First, in August 2018, the FDA approved the immunotherapy nivolumab (Opdivo) for patients with metastatic small-cell lung cancer.
Then, results of a new study showed that atezolizumab (Tecentriq) combined with carboplatin (Paraplatin) plus etoposide (Etopophos) may be a new standard of care for the first-line treatment of extensive-stage small-cell lung cancer (ES-SCLC).
The results of the phase 3 IMpower133 clinical trial were presented at the 2018 International Association for the Study of Lung Cancer World Conference on Lung Cancer.
Atezolizumab plus carboplatin and etoposide improved overall survival (OS) and progression-free survival (PFS). At a median follow-up of 13.9 months, the median OS was 12.3 months in the atezolizumab group versus 10.3 months for the placebo arm, which is a 30% reduction in the likelihood of death (P = .007). The median PFS was 5.2 months in the atezolizumab group and 4.3 months in the placebo group (P = .02).
“IMpower133 is the first trial in more than 20 years to show a clinically meaningful improvement in overall survival compared with the current standard of care in first-line ES-SCLC,” stated the senior investigator of this study, Stephen V. Liu, MD, Assistant Professor, Division of Hematology and Oncology, Georgetown University, Washington, DC.
“These findings suggest that atezolizumab plus carboplatin and etoposide represents a new first-line treatment for ES-SCLC,” he added.
Clinical Benefit versus Financial Toxicity
Conference Co-President Natasha B. Leighl, MD, MSc, FRCPC, Lung Site Group, Princess Margaret Cancer Centre, Toronto, Canada, acknowledged that an improvement in survival in ES-SCLC is an achievement, but she was more cautious about whether this approach would be widely adopted, mainly because of a modest 2-month gain in survival weighed against the considerable cost of treatment with immunotherapy.
“Is the benefit of atezolizumab during induction or in maintenance? Is a 2-month gain in survival clinically significant? We could say that immunotherapy has lots of financial toxicity, maybe grade 3 or 4. So is this small clinical benefit worth the cost of treatment?” she asked listeners.
“The economic hurdle will depend on regulators. But this is the first positive randomized controlled trial in SCLC, with a 30% survival improvement,” Dr Leighl said. “We still need new treatments for ES-SCLC.”
Phase 3 IMpower133 Study
The randomized, placebo-controlled, double-blind phase 3 IMpower133 study enrolled 403 patients with untreated, measurable ES-SCLC at 106 sites in 21 countries.
The study participants were randomized 1:1 to receive 4 cycles of carboplatin plus etoposide with either 1200 mg of atezolizumab on day 1 of each cycle or placebo, followed by maintenance therapy with atezolizumab or placebo according to previous randomization until disease progression or toxicity. The continuation of treatment was allowed after progression if there was evidence of clinical benefit. Tissue samples were requested, but not mandated, for all patients.
“Atezolizumab did not interfere with the ability to give 4 cycles of standard chemotherapy,” Dr Liu said.
Atezolizumab had a consistent benefit over placebo in all subgroups, including sex, age (aged <65 years), Eastern Cooperative Oncology Group score (0 vs 1), the presence of liver metastases, and the level of tumor mutational burden.
Although the objective response rates were similar in the 2 arms (>60%), approximately 3 times as many patients in the atezolizumab arm had an ongoing response (ie, approximately 15% vs 4% for placebo). The tumor mutational burden correlated with the response to atezolizumab.
The safety profile of the combination of all 3 drugs was similar to what was previously reported with each of the drugs individually, and there were no new safety findings. The frequency of adverse events, including hematologic events, was similar in both arms, except that immune-related adverse events were more common in patients who received atezolizumab (39.9% vs 24.5% for placebo).