Abstract
Combining the PD-L1 inhibitor atezolizumab with platinum-based chemotherapy improves overall survival among patients with extensive-stage small cell lung cancer relative to chemotherapy alone. These findings could lead to a new first-line treatment option for patients with the disease.
Recent trials have changed the standard of care for non–small cell lung cancer, with many newly diagnosed patients now receiving a combination of chemotherapy and a checkpoint inhibitor. However, patients with small cell lung cancer (SCLC) have not yet benefited from immunotherapy. Based on the IMpower133 trial, which is assessing the PD-L1 inhibitor atezolizumab (Tecentriq; Roche) as a first-line treatment for the disease, that may soon change.
Data from the trial were recently presented at the World Conference on Lung Cancer in Toronto, Canada, and published concurrently in The New England Journal of Medicine (NEJM).
“This is the first breakthrough in first-line SCLC treatment in over 30 years,” says Leora Horn, MD, of Vanderbilt University Medical Center in Nashville, TN, the study's lead author.
In the trial, 201 patients with newly diagnosed extensive-stage SCLC were treated with atezolizumab plus standard platinum-based chemotherapy, and 202 were treated with placebo plus chemotherapy. After a median follow-up of 13.9 months, interim results were announced: Median overall survival (OS) was 12.3 months in the atezolizumab group and 10.3 months in the placebo group, and median progression-free survival (PFS) was 5.2 versus 4.3 months, respectively. These differences were small but statistically significant.
“Although the median change in overall survival was only about 2 months, this represents a meaningful advance in this extremely aggressive malignancy,” says Lauren Averett Byers, MD, of The University of Texas MD Anderson Cancer Center in Houston, who was not affiliated with the trial.
This finding is notable because a prior phase III trial in SCLC comparing the checkpoint inhibitor ipilimumab (Yervoy; Bristol-Myers Squibb) plus chemotherapy with chemotherapy alone found no difference in OS or PFS between the two arms. Alice Shaw, MD, PhD, of Massachusetts General Hospital in Boston, who also was not affiliated with the trial, believes that the disparate results may indicate that ipilimumab's CTLA4 inhibition in combination with chemotherapy is not beneficial in SCLC, whereas atezolizumab's PD-L1 inhibition is. Although the mechanism underlying the effectiveness of atezolizumab–chemotherapy regimen remains unclear, authors of the NEJM study note that ipilimumab “does not activate T cells in the tumor microenvironment,” whereas atezolizumab might—if carboplatin and etoposide don't “deplete the intratumoral T-cell population.”
Because SCLC is characterized by high initial response rates to first-line chemotherapy followed by rapid relapse—typically within a few months—Byers says researchers must continue following IMpower133′s participants to learn more about the long-term impact of atezolizumab on survival. Significant differences in OS and PFS are already evident between the two arms, but additional data will help investigators determine whether the OS difference continues to grow over time, as well as the proportion of patients who experience long-term benefit from atezolizumab.
Findings from other SCLC studies could be published within the next year. “There are ongoing trials testing other immune checkpoint inhibitors, either with chemotherapy or alone, as maintenance therapy following platinum-based chemotherapy,” says Horn.
Future studies will need to identify which patients are most likely to respond to combined therapy better than chemotherapy alone, says Byers. “This would allow us to avoid potential toxicities from immunotherapy in patients who are not likely to receive additional benefit.”
“Hopefully this is just the beginning of a new era of more-effective therapies for extensive-stage SCLC,” says Shaw. –Kristin Harper
