10162-US01-PRI
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`32328/55344P
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`METHODS FOR TREATING CANCER
`
`BACKGROUND
`
`[0001]
`
`Therat sarcoma (RAS) proto-oncogene has beenidentified as an oncogenic driver of tumorigenesis in
`
`cancers, such as non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). The RAS family consists of
`
`3 closely related genes that express guanosine triphosphate (GTP)-ases responsible for regulating cellular
`
`proliferation and survival. The RASproteins, Kirsten rat sarcoma viral oncogene homolog (KRAS), Harveyrat
`
`sarcoma viral oncogene homolog (HRAS), and neuroblastoma RASviral oncogene homolog (NRAS) can be
`
`mutationally activated at codons 12, 13, or 61, leading to human cancers. Different tumor types are associated
`
`with mutations in certain isoforms of RAS, with 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. Sotorasib, sold in the
`
`United States under the name LUMAKRAS®,is thefirst inhibitor of the RAS GTPase family indicated for the
`
`treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic NSCLC, as determined by
`
`an U.S. Food and Drug Administration (FDA)-approved test, who have received at least one prior systemic
`
`therapy. While sotorasib monotherapy appears to drive substantial anti-tumor activity, combination therapies are
`
`desirable to further improve treatment options available to patients.
`
`SUMMARY
`
`[0002]
`
`Provided herein are methods of treating cancer comprising a KRAS G72C mutationin a patient
`
`comprising (a) administering to the patient a therapeutically effective amount of sotorasib for 14 to 48 days (“an
`
`induction period”), and (b) administering to the patient a therapeutically effective amount of sotorasib and a
`
`therapeutically effective amount of an anti-PD1 antibody or an anti-PD-L1 antibody after the induction period for
`
`the duration of a combination period.
`
`In various embodiments, the induction period is 21 days.
`
`In various
`
`embodiments, the induction period is 42 days.
`
`In various embodiments, the combination period is at least 30
`
`days.
`
`In various embodiments, the combination period is at least 3 months.
`
`In various embodiments,the
`
`combination period is at least 6 months.
`
`In various embodiments, the combination period is at least 8 months.
`
`[0003]
`
`In various embodiments, the therapeutically effective amount of sotorasib administered for the duration
`
`of the induction period is 960 mg.
`
`In various embodiments,the therapeutically effective amount of sotorasib
`
`administered for the duration of the induction period is 360 mg.
`
`In various embodiments, the therapeutically
`
`effective amount of sotorasib administered for the duration of the induction period is 240 mg.
`
`In various
`
`embodiments, the therapeutically effective amount of sotorasib administered for the duration of the induction
`
`period is 120 mg.
`
`In various embodiments, the sotorasib is administered once daily during the induction period.
`
`In various embodiments, the sotorasib is administered twice daily during the induction period, wherein each dose
`
`of sotorasib correspondsto half of the therapeutically effective amount administered during the induction period.
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`

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`10162-US01-PRI
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`32328/55344P
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`[0004]
`
`In various embodiments,the therapeutically effective amount of sotorasib administered for the duration
`
`of the combination period is 960 mg. In various embodiments, the therapeutically effective amount of sotorasib
`
`administered for the duration of the combination period is 360 mg. In various embodiments, the therapeutically
`
`effective amount of sotorasib administered for the duration of the combination period is 240 mg. In various
`
`embodiments, the therapeutically effective amount of sotorasib administered for the duration of the combination
`
`period is 120 mg.
`
`In various embodiments, the sotorasib is administered once daily during the combination
`
`period.
`
`In various embodiments, the sotorasib is administered twice daily during the combination period, wherein
`
`each doseof sotorasib correspondsto half of the therapeutically effective amount administered during the
`
`combination period.
`
`
`
`[0005]=In various embodiments, the anti-PD-L1 antibody is atezolizumab, avelumab, or durvalumab. In
`
`various embodiments, the anti-PD-L1 antibody is atezolizumab.
`
`In various embodiments, the anti-PD1 antibody
`
`is cemiplimab, dostarlimab, pembrolizumab, or nivolumab.
