Sotorasib in Combination With Trastuzumab Deruxtecan for the Treatment of Locally Advanced and Metastatic Non-small Cell Lung Cancer With a KRAS G12C Mutation

Inclusion Criteria:

• Patients must have histologically or cytologically documented locally advanced ormetastatic KRAS^G12C-mutant NSCLC that has previously been treated with a KRAS^G12Cinhibitor AND an immune checkpoint inhibitor (ICI) OR chemotherapy +/- ICI, eithergiven concurrently or sequentially

• Patients must have KRAS^G12C mutation identified by tumor tissue or plasmacirculating tumor deoxyribonucleic acid (ctDNA) profiling using a ClinicalLaboratory Improvement Act (CLIA) certified College of American Pathologists (CAP)accredited platform; local molecular testing will be allowed. Testing must have beendone within the last 5 years before enrollment in this study

• Data must be available for which prior KRAS^G12C inhibitor treatment the patient hasreceived and the dates that they received it (type of KRAS^G12C inhibitor used andstart and end dates must be collected prior to enrollment)

• Data must be available on the date patients received the last dose of KRAS^G12Cinhibitor and the date of disease progression on their last treatment prior toscreening for this trial. Data must be available on the last treatment they receivedand if it was not or did not include a KRAS^G12C inhibitor. The time between lastKRAS^G12C inhibitor and treatment on this trial will be collected prior toenrollment

• Data must be available on historical HER2 immunohistochemistry (IHC) status (date oftest, type of antibody used for the IHC test, scoring system (i.e., breast versus [vs.] gastric), and results must be collected prior to enrollment). Patients who donot have this information available for collection will not be enrolled on thisstudy

• Patients must have measurable disease, as defined by RECIST v1.1 using computedtomography (CT) or magnetic resonance imaging (MRI). Previously irradiated lesionscannot be counted as target lesions unless there has been demonstrated progressionin the lesions since radiotherapy and no other lesions are available for selectionas target lesions

• Age ≥ 18 years at date of informed consent form signature

• Because no dosing or adverse event data are currently available on the use ofsotorasib (AMG-510) in combination with DS-8201a (T-DXd) in patients < 18 yearsof age, children are excluded from this study

• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)

• Hemoglobin ≥ 9 g/dL (within 14 days of enrollment)

• Leukocytes ≥ 3,000/mcL (within 14 days of enrollment)

• Absolute neutrophil count ≥ 1,500/mcL (within 14 days of enrollment)

• No administration of granulocyte colony stimulating factor (G-CSF) is allowedwithin 1 week prior to screening assessment

• Platelets ≥ 100,000/mcL (within 14 days of enrollment)

• No transfusions with red blood cells or platelets are allowed within 1 weekprior to screening assessment

• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (within 14 days ofenrollment), (< 3 x ULN in the presence of documented Gilbert's syndrome or livermetastases at baseline)

• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) ≤ 3 x institutional ULN (within 14 days of enrollment) (< 5 x ULN in participants withliver metastases)

• Serum albumin ≥ 2.5 g/dL (within 14 days of enrollment)

• International normalized ratio (INR)/prothrombin time (PT) and activated partialthromboplastin time (aPTT) ≤ 1.5 x ULN (within 14 days of enrollment)

• Creatinine ≤ 1.5 x institutional ULN OR creatinine clearance (CrCL) ≥ 30 mL/min/ asdetermined by (using actual body weight) (within 14 days of enrollment)

• Patients must have left ventricular ejection fraction (LVEF) ≥ 50% by either anechocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days beforeenrollment

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months are eligible for this trial

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load

• Patients with treated brain metastases are eligible with 1 day washout forstereotactic radiosurgery (SRS) and 2 weeks washout for whole brain radiation (WBRT)

• Patients with new or progressive brain metastases (active brain metastases) areeligible if the treating physician determines that immediate central nervous system (CNS) specific treatment is not required and is unlikely to be required during thefirst cycle of therapy

