SC15.01 The American Perspective

Abstract

The treatment of lung cancer has changed dramatically in the past few years. From a time when treatment decisions were made without regard to histology or genotype, an era of personalized therapy, at least for a subset of patients with lung cancer, is a reality. The treatment of EGFR mutation-positive patients with EGFR inhibitors has resulted in significant improvements in outcomes over standard chemotherapy. Similarly, for patients with ALK- and ROS1-positive non-small cell lung cancer (NSCLC), targeted therapies have proven to be superior. However, for patients with KRAS mutations, which are seen in approximately 25-30% of lung adenocarcinomas, there is no effective targeted therapy option. For nearly 70% of patients with NSCLC, systemic chemotherapy remains the standard approach. The emergence of immune-checkpoint inhibitors has resulted in considerable change in the treatment algorithm for advanced NSCLC. These agents are now preferred salvage therapy after progression following platinum-based chemotherapy. As immunotherapy moves to the first-line therapy setting for advanced NSCLC, it is anticipated that at least 25-30% of the patients without a driver mutation will be treated with immune-checkpoint inhibitors. All of these exciting developments call for careful evaluation of ongoing and planned clinical trials, so that appropriate new priorities are established. The newly established NCI National Clinical Trials Network (NCTN) includes all the adult cancer cooperative groups (ALLIANCE, ECOG-ACRIN, SWOG, & NRG Oncology) is actively engaged in conducting the new generation of clinical trials for lung cancer. Despite, the success with targeted agents in advanced stage NSCLC, patients do not achieve a cure. Using these agents in early stage NSCLC provides the best chance for a cure. The ALCHEMIST study has been launched by the NCTN to evaluate personalized adjuvant therapy for early stage NSCLC. In this study, patients with early-stage lung cancer (stages IB, II and IIIA) are treated with systemic chemotherapy after surgical resection, as per standard of care. Subsequently, their tumor is subjected to molecular testing. Patients with ALK-positive disease are randomized to treatment with crizotinib or placebo. Patients with EGFR mutations are randomized to erlotinib or placebo. Patients who are negative for EGFR and ALK, are randomized to nivolumab or observation. These studies will evaluate the effect of the personalized adjuvant therapy on overall survival and disease-free survival. Another ongoing effort is to understand the therapeutic value of targeted strategies in patients with advanced stage squamous cell lung cancer. The lung-MAP study enrolls patients with advanced stage squamous NSCLC. Following next-gen sequencing, patients with selected targets are treated with an appropriate targeted agent. The study includes a phase 2 component, which can be rapidly adapted to phase 3 if an agent demonstrates the pre-defined level of efficacy. This trial is also designed to accelerate the development of treatments leading to full approval by the FDA by shortening timelines. These individualized treatment approaches based on genotype are likely to answer important questions in a definitive manner. As immunotherapy becomes integrated in the standard treatment paradigms, considerable changes are also warranted for patients without driver mutations. For a subset of patients, as immunotherapy becomes the first line treatment in the advanced stage disease setting, the role of platinum-based chemotherapy in the second line needs to be investigated. It is also important to evaluate the need for continued immunotherapy after disease progression when patients are switched to chemotherapy. Another key question relates to the duration of therapy for patients receiving immune checkpoint inhibitors. Appropriately designed trials to understand the optimum duration of therapy will optimize benefits, reduce toxicity, and decrease cost. Combination strategies using immune checkpoint inhibitors with chemotherapy and other targeted agents is also an important area of priority. The role of biomarkers to select therapy is another critical research priority. We should also make efforts to improve the percentage of patients enrolled to clinical trials. A major reason for this is the stringent eligibility criteria that excludes a significant proportion of patients in order to select the ‘fittest’ candidates for clinical trials. While this is certainly appropriate in early phase drug development, if patients enrolled in clinical trials do not represent the ‘real-world’ patient population, the applicability of the results are limited. The next wave of clinical trials should also take into consideration the impact of new treatments on the overall cost of care and the clinical significance of improvements in efficacy. The national Cooperative groups in the United States are committed to a collaborative approach to address key research questions and improve outcomes for lung cancer. NSCLC, Adjuvant therapy, ALCHEMIST, immunotherapy