`
`In various embodiments, the anti-PD1 antibodyis
`
`pembrolizumab.
`
`In various embodiments, 200 mg pembrolizumabis administered to the patient via IV once
`
`every three weeks during the combination period.
`
`[0006]
`
`In various embodiments, the patient is administered 360 mg sotorasib orally once daily during each of
`
`the induction period and the combination period and 200 mg pembrolizumab via IV once every three weeks
`
`during the combination period.
`
`In various embodiments, the patient is administered 960 mg sotorasib orally once
`
`daily during each of the induction period and the combination period and 200 mg pembrolizumabvia IV once
`
`every three weeks during the combination period.
`
`In various embodiments, the patient is administered 240 mg
`
`sotorasib orally once daily during each of the induction period and the combination period and 200 mg
`
`pembrolizumab via IV once every three weeks during the combination period.
`
`In various embodiments, the
`
`patient is administered 120 mg sotorasib orally once daily during each of the induction period and the
`
`combination period and 200 mg pembrolizumab via lV once every three weeks during the combination period.
`
`[0007]
`
`In various embodiments, the cancer exhibits a PD-L1 tumor proportion score (TPS) of 50% or greater.
`
`In various embodiments, the cancer exhibits a PD-L1 tumor proportion score (TPS) of 1% to 49%.
`
`In various
`
`embodiments, the cancer exhibits a PD-L1 tumor proportion score (TPS) of less than 1%.
`
`In various
`
`embodiments, the canceris a solid tumor.
`
`In various embodiments, the cancer is non-small cell lung cancer,
`
`small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer,
`
`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, melanoma,
`
`ampullary cancer, gastric cancer, sinonasal cancer, or bile duct cancer.
`
`In various embodiments, the canceris
`
`non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown
`
`primary, endometrial cancer, pancreatic cancer, melanoma, ampullary cancer, gastric cancer, sinonasal cancer,
`
`or bile duct cancer.
`
`In various embodiments, the cancer is non-small cell lung cancer, and in some
`
`embodiments,is locally-advanced or metastatic non-small cell lung cancer.
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`

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`[0008]
`
`In various embodiments,the patient exhibits at least a stable disease (SD), as measured by RECIST
`
`1.1 protocol, after the combination period lasts 3, 6, or 8 months.
`
`In various embodiments, the patient exhibits at
`
`least a partial response (PR), as measured by RECIST 1.1 protocol, after the combination period lasts 3, 6, or 8
`
`months.
`
`In various embodiments, the patient exhibits a progression free survival (PFS) of at least 3 months.In
`
`various embodiments, the patient exhibits fewer grade 3 or 4 treatment related adverse events (TRAEs)
`
`compared to a patient administered sotorasib and the anti-PD1 antibody or anti-PD-L1 antibody without an
`
`induction period.
`
`[0009]
`
`In various embodiments, the patient has received at least one priorline of therapy. In various
`
`embodiments, the patient has not previously received treatment with an anti-PD1 or anti-PD-L1 immunotherapy.
`
`In various embodiments, the patient has previously received treatment with anti-PD1 or anti-PD-L1
`
`immunotherapy.
`
`In various embodiments, the patient has previously received treatmentwith (i) anti-PD1 or anti-
`
`PDL1 immunotherapyor(ii) prior platinum-based combination chemotherapy.
`
`In various embodiments, the
`
`patient has previous received treatmentwith (i) anti-PD1 or anti-PD-L1 immunotherapy and(ii) prior platinum-
`
`based combination chemotherapy.
`
`In various embodiments, the patient has previously undergone an EGFR,
`
`ALK or ROS1 targeted therapy if the cancer also exhibited a mutation in EGFR, ALK, or ROS1.
`
`In various
`
`embodiments, the patient has progressed on an EGFR, ALK or ROS1 targeted therapyif the cancer also
`
`exhibited a mutation in EGFR, ALK, or ROS1. In various embodiments, the patient completed neoadjuvant or
`
`adjuvant chemotherapy at least 12 monthsprior to diagnosis of advanced stage cancer.
