Adjuvant or neoadjuvant

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

Adenocarcinoma

Adjuvant or neoadjuvant

Biomarker or biomarker testing

Immune checkpoint inhibitors

Immunotherapy

KRAS

Non-small cell lung cancer (NSCLC)

Stage I

Stage II

Targeted therapy

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

Intercept Lung Cancer Through Immune, Imaging & Molecular Evaluation-InTIME

2017

SU2C-LUNGevity-ALA LC Interception Award

Grant title (if any)

SU2C-LUNGevity Foundation-American Lung Association Lung Cancer Interception Dream Team

This grant was co-funded by Stand Up to Cancer, LUNGevity, and the American Lung Association

Avrum Spira, MD, MSc

Boston University

Boston

Steven Dubinett, MD

UCLA

Los Angeles

Julie Brahmer, MD

Johns Hopkins Kimmel Cancer Center

Baltimore

Sam Gambhir, MD, PhD

Stanford University

Palo Alto

Matthew Meyerson, MD, PhD

Harvard/Dana-Farber Cancer Institute

Boston

Charles Swanton, PhD

Francis Crick Institute

London, England

The SU2C-LUNGevity Foundation-American Lung Association Lung Cancer Interception Dream Team, led by LUNGevity SAB member Dr. Avrum Spira, is developing a combination of diagnostic tools, such as non-invasive nasal swabs, blood tests, and radiological imaging, to confirm whether lung abnormalities found on chest imaging are benign lung disease or lung cancer.

Technical Abstract

Statement of the Problem: Cancer develops in a sequenced manner. Patches of lung cells gain the ability to multiply faster than their neighboring normal cells by acquiring mutations. These patches of cells are called “premalignant lesions" (PMLs). Some of these lesions may eventually become cancer. Knowledge about how some PMLs may develop into lung cancer is central to developing tools for Cancer Interception—interrupting the cancer development process and blocking progression to advanced metastatic disease. However, we lack effective lung cancer interception approaches due to our incomplete understanding of the earliest molecular events associated with the development of lung cancer, as well as the challenge in developing personalized tools for early detection and prevention.

Proposed Solution: The Dream Team will use a holistic approach to understand the genetics, immunology, radiological (imaging) profile, and treatment response of patients who show evidence of abnormal lung tissue that puts them at high risk to develop lung cancer. The Team has access to unique groups of patient populations (adenocarcinoma—ADC and squamous cell carcinoma—SCC) with signs of lung cancer risk, and has assembled a collection of blood and tissue specimens from these individuals. The main objective of the Team is to understand how lung cancer develops and test methods that will block the development of cancer. Their three-pronged approach to solve this problem will include:

Creation of a molecular pre-cancer genome atlas (PCGA) of the lung with the goal of identifying which types of precancerous lung tissue require aggressive treatment and which treatments will block the development of these abnormal lesions to invasive lung cancer.
Development of two diagnostic tools that can be directly applied in the clinic for simple, yet accurate, detection of early lung cancer: 1) the use of nasal swabs, blood tests, and imaging to confirm whether lung abnormalities found on chest imaging are lung cancer or benign lung disease. 2) blood tests that can identify patients at the earliest stages of lung cancer recurrence, thus enabling their timely and effective intervention with therapies such as those that boost the immune system.
Development of tests to identify which individuals are most likely to benefit from a number of treatment strategies to intercept lung cancer, including emerging immunotherapies.

Key words

Adenocarcinoma

Adjuvant or neoadjuvant

Biomarker or biomarker testing

Immune checkpoint inhibitors

Immunotherapy

Interception

Liquid biopsy

Non-small cell lung cancer (NSCLC)

Screening

Squamous cell lung cancer

Stage I

Stage II

Read more about Intercept Lung Cancer Through Immune, Imaging & Molecular Evaluation-InTIME

Neoadjuvant anti-PD-1 antibody, Nivolumab, in resectable NSCLC

2014

Career Development Award

Patrick Forde, MD (MB, BCh)

Johns Hopkins Kimmel Cancer Center

Baltimore

Dr. Forde is working to apply a kind of immunotherapy that has been successful in people with lung cancer in later stages to people with early-stage lung cancer, stimulating their immune system to attack cancer cells. This treatment, nivolumab, uses anti PD-1 antibodies to release the “brakes” on the immune system.

Research Summary

We usually think of our immune system in terms of its role in fighting infections such as flu and other viruses. Equally important, however, is the role of the immune system in preventing the development of cancer. Recent important breakthroughs in cancer research have led to the approval of new drug treatments for prostate cancer and melanoma that work by stimulating the immune system to attack cancer cells. Most recently, another powerful class of agents that release the “brakes” on the human immune system and allow it to attack cancer cells, called anti-PD-1 antibodies, have led to tumor shrinkage and long periods of remission for certain patients with advanced lung cancer for whom chemotherapy has stopped working. This study will enroll patients in a clinical trial to examine the role of an anti-PD-1 antibody called nivolumab given before surgery for earlier stage lung cancer. While some early stage lung cancers may be cured by surgery and chemotherapy, for many patients the cancer returns and effective treatments that reduce the risk of recurrence are urgently needed. This study will also examine how anti-PD-1 affects the immune system in patients with lung cancer. The overall aim of this study is to move anti-PD-1 forward as a treatment for earlier stage lung cancer patients. This research will provide important new insights into how the immune system deals with lung cancer and will allow the planning of future studies of immunotherapy to directly benefit patients.

Technical Abstract

Background & Significance: Phase I studies with the anti-programmed death-1 antibody (anti-PD-1), nivolumab, in advanced non-small-cell lung cancer (NSCLC) have demonstrated remarkably durable responses in heavily pretreated patients that lasted a median 17 months. However, in these studies very few patients have had tumors available for immune analysis, and basic data on immune measures pre- and post-treatment are not available. This study will move the treatment paradigm forward by assessing the safety and feasibility of preoperative anti-PD-1 in NSCLC and providing detailed information on the effect of PD-1 modulation on the lung tumor immune microenvironment.

Methods: Patients with newly diagnosed stage IB-IIIA NSCLC will receive two doses of nivolumab 3mg/kg IV on day-28 and day-14 prior to planned surgery on day 0. Serial blood samples for immune markers will be obtained. The primary endpoint of this study is the safety and feasibility of preoperative nivolumab in resectable NSCLC. For the exploratory immune analyses, initial tumor biopsy, post-treatment resection specimen, and serial peripheral blood samples will be evaluated for expression of immune markers with the primary comparison being intra-patient, pre- and post-treatment.

Experimental Approach & Statistical Analysis Plan: As this is the first time that nivolumab has been administered pre-operatively in NSCLC, the study will commence with a run-in phase where six patients will be monitored continuously for adverse events through eight weeks following surgery. Overall, the study will continue without pause to a 12-patient expansion phase if none or one of the six patients experiences DLT in the run-in. Detailed statistical plans for the safety and feasibility endpoints and exploratory immune endpoints are described in the main body of this application.

Key words

Adjuvant or neoadjuvant

Chemotherapy

Immune checkpoint inhibitors

Immunotherapy

Non-small cell lung cancer (NSCLC)