The final overall survival results from the KEYNOTE-355 study showed a statistically significant 27% reduction in the risk of death for patients with metastatic triple-negative breast cancer whose tumors were strongly positive for PD-L1, defined as a combined positive score (CPS) of at least 10 and who received pembrolizumab vs placebo combined with chemotherapy as first-line therapy. These findings provide strongsupport for this regimen as a standard of care for patients with PD-L1–positive triple-negative breast cancer, according to Hope S. Rugo, MD, FASCO, who presented the analysis at the European Society for Medical Oncology (ESMO) Congress 2021.¹

“These results support pembrolizumab in combination with chemotherapy as a new standard-of-care treatment regimen for metastatic triple-negative breast cancer strongly positive for PD-L1.”

— Hope S. Rugo, MD, FASCO

Tweet this quote

In this subset of patients with a CPS of at least 10, median overall survival was 23.0 months in the investigative arm vs 16.1 months in the control arm (hazard ratio [HR] = 0.73; 95% confidence interval [CI] = 0.55–0.95; P = .0093). Median progression-free survival was 9.7 months vs 5.6 months, respectively (HR = 0.66; 95% CI = 0.50–0.88).

“According to the prespecified statistical criteria (a P value boundary of .0113), pembrolizumab plus chemotherapy significantly improved overall survival compared with placebo and chemotherapy in patients with a CPS ≥ 10, with a P value of .0093. Consistent results were observed across patient subgroups, and findings for the key secondary endpoints of objective response rate, disease control rate, and duration of response also favored pembrolizumab/chemotherapy,” said Dr. Rugo, Professor of Medicine and Director of Breast Oncology and Clinical Trials Education at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center. “These results support pembrolizumab in combination with chemotherapy as a new standard-of-care treatment regimen” for this population, she added.

The cutpoint for PD-L1 expression was important: No benefit was reported for the addition of pembrolizumab by applying a cutoff of a CPS ≥ 1 or CPS > 0.

The current analysis was based on 44 months of median follow-up of 847 randomly assigned patients. The previous analysis, which occurred after about 26 months of -follow-up, led to the approval of pembrolizumab plus chemotherapy by the U.S. Food and Drug Administration for patients with locally recurrent unresectable or metastatic triple-negative breast cancer and a CPS ≥ 10.²

Pembrolizumab is now the sole immune checkpoint inhibitor approved in metastatic triple-negative breast cancer. Atezolizu-mab was withdrawn for this indication by Roche due to complexities in the statistical design and lack of confirmatory data; it had received prior accelerated approval based on IMpassion130.³

Building on Previous Findings

Findings from the previously reported second interim analysis of KEYNOTE-355 led to pembrolizumab’s accelerated approval in this setting in 2020.⁴ At a data cutoff of December 11, 2019, patients with a CPS ≥ 10 treated with pembrolizumab/chemotherapy had a median progression-free survival of 9.7 months, vs 5.6 months with chemotherapy alone (HR = 0.65; P = .0012), meeting one of the study’s primary endpoints.

The pembrolizumab treatment effect increased with PD-L1 enrichment. For patients with a CPS ≥ 1, the difference in median progression-free survival was no longer statistically significant, meaning that under the hierarchical design, any differences in the intention-to-treat population would not be formally tested. In both those subsets, median progression-free survival was approximately 7.5 months in the pembrolizumab arm and 5.6 months in the control arm.

During the ESMO Congress, Dr. Rugo presented the final analysis, which focused on overall survival. Formal statistical testing of other efficacy endpoints was completed in the prespecified interim analyses.

About KEYNOTE-355

Of 1,372 patients screened in the KEYNOTE-355 trial, 847 were randomly assigned to treatment: 566 to the pembrolizumab/chemotherapy group and 281 to the placebo/chemotherapy group. Chemotherapy options included nab-paclitaxel, paclitaxel, gemcitabine, and carboplatin.

