesions, inflammatory breast disease, and leptomeningeal disease are non-measurable.
  • CT/ MRI - Contrast-enhanced CT or MRI should be used to assess all lesions. Optimal visualization and measurement of metastasis in solid tumors requires consistent administration (dose and rate) of IV contrast as well as timing of scanning. CT and MRI should be performed with s 5 mm thick contiguous slices.
  • Target Lesions All measurable lesions up to a maximum of two (2) lesions per organ and five (5) lesions in total, representative of all involved organs should be identified as target lesions and recorded and measured at baseline.
  • Target lesions should be selected on the basis of their size (lesions with the longest diameter) and suitability for accurate repeated measurements.
  • Pathologic lymph nodes (with short axis a 15 mm) may be identified as target lesions. All other pathological nodes (those with short axis 10 mm but ⁇ 15 mm) should be considered non-target lesions. [0296] A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions are calculated and reported as the baseline sum of diameters. The baseline sum of diameters are used as reference by which to characterize objective tumor response.
  • Non-T arget Lesions All other lesions (or sites of disease) including pathological lymph nodes should be identified as non-target lesions and should also be recorded at baseline. Measurements of these lesions are not required, and these lesions should be followed as “present”, “absent”, or “unequivocal progression” throughout the study. In addition, it is possible to record multiple non-target lesions involving the same organ as a single item on the case report form (e.g., “multiple enlarged pelvic lymph nodes” or “multiple liver metastases”).
  • the best overall response is the best response recorded from the start of the study treatment until the end of treatment or disease progression/recurrence (taking as reference for PD the smallest measurements recorded since the treatment started).
  • the subject's best response assignment depends on the findings of both target and nontarget disease and also take into consideration the appearance of new lesions.
  • CR complete response
  • NE Not evaluable
  • PD progressive disease
  • PR partial response
  • SD stable disease
  • Non-CR/non-PD is preferred over “SD” for non-target disease since SD is increasingly used as endpoint for assessment of efficacy in some trials so as to assign this category when no lesions can be measured is not advised.
  • Nodal lesions - Lymph nodes identified as target lesions should always have the actual short axis measurement recorded, even if the nodes regress to below 10 mm on study. In order to qualify for CR, each node must achieve a short axis ⁇ 10 mm, NOT total disappearance. Nodal target lesion short axis measurements are added together with target lesion’ longest diameter measurements to create the sum of target lesion diameters for a particular assessment (time point).
  • Target lesions that become “too small to measure” While on study, all lesions (nodal and non-nodal) recorded at baseline should have their measurements recorded at each subsequent evaluation. If a lesion becomes less than 5 mm, the accuracy of the measurement becomes reduced. Therefore, lesions less than
  • 5 mm are considered as being “too small to measure”, and are not measured. With this designation, they are assigned a default measurement of 5mm. No lesion measurement less than 5mm should be recorded, unless a lesion totally disappears and “0” can be recorded for the measurement.
  • New lesions The term “new lesion” always refers to the presence of a new finding that is definitely tumor. New findings that only may be tumor, but may be benign (infection, inflammation, etc.) are not selected as new lesions, until that time when the review is certain they represent tumor.
  • FDG-PET fluorodeoxyglucose-positron emission tomography
  • PET/CT PET/computed tomography
  • fine needle aspirate/biopsy to confirm the CR status.
  • Duration of overall response The duration of overall response is measured from the time measurement criteria are first met for CR/PR (whichever is first recorded) until the first date the recurrent or progressive disease is objectively documented.
  • Duration of Stable Disease - SD is measured from the start of the treatment until the criteria for disease progression are met, taking as reference the smallest measurements recorded since the treatment started.
  • Class I No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation or dyspnea.
  • Class II Slight limitation of physical activity Comfortable at rest, but ordinary physical activity results in fatigue, palpitation or dyspnea.
  • Class III Marked limitation of physical activity Comfortable at rest, but less than ordinary activity causes fatigue, palpitation or dyspnea.
