ES22.03 New Hope in SCLC?

Abstract

Lung cancer is the leading cause of cancer-related death worldwide. Small cell lung cancer (SCLC) accounts for approximately 15-20% of cases. This aggressive tumor is characterized by rapid growth, early development of disseminated disease and dramatic responses to first line chemotherapy. For decades, first line therapy has traditionally included four to six cycles of platinum-based chemotherapy. While up to 80% of patients respond to first-line chemotherapy, the majority eventually relapse with a median survival of 8 to 12 months for patients with extensive stage disease and 12 to 20 months for those with limited stage disease. Until recently, topotecan was the only FDA approved second line therapeutic option. The shortcomings of traditional chemotherapy, as well as the limited role of targeted therapy in SCLC, led to the investigation of novel mechanisms to target lung cancer and specifically the discovery of immune checkpoint inhibitors. Immune checkpoint inhibitors work by blocking interactions between T cells and antigen presenting cells (APCs) or tumor cells. By inhibiting this interaction, the immune system is effectively upregulated and T-cells become activated against tumor cells. There are three major classes of checkpoint inhibitors. Ipilimumab and tremelimumab inhibit T-lymphocyte antigen-4 (CTLA-4); nivolumab and pembrolizumab target the programmed cell death-1 receptor (PD-1); and atezolizumab, durvalumab, and avelumab block PD-L1, the ligand of PD-1. Prior studies have shown lack of PD-L1 expression on tumor cells in patients with pulmonary and extra pulmonary SCLC. While PD-1 and PD-L1 are expressed in the tumor stroma of small cell carcinomas.[1] In addition PD-L1 has been shown to be prognostic in patients with SCLC.[2] The aggressive nature of SCLC is underscored by its high mutational burden, including loss of the tumor suppressor genes p53 in 75%–90% and retinoblastoma in almost 100% of tumors.[3] Higher tumor mutation burden has been associated with outcome in patients with select tumors treated with checkpoint inhibitor therapy, including non-small cell lung cancer. [4] Recently singly agent nivolumab and combination nivolumab and ipilimumab were shown to have activity in the second and third line setting for patients with advanced SCLC with response rates of approximately 10% and 20% respectively. Combination nivolumab and ipilimumab appeared particularly promising in patients with tumors with high tumor mutation burden and in 2018 nivolumab received approval in the third line setting for patients with advanced SCLC. [5] However, disappointingly Chekckmate 331, a large phase III trial of patients who had progressed on first line platinum-based chemotherapy, found nivolumab was not superior to topotecan or amrubicin in the second line setting. Recently a combined analysis of patients treated on the Keynote 158[6] and 028 trial[7] with pembrolizumab in the second line setting demonstrated a response rate of approximately 20% in patients, with a greater benefit in patients with tumors that were PD-L1 positive. In the first line setting, a single arm phase II trial demonstrated no benefit to maintenance pembrolizumab following induction chemotherapy in patients with advanced SCLC with a progression free survival of less than 2 months. [8] Earlier this year, a phase III trial (Checkmate 451) also found maintenance nivolumab with or without ipilimumab following induction chemotherapy in patients with advanced small cell lung cancer was not superior to placebo, suggesting this is not the optimal strategy in patients with advanced stage disease. Importantly, he Impower 133 phase III trial demonstrated combination chemotherapy with carboplatin, etoposide and atezolizumab was superior to chemotherapy alone in patients with advanced SCLC with a significant improvement in progression free and overall survival leading to FDA approval and a new standard of care for patients with advanced disease. [9] Two large phase III trials Keynote 604 and Poseidon are comparing a similar strategy with pembrolizumab and durvalumab respectively, with data anticipated in the upcoming year. While progress has finally been made. Limited tissue specimens in patients with SCLC remain a challenge and many unanswered questions remain including the optimal patient population in which these agents will have benefit (PD-L1 positive or negative, tumor mutation high or low), the optimal duration of therapy, the appropriate combinations (can we improve upon chemotherapy with a different checkpoint inhibitor), and the safety of these agents long term, particularly in patients with comorbid disease.