Inclusion Criteria:

1. Subjects will be between the ages of 15 and 75, inclusive. 2. Subjects must have a histologically confirmed diagnosis of a solid tumor metastatic to bone, or a histologically confirmed diagnosis of a solid tumor to the bone or metastatic to the bone. 3. Subjects must have measurable disease on anatomic imaging that is also avid for phosphonate compounds as demonstrated by a positive 99mTc diphosphonate bone scan. Not all lesions must be positive on bone scan. 4. Adequate organ function, including: i. Adequate renal function, defined as a measured creatinine clearance >70 mL/min/1.73 m2 or normal radioisotope glomerular filtration rate (GFR). ii. Adequate hematologic function, defined as a platelet count >100,000 cells/mm3 and an absolute neutrophil count (ANC) >1,000 cells/mm3. 5. Life expectancy of at least eight weeks. 6. Karnofsky performance status >50%. 7. Subjects must have adequately recovered from the effects of any prior chemotherapy, as determined by the treating physician and study team, based in part on organ function defined above. Toxicities from previous therapies must have recovered to CTCAE v5.0 grade ≤1. Subjects with Grade 2 anemia per CTCAE v5.0 will be permitted as long as the subject has normal cardiac function. 8. Adequate cardiac function. Subjects with previously identified cardiac disease will be eligible, as 153Sm-DOTMP is not expected to cause cardiac dysfunction and is only expected to result in very transient hypocalcemia. 9. A stem cell product collected either by peripheral stem cell mobilization or bone marrow harvest prior to the infusion of CycloSam® must be available, prior to trial entry. A minimum of 2 x 106 CD34+ cells/kg ideal body weight are required. 10. Female subjects of child-bearing potential (defined as premenopausal and capable of becoming pregnant) must have a negative serum pregnancy test at the Screening visit. Females must be surgically sterile, postmenopausal for at least one year prior to Screening (no other medical cause involved) with a Follicle Stimulating Hormone (FSH) level of greater than 40 mIU/mL or must be using a highly effective method of birth control and agree to its use for at least 30 days following the last dose of 153Sm-DOTMP. Highly effective methods of contraceptive are defined as tubal ligation or an approved hormonal contraceptive such as oral contraceptives, patches, implants, injections, rings, or hormonally-impregnated intrauterine device. 11. Male subjects with partners of child-bearing potential must agree to use highly effective methods of contraception for at least 90 days after the last dose of 153Sm-DOTMP. 12. The subject and/or the subject's legally authorized guardian, if the subject is a minor, must acknowledge in writing that informed consent to become a study subject has been obtained, in accordance with institutional policies approved by the U.S. Department of Health and Human Services. 13. Subjects must have previously received effective treatment for their underlying disease and have no potentially curative options available. 14. The concurrent use of hormonal therapies or bisphosphonates is acceptable, provided the latter do not render target lesions invisible on 99mTc bone scan. Subjects will have the option to re-screen up to once more after seven days if they do not initially meet all of the inclusion criteria

Exclusion Criteria:

1. Subject is pregnant or breastfeeding. 2. Subject is sexually active and does not agree to use accepted, effective forms of contraceptive. 3. Subject has received prior radiotherapy to all known areas of current active disease. 4. Subject has a body mass index (BMI) > 50 kg/m2.

Inclusion Criteria:

• Be willing and able to provide written informed consent for the trial
• Age 18 years or greater
• Be fully active, able to carry on all pre-disease performance without restriction or restricted in physically strenuous activity but able to carry out work of a light or sedentary nature (e.g., light house work, office work)
• Be diagnosed with confirmed locally advanced and nonresectable, or metastatic Stage III Non-Small Cell Lung Cancer
• Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated
• Adequate staging of your disease
• Adequate lung function
• Adequate other organ functions
• No active second cancers
• Be willing and able to comply with all aspects of the protocol
• Female patients of childbearing potential should have a negative pregnancy test within 72 hours prior to receiving the first dose of study medication
• Female participants of childbearing potential should be willing to use two methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication
• Male participants should agree to abstinence or use of an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy

Exclusion Criteria:

• Age less than 18 years
• Weight less than 30 Kg (~66 lbs)
• Pregnant or breastfeeding women
• Have been discontinued in a prior treatment study with immunotherapy drugs due to a severe toxicity (Grade 3 or higher)
• Received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
• Had an allogenic tissue/solid organ transplant
• A diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within seven days prior to the first dose of study drug
• Known active cancer spread to central nervous system
• Known severe hypersensitivity to study treatment components
• An active autoimmune disease that has required systemic treatment in the past two years
• Have inflammatory bowel disease
• Have a history of (non-infectious) pneumonitis that required steroids or have current pneumonitis
• Have a history of interstitial lung disease
• Have an active infection requiring systemic therapy
• Have human immunodeficiency virus (HIV) and/or history of Hepatitis B or C infections,
• Have abnormal electrocardiogram (Prolongation of QT interval)
• Significant cardiovascular impairment: history of congestive heart failure, uncontrolled arterial hypertension, unstable angina, myocardial infarction, or stroke within 6 months of the first dose of study drug; or cardiac arrhythmia
• Major surgery within four weeks before the first dose of study drug
• Inability to take oral medication, or malabsorption syndrome or any other uncontrolled gastrointestinal condition (eg, nausea, diarrhea, or vomiting)
• Have a known psychiatric or substance abuse problems

Inclusion Criteria:

• Participant must have histologically or cytologically confirmed, locally advanced or metastatic, non-small cell lung cancer (NSCLC) that is not amenable to curative therapy including surgical resection or chemoradiation. Additional Cohort specific disease requirements include: Cohorts 1, 3, 3b, 5, 6 and 7: epidermal growth factor receptor (EGFR) exon 19 deletion (Exon19del) or Exon 21 L858R mutation; Cohort 2: EGFR Exon 20ins mutation. Cohorts 1,5,and6: Participant should not have received any prior systemic therapy for locally advanced or metastatic NSCLC. Cohort 2: Participant should not have received any prior systemic therapy for locally advanced or metastatic NSCLC. Cohorts 3and3b: Participant must have progressed on or after osimertinib monotherapy as the most recent line of treatment. Osimertinib must have been administered as either the first-line treatment for locally advanced or metastatic disease or in the second-line setting after prior treatment with first- or second-generation EGFR tyrosine kinase inhibitor (TKI) as a monotherapy. Cohort 4: Participants need to currently be on an amivantamab IV Q2W regimen (1,050 mg or 1,400 mg depending on weight) for at least 8 weeks, as part of standard of care, an expanded access program, or as a rollover from a long-term extension, without any amivantamab dose reduction. Cohort 7: Participants must have progressed on or after the combination of amivantamab and lazertinib as the most recent line of treatment. The combination of amivantamab and lazertinib must have been administered as the first-line treatment for locally advanced or metastatic disease. Cohort 2, 3, 3b, and 7 only: Squamous NSCLC are excluded. EGFR mutation must have been identified as determined by Food and Drug Administration (FDA) approved or other validated test of either circulating tumor deoxyribonucleic acid (ctDNA) or tumor tissue in a clinical laboratory improvement amendments (CLIA) certified laboratory (sites in the United states [US]) or an accredited local laboratory (sites outside of the US). A copy of the initial test report documenting the EGFR mutation must be included in the participant records and a deidentified copy must also be submitted to the sponsor
• All cohorts except Cohort 4: Participants must have at least 1 measurable lesion, according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. If the only target lesion has been previously irradiated, it must show signs of disease progression since radiation was completed If only 1 non-irradiated measurable lesion exists, which undergoes a biopsy and is acceptable as a target lesion, the baseline tumor assessment scans should be performed at least 14 days after the biopsy
• May have a prior or concurrent second malignancy (other than the disease under study) which natural history or treatment is unlikely to interfere with any study endpoints of safety or the efficacy of the study treatment(s)
• Have adequate organ (renal, hepatic, hematological, coagulation and cardiac) functions
• Participant must have eastern cooperative oncology group (ECOG) status of 0 or 1
• Cohort 6: Must be eligible for, and agree to comply with, the use of prophylactic anticoagulation with a direct oral anticoagulant or a low molecular weight heparin during the first 4 months of study treatment
• A participant must agree not to donate eggs (ova, oocytes) or freeze for future use for the purposes of assisted reproduction during the study and for a period of 6 months after receiving the last dose of study treatment. Female participants should consider preservation of eggs prior to study treatment as anti-cancer treatments may impair fertility

Exclusion Criteria:

• Participant has a medical history of interstitial lung disease (ILD), including drug induced ILD or radiation pneumonitis
• Participant has a history of hypersensitivity to any excipients of the investigational products to be used in their enrollment cohort
• Participant has received a live or live attenuated vaccine within 3 months before Cycle 1 Day 1. The seasonal influenza vaccine and non-live vaccines against Coronavirus disease 19 (COVID-19) are not exclusionary
• For all cohorts (with regimens potentially including lazertinib): Participant is currently receiving medications or herbal supplements known to be potent Cytochrome (CYP3A4/5) inducers and is unable to stop use for an appropriate washout period prior to Cycle 1 Day 1
• Other clinically active liver disease of infectious origin
• Participant has a history of clinically significant cardiovascular disease including, but not limited to: a) All cohorts: diagnosis of deep vein thrombosis or pulmonary embolism within 1 month prior to the first dose of study treatment(s), or any of the following within 6 months prior to the first dose of study treatment(s): myocardial infarction, unstable angina, stroke, transient ischemic attack, coronary/peripheral artery bypass graft, or any acute coronary syndrome. Clinically non-significant thrombosis, such as non-obstructive catheter-associated clots, are not exclusionary; b) All cohorts (with regimens potentially including lazertinib): Participant has a significant genetic predisposition to venous thromboembolic events (VTE; such as Factor V Leiden); c) All cohorts (with regimens potentially including lazertinib): Participant has a prior history of VTE and is not on appropriate therapeutic anticoagulation as per NCCN or local guidelines; d) prolonged corrected QT interval by Fridericia (QTcF) interval greater than (>) 480 milliseconds (msec) or clinically significant cardiac arrhythmia or electrophysiologic disease (example, placement of implantable cardioverter defibrillator or atrial fibrillation with uncontrolled rate); e) uncontrolled (persistent) hypertension: systolic blood pressure >160 millimeter(s) of mercury (mmHg); diastolic blood pressure >100 mmHg; f) Congestive heart failure defined as NYHA class III-IV or hospitalization for congestive heart failure (CHF) (any New York Heart Association [NYHA] class) within 6 months of treatment initiation at Cycle 1/day 1 (C1D1); g) pericarditis/clinically significant pericardial effusion; h) myocarditis; i) baseline left ventricular ejection fraction (LVEF) below the institution's lower limit of normal at screening, as assessed by echocardiogram or multigated acquisition (MUGA) scan
• Participant has symptomatic brain metastases. A participant with asymptomatic or previously treated and stable brain metastases may participate in this study. Participants who have received definitive radiation or surgical treatment for symptomatic or unstable brain metastases and have been clinically stable and asymptomatic for at least 2 weeks before Screening are eligible, provided they have been either off corticosteroid treatment or are receiving low-dose corticosteroid treatment (less than or equal to [<=] 10 milligrams per day [mg/day] prednisone or equivalent) for at least 2 weeks prior to treatment allocation

Inclusion Criteria:

• Patients must be < 50 years at the time of enrollment.
• Patients must have =< 4 nodules per lung consistent with or suspicious for metastases, with at least one of which being >= 3 mm and all of which must be =< 3 cm size.
• Note: Patient must have eligibility confirmed by rapid central imaging review.
• Lung nodules must be considered resectable by either open thoracotomy or thoracoscopic surgery. Determination of resectability is made by the institutional surgeon.
• Patients must have a histological diagnosis of osteosarcoma.
• Patients must have evidence of metastatic lung disease at the time of initial diagnosis, or at time of 1st recurrence following completion of therapy for initially localized disease.
• Patients with newly diagnosed disease must have completed successful gross tumor resection for their primary tumor or surgical local control of primary tumor must be planned to be performed simultaneously with thoracic surgery.
• Newly diagnosed patients must be receiving or recently completed (within 60 days) systemic therapy considered by the treating physician to be standard treatment for newly diagnosed osteosarcoma (eg, cisplatin-doxorubicin or ifosfamide-based drug regimens) at the time of enrollment on this study. Dose and drug modifications for toxicity do not exclude patients from participation.
• Patients at time of 1st recurrence must have completed systemic therapy for their initial primary tumor, considered by the treating physician to be standard treatment for newly diagnosed osteosarcoma (eg, cisplatin-doxorubicin or ifosfamide-based drug regimens) at the time of enrollment on this study. Dose and drug modifications for toxicity do not exclude patients from participation.

Exclusion Criteria:

• Patients with unresectable primary tumor.
• Patients with pulmonary metastatic lesions that would require anatomic resection (lobectomy or pneumonectomy) or lesions that are defined as "central" (i.e., central lesion involves or is proximal to segmental bronchi and peripheral is lesion distal to segmental bronchi).
• Patients with chest wall or mediastinal based metastatic lesions, or with significant pleural effusion.
• Patients with disease progression at either the primary or pulmonary metastatic site while on initial therapy. Note: Once the patient has been enrolled on the study, additional computed tomography (CT) scans are not anticipated prior to thoracic surgery. Note: Some variation in nodule size measurements over the course of pre-operative therapy is anticipated and does not qualify for exclusion unless deemed true disease progression by the primary treatment team.
• Patients with evidence of extrapulmonary metastatic disease.
• Patients who received therapeutic pulmonary surgery for lung metastasis prior to enrollment.
• All patients and/or their parents or legal guardians must sign a written informed consent.
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met.

1. Inclusion Criteria: Subjects must meet all the following criteria to participate in

this study. 1. Signed, written informed consent obtained prior to any study procedures. 2. Age > 18 years at the time of informed consent. 3. Metastatic solid tumor with ≥ 10% of tumor cells positive for KK-LC-1 by IHC assay. Due to the low frequency of KK-LC-1 expression in most cancers, screening will focus on gastric, NSCLC, TNBC, and cervix cancers. The IHC test will be performed by the Rutgers Cancer Institute, Department of Biorepository Services. 4. HLA-A*01:01 allele by HLA haplotype test. 5. Measurable disease per RECIST Criteria Version 1.1 at time of enrollment. 6. Prior treatment with cancer type-specific standard of care systemic cancer therapy is required. Standard treatment options must be considered and declined. Documentation of rationale is required if a subject is deemed unsuitable for standard therapy. 7. Subjects with < 3 brain metastases that have been treated with surgery or stereotactic radiosurgery are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for one month before protocol treatment. Patients with surgically resected brain metastases are eligible. 8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at screening. 9. Negative pregnancy test for women under 55 and all women who have had a menstrual period in the last 12 months. A pregnancy tests is not required for women who have had a bilateral oophorectomy or hysterectomy. 10. Women of child-bearing potential must agree to use adequate contraception (i.e., intrauterine device, hormonal barrier method of birth control; abstinence; tubal ligation or vasectomy) prior to study entry and for 12 months after treatment. Should a women become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately. 11. Participants must have organ and marrow function as defined below: 1. Leukocytes > 3,000/mcL 2. Absolute neutrophil count > 1,500/mcL 3. Platelets > 100,000/mcL 4. Hemoglobin > 9.0 g/dL 5. Total bilirubin within normal institutional limits except in participants with Gilbert's Syndrome who must have a total bilirubin < 3.0 mg/dL. 6. Serum AST (SGOT)/ALT (SGPT) < 2.5 x ULN 7. Calculated creatinine clearance (CrCl) >50 mL/min/1.73 m2for participants with creatinine levels above institutional normal (by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation). 8. INR or a PTT ≤1.5 X ULN unless the subject is receiving anticoagulant therapy. Subjects on anticoagulant therapy must have a PT or PTT within therapeutic range and no history of severe hemorrhage. 12. Serology:
• HIV antibody negative
• Hepatitis B antigen negative
• Hepatitis C antibody negative or HCV RNC negative (i.e., no current HCV infection) 13. More than four weeks must have elapsed since any prior systemic therapy at the time the patient receives the KK-LC-1 TCR T cells. Adverse events from prior therapy must have resolved to ≤ grade 1 according to CTCAE Version 5.0 or have demonstrated clinical stability and meet the eligibility criteria for the protocol. 14. Oxygen saturation ≥ 92% on room air. 15. Left ventricular ejection fraction ≥45% by echocardiogram or MUGA for patients 50 years of age or older.