  • Class IV Unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency may be present even at rest. If any physical activity is undertaken, discomfort is increased.
  • TRAEs treatment-related adverse events
  • Grade 3 TRAEs occurred in 30% pts within each dose cohort, with diarrhea being the most common.
  • Eight patients (24.2%) discontinued sotorasib and/or afatinib due to an AE, with diarrhea leading to discontinuation in 5 patients.
  • sotorasib and a pan-ErbB inhibitor, combining sotorasib with afatinib was feasible, and demonstrated clinical activity, in a heavily pre-treated KRAS p.G12C mutated NSCLC population that included 15% who progressed on prior sotorasib.
  • the AEs observed are not new or novel to either agent, with diarrhea being the most common.
  • TRAE treatment-related adverse events
  • the most common TRAEs included diarrhea (23 pts (69.7%) all grades, 8 pts (24.2%) grade S3), nausea (9 pts (27.3%), all grade ⁇ 2), vomiting (7 pts (21.2%), all grade ⁇ 2), increased alanine aminotransferase (4 pts (12.1%) all grades, 3 pts (9.1 %) grade S3), increased aspartate aminotransferase (4 pts (12.1%) all grades, 3 pts (9.1%) grade S3), increased blood alkaline phosphatase (4 pts (12.1 %) all grades, 3 pts (9.1 %) grade S3), and acute kidney injury (3 pts (9.1 %) all grades, 3 pts
  • TRAEs grade 3 TRAEs reported included 1 each of dehydration, dyspnea, hyperbilirubinemia, hypotension, hypokalemia, hypovolemia, respiratory failure, and stomatitis. No new or novel TRAEs to either sotorasib or afatinib were observed.
  • ORR analysis set includes all patients who received &1 dose of investigational products, have &1 measurable lesions at baseline assessed using RECIST 1.1 , and have the opportunity to be followed for 7 weeks starting from day 1
  • T Patient 2 received prior osimertinib and progressed on osimertinib prior to enrollment.
  • PK data are available for subjects with advanced solid tumors with the specific KRAS G12C mutation, with doses ranging from 180 to 960 mg PO QD. Dose-related increases in exposure on day 1 from 180 to 960 mg PO QD were observed. Increases in exposure were less than doseproportional on day 1. There was no accumulation with multiple PO QD dosing for 8 days. The change in exposure from 180 to 960 mg PO QD was less than dose-proportional on day 8. Rapid absorption was observed with tmax between 1 to 2 hours after PO administration. Figure 1 shows the mean plasma concentration time profile after oral administration of 180, 360, 720, or 960 mg sotorasib on Day 1.
  • Figure 2 shows the concentrations after once daily dosing for 8 days (Day 8).
  • the table below provides the pharmacokinetic parameters, where AUCo-24h is the area under the concentration-time curve from time 0 to 24 hr postdose; C ma x is the maximum observed drug concentration during a dosing interval; ti/2, z is the terminal elimination half-life; t ma x is the time to reach C ma x.
  • Data reported are presented as geometric mean (arithmetic CV%) except tmax and tic, which are reported as a median (range) and arithmetic mean (SD), respectively. Values are reported to three significant figures, except CV% and tmax, which are reported to 0 decimal places and 2 significant figures, respectively.
  • This Phase 1 open-label, fixed-sequence study enrolled 14 healthy subjects. Subjects received 960 mg sotorasib on Day 1 , 40 mg omeprazole once daily on Days 4 to 8, and 40 mg omeprazole followed by 960 mg sotorasib on Day 9. All doses were administered under fasted conditions. Blood samples for sotorasib PK were collected predose and up to 48 hours post-so torasib dose. Sotorasib plasma PK parameters were estimated using non-compartmental methods.
  • Example 4 Contraindication with co-administration of sotorasib with acid-reducing agents under fed conditions
  • Geometric least-square mean ratios of sotorasib AUCint and C max were 0.622 and 0.654, respectively when comparing sotorasib coadministered with famotidine and sotorasib alone under fed conditions.
