Phase 2 trial of neoadjuvant KRAS G12C directed therapy in resectable NSCLC

2022

Kristen Marrone, MD

Johns Hopkins School of Medicine

Baltimore

Around one in three patients with non-small cell lung cancer are diagnosed with early-stage disease, where surgery is offered as curative therapy. Unfortunately, the cancer can recur in 50%-60% of patients. The rate of recurrence is higher in patients whose tumors have certain mutations, such as mutations in the KRAS gene. Dr. Marrone and her team will be conducting a phase 2 trial to test whether treatment with a KRAS G12C blocking drug, adagrasib, given as a single drug or in combination with an immunotherapy drug, nivolumab, before a patient undergoes surgery can delay or prevent recurrence in patients whose tumors have a KRAS G12C mutation.

Research Summary

Although one in three patients diagnosed with non- small cell lung cancer (NSCLC) are found to have potentially curable earlier stage disease, for many the cancer will return. Rates of cancer returning are higher in patients whose tumors have certain mutations, such as KRAS. Immunotherapy with immune checkpoint inhibitors has improved survival for patients with later stages of NSCLC and around the time of surgery. Targeted therapies for KRAS are also improving outcomes for patients with advanced NSCLC. The goal of this study is to evaluate if immunotherapy alone or in combination with a targeted pill for a specific KRAS mutation called G12C is safe and can eliminate cancer cells when given prior to surgery for earlier stage NSCLC. Using immunotherapy and targeted therapies in early stage NSCLC may increase rates of cure compared to surgery and chemotherapy alone.

It is important to understand how and why this therapy may improve cure rates in early stage KRAS mutated NSCLC. Therefore, we will also evaluate the quantity and quality of the immune response with this clinical trial therapy. By evaluating the T cells in the tumors after these treatments, we will better understand how to create a deeper and stronger immune response in KRAS-mutated NSCLC. This is essential because we know that a patient’s own immune system can help increase cure rates and control cancer for longer than other therapies alone. Overall, our trial seeks to create new treatment opportunities for surgical lung cancer while improving outcomes across all stages of KRAS-mutated NSCLC.

Technical Abstract

Although about a third of patients with non-small cell lung cancer (NSCLC) present with resectable disease, a majority will experience death and relapse from their cancer. Exciting recent advances in the use of immune checkpoint inhibition in this early stage space presents a promising way forward for our patients. As the most commonly mutated oncogene, activating KRAS mutations are found in 30% of lung adenocarcinomas; G12C mutations have been associated with higher risk of recurrence following resection. Adagrasib (MRTX849), a potent, highly selective novel small molecule inhibitor of KRAS G12C, has shown promise in previously treated advanced NSCLC. Our study represents a novel application of precision oncology in the resectable NSCLC disease setting with the neoadjuvant use of adagrasib monotherapy or in combination with immune checkpoint inhibition. We will identify safety and clinical efficacy signals of both of these therapeutic approaches. Leveraging our institutional expertise of using single- cell transcriptomics of tumor- infiltrating lymphocytes (TIL), we will evaluate neoantigen-specific transcriptional programs with a focus on KRAS-specific changes, and correlate with clinical outcomes. Overall, our study aims to ultimately improve cure rates of resectable KRAS G12C-mutated NSCLC.

Key words

Biomarker or biomarker testing

KRAS

Non-small cell lung cancer (NSCLC)

Phase 2 trial of neoadjuvant KRAS G12C directed therapy in resectable NSCLC

LUNGevity Foundation

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