Phase 2 Trial of Neoadjuvant KRAS G12C Directed Therapy With Adagrasib (MRTX849) With or Without Nivolumab in Resectable Non-Small Cell Lung Cancer (Neo-KAN)
Phase 2 Trial of Neoadjuvant KRAS G12C Directed Therapy With Adagrasib (MRTX849) With or Without Nivolumab in Resectable Non-Small Cell Lung Cancer (Neo-KAN)
This is an open label phase 2 clinical trial evaluating the clinical safety, feasibility and efficacy of neoadjuvant Adagrasib alone or in combination with nivolumab in patients with NSCLC with KRAS G12C mutation.
Approximately 30% of patients with non-small cell lung cancer (NSCLC) present with resectable disease, but following surgery, the majority will experience relapse and death from the cancer. Despite significant advances in therapy for advanced NSCLC, no new systemic neoadjuvant therapies have been approved for resectable NSCLC without an EGFR driver mutation in over 15 years, and these patients are in critical need of new treatments to improve rates of cure. Currently, the standard approach for resectable stage II and III disease is 3-4 cycles of pre- or postoperative chemotherapy, which provides an absolute 5-year survival benefit of only 5% over surgery alone.
Neoadjuvant systemic therapy provides an opportunity to improve outcomes with surgery at a similar rate to adjuvant therapy, and is a more useful platform for advancing the development of new targeted and combination therapies. Pathologic complete response (pCR) and major pathologic response (MPR, ≤10% residual viable tumor) in the resected specimen serve as surrogate endpoints for event-free and overall survival, and are useful early efficacy endpoints to accelerate drug development. In resectable NSCLC, the rates of pCR and MPR with neoadjuvant immunotherapy alone are about 10% and 45% as compared to 4% and 20% with current standard of care chemotherapy. The recent approval of osimertinib in resected EGFR-mutated NSCLC has demonstrated the efficacy of targeted therapy in resectable disease, but is only available to a small minority of NSCLC patients.
KRAS is the most commonly mutated oncogene in cancer representing a vast unmet clinical need, particularly in NSCLC where it is associated with smoking history and mutated in 30% of lung adenocarcinomas. Activating KRAS mutations promote signaling pathways for growth, survival and differentiation. The most common mutant allele is KRAS G12C, present in 1 in 8 patients with NSCLC (12.5%), and represents an aggressive NSCLC phenotype with significantly higher risk of recurrence following resection in stage I-III disease.
Adagrasib is a novel small molecule inhibitor of KRAS G12C producing potent inhibition of KRAS-dependent signal transduction with high selectivity. Adagrasib has shown promise in advanced NSCLC, with 45% confirmed objective response rate and 96% disease control rate in the phase 1/2 KRYSTAL study.
Finally, the investigators anticipate enhanced efficacy of Adagrasib in combination with immune checkpoint blockade. Emerging clinical data suggests that Adagrasib reconditions the tumor immune microenvironment to become more immune-sensitive (e.g. in immune "cold" STK11 co-mutated tumors), and combination treatment with anti-PD-1 therapy resulted in increased durable responses compared to either agent alone in a murine model. Adagrasib is well-tolerated and has been safely combined with anti-PD1 therapy in a phase I trial. This will be the first study to bring this combination forward in resectable lung cancer.
This phase 2 clinical trial investigates the role of targeted KRAS G12C inhibition with and without the anti-PD-1 agent nivolumab in resectable NSCLC
Inclusion Criteria:
Age ≥18 years
Histologically confirmed diagnosis of NSCLC (squamous or nonsquamous) with KRAS G12C mutation.
Stage IB-IIIA NSCLC
Primary resection option for potential cure as assessed by a faculty surgeon at treating institution.
ECOG performance status 0-1 (See Appendix B)
Adequate organ function within the screening period as follows:
Pulmonary Function Testing to include DLCO must be performed to determine feasibility of surgical resection.
Women of child-bearing potential (WOCBP):
Completed informed consent process, including signing IRB/EC-approved informed consent form.
Willing and able to comply with clinical trial instructions and requirements. Subjects must be competent to report AEs, understand the drug dosing schedule, and use of medications to control AEs.
Exclusion Criteria:
Patients presenting with any of the following will not be included in the study:
NSCLC not amenable to curative intent resection based on evaluation by faculty surgeon at treating institution.
Prior systemic treatment for lung cancer including chemotherapy, immune checkpoint inhibitor therapy, or a therapy targeting KRAS G12C mutation.
Prior thoracic radiation.
Any concurrent malignancies for which active therapy is being received.
Brain metastases at time of screening.
Active or prior documented autoimmune or inflammatory disease as follows (Arm B only):
Systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration (Arm B only). Inhaled or topical steroids are permitted.
Major surgery within 4 weeks prior to first dose of study treatment.
History of allogeneic transplant or primary immunodeficiency.
Uncontrolled human immunodeficiency virus (HIV) infection or acute or chronic hepatitis B or C infection.
Any of the following cardiac abnormalities:
Ongoing need for a medication with any of the following characteristics that cannot be switched to alternative treatment prior to study entry (see Appendix D): known risk of Torsades de Pointes; substrate of CYP3A with narrow therapeutic index; strong inducer or inhibitor of CYP3A and/or P-gp; strong inhibitor of BCRP; and proton pump inhibitors.
History of stroke or transient ischemic attack within 6 months prior to first dose of study treatment.
History of intestinal disease or major gastric surgery likely to alter absorption of study treatment or inability to swallow oral medications.
Underlying medical conditions that, in the Investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity or adverse events.
Women who are pregnant or nursing.
Prisoners or subjects who are involuntarily incarcerated or compulsorily detained for treatment of either a psychiatric or physical (e.g. infectious disease) illness.
Receipt of a live vaccine within 30 days prior to first dose of study treatment.