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

Eligibility Criteria

• 1. Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed 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 lung cancer (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 with locally advanced or recurrent disease who are candidates for first-line induction systemic therapies for stage IV NSCLC are also allowed.
• 7. Subjects whose tumors have been tested for PD-L1 expression.
• 8. Demonstrate adequate organ function as defined below. All screening labs to be obtained within 14 days prior to registration.
• * 1.3 × ULN; For subjects receiving warfarin or LMWH, the subjects must, in the site investigator's opinion, be clinically stable with no evidence of active bleeding while receiving anticoagulant therapy. The INR for these subjects may exceed 1.3 × ULN if that is the goal of anticoagulant therapy.
• 9. Recovery to baseline or ≤ Grade 1 CTCAE v5.0 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy.
• 10. Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception (e.g., barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 4 months after the last dose of cabozantinib and 4 months after the last dose of pembrolizumab.
• 11. Females of childbearing potential must have a negative serum pregnancy test within 3 days prior to registration. Female subjects of childbearing potential must not be pregnant at screening. Female subjects are considered to be of childbearing potential unless one of the following criteria is met: documented permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined as 12 months of amenorrhea in a woman \> 45 years-of-age in the absence of other biological or physiological causes. In addition, females \< 55 years-of-age must have a serum follicle stimulating (FSH) level \> 40 mIU/mL to confirm menopause). Note: Documentation may include review of medical records, medical examinations, or medical history interview by study site.
• 12. As determined by the enrolling physician or protocol designee, subjects should be capable of understanding and complying with the protocol requirements and must have signed the informed consent document.
• 13. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
• 1. Active infection requiring systemic therapy.
• 2. Pregnant or breastfeeding. NOTE: breast milk cannot be stored for future use while the mother is being treated on study.
• 3. Prior treatment with cabozantinib.
• 4. Receipt of any type of small molecule kinase inhibitor (including investigational kinase 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 therapy within 4 weeks before first dose of study treatment. Systemic treatment with radionuclides within 6 weeks before first dose of study treatment. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible.
• 7. Radiologically documented evidence of major blood vessel invasion or encasement by cancer.
• 8. Radiographic evidence of central cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease manifestation. Patients with peripheral cavitary lesions prior to induction therapy may be enrolled but will only be allowed to continue maintenance therapy on trial if they have disease control and resolution of cavitation after induction therapy. The development of cavitation recurrence or new intra-thoracic cavitations during maintenance therapy will require Cabozantinib to be stopped during maintenance therapy.
• 9. Patients with targetable genomic aberrations for which FDA-approved targeted therapy is 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:
• 1. Cardiovascular disorders:
• 1. Note: Inhaled, intranasal, intra-articular, or topical steroids are permitted. Adrenal replacement steroid doses \> 10 mg daily prednisone equivalent are permitted. Transient short-term use of systemic corticosteroids for allergic conditions (e.g., contrast allergy) is also allowed.
• 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:
• 1. Prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH).
• 2. Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases who are on a stable dose of the anticoagulant for at least 1 week before first dose of study treatment without clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor.
• 13. Administration of a live, attenuated vaccine within 30 days before first dose of study treatment.
• 14. The subject has uncontrolled, significant intercurrent or recent illness, including, but not limited to, an active or history of autoimmune disease or immune deficiency; idiopathic pulmonary fibrosis, organizing pneumonia, pneumonitis; active infection requiring systemic treatment, infection with human immunodeficiency virus (HIV), AIDS-related illness, acute or chronic hepatitis B or C infection, positive test for tuberculosis, moderate to severe hepatic impairment (Child-Pugh B or C).
• 15. Previously identified allergy or hypersensitivity to components of the study treatment formulations or history of severe infusion-related reactions to monoclonal antibodies. Subjects with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption are also excluded.
• 16. Any other active malignancy at time of first dose of study treatment or diagnosis of another malignancy within 3 years prior to first dose of study treatment that requires active treatment, except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
• 17. Major surgery (e.g., laparoscopic nephrectomy, GI surgery, removal or biopsy of brain metastasis) within 2 weeks before first dose of study treatment. Minor surgeries within 10 days before first dose of study treatment. Subjects must have complete wound healing from major surgery or minor surgery before first dose of study treatment. Subjects with clinically relevant ongoing complications from prior surgery are not eligible.
• 18. Previously received a solid organ transplant or allogeneic progenitor/stem cell transplant.
• 19. Previous exposure or known allergy to cabozantinib or any of its excipients.
• 20. Inability to swallow tablets or unwillingness or inability to receive IV administration.
• 21. Corrected QT interval calculated by the Fridericia formula (QTcF) \> 500 ms per electrocardiogram (ECG) within 14 days before first dose of study treatment. Furthermore, subjects with a history of additional risk factors for torsades de pointes (e.g., long QT syndrome) are also excluded \[add reference for Fridericia formula\].
• 22. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration, interfere with protocol compliance, or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for enrollment in this study.
• 23. Any mental or medical condition that prevents the subject from giving informed consent or participating in the trial.