Ipilimumab Addition Does Not Boost Extensive-Stage SCLC Survival

Overall survival in patients with extensive-stage small-cell lung cancer is not changed with ipilimumab augmentation of chemotherapy

medwireNews: The addition of ipilimumab to etoposide and platinum chemotherapy has failed to significantly improve overall survival (OS) in patients with extensive-stage disease small-cell lung cancer (SCLC), research shows.

The primary endpoint of OS was a median of 11.0 months for the 478 patients randomly assigned to receive four doses of etoposide with cisplatin or carboplatin plus ipilimumab 10 mg/kg every 3 weeks in a phase induction schedule, followed by maintenance ipilimumab every 12 weeks.

This compared with OS of 10.9 months for the 476 patients given the chemotherapy regimen plus placebo, giving a nonsignificant hazard ratio (HR) of 0.94, report Martin Reck, from LungenClinic Grosshansdorf in Germany, and co-investigators.

Nor did OS significantly differ between patients given the cytotoxic T-lymphocyte associated antigen (CTLA)-4 inhibitor and placebo-treated controls in predefined subgroups based on age, gender, race, baseline performance status, smoking status, receipt of cisplatin versus carboplatin, and the presence or absence of central nervous system metastases.

Progression-free survival was longer in ipilimumab-treated patients than controls, at 4.6 versus 4.4 months and an HR of 0.85. But the researchers emphasize that as the primary endpoint was not met, the numerical difference "should not be considered statistically significant".

Treatment-related adverse events occurred in 82% of patients given chemotherapy plus ipilimumab and 76% of those treated with chemotherapy and placebo, with grade 3–4 side effects reported in 48% and 44%, respectively.

Ipilimumab was associated with grade 3–4 neutropenia, anaemia, diarrhoea and a reduced neutrophil count, whereas neutropenia, anaemia and decreased neutrophil count were the most common grade 3–4 effects in controls. Treatment was discontinued in 18% versus 2% of these groups.

The researchers say it is “unclear” why the expected synergistic effects of ipilimumab plus etoposide and platinum chemotherapy did not occur.

“One possible explanation is that without corresponding T-cell activation in the tumor microenvironment, ipilimumab monotherapy, which stimulates peripheral T-cell activation, may not be effective in mounting a sufficiently strong antitumor response in [extensive-stage disease]-SCLC”, they hypothesize in the Journal of Clinical Oncology.

“In addition, concomitant chemotherapy may increase immunosuppression, which may be associated with limited T-cell activation and proliferation.”

The authors conclude that research indicates that programmed cell death protein 1 inhibitor therapy alone or alongside CTLA-4 inhibitors “show[s] the most promise in SCLC”, and they look forward to results from ongoing studies such as the STIMULI trial of ipilimumab and nivolumab in SCLC. 

Reference

Reck M, Luft A, Szczesna A, et al. Phase III randomized trial of ipilimumab plus etoposide and platinum versus placebo plus etoposide and platinum in extensive-stage small-cell lung cancer. J Clin Oncol 2016; Advance online publication 25 July. doi: 10.1200/JCO.2016.67.6601

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