10162-US01-PRI
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`Whatis claimedis:
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`32328/55344P
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`1,
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`A methodoftreating cancer comprising a KRAS G72C mutation in a patient comprising
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`(a) administering to the patient a therapeutically effective amount of sotorasib for 14 to 48 days (“an
`
`induction period”), and
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`(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
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`combination period.
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`2.
`
`The methodof claim 1, wherein the therapeutically effective amount of sotorasib administered
`
`for the duration of the induction period is 960 mg.
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`3.
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`The method of claim 1, wherein the therapeutically effective amount of sotorasib administered
`
`during the induction period is 360 mg.
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`4,
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`The methodof claim 1, wherein the therapeutically effective amount of sotorasib administered
`
`during the induction period is 240 mg.
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`5.
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`The method of claim 1, wherein the therapeutically effective amount of sotorasib administered
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`during the induction period is 120 mg.
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`6.
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`The method of any oneof claims 1 to 5, comprising administering the therapeutically effective
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`amountof sotorasib to the patient once daily during the induction period.
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`7.
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`The method of any oneof claims 1 to 5, comprising administering the therapeutically effective
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`amountof sotorasib to the patient twice daily during the induction period, wherein each dose of sotorasib
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`correspondsto half of the therapeutically effective amount administered during the induction period.
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`8.
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`The methodof any oneof claims 1 to 7, wherein the therapeutically effective amount of
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`sotorasib administered during the combination period is 960 mg.
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`9,
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`The method of any oneof claims 1 to 7, wherein the therapeutically effective amount of
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`sotorasib administered during the combination period is 360 mg .
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`10.
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`The method of any oneof claims 1 to 7, wherein the therapeutically effective amount of
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`sotorasib administered during the combination period is 240 mg .
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`11.
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`The method of any oneof claims 1 to 7, wherein the therapeutically effective amount of
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`sotorasib administered during the combination period is 120 mg.
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`12.
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`The method of any oneof claims 1 to 11, comprising administering the therapeutically effective
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`amountof sotorasib to the patient once daily during the combination period.
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`13.
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`The method of any oneof claims 1 to 11, comprising administering the therapeutically effective
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`amountof sotorasib to the patient twice daily during the combination period, wherein each dose of sotorasib
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`correspondsto half of the therapeutically effective amount administered during the combination period.
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`14.
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`The method of any oneof claims 1 to 13, wherein the anti-PD-L1 antibody is atezolizumab,
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`avelumab, or durvalumab.
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`15.
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`16.
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`The method of claim 14, wherein the anti-PD-L1 antibody is atezolizumab.
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`The method of any oneof claims 1 to 13, wherein the anti-PD1 antibody is cemiplimab,
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`dostarlimab, pembrolizumab, or nivolumab.
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`17.
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`18.
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`The method of claim 16, wherein the anti-PD1 antibody is pembrolizumab.
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`The method of claim 17, comprising administering to the patient 200 mg pembrolizumab via IV
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`once every three weeks during the combination period.
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`19.
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`The method of claim 1, comprising administering to the patient
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`360 mg sotorasib orally once per day during the induction period and the combination period;
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`and
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`and
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`and
`
`and
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`200 mg pembrolizumabvia IV once every three weeks during the combination period.
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`20.
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`The method of claim 1, comprising administering to the patient
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`960 mg sotorasib orally once per day during the induction period and the combination period;
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`200 mg pembrolizumab via IV once every three weeks during the combination period.
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`21.
`
`The methodof claim 1, comprising administering to the patient
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`240 mg sotorasib orally once per day during the induction period and the combination period;
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`200 mg pembrolizumabvia IV once every three weeks during the combination period.
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`22,
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`The method of claim 1, comprising administering to the patient
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`120 mg sotorasib orally once per day during the induction period and the combination period
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`200 mg pembrolizumabvia IV once every three weeks during the combination period.
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`The method of any oneof claims 1 to 22, wherein the induction period is 21 days.
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`The method of any oneof claims 1 to 22, wherein the induction period is 42 days.
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`The method of any oneof claims 1 to 24, wherein the combination period is at least 30 days.
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`The method of claim 25, wherein the combination period is at least 3 months.
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`The methodof claim 26, wherein the combination period is at least 6 months.
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`The methodof claim 27, wherein the combination period is at least 8 months.
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`The method of any oneof claims 1 to 28, wherein the cancer exhibits a PD-L1 tumor
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`23,
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`24,
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`25.
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`26.
`
`af.