Exclusion Criteria: Subjects who meet any of the following criteria will be excluded from

participation in this study: 1. Current treatment with another investigational agent. 2. History of severe allergic reactions to compounds of similar chemical or biologic composition to agents in used in study. 3. Uncontrolled intercurrent illness such as active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations at the time of treatment that would limit compliance with study requirements. 4. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with KK-LC-1 TCR T cells, breastfeeding should be discontinued if the mother is treated with KK-LC-1 TCR cells. The potential risks may also apply to other agents used in this study. 5. Participants with a systemic immunodeficiency including acquired deficiency such as HIV or primary immunodeficiency such as Severe Combined Immunodeficiency Disease are ineligible. The experimental treatment being evaluated in this protocol depends on an intact immune system. Participants who have decreased immune competence may be less responsive to the treatment. 6. Participants on immunosuppressive drugs including corticosteroids unless meeting criteria outlined in Section 6.1 (Prohibited Medications). 7. Subjects with HLA-A*01:01 damaging mutation or allele loss or other molecular resistance detected by clinical or research genomic profiling will not be eligible. 8. Participants with potentially severe autoimmune diseases such as Crohn's disease, ulcerative colitis, rheumatoid arthritis, autoimmune hepatitis, autoimmune pancreatitis, or systemic lupus erythematosus are not eligible. Patients with less severe autoimmune diseases such as hypothyroidism, vitiligo, and other minor autoimmune disorders are eligible. 9. Participants with prior or concurrent malignancy whose natural history or treatment is unlikely to interfere with the safety or efficacy assessments of the investigational regimen are eligible for this trial. Examples include, but are not limited to: 1. Carcinoma in situ 2. Cutaneous skin cancers requiring only local excision 3. Low grade non-muscle invasive bladder cancer 4. Low grade prostate cancer Participants with prior or concurrent malignancy that do not meet the above criteria are excluded. 10. Subjects who received a live vaccine within 30 days prior to enrollment are not eligible. 11. Determination by the Principal Investigator that participation is not in the best interest of the research subject or may jeopardize the safety of the subject or integrity of the clinical trial data.

Inclusion Criteria:

• Provision of signed and dated written ICF prior to any mandatory and non-mandatory study-specific procedures, sampling and analyses.
• Participant must be ≥18 years (≥ 19 years of age in South Korea) at the time of signing the informed consent. All genders are permitted.
• Histologically or cytologically confirmed locally advanced or metastatic NSCLC which is not amenable to curative therapy.
• Must have at least one documented sensitising EGFR mutation: exon19 deletion, L858R mutation, and/or T790M.
• Documented radiologic progression on first- or second-line treatment with osimertinib as the most recent anti-cancer therapy.
• Mandatory provision of FFPE tumour tissue.
• MET overexpression and/or amplification in tumour specimen collected following progression on prior osimertinib treatment.
• Measurable disease as defined by RECIST 1.1.
• Adequate haematological, liver, renal and cardiac functions, and coagulation parameters.
• ECOG performance status of 0 or 1.

Exclusion Criteria:

• Predominant squamous NSCLC, and small cell lung cancer.
• Prior or current treatment with a third-generation EGFR-TKI other than Osimertinib.
• Prior or current treatment with savolitinib or another MET inhibitors.
• Spinal cord compression or brain metastases, unless asymptomatic and are stable.
• History or active leptomeningeal carcinomatosis.
• Unresolved toxicities from any prior therapy greater than CTCAE Grade 1 and prior platinum-therapy related Grade 2 neuropathies with the exception of alopecia and haemoglobin ≥ 9.0 g/dL.
• Active/unstable cardiac diseases currently or within the last 6 months, clinically significant ECG abnormalities, and/or factors/medications that may affect QTc intervals.
• History of liver cirrhosis of any origin and clinical stage; or history of other serious liver disease or chronic disease with relevant liver involvement.
• Known serious active infection including, but not limited to, tuberculosis, or HIV, HBV or HCV or gastrointestinal disease.
• Receipt of live attenuated vaccine (including against COVID-19) within 30 days prior to the first dose of study intervention.
• Past medical history of ILD, drug-induced ILD, radiation pneumonitis, which required steroid treatment, or any evidence of clinically active ILD.
• Participants currently receiving medications or herbal supplements known to be strong inducers of cytochrome P450 (CYP)3A4 or strong inhibitors of CYP1A2.

Inclusion Criteria:

• Participants must have histologically or cytologically confirmed non-small cell lung cancer (NSCLC) which is stage IV or recurrent
• Participants must have received at least one line of anti-PD-1 or anti-PD-L1 therapy for any stage of NSCLC. Anti-PD-1 or anti-PD-L1 may have been given alone or in combination with other therapy
• Participants must have experienced disease progression (in the opinion of the treating physician) more than (>) 84 days following initiation (cycle 1 day 1) of their most recent anti-PD-1 or PD-L1 therapy
• Participants who received anti-PD-1 or anti-PD-L1 therapy for stage IV or recurrent disease, must have had a best response on anti-PD-1 or anti-PD-L1 therapy of stable, partial response or complete response (in the opinion of the treating physician)
• Participants who received neoadjuvant, adjuvant, and/or consolidation anti-PD-1 or anti-PD-L1 therapy as their only line of anti-PD-1 or anti-PD-L1 therapy must have experienced disease progression within (=<) 365 days from initiation (cycle 1 day 1) of anti-PD-1 or PD-L1 therapy
• Participants must have received platinum-based chemotherapy and experienced disease progression (in the opinion of the treating physician) during or after this regimen
• Participants with a known sensitizing mutation for which an Food and Drug Administration (FDA)-approved targeted therapy for NSCLC exists (e.g., EGFR, ALK, ROS1, BRAF, RET, NTRK, KRAS, HER2 and MET sensitizing mutations), must have previously received at least one of the approved therapy(s). Prior targeted therapy for participants with targetable alterations is allowed if all other eligibility criteria are also met
• Participants must be >= 18 years old
• Participants must be able to safely receive the investigational drug combination and the investigator's choice of standard of care regimens per the current FDA approved package insert(s), treating investigator's discretion, and institutional guidelines
• Participants must have Zubrod performance status of 0-2

Exclusion Criteria:

• Participants must not have received more than one line of anti-PD-1 or anti-PD-L1 for stage IV or recurrent disease
• Participants must not be receiving or planning to receive another investigational therapy during study participation

