A Pilot Phase II Study of Maintenance Cabozantinib Plus Pembrolizumab for Patients With Metastatic Squamous Non-Small Cell Lung Cancer (sqNSCLC)

Inclusion Criteria:

1. Written informed consent and HIPAA authorization for release of personal healthinformation prior to registration. NOTE: HIPAA authorization may be included in theinformed consent or obtained separately.

2. Age ≥ 18 years at the time of consent.

3. ECOG Performance Status of 0, 1, or 2 within 28 days prior to registration

4. Life expectancy of 6 months or greater as determined by the site investigator.

5. Subjects with histologically or cytologically confirmed squamous non-small cell lungcancer (sqNSCLC).

6. Subjects with stage IV NSCLC as defined by American Joint Committee on Cancer (AJCC) 8th Edition who have not received prior therapy for stage IV NSCLC. Patients withlocally advanced or recurrent disease who are candidates for first-line inductionsystemic therapies for stage IV NSCLC are also allowed.

• Only patients with disease control, defined as complete response (CR), partialresponse (PR), or stable disease (SD) to induction therapy will be allowed toreceive maintenance cabozantinib plus pembrolizumab arm of trial. Patients who haveprogression of disease (POD) following induction therapy will proceed to second-linetherapy of local clinician's choice. Only those patients who proceed to maintenancecabozantinib and pembrolizumab therapy will be evaluable for primary and secondaryobjectives.

7. Subjects whose tumors have been tested for PD-L1 expression.

8. Demonstrate adequate organ function as defined below. All screening labs to beobtained within 14 days prior to registration.

• White blood cell (WBC): ≥ 2.5K/uL

• Absolute Neutrophil Count (ANC): ≥ 1,500/uL without the support of Filgrastimor ≥ 1,000/L in subjects with constitutional neutropenia

• Hemoglobin (Hgb): ≥ 9 g/dL

• Platelets (Plt): ≥ 100,000/µL without transfusion.

• Serum creatinine: ≤ 1.5 mg/dL

• Calculated creatine clearance: ≥ 40 mL/min; for subjects with serum creatinine > 1.5 mg/dL

• Urine protein/creatinine ratio (UPCR): ≤ 1 mg/mg (≤ 113.2 mg/mmol), or 24-hurine protein ≤ 1 g

• Total Bilirubin or Direct Bilirubin: ≤ 1.5 × upper limit of normal (ULN) or ≤ 3 × ULN for subjects with Gilbert's disease, ≤ ULN for subjects with totalbilirubin levels > 1.5 x ULN

• Aspartate aminotransferase (AST): ≤ 3 × ULN or ≤ 5 x ULN for subjects withknown hepatic metastasis

• Alanine aminotransferase (ALT): ≤ 3 × ULN or ≤ 5 x ULN for subjects with knownhepatic metastasis

• Alkaline phosphatase (ALP): ≤ 3 × ULN or ≤ 5 x ULN with documented bonemetastases.

• Serum albumin: ≥ 2.8 g/dl

• International Normalized Ratio (INR) : ≤ 1.3 × ULN; For subjects receivingwarfarin or LMWH, the subjects must, in the site investigator's opinion, beclinically stable with no evidence of active bleeding while receivinganticoagulant therapy. The INR for these subjects may exceed 1.3 × ULN if thatis the goal of anticoagulant therapy.

9. Recovery to baseline or ≤ Grade 1 CTCAE v5.0 from toxicities related to any priortreatments, unless AE(s) are clinically nonsignificant and/or stable on supportivetherapy.

10. Sexually active fertile subjects and their partners must agree to use medicallyaccepted methods of contraception (e.g., barrier methods, including male condom,female condom, or diaphragm with spermicidal gel) during the course of the study andfor 4 months after the last dose of cabozantinib and 4 months after the last dose ofpembrolizumab.