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`28.
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`29,
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`proportion score (TPS) of 50% or greater.
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`30.
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`The method of any oneof claims 1 to 28, wherein the cancer exhibits a PD-L1 tumor
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`proportion score (TPS) of 1% to 49%.
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`31.
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`The method of any oneof claims 1 to 28, wherein the cancer exhibits a PD-L1 tumor
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`proportion score (TPS) of less than 1%.
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`32,
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`33.
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`The method of any oneof claims 1 to 31, wherein the canceris a solid tumor.
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`The method of any oneof claims 1 to 31, wherein the cancer is non-small cell lung cancer,
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`small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer,
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`pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer,
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`gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and
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`neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, melanoma,
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`ampullary cancer, gastric cancer, sinonasal cancer, or bile duct cancer.
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`34,
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`The method of any oneof claims 1 to 31, wherein the canceris non-small cell lung cancer,
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`small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer,
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`pancreatic cancer, melanoma, ampullary cancer, gastric cancer, sinonasal cancer, or bile duct cancer.
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`35,
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`36.
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`lung cancer.
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`The method of any oneof claims 1 to 31, wherein the canceris non-small cell lung cancer.
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`The methodof claim 35, wherein the canceris locally-advanced or metastatic non-small cell
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`37,
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`The method of any oneof claims 1 to 36, wherein the patient exhibits at least a stable disease
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`(SD), as measured by RECIST 1.1 protocol, after the combination period lasts 3, 6, or 8 months.
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`38.
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`The method of any oneof claims 1 to 36, wherein the patient exhibits at least a partial
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`response (PR), as measured by RECIST 1.1 protocol, after the combination period lasts 3, 6, or 8 months.
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`39,
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`The method of any oneof claims 1 to 36, wherein the patient exhibits a progression free
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`survival (PFS) of at least 3 months.
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`40,
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`The method of any oneof claims 1 to 39, wherein the patient exhibits fewer grade 3 or 4
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`treatment related adverse events (TRAEs) comparedto a patient administered sotorasib and the anti-PD1
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`antibody or anti-PD-L1 antibody without an induction period.
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`41.
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`The method of any oneof claims 1 to 40, wherein the patient has not received anypriorline of
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`therapy.
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`42.
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`The method of any oneof claims 1 to 40, wherein the patient has received at least one prior
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`line of therapy.
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`43,
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`The method of any oneof claims 1 to 42, wherein the patient has not previously received
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`treatment with an anti-PD1 or anti-PD-L1 immunotherapy.
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`44,
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`The method of any oneof claims 1 to 42, wherein the patient has previously received
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`treatment with anti-PD1 or anti-PD-L1 immunotherapy.
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`45.
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`The method of any oneof claims 1 to 40 and 42, wherein the patient has previously received
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`treatment with (i) anti-PD1 or anti-PDL1 immunotherapyor(ii) prior platinum-based combination chemotherapy.
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`46,
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`The method of any oneof claims 1 to 40 and 42, wherein the patient has previous received
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`treatmentwith (i) anti-PD1 or anti-PD-L1 immunotherapy and (ii) prior platinum-based combination
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`chemotherapy.
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`47,
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`The methodof any oneof claims 1 to 40 and 42 to 44, wherein the patient has previously
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`undergone an EGFR, ALK or ROS1 targeted therapyif the cancer also exhibited a mutation in EGFR, ALK, or
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`ROS1,
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`48.
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`The methodof claim 47, wherein the patient has progressed on an EGFR, ALK or ROS1
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`targeted therapy if the cancer also exhibited a mutation in EGFR, ALK, or ROS1,
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`49,
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`The method of any oneof claims 42 to 48, wherein the patient completed neoadjuvantor
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`adjuvant chemotherapy at least 12 months prior to diagnosis of advanced stage cancer.
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`50,
`
`(1)
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`The methodof claim any one of claims 1 to 40, wherein
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`(a) the patient has previously received treatment with (i) anti-PD1 or anti-PD-L1
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`immunotherapyor(ii) prior platinum-based combination chemotherapy; or (b) the patient has previously received
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`treatmentwith (i) anti-PD1 or anti-PD-L1 therapy and(ii) prior platinum-based chemotherapy; and
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`(2)
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`the patient optionally has previously undergone an EGFR, ALK or ROS1 targeted therapyif the
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`cancer also exhibited a mutation in EGFR, ALK, or ROS1.
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`51.
