Overall Survival with Pembrolizumab in Early-Stage Triple-Negative Breast Cancer

Author(s): Peter Schmid, M.D., Javier Cortes, M.D., Rebecca Dent, M.D., Heather McArthur, M.D., Lajos Pusztai, M.D., Sherko Kümmel, M.D., Carsten Denkert, M.D., Yeon Hee Park, M.D. https://orcid.org/0000-0003-4156-9212, Rina Hui, Ph.D., Nadia Harbeck, M.D., Masato Takahashi, M.D., Seock-Ah Im, M.D., Michael Untch, M.D., Peter A. Fasching, M.D., Marie-Ange Mouret-Reynier, M.D., Theodoros Foukakis, M.D. https://orcid.org/0000-0001-8952-9987, Marta Ferreira, M.D., Fatima Cardoso, M.D., Xuan Zhou, Ph.D., Vassiliki Karantza, M.D., Konstantinos Tryfonidis, M.D., Gursel Aktan, M.D., and Joyce O’Shaughnessy, M.D., for the KEYNOTE-522 Investigators*

Source: DOI: 10.1056/NEJMoa2409932

Dr. Anjan Patel's Thoughts

This study confirms what we saw in initial reports showing the addition of pembro increasing the rate of ypathological complete response (ypCR’s) in the neoadjuvant setting for triple-negative breast cancer (TNBC). New data shows a 5% improvement (87 vs 82%) in overall survival (OS) with the quadruplet. Higher gains but at higher cost of toxicity. The fact that adjuvant intraosseous (IO) does not seem to improve outcomes, but neoadjuvant chemo+IO does show intact tumor-immune interactions to create maximum treatment effectiveness is most likely real. Of note, this seems mostly independent of programmed death-ligand 1 (PDL1) status.

BACKGROUND

In patients with early-stage triple-negative breast cancer, the phase 3 KEYNOTE-522 trial showed significant improvements in pathological complete response and event-free survival with the addition of pembrolizumab to platinum-containing chemotherapy. Here we report the final results for overall survival.

METHODS

We randomly assigned, in a 2:1 ratio, patients with previously untreated stage II or III triple-negative breast cancer to receive neoadjuvant therapy with four cycles of pembrolizumab (at a dose of 200 mg) or placebo every 3 weeks plus paclitaxel and carboplatin, followed by four cycles of pembrolizumab or placebo plus doxorubicin–cyclophosphamide or epirubicin–cyclophosphamide. After definitive surgery, patients received adjuvant pembrolizumab (pembrolizumab–chemotherapy group) or placebo (placebo–chemotherapy group) every 3 weeks for up to nine cycles. The primary end points were pathological complete response and event-free survival. Overall survival was a secondary end point.

RESULTS

Of the 1174 patients who underwent randomization, 784 were assigned to the pembrolizumab–chemotherapy group and 390 to the placebo–chemotherapy group. At the data-cutoff date (March 22, 2024), the median follow-up was 75.1 months (range, 65.9 to 84.0). The estimated overall survival at 60 months was 86.6% (95% confidence interval [CI], 84.0 to 88.8) in the pembrolizumab–chemotherapy group, as compared with 81.7% (95% CI, 77.5 to 85.2) in the placebo–chemotherapy group (P=0.002). Adverse events were consistent with the established safety profiles of pembrolizumab and chemotherapy.

CONCLUSIONS

Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab resulted in a significant improvement, as compared with neoadjuvant chemotherapy alone, in overall survival among patients with early-stage triple-negative breast cancer. (Funded by Merck Sharp and Dohme, a subsidiary of Merck [Rahway, NJ]; KEYNOTE-522 ClinicalTrials.gov number, NCT03036488.)