11. Females of childbearing potential must have a negative serum pregnancy test within 3days prior to registration. Female subjects of childbearing potential must not bepregnant at screening. Female subjects are considered to be of childbearingpotential unless one of the following criteria is met: documented permanentsterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) ordocumented postmenopausal status (defined as 12 months of amenorrhea in a woman > 45years-of-age in the absence of other biological or physiological causes. Inaddition, females < 55 years-of-age must have a serum follicle stimulating (FSH)level > 40 mIU/mL to confirm menopause). Note: Documentation may include review ofmedical records, medical examinations, or medical history interview by study site.

12. As determined by the enrolling physician or protocol designee, subjects should becapable of understanding and complying with the protocol requirements and must havesigned the informed consent document.

13. Willingness and ability to comply with scheduled visits, treatment plans, laboratorytests, and other study procedures.

Exclusion Criteria:

1. Active infection requiring systemic therapy.

2. Pregnant or breastfeeding. NOTE: breast milk cannot be stored for future use whilethe mother is being treated on study.

3. Prior treatment with cabozantinib.

4. Receipt of any type of small molecule kinase inhibitor (including investigationalkinase inhibitor) within 2 weeks before first dose of study treatment.

5. Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy (including investigational) within 4 weeks before first dose of study treatment.

6. Radiation therapy for bone metastasis within 2 weeks or any other radiation therapywithin 4 weeks before first dose of study treatment. Systemic treatment withradionuclides within 6 weeks before first dose of study treatment. Subjects withclinically relevant ongoing complications from prior radiation therapy are noteligible.

7. Radiologically documented evidence of major blood vessel invasion or encasement bycancer.

8. Radiographic evidence of central cavitating pulmonary lesion(s) or knownendotracheal or endobronchial disease manifestation. Patients with peripheralcavitary lesions prior to induction therapy may be enrolled but will only be allowedto continue maintenance therapy on trial if they have disease control and resolutionof cavitation after induction therapy. The development of cavitation recurrence ornew intra-thoracic cavitations during maintenance therapy will require Cabozantinibto be stopped during maintenance therapy.

9. Patients with targetable genomic aberrations for which FDA-approved targeted therapyis available (e.g. ROS1, MET exon 14 skipping mutations, BRAFV600E, ALK, EGFR, ALK,RET, and NTRK fusions).

10. The subject has uncontrolled, significant intercurrent or recent illness including,but not limited to, the following conditions:

11. Cardiovascular disorders:

• i. Congestive heart failure New York Heart Association Class 3 or 4, unstableangina pectoris, serious cardiac arrhythmias.
• ii. Uncontrolled hypertension defined as sustained blood pressure (BP) > 140mm Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensivetreatment.
• iii. Stroke (including transient ischemic attack [TIA]), myocardialinfarction (MI), or other ischemic event, or thromboembolic event (e.g., deepvenous thrombosis, pulmonary embolism) within 6 months before first dose ofstudy treatment.
• iv. Subjects with a diagnosis of incidental, subsegmental PE or DVT within 6 months are allowed if stable, asymptomatic, and treated with a stabledose of permitted anticoagulation for at least 1 week before first dose ofstudy treatment.

2. Gastrointestinal (GI) disorders including those associated with a high risk ofperforation or fistula formation:

• i. The subject has evidence of tumor invading the GI tract, active pepticulcer disease, inflammatory bowel disease (e.g., Crohn's disease),diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acutepancreatitis, acute obstruction of the pancreatic duct or common bile duct, orgastric outlet obstruction.
• ii. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominalabscess within 6 months before first dose of study treatment. Note: Completehealing of an intra-abdominal abscess must be confirmed before first dose ofstudy treatment.

3. Other clinically significant disorders that would preclude safe studyparticipation.

• i. Serious non-healing wound/ulcer/bone fracture.
• ii. Malabsorption syndrome.
• iii. Uncompensated/symptomatic hypothyroidism.
• iv. Moderate to severe hepatic impairment (Child-Pugh B or C).
• v. Requirement for hemodialysis or peritoneal dialysis.
• vi. Any condition requiring systemic treatment with either steroid therapy (>10 mg daily prednisone equivalent) or any other form ofimmunosuppressive therapy within 2 weeks prior to first dose of studytreatment. Note: Inhaled, intranasal, intra-articular, or topical steroidsare permitted. Adrenal replacement steroid doses > 10 mg daily prednisoneequivalent are permitted. Transient short-term use of systemiccorticosteroids for allergic conditions (e.g., contrast allergy) is alsoallowed.

10. Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 ml) of red blood, or other history of significant bleeding (e.g., pulmonary hemorrhage) within 12 weeks before first dose of study treatment.

11. Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks prior to first dose of study treatment after radiotherapy or at least 4 weeks prior to first dose of study treatment after major surgery (e.g., removal or biopsy of brain metastasis). Subjects must have complete wound healing from major surgery or minor surgery before first dose of study treatment. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of first dose of study treatment.

12. Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or platelet inhibitors (e.g., clopidogrel). Allowed anticoagulants are the following:

• a. Prophylactic use of low-dose aspirin for cardio-protection (per local applicableguidelines) and low-dose low molecular weight heparins (LMWH).

• b. Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitorsrivaroxaban, edoxaban, or apixaban in subjects without known brain metastases whoare on a stable dose of the anticoagulant for at least 1 week before first dose ofstudy treatment without clinically significant hemorrhagic complications from theanticoagulation regimen or the tumor.

13. Administration of a live, attenuated vaccine within 30 days before first dose ofstudy treatment.

14. The subject has uncontrolled, significant intercurrent or recent illness,including, but not limited to, an active or history of autoimmune disease or immunedeficiency; idiopathic pulmonary fibrosis, organizing pneumonia, pneumonitis; activeinfection requiring systemic treatment, infection with human immunodeficiency virus (HIV), AIDS-related illness, acute or chronic hepatitis B or C infection, positivetest for tuberculosis, moderate to severe hepatic impairment (Child-Pugh B or C).

15. Previously identified allergy or hypersensitivity to components of the studytreatment formulations or history of severe infusion-related reactions to monoclonalantibodies. Subjects with rare hereditary problems of galactose intolerance, theLapp lactase deficiency or glucose-galactose malabsorption are also excluded.

16. Any other active malignancy at time of first dose of study treatment ordiagnosis of another malignancy within 3 years prior to first dose of studytreatment that requires active treatment, except for locally curable cancers thathave been apparently cured, such as basal or squamous cell skin cancer, superficialbladder cancer, or carcinoma in situ of the prostate, cervix, or breast.

17. Major surgery (e.g., laparoscopic nephrectomy, GI surgery, removal or biopsy ofbrain metastasis) within 2 weeks before first dose of study treatment. Minorsurgeries within 10 days before first dose of study treatment. Subjects must havecomplete wound healing from major surgery or minor surgery before first dose ofstudy treatment. Subjects with clinically relevant ongoing complications from priorsurgery are not eligible. a. NOTE: Hepatic biliary stent placement, PleurX catheter, port placement, ureteralstent or other minor surgeries are allowed. NOTE: Subject must have adequatelyrecovered from the toxicity and/or complications of major surgery prior to studyregistration, as determined by the treating physician.

18. Previously received a solid organ transplant or allogeneic progenitor/stem celltransplant.

19. Previous exposure or known allergy to cabozantinib or any of its excipients.

20. Inability to swallow tablets or unwillingness or inability to receive IVadministration.

21. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms perelectrocardiogram (ECG) within 14 days before first dose of study treatment.Furthermore, subjects with a history of additional risk factors for torsades depointes (e.g., long QT syndrome) are also excluded [add reference for Fridericiaformula]. a. Note: If a single ECG shows a QTcF with an absolute value > 500 ms, twoadditional ECGs at intervals of approximately 3 min must be performed within 30 minafter the initial ECG, and the average of these three consecutive results for QTcFwill be used to determine eligibility.

22. Other severe acute or chronic medical or psychiatric condition or laboratoryabnormality that may increase the risk associated with study participation orinvestigational product administration, interfere with protocol compliance, or mayinterfere with the interpretation of study results and, in the judgment of theinvestigator, would make the subject inappropriate for enrollment in this study.

23. Any mental or medical condition that prevents the subject from giving informedconsent or participating in the trial.