Invited study discussant Lisa A. Carey, MD, the Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research and Deputy Director of Clinical Sciences at the University of North Carolina-Chapel Hill, framed her remarks as a tale of two trials.
Dr. Carey asked these questions: “Why did the results [of two IMpassion trials] diverge? Is it the chemotherapy partner? Do steroids, which must be given as premedication for at least part of paclitaxel treatment, impact on the immune checkpoint inhibitor’s effect? Did the trial populations differ? Is it the play of chance?”
Lisa A. Carey, MD
The potential for steroids to attenuate any benefit from immunotherapy is a “theoretical reason for concern” but is not supported by clinical trial data, she said. In patients with PD-L1-positive disease in KEYNOTE-355,1 pembrolizumab paired with a variety of chemotherapy backbones [paclitaxel, nab-paclitaxel, and carboplatin/gemcitabine] conveyed a significant improvement in progression-free survival, with a hazard ratio (0.65) similar to that of IMpassion130 (0.67).
“If anything, the taxane outperformed gemcitabine/carboplatin,” she said, acknowledging there could be differences in benefit between paclitaxel and nab-paclitaxel that may emerge in future analyses. Aside from the chemotherapy backbone, the three relevant first-line trials—IMpassion130, IMpassion131, and KEYNOTE-355—were similar in design and in outcomes, Dr. Carey said.
Finally, one must consider the potential for play of chance, Dr. Carey commented. “The IMpassion131 hazard ratio of 0.82 (95% confidence interval = 0.60–1.12) had a 95% confidence interval that did, in fact, overlap with the IMpassion131 and KEYNOTE-355 estimates. This is the reality of clinical research.”
The bottom line is that the addition of atezolizumab to paclitaxel did not improve progression-free or overall survival, and the reasons for this have yet to be determined, Dr. Carey concluded. “It might involve steroids, and it might be some heterogeneity in the population that we have not measured yet. We really don’t know.”
Clinical Implications
Based on the progression-free and overall survival advantages demonstrated in IMpassion131, Dr. Carey said her first-line preference for patients with PD-L1–positive metastatic triple-negative breast cancer is to prescribe atezolizumab plus nab-paclitaxel. Pembrolizumab plus chemotherapy did meet KEYNOTE-355’s progression-free survival endpoint, with a similar hazard ratio to atezolizumab, but the study has not yet provided overall survival data.
“Although you can say the taxane appeared to outperform gemcitabine/carboplatin in that study, you certainly cannot say that paclitaxel will have that effect. So, given the results of IMpassion131, if using pembrolizumab, I would partner it with nab-paclitaxel.”
DISCLOSURE: Dr. Carey has institutional financial interests with G1 Therapeutics, Genentech/Roche, Immunomedics, Innocrin, Lilly, Merck, Novartis, and Seattle Genetics.
REFERENCE
1. Cortes J, Cescon DW, Rugo HS, et al: KEYNOTE-355: Randomized, double-blind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer. ASCO20 Virtual Scientific Program. Abstract 1000.