Author Affiliations

From the Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, London (P.S.); International Breast Cancer Center, Pangaea Oncology, Quirónsalud Group, and Medical Scientia Innovation Research, Barcelona, and IOB Madrid, Institute of Oncology, Hospital Beata María Ana, and the Faculty of Biomedical and Health Sciences, Department of Medicine, Universidad Europea de Madrid, Madrid — all in Spain (J.C.); National Cancer Center Singapore, Duke–National University of Singapore Medical School, Singapore (R.D.); University of Texas Southwestern Medical Center (H.M.) and Baylor University Medical Center, Texas Oncology, Sarah Cannon Research Institute (J.O.) — both in Dallas; Yale School of Medicine, Yale Cancer Center, New Haven, CT (L.P.); the Breast Unit, Department of Gynecology with Breast Center, Kliniken Essen-Mitte, Essen (S.K.), Charité–Universitätsmedizin Berlin (S.K.) and the Breast Cancer Center, Helios Klinikum Berlin–Buch (M.U.), Berlin, the Institute of Pathology, Philipps University of Marburg and University Hospital Marburg, Marburg (C.D.), the Breast Center, Department of Obstetrics and Gynecology and Comprehensive Cancer Center Munich, LMU University Hospital, Munich (N.H.), and University Hospital Erlangen, Comprehensive Cancer Center Erlangen–European Metropolitan Region of Nuremberg, Erlangen (P.A.F.) — all in Germany; Samsung Medical Center, Sungkyunkwan University School of Medicine (Y.H.P.), and Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul National University (S.-A.I.) — both in Seoul, South Korea; Westmead Breast Cancer Institute, Westmead Hospital and the University of Sydney, Sydney (R.H.); the Center of Cancer Medicine, School of Clinical Medicine, University of Hong Kong, Hong Kong (R.H.); Hokkaido University Hospital, Sapporo, Japan (M.T.); Centre Jean-Perrin, Clermont-Ferrand, France (M.-A.M.-R.); the Department of Oncology–Pathology, Karolinska Institutet, and Breast Center, Theme Cancer, Karolinska University Hospital, Stockholm (T.F.); Instituto Português de Oncologia do Porto Francisco Gentil, Porto (M.F.), and the Breast Unit, Champalimaud Clinical Center–Champalimaud Foundation, Lisbon (F.C.) — both in Portugal; and the Department of Oncology, Merck, Rahway, NJ (X.Z., V.K., K.T., G.A.).

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Among 1,545 women included with a median follow-up of 9.4 years in postmenopausal women, breast cancer events occurred in 40 of 335 receiving low-dose tamoxifen versus 93 of 401 controls HR, 0.51, with a 10-year absolute reduction of 11.2%. Among premenopausal women, no significant reduction was observed dose was 5mg daily of 10mg every other day in ductal carcinoma in situ (DCIS) and high-risk pts. Less is as good.

Datopotamab deruxtecan in patients with untreated, advanced triple-negative breast cancer (TROPION-Breast02): a randomised, open-label, international, phase III trial

644 patients who are triple-negative breast cancer (TNBC) not candidates for immunotherapy were randomly assigned to receive Dato-DXd (n = 323) or chemotherapy (n = 321). Median progression-free survival (PFS) was 10.8 months with Dato-DXd and 5.6 months with chemotherapy. Median overall survival (OS) was 23.7 months and 18.7 months with Dato-DXd and chemotherapy, respectively HR 0.79; P = 0.029]. Treatment-related adverse events (TRAEs) of grade ≥3 were reported in 105 (33%) and 89 (29%) patients who received Dato-DXd and chemotherapy, respectively, they were more treatment discontinuation in the chemotherapy arm secondary to treatment related adverse events in 14 (4%) and 23 (7%) patients. There were no treatment-related deaths in either arm. New standard of care? Recall this is on patients not eligible for immunotherapy.

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Progression-free survival (PFS) was statistically significantly improved with addition of tucatinib versus placebo 24.9 v 16.3 months regardless of the presence/absence of BM or hormone receptor status.

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1467 pts with RS > 25 and 551 with clinically (neoadjuvant cohort in ADAPT-HR+/HER2-) or pathologically N2, (longer) docetaxel-based CTx showed better distant, invasive disease-free survival in N2-3 pts patients with RS ≤25, OS was also shown in pts with RS>25 anthracycline regimens did not show a significant survival difference in high-risk HR+/HER2 whether used in neoadjuvant or adjuvant setting. So may be no anthracycline for HR+ve pts who are high risk disease.