Pembrolizumab added to chemotherapy extends OS in triple-negative breast cancer
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The addition of pembrolizumab to first-line chemotherapy led to statistically significant improvement in PFS and OS among patients with PD-L1-positive metastatic triple-negative breast cancer, according to results of the KEYNOTE-355 trial.
The clinically meaningful survival benefit of the combination appeared consistent across patient subgroups, Hope S. Rugo, MD, professor of medicine and director of breast oncology and clinical trials education at University of California, San Francisco, said after presenting updated results of the trial during the virtual ESMO Congress 2021.
“These results support [pembrolizumab plus chemotherapy] as a new standard-of-care treatment regimen for patients with locally recurrent, unresectable or metastatic [triple-negative breast cancer] whose tumors express PD-L1 with [a combined positive score] of 10 or more,” Rugo said.
Previous results of the randomized phase 3 KEYNOTE-355 trial showed statistically significant improvement in PFS with the addition of the anti-PD-1 therapy pembrolizumab (Keytruda, Merck) to chemotherapy as first-line treatment of patients with metastatic triple-negative breast cancer and a PD-L1 combined positive score (CPS) of 10 or greater. These results served as the basis for FDA approval of the combination for this patient population.
Part two of KEYNOTE-355 included 847 adults (median age, 53 years; 68% white) with previously untreated locally recurrent or metastatic triple-negative breast cancer and a disease-free interval of at least 6 months following chemotherapy completion for early-stage disease. Researchers randomly assigned 566 women to 200 mg pembrolizumab 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.
Baseline characteristics were well-balanced between the treatment groups, Rugo said. About 75% of patients had PD-L1 tumor expression with a CPS of 1 or greater, and 38% had a PD-L1 CPS of 10 or greater.
Stratification factors included chemotherapy type on study, PD-L1 tumor status (CPS of 1 or greater vs. less than 1) and prior treatment in the neoadjuvant or adjuvant setting with the same class of chemotherapy.
Although the study was not designed to compare the efficacy of the chemotherapy regimens, when asked which chemotherapy partner works best with pembrolizumab, Rugo said nab-paclitaxel and paclitaxel both are good options for patients without resistance to taxanes.
PFS and OS among patients with PD-L1-positive tumors and among the intention-to-treat population served as the primary endpoints. Secondary endpoints included objective response rate, duration of response, disease control rate and safety.
Data cutoff for the final analysis occurred June 15.
Median follow-up was approximately 44 months in both groups.
About 92% of patients discontinued treatment, mostly due to disease progression. Median duration of treatment was 26 weeks in the pembrolizumab group and 23 months in the placebo group.
Results showed median OS among of 23 months in the pembrolizumab group vs. 16.1 months in the placebo group (HR = 0.73; 95% CI, 0.55-0.95) among patients with a PD-L1 CPS of 10 or higher. The difference in OS among patients with a CPS of 1 or higher did not meet the prespecified criteria for statistical significance (17.6 months vs. 16 months; HR = 0.86; 95% CI, 0.72-1.04). Median OS in the intention-to-treat population was 17.2 months with pembrolizumab vs. 15.5 months with placebo (HR = 0.89; 95% CI, 0.76-1.05). Formal testing of statistical significance was not performed in this group.
A consistent survival benefit occurred across most subgroups, and updated PFS results appeared consistent with previously reported data.
Those with a CPS of 10 or higher derived the greatest ORR benefit with pembrolizumab vs. chemotherapy (52.7% vs. 40.8%), followed by patients with a CPS of 1 or higher (44.9% vs. 38.9%) and the intention-to-treat population (40.8% vs. 37%). Patients in all three groups also had longer duration of response with the pembrolizumab regimen.
Grade 3 or higher treatment-related adverse events occurred among 68.1% of patients in the pembrolizumab group and 66.9% of patients in the placebo group and included anemia, neutropenia and nausea. Treatment-related adverse events led to discontinuation among 18.3% of patients in the pembrolizumab group and 11% of patients in the chemotherapy group. Two patients in the pembrolizumab died due to treatment-related events.
Grade 3 or higher immune-mediated adverse events occurred among 5.3% of patients in the pembrolizumab group vs. no patients in the chemotherapy group.
“Safety was consistent with the known profiles or each regimen, with no new safety concerns,” Rugo said.
Perspective
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Immunotherapy has been a game changer in the treatment of cancer overall, but this is the first time it has been shown that immunotherapy, when added to chemotherapy, significantly improves OS among patients with triple-negative breast cancer who are PD-L1 positive (CPS 10 or greater). The KEYNOTE-355 trial previously had shown improvement in PFS, but with further follow-up/analysis, this survival benefit is very exciting.
Triple-negative breast cancer is a subtype of breast cancer for which we did not have targeted therapy. These are aggressive cancers for which we don’t have many great treatment options. Moreover, it is very rare for any combinations in metastatic breast cancer to show a survival benefit compared with single-agent therapy.
This trial looked at the benefit specifically of pembrolizumab in combination with standard chemotherapy (paclitaxel, nab-paclitaxel or gemcitabine plus carboplatin) in the front-line setting among 847 patients. The updated data being presented at ESMO shows that at median follow-up of 44 months, OS for patients with a CPS of 10 or higher was 16 months with single-agent chemotherapy vs. 23 months with the combination of chemotherapy and pembrolizumab. There was no OS benefit for patients with a CPS of 1 or higher, suggesting that greater PD-L1 enrichment is an important requirement. Of note, there were not more serious toxicities associated with the chemoimmunotherapy combination as compared with chemotherapy alone.
Perspective
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Yuan Yuan, MD, PhD
The OS results with pembrolizumab plus chemotherapy after median follow-up of nearly 4 years reconfirmed the benefit of immunotherapy in metastatic triple-negative breast cancer (TNBC) and are consistent with earlier PFS data that led to FDA approval. These data also echoed the EFS benefit seen in early-stage TNBC in the KEYNOTE-522 trial, when pembrolizumab was added to chemotherapy backbone in the neoadjuvant setting, which led to FDA approval for high-risk, early-stage TNBC. Researchers noted that benefit was seen only in the group with a CPS of 10 higher, which accounts for approximately 25% to 38% of metastatic TNBC.
There are a couple unanswered questions with the landscape shift of treatment in TNBC:
- Would patients still benefit from the pembrolizumab-chemotherapy combination if they have received pembrolizumab for treatment of early-stage TNBC and developed metastatic disease thereafter?
- Does the benefit extend to patients who had not had the opportunity to use pembrolizumab as front-line therapy? For example, what would be the efficacy when the combination is used beyond first-line therapy?
Future clinical trials are warranted to address these questions.
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Rugo HS, et al. Abstract LBA16. Presented at: European Society for Medical Oncology Congress (virtual meeting); Sept. 17-21, 2021.
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