  • Geometric least-square mean ratios of sotorasib AUCint and C max were 0.430 and 0.349, respectively, when comparing sotorasib coadministered with omeprazole and sotorasib alone.
  • Doses of 960 mg sotorasib were safe and well tolerated with coadm concluded with a single dose of 40 mg famotidine and following multiple daily dosing of 40 mg omeprazole under fed conditions to healthy subjects.
  • This Phase 1, open-label, fixed-sequence study enrolled 14 healthy subjects. Each subject received 960 mg sotorasib on Days 1, 3 and 18, and 600 mg rifampin on Day 3 and Days 5 to 19. Blood samples for sotorasib PK were collected predose and up to 48 hours post-sotorasib dose. Sotorasib plasma PK parameters were estimated using non-compartmental methods.
  • Geometric mean sotorasib AUCw area under the curve from time zero to infinity
  • C max maximal plasma concentration following coadministration of single dose of rifampin with sotorasib (19600 h*ng/mL and 5340 ng/mL, respectively)
  • Geometric mean sotorasib AUCint and C max following coadministration of multiple doses of rifampin with sotorasib (12400 h*ng/mL and 4110 ng/mL, respectively) were lower compared to those of sotorasib alone (25600 h*ng/mL and 6350 ng/mL, respectively).
  • Sotorasib was safe and well tolerated when coadministered with 600 mg rifampin or administered alone to healthy subjects.
  • Single dose of rifampin did not have a clinically meaningful effect on sotorasib PK indicating sotorasib is not a substrate of OATP1 B1.
  • Multiple doses of rifampin decreased sotorasib AUCint by 51 % and C max by 35%, indicating sotorasib is a CYP3A4 substrate, consistent with in vitro data.
  • This Phase 1 open-label, fixed-sequence study enrolled 5 subjects with previously untreated NSCLC who received a single, oral dose of 2 mg midazolam alone of day -1, 960 mg sotorasib orally on days 1 through 14, and a single oral dose of 2 mg midazolam at approximately the same time as an oral dose of 960 mg sotorasib on day 15.
  • Blood samples for sotorasib PK were collected predose and up to 48 hours post-sotorasib dose. Sotorasib plasma PK parameters were estimated using non-compartmental methods.
  • This Phase 1, open-label, fixed-sequence study enrolled 14 healthy subjects. Each subject received 0.5 mg digoxin on Day 1 and 960 mg sotorasib followed by 0.5 mg digoxin on Day 7. Blood samples for digoxin PK were collected predose and up to 144 hours post-digoxin dose. Samples were measured using validated high- performance liquid chromatography tandem mass spectrometry methods. PK parameters were estimated using non-compartmental methods. Safety and tolerability were monitored throughout the study. [0350] Digoxin median time to maximal plasma concentration (t ma x) and mean terminal half-life (ti/2) were similar following coadministration of digoxin with sotorasib compared to those of digoxin alone.
  • Geometric mean digoxin AUCint (area under the curve from time zero to infinity) following coadministration of digoxin with sotorasib (40.3 h*ng/mL) was similar to that of digoxin alone (33.2 h*ng/mL).
  • Geometric mean digoxin C ma x (maximal plasma concentration) following coadministration of digoxin with sotorasib (3.64 ng/mL) was higher compared to that of digoxin alone (1 .90 ng/mL).
  • Single doses of 0.5 mg digoxin were safe and well tolerated when administered alone or coadministered with 960 mg sotorasib.
  • NCI CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events v5.0

Abstract

La présente invention concerne des méthodes de traitement du cancer comprenant une mutation KRAS G12C chez un patient, comprenant l'administration au patient de sotorasib et d'afatinib en quantités efficaces pour traiter le cancer.
PCT/US2022/044557 2021-09-24 2022-09-23 Sotorasib et afatinib pour le traitement du cancer comprenant une mutation kras g12c WO2023049363A1 (fr)

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US11896677B2 (en) 2020-03-23 2024-02-13 Hdt Bio Corp. Compositions and methods for delivery of RNA

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