Inclusion Criteria:

• The participant (or legally acceptable representative if applicable) must provide written informed consent for the study. The participant may also provide consent for future unspecified research samples. However, the participant may participate in the study without participating in the future unspecified research sample collection. NOTE: Initial informed consent will remain valid throughout the 12-week period between surgical resection and study registration unless, in the opinion of the treating investigator, the participant experiences a significant change in medical or mental status.
• Males and females age ≥ 18 years at the time of consent.
• ECOG Performance Status of 0-1 within 28 days prior to registration.
• Patients must have undergone complete surgical resection of their stage I NSCLC between 4-12 weeks prior to registration and have negative surgical margins (R0).
• NOTE: Both squamous and non-squamous histologies are allowed into the study. Cancers with a histology of "adenosquamous" are considered a type of adenocarcinoma and thus "non-squamous histology".
• NOTE: Staging will be according to the AJCC 8th edition.
• Pathological tumor size must be 1.0 - 4.0 cm in greatest dimension. NOTE: According to AJCC 8th edition, subjects with lepidic predominant adenocarcinoma should be staged based on their invasive tumor size and not their total tumor size (i.e., subjects with lepidic predominant tumors whose invasive tumor size is less than 1 cm are not eligible, even if their total tumor size is 1.0 cm or greater).
• Surgery for this lung cancer must be completed at least 28 days prior to registration.
• Must have either previous NGS and PD-L1 results available using the Dako 22C3 antibody or have archival tissue of surgical specimen from current diagnosis available to perform analyses. If prior PD-L1 results with Dako 22C3 antibody are not available from a CLIA-accredited laboratory, subjects must be able to provide 5 x 5µm unstained slides for prospective analysis to be used for stratification. If NGS results are not available, subjects must be able to provide at least 10 x 10µm unstained and 1 x 4µm H&E slides from current diagnosis for future NGS and/or other genetic analyses.
• Demonstrate adequate organ function as defined in the protocol; all screening labs to be obtained within 28 days prior to registration.
• Females of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to registration. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. For subjects randomized to the pembrolizumab arm: If there is > 72 hours between the screening test and C1D1, another pregnancy test (urine or serum) must be performed and must be negative before the subject may start C1D1.
• NOTE: Females are considered of childbearing potential unless: they are postmenopausal; are surgically sterile; or they have a congenital or acquired condition that prevents childbearing. See Section 5.1.4 for definitions.
• NOTE: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
• A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
• Not a woman of childbearing potential (WOCBP) OR
• A WOCBP who is using a highly effective contraceptive method (failure rate of <1% per year), or is abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) during the intervention period and for at least 120 days after the last dose of study drug. The investigator should evaluate the potential for contraceptive method failure (i.e., noncompliance, recently initiated) in relationship to the first dose of study drug. See contraceptive guidance in Section 5.1.4 of the protocol.
• As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study

Exclusion Criteria:

• Current lung cancer is <1 cm or > 4 cm in size or is stage II, III, or IV.
• Patients with tumors that are known to harbor actionable EGFR mutations.
• Prior chemotherapy, radiation therapy, or immunotherapy for the treatment of this lung cancer.
• Has a known active additional malignancy that is progressing or has required active treatment within the past 3 years. NOTE: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma in situ, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
• Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
• Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines is allowed.
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.
• Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to randomization.
• Has had an allogenic tissue/solid organ transplant.
• Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
• Has an active infection requiring systemic therapy.
• Has a known history of Human Immunodeficiency Virus (HIV). Note: HIV testing is not required unless mandated by local health authority.
• Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Note: Hepatitis B and Hepatitis C testing is not required unless mandated by local health authority.
• Has active TB (Bacillus Tuberculosis) infection.
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.

Inclusion Criteria:

Participants eligible for inclusion in the study must meet all inclusion criteria within28 days of randomization into the study.
• Sign and date the Tissue Screening and Main Informed Consent Forms, prior to the start of any study-specific qualification procedures.
• Adults ≥18 years or the minimum legal adult age (whichever is greater) at the time of informed consent.
• Histologically documented NSCLC that meets all of the following criteria: 1. Stage IIIB or IIIC disease and not candidates for surgical resection or definitive chemoradiation, or Stage IV NSCLC disease at the time of randomization (based on the American Joint Committee on Cancer, Eighth Edition). Participants with early-stage NSCLC who have relapsed should be restaged during screening to ensure their eligibility for the study. 2. Documented negative test results for epidermal growth factor receptor (EGFR), lymphoma kinase (ALK), and proto-oncogene1 (ROS1) actionable genomic alterations based on analysis of tumor tissue. 3. No known actionable genomic alterations in neurotrophic tyrosine receptor kinase (NTRK), proto-oncogene B-raf (BRAF), rearranged during transfection (RET), mesenchymal-epithelial transition factor (MET), or other actionable driver kinases with locally approved therapies.
• Has provided a formalin-fixed tumor tissue sample for the measurement of trophoblast cell surface protein 2 (TROP2) protein expression and for the assessment of other exploratory biomarkers.
• Tumor has high programmed death receptor-1 (PD-L1) expression (TPS ≥50%) as determined by PD-L1 immunohistochemistry (IHC) 22C3 pharmDx assay by central testing (minimum of 6 slides).
• Has an adequate treatment washout period before Cycle 1 Day 1.
• Measurable disease based on local imaging assessment using RECIST Version 1.1.
• Has left ventricular ejection fraction (LVEF) ≥50% by either an echocardiogram (ECHO) or multigated acquisition scan (MUGA) within 28 days before randomization.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 at screening.
• Has a life expectancy of at least 3 months.
• Adequate bone marrow function within 7 days before randomization.

