LBA85 REACTION: A phase II study of etoposide and cis/carboplatin with or without pembrolizumab in untreated extensive small cell lung cancer

Abstract

Background: Concurrent chemotherapy and thoracic radiotherapy (CRT) followed by prophylactic cranial irradiation (PCI) is the standard strategy in limited stage small cell lung cancer (LS-SCLC).Methods: STIMULI is a 1:1 randomized phase II international trial aiming to demonstrate superiority of consolidation immunotherapy treatment (C) vs observation (O) after standard CRT and PCI, in patients (pts) with LS-SCLC. C consisted of four cycles of nivolumab (1 mg/kg, Q3W) plus ipilimumab (3 mg/kg, Q3W), followed by nivolumab monotherapy (240 mg, Q2W) for up to 12 months (m). The trial was designed to test two co-primary endpoints, progression-free survival (PFS) by RECIST 1.1 criteria, and overall survival (OS), at 1-sided alpha of 1% and 4%, respectively. Trial enrollment closed prematurely due to slow accrual, after half the initial sample size. The statistical analyses plan was updated to address PFS as primary endpoint to be tested at the full 5% 1-sided significance level. 81 PFS events were needed to achieve a power of 80% for testing an HR of 0.57. Secondary endpoints include OS, time to treatment failure (TTF), and safety.Results: 222 pts were enrolled with 153 randomized after completion of CRT and PCI, 78 to C and 75 to O. Median age 62 years, 60% males, 34%/65% current/former smokers, 31%/66% ECOG PS 0/1. In C, 40 PFS events were observed, with median PFS 10.7 m (95% CI 7.0-Not Estimable (NE)) vs 42 events and median 14.5 m (8.2-NE) in O, HR¼1.02 (0.66-1.58), 2-sided p¼0.93. Two-year PFS rate was 43% (31-55) and 40% (28-52) in C and O respectively. Median OS was not reached in C, while it was 31.6 m (26.1-NE) in O, HR¼1.06 (0.61-1.86), p¼0.83. One-year OS rate was 79% (68-87) in C and 89% (78-94) in O. Exploratory subgroups will be presented. In C, median time to treatment discontinuation was only 1.7 m. Grade!3 AEs were experienced by 62% pts in C and 25% in O, with 4 and 1 fatal AE, respectively.Conclusions: PFS for LS-SCLC pts is not found different between C and O, possibly due to the short period on active treatment observed in the study. Clinical trial identification: NCT02046733.Legal entity responsible for the study: European Thoracic Oncology Platform (ETOP).

Novel patterns of progression upon immunotherapy in other thoracic malignancies and uncommon populations

“…In the first 3 months, ED rate was 11% (30/268), similar to the ED rates in the chemotherapy or durvalumab plus chemotherapy arms (50). Finally, combination of platinumetoposide and pembrolizumab was tested as maintenance therapy after induction with two cycles of platinumetoposide in one EORTC phase 2 study (REACTION), showing improvement in OS with similar ED rate (7%) in the immunotherapy and in the placebo arm (51).…”

Small cell lung cancer: a slightly less orphan disease after immunotherapy

“…Although the trial reported statistically significant OS benefit (12.3 versus 10.4 months, HR 0.73; 80% CI: 0.54-1.00, P ¼ 0.97, significance with a one-sided alpha of 10%) despite a 30% crossover rate, the primary PFS endpoint was not met (4.7 versus 5.4 months, HR 0.84; 80% CI: 0.65-1.09, P ¼ 0.194). 28 Similarly, the ECOG-ACRIN5161 trial did not reach the prespecified 60% improvement in the median PFS with the immuno-chemotherapy strategy. 29 In terms of the safety profile, none of the immunochemotherapy combinations significantly increased the rate of grade 3 or higher toxicity compared with chemotherapy alone.…”

“…However, this benefit was not confirmed in a phase III trial 22 with ipilimumab (10 mg/kg) versus placebo added to platinumetoposide from cycle 3 to 6, every 3 weeks, followed by ipilimumab or placebo as maintenance treatment every 12 weeks that failed to improve OS, the primary endpoint (11.0 versus 10.9 months; HR 0.94; 95% CI, 0.81-1.09; P ¼ 0.377) and PFS (4.6 versus 4.4 months; HR 0.85; 95% CI, 0.75-0.97; P ¼ 0.161). 22 The immuno-chemotherapy strategy with anti-PD-L1 has been tested in three randomized phase III trials in the firstline setting (IMpower133 23,24 with atezolizumab, CASPIAN 25,26 testing durvalumab with or without tremelimumab and KEYNOTE 604 27 with pembrolizumab), as well as two randomized phase II trials (REACTION 28 with pembrolizumab and ECOG-ACRIN5161 29 with nivolumab). All of these trials [23][24][25][26][27][28][29] have demonstrated that the addition of an anti-PD-L1 to standard platinum-etoposide chemotherapy improves survival compared with chemotherapy alone (Figure 2), improving median OS by approximately 2 months and reducing the risk of death by approximately 25% compared with chemotherapy alone, providing 1-year and 2-year OS rates of w50% and w20%, respectively.…”

“…22 The immuno-chemotherapy strategy with anti-PD-L1 has been tested in three randomized phase III trials in the firstline setting (IMpower133 23,24 with atezolizumab, CASPIAN 25,26 testing durvalumab with or without tremelimumab and KEYNOTE 604 27 with pembrolizumab), as well as two randomized phase II trials (REACTION 28 with pembrolizumab and ECOG-ACRIN5161 29 with nivolumab). All of these trials [23][24][25][26][27][28][29] have demonstrated that the addition of an anti-PD-L1 to standard platinum-etoposide chemotherapy improves survival compared with chemotherapy alone (Figure 2), improving median OS by approximately 2 months and reducing the risk of death by approximately 25% compared with chemotherapy alone, providing 1-year and 2-year OS rates of w50% and w20%, respectively. 24,26,27 In the phase III trials, crossover was not allowed, and only 5% to 10% of patients enrolled in the chemotherapy arm received a subsequent ICI treatment.…”

Old but gold: the role of drug combinations in improving response to immune check-point inhibitors in thoracic malignancies beyond NSCLC

“…Besse et al [31] at ESMO 2020 presented the results of REACTION study, a multicenter open-label randomized phase II trial. They randomized patients with extensive SCLC, unselected for PD-L1, and controlled brain metastases who detained an objective response after 2 cycles of chemotherapy with platinum and etoposide to receive pembrolizumab in combination with four additional cycles of platinum etoposide then pembrolizumab up to 35 cycles (experimental arm) vs. four additional platinum etoposide cycles (control arm).…”