KEY TAKEAWAYS
- The eNERGY trial is a phase 2 study that compared the combination of nivolumab and ipilimumab (N-I) to platinum doublet chemotherapy in elderly or PS2 patients with advanced(NSCLC).
- The primary aim of the trial was to evaluate the(OS) of N-I versus chemotherapy, with secondary endpoints including (PFS), (ORR), and safety.
- An interim analysis after observing 33% of deaths showed a risk of futility, especially for PS2 patients, leading to a halt in randomization but continued follow-up of patients.
- The subgroup analysis showed a significant benefit of the N-I combination compared to chemotherapy for elderly PS 0/1 patients, with a median OS of 22.6 vs 11.8 months.
- The safety profile was similar between the two arms, with 31.4% of patients experiencing grade ≥ 3 related serious adverse events in the N-I arm compared to 49.5% in the chemotherapy arm.
Although data for healthy elderly or PS2 patients is limited, anti-PD1 and anti-CTLA4 combinations have shown superiority to chemotherapy (CT) in advanced non-small cell lung cancer (NSCLC). For patients over 65 or with PS2 who have advanced NSCLC, eNErgy compared the combination of nivolumab and ipilimumab (N-I) to a platinum doublet. Overall survival (OS) was the primary endpoint, with PFS, objective response rate(ORR), and safety as secondary endpoints. Patients who met the primary inclusion criteria of stage IV histologically proven NSCLC, age ≥ 70 years, performance status (PS) 0/1/2, or age <70 years, PS2, EGFR ALK/ROS1 negativity, and good enough health to receive a platinum doublet were considered. Patients with active cerebral metastases or ineligible for N-I were primarily screened out. Patients were chosen at random (1:1) according to age ( ≥ 70 vs < 70 y), performance status (0:1 vs 2:2), and histology (squamous vs no-squamous).
The combination of nivolumab (240 mg, 2w) and ipilimumab (1 mg/kg, 6w) was given until disease progression or intolerable toxicity occurred. To detect a treatment effect hazard ratio (HR) on OS of 0.65, CT was designed to include 4 cycles of carboplatin (AUC5) and pemetrexed (500 mg/m2, 3w) or paclitaxel (90 mg/m2, d1,d8, d15); 242 patients were required to be randomized at a 2-sided alpha level of 5%. After observing 33 per cent of deaths among 174 randomized patients, an interim analysis revealed a risk of futility, with a hazard ratio (HR) of 1.8 (95% CI, 0.99-3.3) for PS 2 patients in particular.
Because of this decision, further randomization has been put on hold, though the 204 patients already assigned will still be followed. This final analysis was performed 18 months after the last patient was enrolled, and its participants were predominantly male (71%), middle-aged (median age 74; range, 51-89), had a PS of 0/1/2 (37.5%) or higher (36.6%), and were either current or former smokers (25.5% and 64.4%), with 62% having adenocarcinoma. HR 0.85, 95% CI 0.62-1.16; median OS, 14.7 (95% CI, 8.0-19.7) months; chemo arm, 9.9 (95% CI, 7.7-12.3) months; both groups. Subgroup analyses revealed that older PS 0/1 patients benefited more from the association N-I than CT, with a median OS of 22.6 (95% CI, 18.1-36) months versus 11.8 (95% CI, 8.9-20.5) months, p = 0.02. Median overall survival (OS) between the N-I and CT arms for PS2 patients was 2.9 (1.4-4.8) months versus 6.1 (3.5-10.4) months (p = 0.22). Overall, the N-I arm had a longer median PFS (5.5 months, 95% CI: 2.8-8.7) than the control arm (4.6 months, 95% CI: 3.5-5.6); p = 0.015. In the N-I arm, 31.4% of patients experienced SAES of grade 3, compared to 49.5% of patients in the CT arm. Overall, 28.6% of patients in the N-I arm and 22.3% in the CT arm discontinued treatment due to toxicity. A clinical signal of efficacy was observed for the N-I combination over platinum doublet in elderly NSCLC patients with PS 0-1; these patients had a significantly longer overall survival (OS) of 22.6 months compared to 11.8 months for the CT arm.
Source: https://meetings.asco.org/abstracts-presentations/209492
Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT03351361
Herve Lena, Isabelle Monnet, Olivier Bylicki, Clarisse Audigier-Valette, Lionel Falchero, Alain Vergnenegre, Pierre Demontrond, Laurent Greillier, Margaux Geier, Florian Guisier, Chantal Decroisette, Chrystele Locher, Romain Corre, Claire Cropet, Christos Chouaid, Charles Ricordel/Randomized phase III study of nivolumab and ipilimumab versus carboplatin-based doublet in first-line treatment of PS 2 or elderly (≥ 70 years) patients with advanced non–small cell lung cancer (Energy-GFPC 06-2015 study)/J Clin Oncol 40, 2022 (suppl 16; abstr 9011)DOI10.1200/JCO.2022.40.16_suppl.9011