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`The method of any oneof claims 1 to 40, wherein the patient
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`(1) has a cancer that exhibits a PD-L1 tumer proportion score (TPS) of 50% or greater; and
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`(2) has not received any systemic therapy for locally advanced or metastatic non-small cell lung cancer;
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`(i) but for a EGFR, ALK, or ROS1 targeted cancer therapy, if cancer exhibited a mutation in
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`EGFR,ALK, or ROS1, and the patient has progressed on the targeted cancer therapy; and
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`(ii) but for neoadjuvant or adjuvant chemotherapy completed at least 12 monthsprior to the
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`start of the induction period and has not received immune checkpoint inhibitor therapy.
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`52.
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`The method of any oneof claims 1 fo 51, wherein the patient has an Eastern Cooperative
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`Oncology Group (ECOG)performance status of less than or equalto 2.
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`53.
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`The method of any oneof claims 1 to 52, wherein the patient does not have active
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`(symptomatic) brain metastases.
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`54,
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`The method of any oneof claims 1 to 53, wherein
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`(i) the patient
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`had brain metastases resected, or
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`received whole brain radiation therapy ending at least 4 weeksprior to start of the induction period, or
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`received stereotactic radiosurgery ending at least 2 weekspriorto start of the induction period, and
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`(ii) the patient
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`exhibits residual neurological symptoms of grade 2 or less, and
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`has not been administered steroids for at least 14 days prior to the start of the induction period, and
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`has an magnetic resonance imaging (MRI) performed within 14 days priorto start of the induction period
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`that shows no evidence of progression of the brain metastases.
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`55,
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`The methodof any oneof claims 1 to 54, wherein the patient does not have leptomeningeal
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`disease.
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`56.
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`The method of any oneof claims 1 to 55, wherein the patient is not suffering from a hepatitis B
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`infection or a hepatitis C infection.
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`57,
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`The method of any oneof claims 1 to 56, wherein the patient has not received a prior therapy
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`with a KRAS&?2¢ inhibitor.
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`58.
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`59.
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`The method of claim 57, wherein the KRASS&"2¢ inhibitor is sotorasib or adagrasib.
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`The method of any oneof claims 1 to 58, wherein the patient is in further need of treatment
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`with an acid-reducing agent.
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`60.
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`The method of claim 59, wherein the acid-reducing agent is a proton pumpinhibitor (PPI), a H2
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`receptor antagonist (H2RA), or a locally acting antacid.
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`61,
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`The method of claim 59 or claim 60, wherein the acid-reducing agent is a locally acting antacid,
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`and wherein sotorasib is administered about 4 hours before or about 10 hours after the locally acting antacid.
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`62,
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`The methodof claim 60 or 61, wherein the locally acting antacid is sodium bicarbonate,
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`calcium carbonate, aluminum hydroxide, or magnesium hydroxide.
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`63.
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`The methodof any oneof claims 60 to 62, wherein the patientis in further need of treatment
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`with a proton pumpinhibitor (PPI) or H2 receptor antagonist (H2RA).
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`64.
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`The methodof claim 63, wherein the patient is not administered a PPI or a H2RA in
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`combination with sotorasib.
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`65.
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`The method of any oneof claims 60, 63 or 64, wherein the PPI is omeprazole, pantoprazole,
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`esomeprazole, lansoprazole, rabeprazole, or dexlansoprazole.
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`66.
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`The method of any oneof claims 60, 63 or 64, wherein the H2RA is famotidine, ranitidine,
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`cimetidine, nizatidine, roxatidine orlafutidine.
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`67,
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`The method of any oneof claims 1 to 66, wherein the patientis in further need of treatment
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`with a CYP3A4 inducer.
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`66
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`68.
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`The methodof claim 67, wherein the patient is not administered a CYP3A4 inducerin
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`combination with sotorasib.
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`69.
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`The methodof claim 67 or 68, wherein the CYP3A4 induceris a apalutamide, avasimibe,
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`barbiturate, brigatinib, carbamazepine, clobazam, dabrafenib, efavirenz, elagolix, enzalutamide, eslicarbazepine,
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`glucocorticoids, ivosidenib, letermovir, lorlatinib, lumacaftor, mitotane, modafinil, nevirapine, oritavancin,
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`oxcarbazepine, perampanel, phenobarbital, phenytoin, pioglitazone,rifabutin, rifampin, rifapentine, St. John’s
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`wort, telotristat, or troglitazone.
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`70.
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`71.
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`The methodof claim 67 or 68, wherein the CYP3A4 induceris a strong CYP3A4 inducer.
