Neoadjuvant immunotherapy for resectable non-small-cell lung cancer

Abstract

Lung cancer is the commonest cause of cancer death worldwide and approximately 85% of cases are non-small-cell cancer (NSCLC). In the decade from 2010 to 2020 there were many new systemic therapies developed and approved for the treatment of advanced NSCLC however no major therapeutic advances in the treatment of surgically resectable disease. Patients with stage II or III NSCLC, despite ostensibly curative surgery, have a survival rate at five years of The five studies included in this PhD encompass the clinical development of neoadjuvant anti-PD-1 immunotherapy with the monoclonal antibody, nivolumab, for resectable NSCLC including the first description of potential biomarkers of response.  In chapter 1, in the first study, I reported the initial results of a 21 patient investigator-initiated clinical trial of neoadjuvant nivolumab for patients with surgically resectable lung cancer. This was the first reported study of neoadjuvant anti-PD-1 for early stage lung cancer, this class of drugs has revolutionized the treatment of advanced lung cancer over the past 10 years. In the study I found that neoadjuvant anti-PD-1 was safe and feasible, that 45% of patients who underwent surgical resection had a major pathologic response after 2 doses of nivolumab, and that tumor mutational burden (TMB) appeared to predict pathologic response, the first descriptions of each of these findings.  Further exploring the potential role of biomarkers in predicting tumor response to PD-1 pathway blockade, chapter 2 exploresthe potential role of circulating tumor DNA (ctDNA) in predicting tumor response to immunotherapy. This study demonstrated for the first time that ctDNA dynamics during the neoadjuvant immunotherapy isa potential predictor of pathologic response in NSCLC and I expanded upon these findings in the phase 3 Check Mate 816 trial.  Chapter 3 constitutes a study of neoadjuvant combination immunotherapy with nivolumab and the anti-CTLA4 antibody, ipilimumab, for patients with resectable NSCLC, a regimen which has been shown survival in advanced NSCLC. Despite promising pathologic responses in this study, neoadjuvant ipilimumab plus nivolumab was also associated with increased toxicity eventually leading to enrolment being halted early.  In chapter 4, building on my original pilot trial of neoadjuvant nivolumabI led the phase 3 trial, Check Mate 816, studying the combination of chemotherapy plus nivolumab compared chemotherapy alone prior to surgery for stage IB to IIIA NSCLC. This study was aimed at showing higher rates of pathologic complete response and improved event-free survival with the combination of chemo-immunotherapy. Ultimately the results were positive for both primary endpoints leading to the regulatory approval of neoadjuvant chemotherapy plus nivolumab as a treatment for NSCLC in the United States and European Union among other jurisdictions. The study also demonstrated that pathologic response is a potential predictor of event-free survival building on my earlier findings that ctDNA clearance during neoadjuvant therapy may portend an improved long term outcome.   Finally, in chapter 5,I reported five year outcomes from my initial trial of neoadjuvant nivolumab showing that patients who experienced a tumor major pathologic response to nivolumab had an excellent long term outcome.  In conclusion, these studies contribute valuable insights into the use of neoadjuvant immunotherapy for NSCLC and have led directly to adoption of neoadjuvant nivolumab plus chemotherapy as a standard therapy in countries worldwide. </p