`
`In various
`
`embodiments, (1) (a) the patient has previously received treatment with (i) anti-PD1 or anti-PD-L1
`
`immunotherapyor(ii) prior platinum-based combination chemotherapy; or (b) the patient has previously received
`
`treatment with (i) anti-PD1 or anti-PD-L1 therapy and(ii) prior platinum-based chemotherapy; and (2) the patient
`
`optionally has previously undergone an EGFR, ALK or ROS1 targeted therapyif the cancer also exhibited a
`
`mutation in EGFR, ALK, or ROS1.
`
`In various embodiments, the patient (1) has a cancerthat exhibits a PD-L1
`
`tumor proportion score (TPS) of 50% or greater; and (2) has not received any systemic therapy for locally
`
`advanced or metastatic non-small cell lung cancer: (i) but for a EGFR, ALK, or ROS1 targeted cancertherapy,if
`
`cancer exhibited a mutation in EGFR, ALK, or ROS1, and the patient has progressed on the targeted cancer
`
`therapy; and (ii) but for neoadjuvant or adjuvant chemotherapy completed at least 12 months prior to the start of
`
`the induction period and has not received immune checkpoint inhibitor therapy.
`
`BRIEF DESCRIPTION OF THE FIGURES
`
`[0010]
`
`Figure 1 showstheefficacy of patients treated with a combination therapy of sotorasib with
`
`atezolizumab and of sotorasib with pembrolizumab, with or without a lead-in treatment of sotorasib alone, where
`
`CRis complete response, DCRis disease control rate, DpR is median depth of response, ORRis objective
`
`response rate, PD is progressive disease, PR is partial response, and SDis stable disease.
`
`[0011]
`
`Figure 2 showstheefficacy of sotorasib and pembrolizumabat different doses of sotorasib, with or
`
`without a lead-in sotorasib monotherapy, where ORRis objective responserate, and SDis stable disease.
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`

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`10162-US01-PRI
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`32328/55344P
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`DETAILED DESCRIPTION
`
`[0012]
`
`Kristen rat sarcoma (KRAS) G12C mutation has been identified as a putative oncogenic driverin
`
`several types of solid tumors including non-small cell lung cancer (NSCLC). Sotorasib, a covalentinhibitor of
`
`KRAS®12¢ has shown promising anti-tumor activity in a Phase 1/2 Study (Clinical Trial 20170543).
`
`Inhibition of
`
`programmed death-ligand 1 (PD-L1) has beenaneffective strategy in the treatment of NSCLC. Preclinically,
`
`combined treatment with sotorasib and anti-programmedcell death protein-1 (PD-1) therapy increasedinfiltration
`
`of CD8+T cells into tumors and greatly enhanced anti-tumor efficacy compared to treatment with either single
`
`agent in vivo (Canonetal, 2019). The addition of anti PD1 or PD-L1 therapy may therefore enhancethe anti-
`
`tumoractivity of therapy targeted to mutant KRAS.
`
`[0013]
`
`The combination of immunotherapy agents (e.g., anti-PD1, anti-PDL-1, anti CTLA-4 therapy) and
`
`targeted small molecule therapies (¢.g., epidermal growth factor receptor [EGFR] inhibitors, BRAF inhibitors,
`
`vascular endothelial growth factor [VEGF]inhibitors) has frequently led to an unexpected increase in frequency
`
`and/or severity of adverse events. Some examplesinclude liver enzyme elevations with or without concomitant
`
`bilirubin elevation (ipilimumab and vemurafenib, durvalumab and gefitinib, pembrolizumab and axitinib,
`
`durvalumab and osimertinib, pembrolizumab andgefitinib) (Ahn et al, 2016; Gibbonset al, 2016; Ribas etal,
`
`2013; Rini et al, 2019; Yang et al, 2019) andinterstitial lung disease (osimertinib and durvalumab) (Ahn etal,
`
`2016). Some approachesthat have been explored to improvethe tolerability of these combinations include
`
`modulating the dose of the targeted therapy agent and/or exploring sequential dosing with aninitial run in for a
`
`period of 3 to 6 weeks with the targeted therapy agent followed bytheinitiation of the immunotherapy agent (Ahn
`
`et al, 2016; Sullivan et al, 2019).
