SCLC,Extensive Stage Clinical Trial
Official title:
Phase 2 Trial of Translational Approach to First Line cHemoimmunotherapy Followed by Maintenance With pembrOlizumab and Olaparib in Extensive-Stage Small-Cell Lung CanceR.
This is an open-label, single arm, phase 2 trial enrolling patients with untreated Extensive-Stage Small-Cell Lung Cancer (ES SCLC), with a strong translational attitude.
SCLC is a very aggressive disease with an overall survival (OS) of 12 months in the extensive stage (ES). Platinum-based as the first line of treatment has an overall response rate (ORR) of approximately 70% with a progression-free survival (PFS) of 5.5 months and an OS of almost 10 months. Prophylactic cranial irradiation, performed in order to prevent progression in brain, one of the major sites of recurrence, was associated with an increase in median disease-free survival of 12.0-14.7 weeks and in median OS of 5.4-6.7 months with a 1-year survival rate of 27.1%. At recurrence few therapeutic options are available. In order to improve clinical results, several strategies are under evaluation. Given the strong activity shown in several settings, immunotherapy is studied both as a single agent and in combinations. Pembrolizumab has shown as maintenance after chemotherapy a PFS of 6.9 months in Programmed Cell Death 1 Ligand 1 (PD-L1) positive patients and as a monotherapy in 2nd and further lines an ORR of 19.3%, with major responses in PD-L1 positive patients and 61% of responders lasting ≥18 months. Recently the addition to standard chemotherapy of atezolizumab in patients with untreated ES-SCLC has led to an improvement of 2 months in OS (12.3 in the combo arms vs. 10.3 months in the control arm) and a slight improvement in PFS (5.2 vs. 4.3 months, respectively), without new safety data. Similarly addition of durvalumab to standard chemotherapy has led to a 2.7 months OS improvement (13 in the combo arms vs. 10.3 months in the control arm) with a relevant improvement in ORR (79.5 vs 70.3% respectively), without any improvement in PFS. Finally pembrolizumab combined with chemotherapy has shown significant improvement in PFS (hazard ratio (HR), 0.75; 95% confidence interval (CI), 0.61-0.91) but not in OS. Finally, considering the role of DNA damage repair systems in the tumorigenesis of SCLC, Olaparib has been also evaluated together with durvalumab in pre-treated ES-SCLC obtaining a clinical benefit of 21.1% and confirmed responses or stable disease for ≥8 months. Tumor responses were observed in all instances in which pretreatment tumors showed an inflamed phenotype. Despite biologic knowledge is growing, no clinically relevant molecular features have been identified. Recent publications in fact have proposed a new classification of SCLC in 3 major subgroups according to the expression of the neuronal basic helix-loop-helix transcription factors achaete-scute homologue 1 (ASCL1), involved in the neuroendocrine characterization, and the neurogenic differentiation factor 1 (NEUROD1). The so-called "classic type" shows expression of ASCL1, the "variant type" expresses NEUROD1 and the third type is negative for both the two previous biomarkers. In terms of gene profiling these subgroups are distinct but without a clear prognostic and predictive role. No driver mutations have been found. Many pathways are under evaluations. In particular Poly(ADP-Ribose) Polymerase (PARP) protein levels are up - regulated in SCLC relative to other lung cancers. In particular, Poly(ADP-Ribose) Polymerase 1 (PARP1) has been found to be highly expressed at both the messenger RNA (mRNA) and protein levels in SCLC samples. Given these data the combination proposed (Induction Phase with platinum/etoposide/pembrolizumab followed by a Maintenance Phase with pembrolizumab/olaparib) may be a new therapeutic option to be explored for patients. Moreover the evaluation of molecular features performed before, during and after this treatment may produce new evidence for further clinical trials. The primary objective of the study is to evaluate the efficacy of chemo-immunotherapy induction followed by maintenance with pembrolizumab and olaparib in terms of Progression-free Survival (PFS). Patients with extensive stage (ES) SCLC will receive pembrolizumab 200 mg 1q21 with platinum compound (cisplatin 75 mg/m2 or carboplatin area under the curve of 5 mg per milliliter per minute) 1q21 plus etoposide 100 mg/m2 1-3q21 for 4 cycles (Induction Phase) (two additional cycles are allowed at discretion of the Investigator). In case of responsive or stable disease, patients will receive pembrolizumab 200 mg 1q21 plus olaparib 300 mg twice daily until progression (Maintenance Phase) or up to a maximum of 35 cycles. Patients will be accrued for a period of 24 months and follow-up will continue for a period of 12 months after the last patient is enrolled. The Kaplan-Meier approach will be used to estimate PFS. ;