Sharing their thoughts on KEYNOTE-355 were Amy Tiersten, MD, Professor of Medicine at Icahn School of Medicine at Mount Sinai, New York, and Erika Hamilton, MD, Director of the Breast and Gynecologic Research Program at Sarah Cannon Research Institute/Tennessee Oncology, Nashville, who presented the meeting’s Breast Cancer Highlights.
Amy Tiersten, MD
Erika Hamilton, MD
“It is very exciting to see that a checkpoint inhibitor has activity with chemotherapy agents other than nab-paclitaxel for front-line therapy of triple-negative breast cancer,” Dr. Tiersten said. “Currently, we have only randomized data for atezolizumab in combination with nab-paclitaxel. This regimen is limited in that, unfortunately, many of our patients with triple-negative breast cancer have a relatively short disease-free interval after completing neoadjuvant or adjuvant therapy containing a taxane. In these cases, it is an important option to treat them with alternative chemotherapy agents.”
Treatment Setting and PD-L1 Enrichment
In her discussion, Dr. Hamilton noted that the benefits of checkpoint inhibitors in triple-negative breast cancer are dependent on the treatment setting and, in some settings, PD-L1 enrichment.
“We have positive data in the neoadjuvant setting for all-comers in KEYNOTE-522, a 13.6% improvement in pathologic complete response.1 NeoTrip, however, failed to show an increase in pathologic complete response when atezolizumab was added to nab-paclitaxel and carboplatin.2 Whether this is due to the chemotherapy backbone, a different study population, or the drug itself remains unknown,” she said.
In the first-line metastatic setting, in both KEYNOTE-355 and IMpassion130,3 which evaluated atezolizumab, significant benefit was restricted to patients with PD-L1–expressing tumors. Checkpoint inhibition has not conferred benefit in unselected patients with metastatic disease in the first or later lines, nor has it done so in PD-L1–enriched patients in later lines, she said. “This isn’t surprising from a biologic point of view,” she noted, since primary tumors behave differently in terms of T-cell infiltrates, antigen presentation, and tumor microenvironment.
Risk for Immune-Related Toxicity
Dr. Hamilton questioned whether the benefit is great enough in early disease to justify the risk for immune-related adverse events. “Although I think we are quite comfortable using immunotherapy in the first-line metastatic setting, considering the benefit it provides, we need to think about these adverse events (some of which are irreversible and significant) for our patients who may conceivably be cured without the addition of immunotherapy,” she said.
“We can only accept additional toxicity when there is truly a significant improvement,” Dr. Hamilton concluded. “I argue that pathologic complete response is not enough. We likely need disease-free and overall survival benefits and very good shared decision-making conversations with patients.”
DISCLOSURE: Dr. Tiersten has received honoraria from Amgen and Tesaro; has served as a consultant or advisor to AstraZeneca, Eisai, Immunomedics, Novartis, Puma Biotechnology, and Roche/Genentech; has participated in a speakers bureau for Amgen and Tesaro; has received research funding from AstraZeneca, Genentech/Roche, Lilly, Novartis, and Pfizer; and has been reimbursed for travel, accommodations, or other expenses by Amgen and Tesaro. Dr. Hamilton has received consulting fees (paid to institution only) from Pfizer, Genentech/Roche, Lilly, Puma Biotechnology, Daiichi Sankyo, Mersana Therapeutics, Boehringer Ingelheim, AstraZeneca, Novartis, Silverback Therapeutics, Black Diamond, and NanoString; and has received institutional research support from Seattle Genetics, Puma, AstraZeneca, Hutchinson MediPharma, OncoMed, MedImmune, StemCentrx, Genentech/Roche, Curis, Verastem, Zymeworks, Syndax, Lycera, Rgenix, Novartis, Mersana, Millenium, TapImmune, Lilly, BerGenBio, Medivation, Pfizer, Tesaro, Boehringer Ingelheim, Eisai, H3 Biomedicine, Radius Health, Acerta, Takeda, MacroGenics, AbbVie, Immunomedics, FujiFilm, Effector, Merus, Nucana, Regeneron, Leap Therapeutics, Taiho Pharmaceutical, EMD Serono, Daiichi Sankyo, ArQule, Syros, Clovis, Cytomx, InventisBio, Deciphera, Unum Therapeutics, Sermonix Pharmaceuticals, Sutro, Aravive, Zenith Epigenetics, Arvinas, Torque, Harpoon, Fochon, Black Diamond, Orinove, Molecular Templates, Silverback Therapeutics, Compugen, G1Therapeutics, Karyopharm Therapeutics, and Torque Therapeutics.
1. Schmid P, Cortes J, Pusztai L, et al: Pembrolizumab for early triple-negative breast cancer. N Engl J Med 382:810-821, 2020.
2. Gianni L, Huang CS, Egle D, et al: Pathologic complete response to neoadjuvant treatment with or without atezolizumab in triple negative, early high-risk and locally advanced breast cancer: NeoTRIPaPDL1 Michelangelo randomized study. 2019 San Antonio Breast Cancer Symposium. Abstract GS3-04. Presented December 12, 2019.
3. Schmid P, Rugo HS, Adams S, et al: Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): Updated efficacy results from a randomised, double-blind, placebo-controlled, phase III trial. Lancet Oncol 21:44-59, 2020.
In the phase III KEYNOTE-355 trial, pembrolizumab combined with several chemotherapy partners yielded a statistically significant and clinically meaningful improvement in progression-free survival vs chemotherapy alone in patients with previously untreated locally advanced or metastatic...