`
`[0014]
`
`Sotorasib in combination with a fixed dose of pembrolizumab (200 mg Q3W starting from day 1) is
`
`being explored given concurrently in a cohort of patients with previously treated NSCLC in Study 20170543.
`
`While no dose-limiting toxicities (DLTs) were observed at a dose of 960 mg and 720 mg of sotorasib, all patients
`
`enrolled at these dose levels experienced grade 3 adverse events requiring treatment interruptions and in some
`
`cases, treatment discontinuation. The study continues to explore a lower dose of sotorasib at 360 mg daily (QD)
`
`in combination with pembrolizumab. But, further investigations are warranted for a dosing regimen for sotorasib
`
`and a PD1 or PDL1 inhibitor that could minimize adverse events and avoid or reduce doseinterruptions or
`
`treatment discontinuation.
`
`[0015]
`
`The term “patient” as used herein refers to a subject, such as a human, whois in need of treatment
`
`with one or more methods disclosed herein.
`
`[0016]
`
`KRAS Pathway and PD-L1
`
`[0017]
`
`The KRAS G12C mutation is estimated to occur in approximately 13% of lung adenocarcinoma (The
`
`American Association for Cancer Research [AACR] Project GENIE Consortium, 2017; Biernacka et al, 2016:
`
`Neumann etal, 2009). Enhancementof anti-tumor immunity through inhibition of PD-(L)-1 has been effective in
`
`treatment of many malignancies.
`
`Immune checkpointinhibition (ICI) is now the mainstayoffirst-line treatment of
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`

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`10162-US01-PRI
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`metastatic NSCLC without EGFR or anaplastic lymphoma kinase (ALK) genomic tumoraberrations, either as
`
`monotherapy or as combination therapy (with chemotherapy =+ anti-angiogenic therapy). Results of published
`
`studies arestill limited concerning the association between KRAS mutations and the response to anti-PD1 or
`
`anti-PD-L1 antibodies. Recent exploratory analysis from the KEYNOTE-042 study (Herbstet al, 2019)
`
`comparing first line pembrolizumab versus chemotherapy for patients with PD-L1 positive (tumor proportion
`
`score [TPS] 2 1%) advanced NSCLC showed that patients with KRAS mutation show higher PD-L1 TPS (median
`
`60%) compared with those without (median 35%). For patients with KRAS G12C mutation, median progression-
`
`free survival (PFS) was 15 months on the pembrolizumab arm versus 6 months on chemotherapy (HR 0.27; 95%
`
`Cl: 0.10-0.71). Similarly, median overall survival (OS) was longerfor patients who received pembrolizumab
`
`(median NR versus chemotherapy [8 months, HR 0.28; 959% Cl: 0.09-0.86]). A meta-analysis of 3 studies that
`
`compared second-line ICI (nivolumab Checkmate 057 Study and atezolizumab OAK and POPLARstudies) with
`
`docetaxel showedthat in patients with KRAS mutation, the pooled HR for overall survival was 0.65 (95% Cl:
`
`0.44-0.97; p = 0.03) (Leeetal, 2018).
`
`[0018]
`
`Results from the IMMUNOTARGETregistry that investigated the efficacy of ICI in tumors with
`
`oncogenic driver mutations showed that response rates were higher in KRAS mutated NSCLC compared to other
`
`mutations like ALK or EGFR) (Mazieres et al, 2019). This is consistent with other published reports (Borghaei
`
`and Brahmer, 2016). However, KRAS mutated NSCLC may also express higherlevels of PD-1 and PD-L1
`
`(Chen etal, 2017).
`
`[0019]
`
`The methods disclosed herein comprise administering sotorasib alone during an “induction period” then
`
`administering sotorasib and an anti-PD1 or anti-PDL1 antibody as a combination therapy (in a “combination
`
`period”). The induction period, where the patient is administered sotorasib alone,is for 14 to 48 days, e.g., 14 to
`
`42 days, 21 to 48 days, or 21 to 42 days. In some embodiments,the induction period is 21 days. In some
`
`embodiments, the induction period is 42 days. The combination period is the period of time the patient is on the
`
`combination therapy as disclosed in the methods herein. The combination period can be at least 30 days, at
`
`least 2 months, at least 3 months, at least 6 months,at least 8 months, at least 12 months, at least 18 months,at
`
`least 2 years, or at least 3 years.
