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Department of Medicine
Medical Director, Breast Oncology
Samuel Oschin Comprehensive Cancer Center
Cedars-Sinai Medical Center
Los Angeles, California
Heather McArthur, MD, MPH, has disclosed that she has received funds for research support from Bristol-Myers Squibb and Merck and consulting fees from AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Genentech, Genomic Health, Merck, Pfizer, and Puma.
On November 13, 2020, the FDA approved pembrolizumab plus chemotherapy for patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) that is PD-L1 positive (combined positive score [CPS] ≥ 10). This approval increases the number of meaningful options beyond chemotherapy for our patients with this challenging disease. Below, I discuss the clinical implications of this approval.
Data Leading to Approval
Pembrolizumab plus chemotherapy was approved based on positive results from the ongoing phase III KEYNOTE-355 trial. KEYNOTE-355 enrolled patients with advanced/metastatic TNBC who were previously untreated or had a disease-free interval for ≥ 6 months and randomized them to receive pembrolizumab plus chemotherapy vs placebo plus chemotherapy. Of importance, physicians could choose from 3 chemotherapy backbones: paclitaxel, nab‑paclitaxel, or gemcitabine and carboplatin. The primary endpoints are PFS and OS, but the OS data are not mature.
In the intention-to-treat population, median PFS was improved from 5.6 months with placebo plus chemotherapy to 7.5 months with pembrolizumab plus chemotherapy. This PFS benefit was especially pronounced in patients with PD-L1–positive tumors (CPS ≥ 10), for whom median PFS was 5.6 vs 9.7 months, respectively—translating to a statistically significant 35% reduction in risk for progression (P = .0012). No new safety signals were observed, with immune-mediated adverse events occurring in 25.6% of patients receiving pembrolizumab plus chemotherapy, although most events were low grade. Hypothyroidism had the highest incidence in the pembrolizumab arm (15.5%), followed by hyperthyroidism (4.8%) and pneumonitis (2.5%).
Clinical Implications: My Thoughts
One limitation of this regimen is that we do not yet know whether it has an OS benefit. This contrasts with the known OS benefit for atezolizumab plus nab-paclitaxel, which was approved in this setting based on the similarly designed phase III IMpassion130 trial. In previously untreated patients with PD-L1–positive metastatic TNBC, median OS was 25.0 months with atezolizumab plus nab-paclitaxel vs 15.5 months with placebo plus nab-paclitaxel.
One aspect that distinguishes the KEYNOTE‑355 trial from IMpassion130 is the flexibility in the chemotherapy backbone. This flexibility will allow physicians to make recommendations tailored to the needs of individual patients and to account for sensitivities or toxicities experienced with specific chemotherapies. This is particularly helpful during the ongoing COVID-19 pandemic, because we sometimes need to adjust doses, schedules, or drug selection.
New Approvals, New Challenges
Upcoming FDA decisions will address immune checkpoint inhibitor–based therapies for high-risk, early-stage TNBC. In 2021, the FDA will announce a decision based on the phase III KEYNOTE-522 trial. This trial found promising pathologic CR results with pembrolizumab plus chemotherapy compared with placebo plus chemotherapy in the neoadjuvant setting followed by pembrolizumab or placebo adjuvant therapy. The FDA will also evaluate atezolizumab plus chemotherapy based on improvements in pathologic CR observed in the IMpassion031 trial.
In contrast to the metastatic setting, the benefit of immune therapy in the curative-intent setting does not depend on PD-L1 expression. If these immune checkpoint inhibitor–based therapies are approved in 2021, it is plausible that most patients with early-stage TNBC will receive these therapies. This creates a clinical dilemma when progression occurs, as we do not yet have data informing treatment selection after immune checkpoint inhibitor–based therapy in this setting. There is also the challenge of overcoming primary and secondary resistance to checkpoint blockade.
Clinical trials focusing on these issues are under discussion, but I am not aware of studies open to accrual that specifically address this question. I want to underscore that the improved survival possible now in our patients with TNBC was made possible only because of the brave patients who participated in earlier clinical trials. Clinical trials are the only way we can move the field forward and improve clinical outcomes, so it is important that we continue to support these programs.
How do you plan to use pembrolizumab plus chemotherapy in your management of patients with advanced/metastatic TNBC? I encourage you to answer the polling question and post your thoughts and questions in the discussion box below.
Want to hear more from the experts on how to leverage immune-targeted therapies for managing patients with early stage through metastatic TNBC? Join Dr. Heather McArthur and her colleagues, Dr. Kevin Kalinsky and Dr. Rita Nanda, for a live Webinar on Tuesday, December 8, 2020, during the virtual SABCS 2020 conference. Please register here.