MS09.02 Clincal and Molecular Biomarkers for Selection of Sclc Patients Candidate to Immunecheckpoint Blockade

Abstract

Immunotherapy has dramatically altered the treatment options available to patients with lung cancer. In the past year, small cell lung cancer (SCLC) fully joined the immunotherapy era with approvals by the US Federal Drug Administration (FDA) for three separate immune checkpoint inhibitors – atezolizumab for frontline therapy in patients with extensive stage SCLC (ES-SCLC) (in combination with platinum-etoposide chemotherapy) and nivolumab and pembrolizumab (each as monotherapy) for relapsed SCLC. The combination of nivolumab plus ipilimumab also demonstrated durable activity in a subset of patients treated on the Phase 1/2 CheckMate032 trial, with an overall response rate of 22% and a 2 year overall survival rate of 26%.1 The addition of atezolizumab to carboplatin and etoposide as a new standard of care was based on results from the Phase 3 IMpower133 trial.2 In that randomized trial, the addition of atezolizumab to carboplatin-etoposide, followed by atezolizumab maintenance, led to improvements in both progression free survival (PFS) (4.3 months in the placebo control arm versus 5.2 months in patients receiving atezolizumab) and overall survival (OS) (10.3 months with placebo versus 12.3 months with atezolizumab). Additional randomized trials testing other immune checkpoint inhibitors in combination with standard platinum-etoposide chemotherapy are ongoing, with clinical findings expected in the next several months. This includes the phase 3 trial of durvalumab plus platinum-etoposide (CASPIAN), which has now been reported to show improved overall survival (OS) with the addition of durvalumab at a planned interim analysis (press release). Despite these landmark approvals for immune checkpoint inhibitors in ES-SCLC, a large number of patients with SCLC do not appear to receive clinic benefit with the currently available inhibitors of PD-1/PD-L1 and/or CTLA-4. Furthermore, there are not yet established biomarkers for identifying those patients with SCLC who are likely to respond. As with non-small cell lung cancer, immunohistochemistry (IHC) for PD-L1 levels and tumor mutation burden (TMB) are both candidate biomarkers.3,4 However, neither of these have been prospectively validated to date in SCLC and there may be important differences in their performance depending on how testing is done (e.g., variation between antibodies, scoring methods/cutoffs, or technical differences between molecular platforms). Recently, new combinations of targeted therapies together with immune checkpoint inhibitors (such as inhibitors of DNA damage response (DDR) such as PARP1 or Chk1 to enhance STING pathway activation) have demonstrated promise in preclinical studies of SCLC and are being translated into the clinic for further investigation.5 In addition, other new immunotherapeutic approaches are being tested in ongoing trials. Examples of these include studies of chimeric antigen receptor T-cells (CAR-T) and bi-specific T-cell engagers (BiTE molecules) targeting the notch inhibitor ligand DLL3 for patients with relapsed SCLC. In this context, additional biomarkers related to specific combinations of targeted and immune-therapies and/or new classes of immunotherapy (e.g., SLFN11 levels for PARP inhibitors; cMyc status for Chk1 inhibitors; markers of STING pathway activation; or DLL3 expression levels) may emerge as additional biomarkers relevant to immune responses. Finally, a better understanding of tumor and immune environment heterogeneity between patients – as well as intra-tumoral heterogeneity – will lead to more effective strategies for matching patients to specific immunotherapies and overcoming immunotherapy resistance. REFERENCES 1. Della Corte CM, Gay CM, Byers LA. Beyond chemotherapy: Emerging biomarkers and therapies as small cell lung cancer enters the immune checkpoint era. Cancer 2019;125:496-8. 2. Horn L, Mansfield AS, Szczesna A, et al. First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N Engl J Med 2018;379:2220-9. 3. Antonia SJ, Lopez-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol 2016;17:883-95. 4. Hellmann MD, Callahan MK, Awad MM, et al. Tumor Mutational Burden and Efficacy of Nivolumab Monotherapy and in Combination with Ipilimumab in Small-Cell Lung Cancer. Cancer Cell 2018;33:853-61 e4. 5. Sen T, Rodriguez BL, Chen L, et al. Targeting DNA Damage Response Promotes Antitumor Immunity through STING-Mediated T-cell Activation in Small Cell Lung Cancer. Cancer Discov 2019;9:646-61. Immunotherapy, biomarkers, small cell lung cancer (SCLC)