`
`In various embodiments, the combination period ends whenthe patient
`
`demonstrates a complete response (CR), a partial response (PR), or stable disease (SD) as determined by
`
`Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 protocol (Eisenhauer, et al., 2009).
`
`[0020]
`
`For the methods disclosed herein, it has been discovered that administration of sotorasib to a patient
`
`for an induction period prior to administration of sotorasib with an anti-PD1 antibody or anti-PD-L1 antibody
`
`resulted in fewer grade 3 or 4 treatment related adverse events (TRAEs), compared to a patient administered
`
`sotorasib and the anti-PD1 antibody or anti-PD-L1 antibody without an induction period. Fewer severe TRAEs
`
`meansa safer treatment protocol, and may allow the patient to stay on the treatment protocol longer, which may
`
`provide a more effective treatment for the cancer.
`
`[0021]
`
`Sotorasib
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`

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`10162-US01-PRI
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`32328/55344P
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`[0022]
`
`Sotorasib is a small molecule that irreversibly inhibits the KRAS®'2© mutant protein. Sotorasib is also
`
`referred to as AMG 510 or6-fluoro-7-(2-fluoro-6-hydroxy phenyl)-(1M)}-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4-
`
`[(2S)-2-methyl-4-(prop-2-enoyl) piperazin-1-yl]pyrido[2,3-d]pyrimidin-2(1H)-one and hasthe following structure:
`
`
`
`[0023]
`
`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&"2 in an inactive, guanosine diphosphate (GDP) bound conformation. This blocks the
`
`interaction of KRAS with effectors such as rapidly accelerated fibrosarcoma (RAF), thereby preventing
`
`downstream signaling, including the phosphorylation of extracellular signal regulated kinase (ERK) (Cully and
`
`Downward, 2008; Ostrem et al., 2013; Simanshu et al., 2017).
`
`Inactivation of KRAS by RNAinterference (RNAi)
`
`or small molecule inhibition has previously demonstrated an inhibition of cell growth and induction of apoptosis in
`
`tumorcell lines and xenografts harboring KRAS mutations (including the KRAS G12C mutation) (Janesetal.,
`
`2018; McDonald et al., 2017; Xie et al., 2017; Ostrem and Shokat, 2016; Patricelli et al., 2016). Studies with
`
`sotorasib have confirmed these /n vitro findings and have likewise demonstrated inhibition of growth and
`
`regression ofcells and tumors harboring KRAS G12C mutations (Canonet al., 2019). See also, LUMAKRAS®
`
`US Prescribing Information, Amgen Inc., Thousand Oaks, California, 91320 (revision 5/2021), which is herein
`
`incorporated by referencein its entirety.
`
`[0024]
`
`Anti-PD1 or Anti-PD-L1 Antibodies
`
`[0025]
`
`The anti-PD1 antibody used in the methods disclosed herein can be, for example, balstilimab,
`
`budigalimab, cadonilimab, camrelizumab, cetrelimab, cemiplimab, dostarlimab, ezabenlimab, finotonlimab,
`
`nivolumab, penpulimab, pembrolizumab, pucotenlimab,retifanlimab, rulonilimab, sasanlimab, serplulimab,
`
`sintilimab, spartalizumab, tebotelimab, tislelizumab, toripalimab, zeluvalimab (AMG 404), or zimberelimab.
`
`In
`
`some embodiments, the anti-PD1 antibody is cemiplimab, dostarlimab, pembrolizumab, or nivolumab.