Exclusion Criteria:

• Has received prior systemic treatment for advanced or metastatic NSCLC.
• Has received prior treatment for NSCLC with any of the following, including in the adjuvanteoadjuvant setting: 1. Any agent, including an antibody-drug conjugate, containing a chemotherapeutic agent targeting topoisomerase I. 2. TROP2-targeted therapy. 3. Any anti-programmed death receptor-1 (PD-1), anti-PD-L1, or anti-PD-ligand 2 (L2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX40, CD137). 4. Any other immune checkpoint inhibitors. Participants who received adjuvant or neoadjuvant therapy OTHER than those listed above, are eligible if the adjuvanteoadjuvant therapy was completed at least 6 months prior to the diagnosis of advanced/metastatic disease.
• Has spinal cord compression or active and untreated central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable.
• Has received prior radiotherapy ≤4 weeks of start of study intervention or more than 30 Gy (unit of ionizing radiation dose in the International System of Units) to the lung within 6 months of Cycle 1 Day 1.
• History of another primary malignancy (beyond NSCLC) except for: 1. Malignancy treated with curative intent and with no known active disease ≥3 years before the first dose of study treatment and of low potential risk for recurrence. 2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. 3. Adequately treated carcinoma in situ without evidence of disease. 4. Participants with a history of prostate cancer (tumorode/metastasis stage) of Stage ≤T2cN0M0 without biochemical recurrence or progression and who in the opinion of the Investigator are not deemed to require active intervention.
• Has a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis including radiation pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
• Clinically severe pulmonary compromise, as judged by the investigator, resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder, or any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement or prior complete pneumonectomy.
• Uncontrolled or significant cardiovascular disease, including: 1. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) interval >470 msec regardless of sex (based on the average of the 12-lead electrocardiogram determination at screening). 2. Myocardial infarction within 6 months prior to randomization. 3. Uncontrolled angina pectoris within 6 months prior to randomization. 4. LVEF <50% by ECHO or MUGA scan within 28 days before randomization. 5. New York Heart Association Class 2 to 4 congestive heart failure (CHF) at screening. 6. Uncontrolled hypertension (resting systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg) within 28 days before randomization.Participants with a history of Class 2 to 4 CHF prior to screening, must have returned toClass 1 CHF and have LVEF ≥50% (by either an ECHO or MUGA scan within 28 days beforerandomization) in order to be eligible.
• Clinically significant corneal disease.
• Has received a live vaccine or live-attenuated vaccine (messenger ribonucleic acid and replication-incompetent adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first dose of study drug. For any participant receiving an approved severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) vaccine, please follow the vaccine label and/or local guidance.
• Active, known, or suspected autoimmune disease (has an active autoimmune disease that has required systemic treatment in the past 2 years).
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosage >10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy ≤7 days prior to the first dose of study drug.
• Has known human immunodeficiency virus (HIV) infection that is not well controlled.
• Has an active hepatitis or uncontrolled hepatitis B or active hepatitis C infection.
• Has an uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.
• Had an allogeneic tissue/solid organ transplant.
• Has a history of severe hypersensitivity reactions to either the drug or inactive ingredients (including but not limited to polysorbate 80) of Dato-DXd or pembrolizumab.

• Patients must have histologically or cytologically confirmed stage IV NSCLC (includes M1a, M1b, and M1c stage disease, AJCC 8th edition). Patients with Stage IIIB and IIIC disease are eligible if they are not candidates for combined chemotherapy and radiation; such cases should be discussed in a multidisciplinary tumor board.
• Eligible NSCLC tissue histologies will include squamous cell carcinoma (enrolled and treated in Arm 1), and nonsquamous histologies (e.g. adenocarcinoma, large cell carincoma, etc.; enrolled and treated in Arm 2). Patients with mixed squamous, e.g., adenosquamous, histology will be enrolled and treated on Study Arm 1. Patients with any evidence of Small Cell Carcinoma will be excluded from study participation.
• Patients may have ANY PD-L1 expression Tumor Proportion Score (TPS) status. Tissue testing for PD-L1 is strongly recommended. If PD-L1 expression TPS is unevaluable or the testing could not be completed, the patient may still be eligible.
• Patients must have measurable or non-measurable disease. The presence of malignant pleural fluid alone is sufficient to satisfy this eligibility criterion. Baseline imaging assessments and measurements used to evaluate all measurable or non-measurable sites of disease must be done within 4 weeks prior to study registration. NOTE: If patient receives pemetrexed, follow institutional guidelines to drain fluids.
• Patients must be ≥ 18 years of age.
• Patients must have an ECOG Performance Status of 0 to 2
• Patients must NOT have received the following:
• Prior systemic chemotherapy or immunotherapy for advanced metastatic NSCLC. Patients treated with any prior checkpoint inhibitors for metastatic lung cancer are ineligible. Chemotherapy and immunotherapy for non-metastatic disease (e.g. adjuvant therapy) or immunotherapy for locally advanced Stage III disease is allowed if at least 6 months have elapsed between the last dose of the prior therapy and study registration. Local therapy, e.g. palliative radiation, is allowed as long as a period of 7 days has passed between

