Introduction and Identifying Predictive Biomarkers

Vivek Subbiah, MD: Welcome to this OncLive® News Network® presentation, “Recent Advances in Small-Cell Lung Cancer.” We are going to spend the next 45 minutes focused on recent advances concerning both frontline and relapsed/refractory disease. I am your host, Dr Vivek Subbiah, a medical oncologist and clinical trials investigator from The University of Texas MD Anderson Cancer Center. Today, I am joined by my colleagues, who are experts in thoracic oncology: Dr Anne Chiang from the Yale University School of Medicine Smilow Cancer Hospital in New Haven, Connecticut; and Dr Apar Ganti from the University of Nebraska Medical Center in Omaha. Let’s get started.

Small-cell lung cancer (SCLC) is a highly aggressive, lethal, and widely metastatic lung cancer that kills an estimated 250,000 people worldwide yearly. This is based on the fact that small-cell lung cancer has an estimated 15% global lung cancer incidence and a 7% 5-year survival. Small-cell lung cancer is categorized by rapid tumor growth, high vascularity, genomic instability, early metastatic dissemination, and almost universal inactivation of TP53 and RB1 genes and frequent disruption of several characteristics signaling networks. Almost all patients with small-cell lung cancer are current or former heavy smokers. At this point, after decades of research, the prognosis for small-cell lung cancer patients remains poor, and treatment options are limited. Small-cell lung cancer is associated with more paraneoplastic syndromes than any other cancer type. To begin, let’s jump on frontline therapy for extensive-stage small-cell lung cancer.

Around 70% of patients with small-cell lung cancer present with extensive-stage disease on diagnosis. The remaining 30% of patients have limited-stage disease, in which the tumor involvement is confined to 1 hemithorax and can be treated in a tolerable radiation field. Let’s turn to an expert, Dr Apar Ganti from Nebraska. What has been the progress in identifying predictive biomarkers? Do you test for PD-L1 or tumor mutation burden (TMB) in small-cell lung cancer?

Apar Ganti, MD: Currently, there is no evidence to suggest that either PD-L1 levels or tumor mutation burden have a predictive role in small-cell lung cancer. Unlike non–small-cell lung cancer, where we know that increasing PD-L1 expression predicts increased response to checkpoint inhibitors, we do not have the same evidence yet in small-cell lung cancer. None of the recent frontline trials used either PD-L1 expression or tumor mutation burden as inclusion criteria, so the current standard of care is to not to check for either PD-L1 expression or tumor mutation burden in this cohort of patients.

Vivek Subbiah, MD: We know that small-cell lung cancer is an immunogenic tumor with high somatic mutation rates. This is mainly because these patients have tobacco exposure or a history of tobacco exposure resulting in potential new antigens, the presence of suppressed new responses, and the occurrence of paraneoplastic disorders. Dr Chiang, can you comment on PD-L1 and TMB in SCLC?

Anne Chiang, MD, PhD: As Dr Ganti said, PD-L1 expression is not predictive. It’s typically very low in small-cell, so that’s different from non–small-cell. There is 1 trial with pembrolizumab that looked at the combined positive score to take into consideration both the expression on tumor cells and immune cells. But on the whole, if you look at the regular assays that we use, small-cell is pretty much a negative tumor. There’s a lot of interest in TMB. It’s not standard of care, but the idea is that small-cell is a tumor. It’s within the top 10 tumor types. If you have a very high TMB and the presence of multiple antigens, there are more neoantigens that can boost the immune system response. Look at the original CheckMate 032 trial, which was presented at World Conference on Lung Cancer a couple of years ago. If you look at the response rate to immunotherapy, either nivolumab alone or nivolumab/ipilimumab, that was much higher in the TMB high—up to 46% response rate in that population. It’s a very intriguing marker. We’ll talk a little about that in the frontline trials that we’ll discuss, but so far, it hasn’t changed our standard of care to order those studies upfront on small-cell.

Transcript Edited for Clarity