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`The method of claim 70, wherein the strong CYP3A4 induceris rifampin, mitotane, avasimibe,
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`rifapentine, apalutamide, ivosidenib, phenytoin, carbamazepine, enzalutamide, St John's Wort extract, or
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`lumacaftor.
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`72,
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`The method of any oneof claims 1 to 71, wherein the patient is in further need of treatment
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`with a CYP3A4substrate.
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`73.
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`The methodof claim 72, wherein the patient is not administered a CYP3A4 substrate in
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`combination with sotorasib.
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`74.
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`The methodof claim 70 or 71, wherein the CYP3A4 substrate is abemaciclib, abiraterone,
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`acalabrutinib, alectinib, alfentanil, alprazolam, amitriptyline, amlodipine, apixaban, aprepitant, aripiprazole,
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`astemizole, atorvastatin, avanafil, axitinib, boceprevir, bosutinib, brexpiprazole, brigatinib, buspirone, cafergot,
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`caffeine, carbamazepine,cariprazine, ceritinib, cerivastatin, chlorpheniramine, cilostazol, cisapride, citalopram,
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`clarithromycin, clobazam, clopidogrel, cobimetinib, cocaine, codeine, colchicine, copanlisib, crizotinib,
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`cyclosporine, dabrafenib, daclatasvir, dapsone, deflazacort, dexamethasone, dextromethorphan, diazepam,
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`diltiazem, docetaxel, dolutegravir, domperidone, doxepin, elagolix, eloasvir/grazoprevir, eliglustat, enzalutamide,
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`eplerenone, erythromycin, escitalopram, esomeprazole, estradiol, felodipine, fentanyl, finasteride,flipanserin,
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`imatinib, haloperidol, hydrocortisone,ibrutinib, idelalisib, indacaterol, indinavir, irinotecan, isavuconazonium,
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`ivabradine, ivacaftor, lansoprazole, lenvatinib, lercanidipine, lidocaine,linagliptin, lovastatin, macitentan,
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`methadone, midazolam, naldemedine, naloxegol, nateglinide, nelfinavir, neratinib, netupitant/palonosetron,
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`nevirapine, nifedipine, nisoldipine, nitrendipine, olaparib, omeprazole, ondansetron, osimertinib, ospemifene,
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`palbociclib, panobinostat, pantoprazole, perampanel, pimavanserin, pimozide, pomalidomide, ponatinib,
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`progesterone, propranolol, quetiapine, quinidine, quinine, regorafenib, ribociclib, rilpivirine, risperidone, ritonavir,
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`rivaroxaban, roflumilast, rolapitant, romidepsin, ruxolitinib, salmeterol, saquinavir, selexipag, sildenafil,
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`simeprevir, simvastatin, sirolimus, sonidegib, sorafenib, sunitinib, suvorexant, tacrolimus(fk506), tamoxifen,
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`tasimelteon, taxol, telaprevir, telithromycin, terfenadine, testosterone, ticagrelor, tofacitinib, tolvaptan, torisel,
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`tramadol, trazodone, valbenazine, vandetanib, velpatasvir, vemurafenib, venetoclax, venlafaxine, verapamil,
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`vilazodone,vincristine, vorapaxar, voriconazole, zaleplon, or ziprasidone.
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`15.
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`The methodof claim 72 or 73, wherein the CYP3A4 substrate is a CYP3A4 substrate with a
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`narrow therapeutic index.
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`76.
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`The methodof claim 75, wherein the CYP3A4 substrate with a narrow therapeutic index is
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`alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, primozide, quinidine, tacrolimus, or
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`sirolimus.
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`Tf.
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`The methodof any oneof claims 1 to 76, wherein the patient is in further need of treatment
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`with a P-glycoprotein (P-gp) substrate.
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`18,
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`The methodof claim 77, wherein the patient is not administered a P-gp substrate in
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`combination sotorasib.
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`79.
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`The method of claim 77 or 78, wherein the P-gp substrate is etexilate, digoxin, fexofenadine,
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`everolimus, cyclosporine, sirolimus, tacrolimus,or vincristine.
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`80.
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`The method of claim 77 or 78, wherein the P-gp substrate is a P-gp substrate with a narrow
`
`therapeutic index.
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`81,
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`The method of claim 80, where in the P-gp substrate with a narrow therapeutic index is
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`digoxin, everolimus, cyclosporine, tacrolimus, sirolimus, or vincristine.
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`68
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