Data confirm efficacy of pembrolizumab regimen for certain breast cancer subgroups
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The addition of pembrolizumab to first-line chemotherapy conferred clinically meaningful benefit to patients with inoperable or metastatic triple-negative breast cancer, according to results presented at San Antonio Breast Cancer Symposium.
A final analysis of the randomized phase 3 KEYNOTE-355 trial showed a PD-L1 combined positive score (CPS) of 10 or higher is “a reasonable cutoff” to identify the patient population most likely to derive benefit from the combination, researchers concluded.
“Several clinical trials have shown activity when combining pembrolizumab with chemotherapy among patients with triple-negative metastatic breast cancer,” Javier Cortes, MD, PhD, head of the breast cancer program at IOB Institute of Oncology in Spain, said during a presentation. “KEYNOTE-355 has shown that pembrolizumab plus chemotherapy resulted in a statistically significant improvement in PFS and OS compared with chemotherapy alone in the frontline setting in tumors that expressed PD-L1 and a CPS of 10 or higher.”
As Healio previously reported, part two of the phase 3 KEYNOTE-355 trial included 847 patients (median age, 53 years; 68% white) with previously untreated, locally recurrent inoperable or metastatic disease whose tumors expressed PD-L1.
Researchers randomly assigned 566 women to 200 mg pembrolizumab (Keytruda, Merck) every 3 weeks plus investigator’s choice of chemotherapy, including nab-paclitaxel (Abraxane, Celgene), paclitaxel or gemcitabine/carboplatin, for up to 35 administrations. The other 281 patients received chemotherapy alone.
Median follow-up was 44 months in both groups.
In the final analysis, Cortes and colleagues assessed outcomes in subgroups of patients with PD-L1 CPS of less than 1, 1 to 9, 10 to 19, and 20 or higher.
Baseline characteristics appeared well-balanced between treatment groups, Cortes said.
Results showed the improvement in median OS conferred by pembrolizumab increased as PD-L1 expression increased: CPS less than 1 (16.2 months vs. 14.7 months; HR = 0.97; 95% CI, 0.72-1.32); CPS 1 to 9 (13.9 months vs. 15.5 months; HR = 1.09; 95% CI, 0.85-1.4); CPS 10 to 19 (20.3 months vs. 17.6 months; HR = 0.71; 95% CI, 0.46-1.09); and CPS 20 or higher (24 months vs. 15.6 months; HR = 0.72; 95% CI, 0.51-1.01).
The improvement in median PFS with pembrolizumab also increased with higher PD-L1 expression: CPS less than 1 (6.3 months vs. 6.2 months; HR = 1.09; 95% CI, 0.78-1.52); CPS 1 to 9 (5.7 months vs. 5.6 months; HR = 0.85; 95% CI, 0.65-1.11); CPS 10 to 19 (9.9 months vs. 7.6 months; HR = 0.7; 95% CI, 0.44-1.09); and CPS 20 or higher (9.2 months vs. 5.4 months; HR = 0.62; 95% CI, 0.44-0.88).
Researchers reported no new safety signals.
“These results provide further support for pembrolizumab in combination with chemotherapy as a good treatment option and perhaps a new standard of care treatment regimen for certain patients with locally recurrent unresectable or metastatic triple-negative breast cancer whose tumors express PD-L1 with a CPS of 10 or higher,” Cortes said. “We still have so many unanswered questions, and future studies may help us better define the best group of patients who will achieve optimal benefit from the addition of immune checkpoint inhibitors not only in the metastatic disease setting but also in the early-stage setting.”
Perspective
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Hope S. Rugo, MD, FASCO
This trial demonstrated an improvement in PFS and OS in the 38% of patients who had PD-L1-positive disease defined by a CPS of 10 or greater. The data clearly demonstrated that a CPS of 10 is the optimal cutoff for differentiating benefit from pembrolizumab and confirming that pembrolizumab plus chemotherapy is the standard of care in this population. What are the questions for use of checkpoint inhibitor in patients with metastatic triple-negative breast cancer? Clearly, the test ordered should be matched to the planned checkpoint inhibitor, and we look forward to further data from KEYNOTE-355 about relative overlap. For excellent responders, can chemotherapy and eventually immunotherapy be discontinued, and when is it optimal? How long should we be continuing combination treatment and how long should we continue the checkpoint inhibitor alone? In my own clinical practice, among the excellent responders, it is difficult to know when to stop the checkpoint inhibitor but sometimes toxicity tells us the answer to that question. At some point, we need to stop therapy and understand what happens to those patients. Lastly, only 38% of patients benefited from pembrolizumab. How can we amplify the immune response in those patients who do not have PD-L1-positive disease to further extend this benefit, and can we extend the efficacy to other subtypes? There are ongoing studies evaluating this question. Perhaps we can understand the differential impact of PD-L1-positivity comparing primary to metastatic disease. Various studies are examining potential ways to amplify this response, including induction with chemotherapy, combinations with other immune-active agents, and combinations with antibody-drug conjugates, PARP inhibitors and radiation.
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Cortes J, et al. Abstract GS1-02. Presented at: San Antonio Breast Cancer Symposium (virtual meeting); Dec. 7-10, 2021.
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