• Patients must have a life expectancy of ≥ 12 weeks

• Patients must have a corrected QT interval (QTc) ≤ 470 msec for women and ≤ 450 msecfor men (based on average screening triplicates)

• Patients must be willing to undergo a mandatory pre-treatment biopsy (28 days beforetreatment starts on cycle 1 day 1 [C1D1]) for patients enrolled into the expansionphase (phase II). The pre-treatment biopsy is optional for patients enrolled intothe dose escalation phase (phase I)

• Patients must have the ability to ingest and retain oral (PO) medications

• The effects of the combination of sotorasib (AMG-510) and DS-8201a (T-DXd) on thedeveloping human fetus are unknown. For this reason and because HER-2-directedantibody conjugated to a topoisomerase 1 inhibitor agents are known to beteratogenic, women of child-bearing potential (WOCBP) must agree to use dual methodsof contraception and must have a negative serum pregnancy testing at screening.Should a woman become pregnant or suspect she is pregnant while she or her partneris participating in this study, she should inform her treating physicianimmediately. Women treated or enrolled on this protocol must agree to use a highlyeffective method of contraception, if sexually active, or avoid intercourse duringthe study treatment and for 7 months following the last dose of study drug.Sotorasib (AMG-510) may reduce the effectiveness of hormonal contraceptives, andtherefore women using hormonal contraceptives should add a barrier method on studyand for an additional 7 days after the last dose of sotorasib (AMG-510). Men treatedor enrolled on this protocol must also agree to use a highly effective barriermethod of contraception, if sexually active, or avoid intercourse throughout theduration of the study and for 4 months following the last dose of study drug. Toprevent exposure of the unborn child to sotorasib (AMG-510) through semen, malesubjects will be required to practice true sexual abstinence (not have sex) or mustwear a condom during vaginal sex

• Women of non-child-bearing potential defined as pre-menopausal females with adocumented tubal ligation or hysterectomy; or postmenopausal defined as 12 months ofspontaneous amenorrhea (in questionable cases, a blood sample with simultaneousfollicle-stimulating hormone [FSH] > 40 mIU/mL and estradiol < 40 pg/mL [< 147pmol/L] is confirmatory) are eligible. Females on hormone replacement therapy (HRT)and whose menopausal status is in doubt will be required to use one of thecontraception methods outlined for women of child-bearing potential if they wish tocontinue their HRT during the study. Otherwise, they must discontinue HRT to allowconfirmation of post-menopausal status prior to study enrollment. For most forms ofHRT, at least 2-4 weeks will elapse between the cessation of therapy and the blooddraw; this interval depends on the type and dosage of HRT. Following confirmation oftheir post-menopausal status

• Male subjects must not freeze or donate sperm starting at screening and throughoutthe study period, and at least 4 months after the final study drug administration.Preservation of sperm should be considered prior to enrollment in this study

• Female subjects must not donate, or retrieve for their own use, ova from the time ofscreening and throughout the study treatment period, and for at least 7 months afterthe final study drug administration

• Ability to understand and the willingness to sign a written informed consentdocument. Legally authorized representatives may sign and give informed consent onbehalf of study participants

Exclusion Criteria:

• Patients with a history of (non-infectious) interstitial lung disease (ILD) thatrequired steroids, has current ILD, or where suspected ILD cannot be ruled out byimaging at screening. These patients will be excluded because DS-8201a (T-DXd) isknown to increase the risk of developing ILD and pneumonitis

• Patients with clinically severe pulmonary compromise resulting from intercurrentpulmonary illnesses including, but not limited to, any underlying pulmonary disorder (i.e., pulmonary emboli within three months of the study enrollment, severe asthma,severe chronic obstructive pulmonary disease [COPD], restrictive lung disease, priorcomplete pneumonectomy), and any autoimmune, connective tissue or inflammatorydisorders (e.g., rheumatoid arthritis, Sjogren's, sarcoidosis, etc.) where there isdocumented or a suspicion of pulmonary involvement or pneumonectomy at the time ofscreening. These patients will be excluded because DS-8201a (T-DXd) is known toincrease the risk of developing ILD and pneumonitis

