November 13, 2020 - The FDA has granted an accelerated approval to pembrolizumab for use in combination with chemotherapy in the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer whose tumors express PD-L1 as determined by an FDA-approved test.
The FDA has granted an accelerated approval to pembrolizumab (Keytruda) for use in combination with chemotherapy in the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (combined positive score [CPS] ≥10) as determined by an FDA-approved test.
The regulatory agency also approved the PD-L1 IHC 22C3 pharmDx, developed by Dako North America, Inc, for use as a companion diagnostic to select patients with TNBC who may be appropriate candidates for the PD-1 agent.
The regulatory decision was was based on data from the KEYNOTE-355 trial (NCT02819518), which showed that at a median follow-up of 26.1 months, pembrolizumab plus chemotherapy resulted in a median progression-free survival (PFS) of 9.7 months (95% CI, 7.6-11.3) versus 5.6 months (95% CI, 5.3-7.5) with placebo/chemotherapy (HR, 0.65; 95% CI, 0.49-0.86; one-sided P =.0012).
Additionally, in patients whose tumors had a PD-L1 CPS of 1 or higher, the median PFS was reported to be 7.6 months with pembrolizumab/chemotherapy versus 5.6 months with chemotherapy alone (HR, 0.74; 0.61-0.90; P = .0014), although this was not determined to be statistically significant.
In the intent-to-treat (ITT) population, the median PFS with the pembrolizumab combination was 7.5 months versus 5.6 months with chemotherapy alone, translating to an 18% reduction in the risk of death (HR, 0.82; 95% CI, 0.69-0.97). Statistical significance was not evaluated in this patient population.
In the multicenter, double-blind, randomized, placebo-controlled trial investigators examined pembrolizumab in combination with investigator's choice of either nab-paclitaxel (Abraxane), paclitaxel, or gemcitabine/carboplatin compared with placebo plus 1 of the 3 chemotherapy agents in patients with previously untreated locally recurrent inoperable or metastatic TNBC.
To be eligible for enrollment, patients had to be at least 18 years of age, have central determination of TNBC and PD-L1 expression, and they had to have completed treatment with curative intent at least 6 months before their first disease recurrence. Patients also had to have an ECOG performance status of either 0 or 1, a life expectancy of 12 weeks or longer from randomization, acceptable organ function, no required use of systemic steroids, no central nervous system metastases, and had no active immune disease.
In part 1 of the trial, investigators examined the safety and tolerability of pembrolizumab in combination with 1 of the chemotherapy regimens in a total of 30 patients.
Part 2 evaluated 847 patients who were randomized 2:1 to receive either placebo (n = 281) or pembrolizumab (n = 566) at an intravenous (IV) dose of 200 mg on day 1 of each 21-day cycle in combination with either nab-paclitaxel at 100 mg/m2 IV on days 1, 8 and 15 of each 28-day cycle; paclitaxel at 90 mg/m2 IV on days 1, 8 and 15 of each 28-day cycle; or 1000 mg/m2 of gemcitabine and area under the curve (AUC) 2 of carboplatin on days 1 and 8 of each 21-day cycle. Notably, the trial was not designed to compare the efficacy of the different chemotherapy regimens. Treatment was continued until progressive disease or cessation of study therapy.
The coprimary end points of the trial included PFS and overall survival in patients with PD-L1–positive tumors and in the ITT population, while key secondary end points comprised objective response rate, duration of response, disease control rate, and safety. Baseline characteristics were observed to be balanced between the arms.
Additional findings from KEYNOTE-355 presented during the 2020 ASCO Virtual Scientific Program showed that the 1-year PFS rate was 39.1% with pembrolizumab/chemotherapy and 23.0% with chemotherapy alone in patients whose tumors had a PD-L1 CPS of 10 or higher; these rates were 65.0% and 46.9%, respectively, at 6 months. Notably, the PFS benefit observed in patients whose tumors had a PD-L1 CPS of 10 or higher was demonstrated across most subgroups analyzed, with the exception of those whose disease-free interval was 12 months or longer (HR, 1.00; 95% CI, 0.51-1.95).
For patients whose tumors had a PD-L1 CPS of 1 or higher, the 1-year PFS rates reported with pembrolizumab/chemotherapy and chemotherapy alone were 31.7% and 19.4%, respectively; the 6-month PFS rates were 56.4% and 46.6%, respectively.
In the ITT population, 1-year PFS rates were 29.8% with the addition of pembrolizumab versus 20.9% with chemotherapy alone; at 6 months, these rates were 55.4% and 47.8%, respectively. The PFS benefit with pembrolizumab was observed across subgroups analyzed in the ITT population and in those with a PD-L1 CPS of 1 or higher.
Additionally, patients who had a CPS of 20 or higher, also experienced substantial benefit from the combination, with a median PFS of 9.5 months (HR, 0.61; 95% CI, 0.43-0.87).
With regard to safety, the most commonly reported toxicities observed in patients who received the pembrolizumab/chemotherapy combination included fatigue, nausea, diarrhea, constipation, vomiting, alopecia, rash, cough, decreased appetite, and headache.
Additionally, the most common laboratory abnormalities that occurred in 20% of patients or more who received pembrolizumab plus chemotherapy included anemia, leukopenia, neutropenia, lymphopenia, thrombocytopenia, elevated alanine aminotransferase and aspartate transaminase, hyperglycemia, hypoalbuminemia, increased alkaline phosphatase, hypocalcemia, hyponatremia, hypophosphatemia, and hypokalemia.