  completion of local therapy and study registration. Registration prior to

  treatment during the 7 days is allowed. Palliative radiation must be to non-target lesions.
  • Methotrexate (MTX) given in low doses for non-malignant conditions with last dose at least 14 days prior to date of registration will be allowed. Other low dose chemotherapeutics for non-malignant conditions will be considered, but review by the study chair is required.
  • For Arm 1 (Squamous Lung Cancer): Patients must not have pre-existing peripheral neuropathy that is ≥ Grade 2 by CTCAE v.5.0. Patients must not have known sensitivity to any component of carboplatin or paclitaxel or nabpaclitaxel.
  • Patients with known EGFR mutations (except exon 20 insertion), BRAF mutations (V600), MET Exon14 skipping or ALK or ROS1 translocations that can be treated with oral tyrosine kinase inhibitors are excluded.
  • Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression. Patients with asymptomatic new (at screening) or progressive brain metastases (active brain metastases at screening) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy.
  • Patients are eligible if off steroids for at least 7 days prior to protocol treatment.
  • Palliative radiation to non-target lesions (bone metastasis) is allowed if patient develops symptoms.
  • Anticonvulsants are allowed.
  • Patients with asymptomatic, sub-centimeter brain metastasis who at the discretion of investigators do not need immediate CNS directed therapies are eligible.
  • Patients with prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
  • Patients must not have known pre-existing and clinically active interstitial lung disease, or a known history of (non-infectious) pneumonitis that required steroids, or current pneumonitis.
  • Patients must not have significant gastrointestinal disorders with diarrhea as a major symptom (e.g. Crohn's disease, malabsorption, etc.)
  • Patients must not have history of auto-immune condition requiring ongoing or intermittent systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  • Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class II or better.
  • Patients must not have any other concomitant serious illness or organ system dysfunction that in the opinion of the investigator would either compromise patient safety or interfere with the evaluation of the safety of the study drug.
  • Patients must not receive any other investigational agents during the course of therapy.
  • Women must not be pregnant or breast-feeding due to potential harm to the fetus or infant from cytotoxic chemotherapy and the unknown risk of MK-3475 (pembrolizumab). Patients must also not expect to conceive or father children from the time of registration, while on study treatment, and until at least 120 days after the last dose of study treatment.All females of childbearing potential must have a blood test or urine study within 72hours prior to registration to rule out pregnancy.A female of childbearing potential is any woman, regardless of sexual orientation orwhether they have undergone tubal ligation, who meets the following criteria: 1) hasachieved menarche at some point; 2) has not undergone a hysterectomy or bilateraloophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancertherapy does not rule out childbearing potential) for at least 24 consecutive months(i.e., has had menses at any time in the preceding 24 consecutive months).
  • Women of childbearing potential and sexually active males must use an accepted and effective method of contraception or abstain from sexual intercourse from time of registration, while on study treatment, and continue for 120 days after the last dose of study treatment.
  • Patient must have the ability to understand and the willingness to sign a written informed consent document.
  • Patients must meet the following laboratory values within 14 days of randomization:
  • ANC ≥ 1500/mm3
  • Platelets ≥ 100,000/mm3
  • Hgb > 8 g/dL (Note: Patient may be transfused to meet this criteria)
  • PT/INR ≤ 1.5
  • Or if patient on therapeutic anticoagulation with Warfarin, PT/INR ≤ 3.0
  • Patients must have adequate liver function as determined by the following tests obtained within 14 days of randomization:
  • Total Bilirubin ≤ 1.5 mg/dL
  • SGOT (AST) < 5X upper limit of normal (ULN)
  • SGPT (ALT) < 5X upper limit of normal ULN)
  • Patients must have adequate renal function as determined by the following tests obtained within 14 days prior to randomization:Calculated creatinine clearance ≥ 45ml/min to be eligible to receive pemetrexed Serumcreatinine ≤ 1.5X institutional upper limit of normal (ULN)
  • Patients must not have a known history of active tuberculosis (TB).
  • Patients must not have a diagnosis of immunodeficiency or receive systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of protocol treatment.
  • Patients must not have received a live vaccine within 30 days prior to randomization. Seasonal flu vaccines that do not contain live virus are permitted. COVID-19 vaccination per guidelines for cancer patients is permitted and encouraged.
  • Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
  • For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable or on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.Head and Neck Cancer (Arm 3)
  • Patient must have histologically confirmed recurrent/metastatic squamous cell carcinoma of the head and neck (HNSCC) (excluding SCC of salivary glands, nasopharynx and skin) that is considered incurable by local therapies. The eligible primary tumor locations include oropharynx, oral cavity, hypopharynx, and larynx. Unknown primary site will also be considered eligible.
  • Patients may have ANY PD-L1 expression Tumor Proportion Score (CPS) status. Tissue testing for PD-L1 IHC on samples demonstrating recurrent/metastatic disease is strongly recommended, though testing may be performed on initial diagnostic specimens. If PD-L1 expression CPS is unevaluable or the testing could not be completed, the patient will still be considered eligible.
  • Tumor expression of p16 by immunohistochemistry is highly desirable for patients with Oropharyngeal primaries. Positive p16 expression is defined as strong and diffuse nuclear and cytoplasmic staining in 70% or more of the tumor cells. If HPV status was previously tested using this method, no additional testing is required. If results are not available or are not possible patient will still be considered eligible.Note: Oral cavity, hypopharynx, and larynx cancer are not required to undergo HPV testingby p16 IHC as by convention these tumor locations are assumed to be HPV negative.
  • Patients must have measurable or non-measureable disease. The presence of malignant pleural fluid or bone disease alone is sufficient to satisfy this eligibility criterion. Baseline imaging assessments and measurements used to evaluate all measurable or non-measurable sites of disease must be done within 4 weeks prior to study registration. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
  • Patient must be ≥ 18 years of age.
  • Patient must have an ECOG performance status 0-2.
  • Patients must NOT have received the following:
  • Prior systemic chemotherapy or immunotherapy for recurrent/metastatic head and neck squamous cell carcinoma. Patients treated with any prior checkpoint inhibitors for recurrent/metastatic head and neck cancer are ineligible. NOTE: Patients who have received prior chemotherapy or cetuximab with radiation for curative intent treatment of locally advanced head and neck cancer whose disease has progressed after at least 6 months will be eligible.
  • Methotrexate (MTX) given in low doses for non-malignant conditions with last dose at least 14 days prior to date of registration will be allowed. Other low dose chemotherapeutics for non-malignant conditions will be considered, but review by the study chair is required.
  • Patients who have endocrinopathies but are now stable on hormone supplementation and/or a daily prednisone dose of ≤ 10 mg (or equivalent doses of another glucocorticoid), will be permitted on this trial.
  • Patient must not have a severe infection within 4 weeks prior to randomization, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia. Patients must not have active tuberculosis.
  • Patient must not have a history of non-infectious pneumonitis requiring steroids at doses greater than or equal to 10 mg per day of prednisone or the equivalent on first line immunotherapy.
  • Patient must not have a history of solid organ transplantation or stem-cell transplant.
  • Patient must not be on immunosuppressive medication within 7 days prior to randomization except for: intranasal, inhaled, or topical steroids, local steroid injection, systemic corticosteroids at doses less than or equal to 10 mg per day of prednisone or the equivalent, or steroids used as premedication for hypersensitivity reactions.
  • Patient must not have an active autoimmune disease that requires systemic treatment within 2 years prior to randomization. Patients who are receiving replacement therapy for adrenal or pituitary insufficiency will not be excluded.
  • Patient must not have had a severe hypersensitivity reaction to any of the drug components used on this protocol or to chimeric or humanized antibodies or fusion proteins.
  • Patient must not have received any live vaccine within 30 days prior to randomization and while participating in the study. Live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Patients are permitted to receive inactivated vaccines and any non-live vaccines including those for the seasonal influenza and COVID-19 (Note: intranasal influenza vaccines, such as Flu-Mist® are live attenuated vaccines and are not allowed). If possible, it is recommended to separate study drug administration from vaccine administration by about a week (primarily, in order to minimize an overlap of adverse events).
  • Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used.All patients of childbearing potential must have a blood test or urine study within 14days prior to randomization to rule out pregnancy.A patient of childbearing potential is defined as anyone, regardless of sexualorientation or whether they have undergone tubal ligation, who meets the followingcriteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy orbilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea followingcancer therapy does not rule out childbearing potential) for at least 24 consecutivemonths (i.e., has had menses at any time in the preceding 24 consecutive months).
  • Patients must not expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the study and for 120 days after last dose of study therapy.
  • Patient must have the ability to understand and the willingness to sign a written informed consent document.
  • Patient must have adequate organ and marrow function as defined below (these labs must be obtained ≤ 14 days prior to protocol randomization):
  • Absolute neutrophil count (ANC) ≥ 1,500/mcL
  • Platelets ≥ 100,000/mcL
  • Hgb > 8 g/dL (Note: Patient may be transfused to meet this criteria)
  • Total bilirubin ≤1.5xULN OR Direct bilirubin ≤ULN for subjects with total bilirubin levels >1.5xULN
  • AST (SGOT)/ALT (SGPT) ≤ 2.5 × institutional ULN (< 5.0 x institutional ULN if hepatic metastases present)
  • Creatinine ≤ 1.5 x institutional ULN OR Measured or Calculated Creatinine Clearance ≥60 mL/min for subject with creatinine levels >1.5x institutional ULN
  • PT/INR ≤ 1.5
  • Or if patient on therapeutic anticoagulation with Warfarin, PT/INR ≤ 3.0
  • Patients with uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL) must have their calcium levels corrected prior to randomization.
  • Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of randomization are eligible for this trial.
  • For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
  • Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
  • Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression. Patients must not have untreated brain metastases or leptomeningeal disease.
  • Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
  • Patient must not have significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to randomization, or unstable arrhythmia or unstable angina at the time of randomization.
  • Patient must not receive any other chemotherapy, immunotherapy, antitumor hormonal therapy (excluding contraceptives and replacement steroids), radiation therapy, or experimental medications while on protocol treatment. Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) amenable to palliative radiotherapy should be treated prior to randomization and patients must be recovered from the effects of radiation (there is no required minimum recovery period).
  • Patient must not have any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of the agents used in this protocol, may affect the interpretation of the results, or may render the patient at high risk from treatment complications.