`
`In some
`
`embodiments, the anti-PD1 antibody is pembrolizumab (KEYTRUDA®). Pembrolizumab is a humanized
`
`immunoglobulin G4 monoclonal antibody (mAb) with high specificity of binding to the PD1 receptor, thus
`
`inhibiting its interaction with PD-L1 and PD-L2. Pembrolizumab is approved as a single agentforthefirstline
`
`treatmentof patients with metastatic NSCLC expressing PD-L1 (TPS 2 1%) as determined by an FDA-approved
`
`test, with disease progression on or after platinum containing chemotherapy. Patients with EGFR or ALK
`
`genomic tumor aberrations should have disease progression on FDA approved therapy for these aberrations
`
`prior to receiving pembrolizumab. Complete information about pembrolizumab (KEYTRUDA®) preparation,
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`dispensing, dosage, and administration schedule can be found in the local packageinsert (for the United States
`
`see, e.g., KEYTRUDA® U.S. Prescribing Information, Merck & Co., Inc., Whitehouse Station, New Jersey, 08889
`
`(revision 2/2022), which is herein incorporated by referencein its entirety).
`
`[0026]
`
`The anti-PD-L1 antibody used in the methods disclosed herein can be, for example, adebrelimab,
`
`atezolizumab, avelumab, cosibelimab, durvalumab, envafolimab, erfonrilimab, garivulimab, lodapolimab,
`
`opucolimab, sugemalimab, socazolimab,or tagitanlimab.
`
`In various embodiments, the anti-PD-L1 antibody is
`
`atezolizumab (TECENTRIQ®), durvalumab (IMFINZI®), or avelumab (BAVENCIO@). In various embodiments,
`
`the anti-PD-L1 antibody is atezolizumab (TECENTRIQ®). Complete information about atezolizumab
`
`(TECENTRIQ®)preparation, dispensing, dosage, and administration schedule can be found in the local package
`
`insert (for the United States see, e.g., TECENTRIQ® U.S. Prescribing Information, Genentech, Inc., South San
`
`Francisco, California, 94080 (revision 1/2022), which is herein incorporated by referencein its entirety).
`
`Complete information about durvalumab (IMFINZI®) preparation, dispensing, dosage, and administration
`
`schedule can be found in the local package insert (for the United States see, e.g., IMFINZI® U.S. Prescribing
`
`Information, AstraZeneca Pharmaceuticals LP, Wilmington, Delaware, 19850 (revision 7/2021), which is herein
`
`incorporated by referencein its entirety). Complete information about avelumab (BAVENCIO@)preparation,
`
`dispensing, dosage, and administration schedule can be found in the local packageinsert (for the United States
`
`see, e.g., BAVENCIO® U.S. Prescribing Information, EMD Serono,Inc., Rockland, Maryland, 02370 (revision
`
`11/2020), which is herein incorporated by referencein its entirety).
`
`[0027]
`
`Dosing Regimens
`
`[0028]
`
`The methods disclosed herein comprise administering a therapeutically effective amount of sotorasib
`
`(alone during the induction period) and a therapeutically effective amount of sotorasib and a therapeutically
`
`effective amount an anti-PD1 or anti-PD-L1 antibody as a combination therapy (during the combination period).
`
`[0029]
`
`In some embodiments, the methods comprise administering 960 mg sotorasib to the patient during the
`
`induction period. In some embodiments, the methods comprise administering 360 mg sotorasib to the patient
`
`during the induction period. In some embodiments, the methods comprise administering 240 mg sotorasib to the
`
`patient during the induction period. In some embodiments, the methods comprise administering 120 mg sotorasib
`
`to the patient during the induction period. In some embodiments, the sotorasib is administered to the patient once
`
`daily during the induction period.
`
`In some embodiments, the sotorasib is administered to the patient twice daily
`
`during the induction period, wherein each dose of sotorasib correspondsto half of the therapeutically effective
`
`amount administered during the induction period.
`
`[0030]
`
`In some embodiments, the methods comprise administering 960 mg sotorasib to the patient during the
`
`combination period. In some embodiments, the methods comprise administering 360 mg sotorasib to the patient
`
`during the combination period. In some embodiments, the methods comprise administering 240 mg sotorasib to
`
`the patient during the combination period. In some embodiments, the methods comprise administering 120 mg
`
`sotorasib to the patient during the combination period. In some embodiments, the sotorasib is administered to the
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`patient once daily during the combination period.
