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

2014

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

Chemotherapy

Immune checkpoint inhibitors

Immunotherapy

Non-small cell lung cancer (NSCLC)

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

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