Inclusion Criteria:

• Participants at least 18 years of age
• Locally advanced and unresectable NSCLC, not amenable to curative therapy, or metastatic disease
• Histologically documented non-squamous NSCLC with HER2 mutation in exons 19 or 20 by tissue NGS or ctDNA
• Treatment-naïve for palliative intent systemic therapy for locally advanced or metastatic disease
• Left ventricular ejection fraction (LVEF) ≥ 50%
• Measurable disease assessed by Investigator based on RECIST 1.1
• Protocol-defined adequate organ function including cardiac, renal, hepatic function
• ECOG 0-1
• Having tumour tissue available for central testing

Exclusion Criteria:

• Tumors with targetable alterations to EGFR (or other targetable mutations including but not limited to ALK, if routinely tested as a targetable alteration with approved available therapy)
• Any untreated brain metastases, including asymptomatic or clinically inactive brain metastases
• Active autoimmune or inflammatory disorders
• Medical history of myocardial infarction within 6 months prior to randomization
• History of non-infectious pneumonitis/ILD, current or suspected ILD
• Lung-specific intercurrent clinical significant severe illness
• Contraindication to platinum-based doublet chemotherapy or pembrolizumab

Inclusion Criteria:

• At least 18 years of age
• Histologically confirmed or clinically diagnosed non-small cell lung cancer where the plan is for definitive treatment that includes radiation
• Able to give written informed consent

Exclusion Criteria:

• Pregnant or breast-feeding
• Prior treatment with anthracyclines
• Radiation treatment not expected to involve any heart exposure as determined by treating provider
• ECOG performance status greater than 2
• Vulnerable patients, including pregnant women and prisoners
• Contraindication to rest/vasodilator stress PET/CT, including: asthma with ongoing wheezing at time of enrollment; known Mobitz Type II AV block, 3rd degree AV block, or sick sinus syndrom, without a pacemaker; systolic blood pressure less than 90mmHg; known hypersensitivity to Regadenoson and adenosine; profound sinus bradycardia (heart rate less than 40bpm).