`
`In some embodiments, the sotorasib is administered to the
`
`patient twice daily during the combination period, wherein each dose of sotorasib correspondsto half of the
`
`therapeutically effective amount administered during the combination period.
`
`[0031]
`
`In some embodiments, the anti-PD-L1 antibody administered to the patient during the combination
`
`period in the methods disclosed herein is atezolizumab, avelumab, or durvalumab.
`
`In some embodiments, the
`
`anti-PD-L1 antibody administered during the combination period is atezolizumab.
`
`In various embodiments, the
`
`anti-PD1 antibody administered to the patient during the combination period in the methods disclosed herein is
`
`cemiplimab, dostarlimab, pembrolizumab, or nivolumab.
`
`In some embodiments, the anti-PD1 antibody
`
`administered during the combination period is pembrolizumab.
`
`In some embodiments, pembrolizumabis
`
`administered during the combination period at a therapeutically effective amount of 200 mg. In some
`
`embodiments, the 200 mg pembrolizumabis administered via |V to the patient once every three weeks during
`
`the combination period.
`
`[0032]
`
`In some embodiments, the patient is administered 360 mg sotorasib orally once per day during the
`
`induction period and during the combination period and 200 mg pembrolizumab via IV once every three weeks
`
`during the combination period.
`
`[0033]
`
`In some embodiments,the patient is administered 960 mg sotorasib orally once per day during the
`
`induction period and during the combination period and 200 mg pembrolizumab via IV once every three weeks
`
`during the combination period.
`
`[0034]
`
`In some embodiments, the patient is administered 240 mg sotorasib orally once per day during the
`
`induction period and during the combination period and 200 mg pembrolizumab via IV once every three weeks
`
`during the combination period.
`
`[0035]
`
`In some embodiments,the patient is administered 120 mg sotorasib orally once per day during the
`
`induction period and during the combination period and 200 mg pembrolizumab via IV once every three weeks
`
`during the combination period.
`
`[0036]
`
`In various embodiments, sotorasib is administered with food. In various embodiments, sotorasib is
`
`administered without food.
`
`[0037]
`
`In various embodiments,the patient is in further need of treatment with an acid-reducing agent. Acid-
`
`reducing agents include, but are not limited to, a proton pumpinhibitor (PPI), a H2 receptor antagonist (H2RA),
`
`and a locally acting antacid.
`
`In some embodiments, the patient is further in need of treatment with a PPI or a
`
`H2RA. Exemplary PPIs include, but are notlimited to, omeprazole, pantoprazole, esomeprazcle, lansoprazole,
`
`rabeprazole, or dexlansoprazole. Exemplary H2RAsinclude, but are not limited to, famotidine, ranitidine,
`
`cimetidine, nizatidine, roxatidine and lafutidine. Exemplary locally acting antacids include, but are notlimited to,
`
`sodium bicarbonate, calcium carbonate, aluminum hydroxide, and magnesium hydroxide.
`
`In some
`
`embodiments, the patient, whois in further need of treatment with an acid reducing agent, is not administered a
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`10162-US01-PRI
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`32328/55344P
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`proton pumpinhibitor or a H2 receptor antagonist in combination with sotorasib.
`
`In some embodiments, the
`
`patient, whois 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.
`
`In some embodiments, sotorasib is administered about 4 hours before or about 10
`
`hours after a locally acting antacid.
`
`[0038]
`
`In various embodiments,the patient is in further need of treatment with a CYP3A4 inducer.
`
`In some
`
`embodiments, the patient is not administered a CYP3A4 inducer in combination with sotorasib. Exemplary
`
`CYP3A4inducersinclude, but are not limited to, apalutamide, avasimibe, barbiturate, brigatinib, carbamazepine,
`
`clobazam, dabrafenib, efavirenz, elagolix, enzalutamide, eslicarbazepine, glucocorticoids, ivosidenib, letermovir,
`
`lorlatinib, lumacaftor, mitotane, modafinil, nevirapine, oritavancin, oxcarbazepine, perampanel, phenobarbital,
`
`phenytoin, pioglitazone,rifabutin, rifampin, rifapentine, St. John’s wort, telotristat, and troglitazone. See, e.g.,
`
`Flockhart DA, Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine
`
`(2007), www.drug-interactions.medicine.iu.edu, accessed May 2021.
