Pembrolizumab Receives FDA Approval for Advanced Triple-Negative Breast Cancer

On 13 November 2020, the United States Food and Drug Administration (FDA) granted accelerated approval for treating patients whose tumors are PD-L1 positive (CPS ≥10), with metastatic or locally recurrent unresectable triple-negative breast cancer, using chemotherapy together with pembrolizumab (Keytruda), an immunotherapy.

The FDA also approved PD-L1 IHC 22C3 PharmDx (Dako North America, Inc.) as an auxiliary genetic testing tool to help select patients with triple-negative breast cancer for pembrolizumab.

The KEYNOTE-355 Study

The approval for patients with locally recurrent unresectable or metastatic triple-negative breast cancer who had not previously received chemotherapy in the metastatic setting was based on a multicenter, double-blind, randomized, placebo-controlled clinical trial, KEYNOTE-355. Patients were randomized to receive pembrolizumab 200 mg on day 1 every 3 weeks by intravenous infusion or placebo in combination with different chemotherapy treatments (nab-paklitaksel or paklitaksel or gemsitabin plus karboplatin), in a 2:1 ratio.

The main efficacy outcome measure, assessed by blinded independent review and tested in the subgroup of patients with PD-L1 ≥10, was progression-free survival (PFS).

The Main Study Result

Median PFS in the pembrolizumab plus chemotherapy arm was 9.7 months (95% CI: 7.6, 11.3), and in the placebo arm 5.6 months (95% CI: 5.3, 7.5) (HR 0.65; 95% CI: 0.49, 0.86; one-sided p-value = 0.0012).

Side Effects

The most common (≥ 20%) side effects in patients receiving pembrolizumab plus chemotherapy in KEYNOTE-355 were fatigue, nausea, diarrhea, constipation, vomiting, alopecia, rash, cough, decreased appetite, and headache.

The most common (≥ 20%) laboratory abnormalities in patients receiving pembrolizumab plus chemotherapy were anemia, leukopenia, neutropenia, lymphopenia, thrombocytopenia, elevated ALT and AST, hyperglycemia, hypoalbuminemia, increased alkaline phosphatase, hypocalcemia, hyponatremia, hypophosphatemia, and hypokalemia.

Recommended Dose

For adult patients with locally recurrent unresectable or metastatic triple-negative breast cancer, the recommended dose of pembrolizumab, before chemotherapy, is 200 mg every 3 weeks or 400 mg every 6 weeks until disease progression, unacceptable toxicity, or up to 24 months.

When given with pembrolizumab, nab-paklitaksel is administered every 28 days on days 1, 8, and 15 at 100 mg/m2, or pankştaksel every 28 days on days 1, 8, and 15 at 90 mg/m2, or gemsitabin 1000 mg/m2 plus karboplatin AUC 2 mg/ml/min on days 1 and 8 every 21 days, by intravenous infusion.

Immunotherapies in Triple-Negative Breast Cancer

Previously, on 8 March 2019, the FDA had granted accelerated approval for the first-line treatment of PD-L1-positive, unresectable locally advanced or metastatic triple-negative breast cancer, together with nab-paklitalsek chemotherapy, to atezolizumab (Tecentriq). With the new Keytruda approval, 2 different immunotherapies had received approval in breast cancer. A notable difference between the earlier atezolizumab approval and the new pembrolizumab approval is that, while atezolizumab was approved for all PD-L1-positive cases, pembrolizumab was approved for patients with PD-L1 ≥10, and pembrolizumab can be used with chemotherapies other than nab-paklitaksel.

In triple-negative breast cancer, the reported median progression-free survival with the addition of atezolizumab to chemotherapy was 7.5 months, compared with 5 months in the placebo arm.