Patients had relapsed at least 6 months after their treatment in the curative setting or had de novo metastatic disease. Although PD-L1 positivity was not a requirement for enrollment, 75% of patients had a CPS ≥ 1, and about 38% had a CPS ≥ 10. CPS is determined by the antibody 22C3 pharmDx assay and reflects PD-L1 positivity on tumor cells, lymphocytes, and macrophages.

The trial had two primary endpoints: progression-free survival and overall survival in patients with PD-L1–positive (a CPS ≥ 10 and a CPS ≥ 1) disease and in the intent-to-treat population.

In the population with a CPS ≥ 10, the addition of pembrolizumab significantly reduced the risk of death by 27%, reflecting almost a 7-month difference between the arms. Benefits were far less pronounced in the other two assessed populations. Median overall survival was 17.6 months vs 16.0 months for the CPS ≥ 1 group (HR = 0.86; P = .0563 [not significant]) and 17.2 vs 15.5 months, respectively, in the intention-to-treat group (HR = 0.89; 95% CI = 0.76–1.05 [not tested]).

For the group that had a CPS ≥ 10, a landmark analysis conveyed the clear benefit of adding pembrolizumab. At 18 months, within this population, 58.3% of patients treated with pembrolizumab/chemotherapy were alive vs 44.7% of those treated with chemotherapy alone; these rates at 24 months were 48.2% and 34.0%, respectively.

An update of the progression-free survival data showed the same benefits and hazard ratios as in the second interim analysis. Median progression-free survival for the population with a CPS ≥ 10 was 9.7 months vs 5.6 months (HR = 0.66; 95% CI = 0.50–0.88). In the latest analysis, the objective response rate was improved by 12% with the addition of pembrolizumab, and the disease control rate was improved as well to 65%, she said.

The median duration of response in the population with a CPS ≥ 10 was 12.8 months with pembrolizumab/chemotherapy and 7.3 months with chemotherapy alone. Similar differences between the arms were observed in the CPS ≥ 1 and intention-to-treat populations.

The benefit of the pembrolizumab addition was clear across virtually all subgroups. Although patients with a disease-free interval of less than 12 months appeared to benefit less, that subset was small (65 patients), and the trial was not powered to look for that difference. This finding, therefore, should be interpreted with caution, Dr. Rugo added.

Safety Profile

The final analysis identified no new safety signals. Grades 3 to 5 immune-related toxicities were observed in 5.3% of those given pembrolizumab vs 0% of those given placebo. Immune-mediated adverse events led to discontinuation of therapy in 2.8% vs 0%, respectively. The most common immune-related toxicities were thyroid-related (19.0%), followed by pneumonitis (2.5%). Two patients died of treatment-related toxicity in the pembrolizumab arm (one of pneumonia and the other of acute kidney injury). 

DISCLOSURE: Dr. Rugo has served as a consultant or advisor to Puma Biotechnology, Napo, and Samsung; has received institutional research funding from AstraZeneca, Ayala, Boehringer Ingelheim, Daiichi Sankyo, Genentech, Gilead, Lilly, Merck, Novartis, OBI Pharma, Pfizer, Polyphor, Sermonix, and Seattle Genetics.

REFERENCES

1. Rugo HS, Cortes J, Cescon DW, et al: KEYNOTE-355: Final results from a randomized, double-blind phase III study of first-line pembrolizumab + chemotherapy vs placebo + chemotherapy for metastatic triple-negative breast cancer. ESMO Congress 2021. Abstract LBA16. Presented September 19, 2021.

2. Cortés J, Cescon DW, Rugo HS, et al: KEYNOTE-355: Final results from a randomized, double-blind phase III study of first-line pembrolizumab plus chemotherapy vs placebo plus chemotherapy for metastatic TNBC. Ann Oncol 32:S1289-S1290, 2021.

3. Schmid P, Adams S, Rugo HS, et al: Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med 379:2108-2121, 2018.

4. Cortes J, Cescon DW, Rugo HS, et al: Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): A randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet 396:1817-1828, 2020.