`
`In some embodiments, the patient is not
`
`administered a strong CYP3A4 inducer in combination with sotorasib. Exemplary strong CYP3A4 inducers
`
`include, but are notlimited to, rifampin, mitotane, avasimibe, rifapentine, apalutamide, ivosidenib, phenytoin,
`
`carbamazepine, enzalutamide, St John's Wort extract, and lumacaftor.. See, e.g., www. fda.gov/drugs/drug-
`
`interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers, accessed
`
`May 2021,
`
`[0039]
`
`In various embodiments, the patient is in further need of treatment with a CYP3A4 substrate.
`
`In some
`
`embodiments, the patient is not administered a CYP3A4 substrate in combination with sotorasib. Exemplary
`
`CYP3A4 substrates include, but are notlimited 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, citalopram, clarithromycin, clobazam,
`
`clopidogrel, cobimetinib, cocaine, codeine, colchicine, copanlisib, crizotinib, cyclosporine, dabrafenib, daclatasvir,
`
`dapsone, deflazacort, dexamethasone, dextromethorphan, diazepam, diltiazem, docetaxel, dolutegravir,
`
`domperidone, doxepin, elagolix, elbasvir/grazoprevir, eliglustat, enzalutamide, eplerenone, erythromycin,
`
`escitalopram, esomeprazole, estradiol, felodipine, fentanyl, finasteride, flibanserin, imatinib, haloperidol,
`
`hydrocortisone,ibrutinib, idelalisib, indacaterol, indinavir, irinotecan, isavuconazonium, ivabradine, ivacaftor,
`
`lansoprazole, lenvatinib, lercanidipine, lidocaine, linagliptin, lovastatin, macitentan, methadone, midazolam,
`
`naldemedine, naloxegol, nateglinide, nelfinavir, neratinib, netupitant/palonosetron, nevirapine, nifedipine,
`
`nisoldipine, nitrendipine, olaparib, omeprazole, ondansetron, osimertinib, ospemifene, palbociclib, panobinostat,
`
`pantoprazole, perampanel, pimavanserin, pimozide, pomalidomide, ponatinib, progesterone, propranolol,
`
`quetiapine, quinidine, quinine, regorafenib, ribociclib, rilpivirine, risperidone, ritonavir, rivaroxaban, roflumilast,
`
`rolapitant, romidepsin, ruxolitinib, salmeterol, saquinavir, selexipag, sildenafil, simeprevir, simvastatin, sirolimus,
`
`sonidegib, sorafenib, sunitinib, suvorexant, tacrolimus(fk506), tamoxifen, tasimelteon, taxol, telaprevir,
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`10162-US01-PRI
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`telithromycin, terfenadine, testosterone,ticagrelor, tofacitinib, tolvaptan, torisel, tramadol, trazodone,
`
`valbenazine, vandetanib, velpatasvir, vemurafenib, venetoclax, venlafaxine, verapamil, vilazodone,vincristine,
`
`vorapaxar, voriconazole, zaleplon, and ziprasidone. See, e.g., Flockhart DA, Drug Interactions: Cytochrome
`
`P450 Drug Interaction Table. Indiana University School of Medicine (2007), https://drug-
`
`interactions.medicine.iu.edu, accessed May 2021.
`
`In some embodiments, the CYP3A4 substrate is a CYP3A4
`
`substrate with a narrow therapeutic index. Exemplary CYP3A4 substrates with a narrow therapeutic index
`
`include, but are notlimited to, alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl,
`
`primozide, quinidine, tacrolimus, and sirolimus.
`
`[0040]
`
`=In various embodiments, the patient is in further need of treatment with a P-glycoprotein (P-gp)
`
`substrate. In some embodiments, the patient is not administered a P-gp substrate in combination with sotorasib.
`
`Exemplary P-gp substrates include, but are not limited to, etexilate, digoxin, fexofenadine, everolimus,
`
`cyclosporine, sirolimus, tacrolimus, 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.
`
`In some embodiments, the patient is not administered a P-gp substrate in