• Patients who have had chest radiation therapy within 4 weeks (2 weeks for palliativestereotactic body radiation therapy). These patients will be excluded becauseDS-8201a (T-DXd) and sotorasib (AMG-510) are known to increase the risk ofdeveloping pneumonitis

• Patients who have had a major surgery and are not yet fully healed from surgicalincisions

• Patients who have had prior treatment with an antibody drug conjugate with atopoisomerase 1 inhibitor payload (i.e., sacituzumab govitecan, datopotomabderuxtecan, or trastuzumab deruxtecan) or with a topoisomerase inhibitor

• Patients with a history of significant lung disease requiring systemiccorticosteroids treatment (> 10 mg of prednisone daily) within the last six monthsof registration

• Based on pre-clinical data, DS-8201a (T-DXd) is associated with corneal disease.Patients with clinically significant corneal disease, in the opinion of theinvestigator, will be excluded from this study

• Patients with spinal cord compression, defined as untreated and symptomatic, orrequiring therapy with corticosteroids or anticonvulsants to control associatedsymptoms

• Patients with an uncontrolled infection requiring IV antibiotics, antivirals, orantifungals

• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia. Subjectswith chronic grade 2 toxicities (i.e., defined as no worsening to > grade 2 for atleast 3 months prior to first exposure to study intervention and managed withstandard of care treatment) may be eligible per the discretion of the investigatorafter consultation with the sponsor medical monitor or designee (e.g., grade 2chemotherapy-induced neuropathy). Subjects should no longer be symptomatic norrequire treatment with corticosteroids (prednisone > 10 mg or equivalent) oranticonvulsants and must have recovered from the acute toxic effect of radiotherapy

• Patients who are receiving any other investigational agents

• Patients with a history of allergic reactions attributed to compounds of similarchemical or biologic composition to sotorasib (AMG-510), such as adagrasib, orDS-8201a (T-DXd)

• Patients who have a history of severe hypersensitivity reactions to other monoclonalantibodies

• Patients who are taking strong CYP3A4 inducers should be switched to an alternativedrug

• Avoid coadministration with P-glycoprotein (P-gp) substrates for which minimalconcentration changes may lead to serious toxicities. If coadministration cannot beavoided, dose adjustment of the substrate may be required. Please refer to theprescribing information for the substrate

• Patients with uncontrolled intercurrent illness or any other significantcondition(s) that would make participation in this protocol unreasonably hazardousor interfere with the evaluation of the clinical study results

• Pregnant women are excluded from this study because DS-8201a (T-DXd) is aHER2-directed antibody conjugated to a topoisomerase 1 inhibitor agent with thepotential for teratogenic or abortifacient effects. Because there is an unknown butpotential risk for adverse events in nursing infants secondary to treatment of themother with DS-8201a (T-DXd) breastfeeding should be discontinued if the mother istreated with DS-8201a (T-DXd). These potential risks may also apply to other agentsused in this study

• Patients with uncontrolled or significant cardiovascular disease (i.e., history ofmyocardial infarction within 6 months from screening, symptomatic congestive heartfailure [CHF] [New York Heart Association class II to IV], troponin levelsconsistent with myocardial infarction 28 days prior to enrollment, history ofunstable angina, or serious cardiac arrhythmia)

• Patients with prior history of pneumonitis grade 2 or higher or ILD

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial

• Patients unable to receive both iodinated contrast for CT scans and gadoliniumcontrast for MRI scans

• Patients that have pleural effusion, ascites, or pericardial effusion that requiresdrainage within 2 weeks of study screening procedures, peritoneal shunt, orcell-free and concentrated ascites reinfusion therapy (CART)

• Patients that have received a live vaccine within 30 days prior to the first dose ofstudy drug will be excluded. Examples of live vaccines include, but are not limitedto, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellowfever, rabies, bacillus Calmette- Guérin (BCG), and typhoid vaccine. Seasonalinfluenza vaccines for injection are generally killed virus vaccines and areallowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuatedvaccines and are not allowed