Adam M. Brufsky, MD, PhD
Adam M. Brufsky, MD, PhD, Professor of Medicine at the University of Pittsburgh School of Medicine and Co-Director of the Comprehensive Breast Cancer Center, commented on the KEYNOTE-355 final analysis1 for The ASCO Post.
“We now have a drug with full approval of the U.S. Food and Drug Administration for first-line treatment of triple-negative breast cancer. For patients with a combined positive score (CPS) ≥ 10, there’s a real survival benefit,” he said. “There is now clear evidence that pembrolizumab has both a progression-free and an overall survival benefit as a checkpoint inhibitor in the first line for metastatic breast cancer.”
As Dr. Rugo reported, for the population with a CPS ≥ 10, median overall survival was 23.0 months in the investigative arm vs 16.1 months in the control arm (hazard ratio [HR] = 0.73; P = .0093). Median progression-free survival was 9.7 months vs 5.6 months, respectively (HR = 0.66; 95% confidence interval = 0.50–0.88).
Comparison With IMpassion130 and IMpassion131
“It’s interesting that the survival advantage looks very similar to the survival advantage in patients with PD-L1–positive tumors with atezolizumab in IMpassion130,” which failed statistically to meet its overall survival endpoint, Dr. Brufsky said.2
In the confirmatory IMpassion131 study of paclitaxel and atezolizumab in this patient population,3 median progression-free survival in the PD-L1–positive cohort was 6.0 vs 5.7 months (HR = 0.82; P = .20), and overall survival was 22.1 vs 28.3 months (HR = 1.12). In both studies, the addition of the immune checkpoint inhibitor resulted in a median overall survival of about 23 months. However, in IMpassion131, which failed to meet its primary endpoints, median overall survival in the control arm was unusually long [28 months].
The statistical design of IMpassion130 followed hierarchical testing, where the primary endpoint—investigator-assessed progression-free survival—was tested first in the PD-L1–positive population. A statistically significant result (based on a hazard ratio of 0.62 and a median progression-free survival increasing from 5 to 8 months) would lead to testing in the intent-to-treat population. Secondary endpoints, including overall survival, would be formally tested only if previous tests were significant.
Although atezolizumab is no longer available in this setting for U.S. clinicians to prescribe, it still has the approval of the European Medicines Agency, he noted.
What Next?
Dr. Brufsky is interested in seeing the survival analysis of the subset of patients who experienced disease progression within 12 months. For this subgroup, there did not appear to be any benefit to pembrolizumab.
The future of immunotherapy as first-line treatment of metastatic triple-negative breast cancer is likely to involve combinations. “We will probably use checkpoint inhibitors as the backbone and possibly add other immune-targeted drugs, such as anti-TIGIT or anti-LAG 3 antibodies. We will also be looking for ways to turn ‘cold’ tumors into ‘hot’ tumors with a variety of other approaches.”
DISCLOSURE: Dr. Brufsky has served as a consultant or advisor to AbbVie, Agendia, Bayer, Biotheranostics, Daiichi Sankyo/Lilly, Eisai, Genentech/Roche, Immunomedics, Merck, Michael J. Hennessy and Associates, Myriad Pharmaceuticals, OncLive, Novartis, Pfizer, Puma Biotechnology, Seattle Genetics, and Tyme; and has provided expert testimony on behalf of Pfizer.
REFERENCES
1. Rugo HS, et al: KEYNOTE-355. ESMO Congress 2021. Abstract LBA16. Presented September 19, 2021.
2. Emens LA, et al: IMpassion130. ESMO Congress 2020. Abstract LBA16. Presented September 19, 2020.
3. Miles DW, et al: Primary results from IMpassion131, a double-blind placebo-controlled randomised phase III trial of first-line paclitaxel ± atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer. ESMO Virtual Congress 2020. Abstract LBA15. Presented September 19, 2020.
