Pembrolizumab/Chemo Nears EU Approval for Select TNBC With PD-L1 CPS ≥10

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion of pembrolizumab (Keytruda) plus chemotherapy in the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors have a PD-L1 combined positive score (CPS) of 10 or higher and who have not previously received chemotherapy for metastatic disease.¹

The recommendation is based on survival data from the phase 3 KEYNOTE-355 trial (NCT02819518), which demonstrated that the addition of the immunotherapy to nab-paclitaxel (Abraxane), paclitaxel, or gemcitabine/carboplatin resulted in a significant improvement in progression-free survival (PFS) and overall survival (OS) vs chemotherapy alone in this patient population.

At a median follow-up of 26.1 months, pembrolizumab plus different chemotherapy partners (n = 220) resulted in a median PFS of 9.7 months vs 5.6 months with chemotherapy alone (n = 205) in the subset of patients with a PD-L1 CPS of 10 or higher (HR, 0.65; 95% CI, 0.49-0.86; P = .0012). The 6-month PFS rates in the investigative and placebo arms were 65.0% and 46.9%, respectively; at 12 months, these rates were 39.1% and 23.0%, respectively.

In the subset of patients with a PD-L1 CPS of 1 or higher, pembrolizumab/chemotherapy (n = 425) resulted in a median PFS of 7.6 months vs 5.6 months with chemotherapy alone (n = 211; HR, 0.75; 95% CI, 0.61-0.90; P = .0014). The 6-month PFS rates in this subset were 56.4% and 46.6%, respectively; the 12-month rates were 31.7% and 19.4%, respectively.

In the ITT population, the median PFS in the investigative arm (n = 566) was 7.5 months vs 5.6 months in the control arm (n = 281; HR, 0.82; 95% CI, 0.69-0.97). The 6-month PFS rates were 55.4% and 47.8%, respectively, and the 12-month PFS rates were 29.8% and 20.9%, respectively.

OS data will be presented at the 2021 ESMO Congress.

“TNBC grows and spreads faster than other types of breast cancer and consequently has a worse prognosis,” Vicki Goodman, vice president of clinical research at Merck Research Laboratories, stated in a press release. “This positive CHMP opinion is an important step forward in bringing a new immunotherapy treatment opinion with [pembrolizumab] to appropriate patients in Europe with metastatic TNBC. Importantly, this treatment regimen can be used in combination with different chemotherapy agents. We look forward to the European Commission’s decision in the coming months.”

KEYNOTE-355 enrolled patients aged 18 years or older who had a central determination of TNBC and PD-L1 expression and had completed treatment with curative intent at least 6 months prior to their first disease recurrence. Patients needed to have an ECOG performance status of 0 or 1, a life expectancy of at least 12 weeks from randomization, and acceptable organ function.

If patients received systemic steroids, had active central nervous system metastases, or had active autoimmune disease, they were excluded.

Study participants were randomized 2:1 to receive either pembrolizumab plus chemotherapy or chemotherapy alone. Treatment was given until either progressive disease or study cessation. Patients were stratified based on chemotherapy received on study (taxane vs gemcitabine/carboplatin), PD-L1 expression (CPS ≥1 vs CPS <1), and whether prior treatment with the same class of chemotherapy was received in the neoadjuvant or adjuvant setting (yes vs no).

The primary end point of the trial was PFS in patients whose tumors had PD-L1 positivity (CPS ≥10 and CPS ≥1) and in the intention-to-treat (ITT) population, as well as OS in the same populations. Secondary end points comprised overall response rate (ORR), duration of response (DOR), disease control rate (DCR), and safety in all patients who received treatment.

Baseline characteristics were well balanced between the arms. The median age of patients was 53 years, 39.7% of patients had an ECOG performance status of 1, 75.1% had a PD-L1 CPS of 1 or higher, and 37.8% had a CPS of 10 or higher.

Approximately 45% of patients received a taxane on the study and 54.9% received gemcitabine/carboplatin. Most patients did not receive the same class of chemotherapy that they had received previously. Additionally, 29.7% of patients had de novo metastasis. Approximately 20% had a disease-free interval of less than 12 months, and 50% had an interval of 12 months or longer.

Earlier findings from KEYNOTE-355 presented during the 2021 ASCO Annual Meeting showed that any-grade treatment-related adverse effects (TRAEs) were experienced by 96.3% of patients who received pembrolizumab plus chemotherapy vs 95.0% of those who were given chemotherapy alone; grade 3 to 5 TRAEs were reported in 68.1% and 66.9% of patients, respectively.

Moreover, 0.4% of patients on the investigative arm experienced TRAEs that resulted in death vs no patients on the control arm. One patient died from acute kidney injury and another died from pneumonia. TRAEs resulted in discontinuation of any drug in 18.1% and 11.0% of those on the pembrolizumab/chemotherapy and chemotherapy-alone arms, respectively.

TRAEs reported in the investigative and control arms, respectively, included anemia (48.9% vs 45.9%), neutropenia (41.1% vs 38.1%), nausea (39.3% vs 40.9%), alopecia (33.1% vs 33.5%), fatigue (28.5% vs 29.5%), decreased neutrophil count (22.2% vs 26.3%), and increased alanine aminotransferase (20.5% vs 16.4%).

Immune-mediated toxicities were experienced by 25.6% of those who received pembrolizumab/chemotherapy and 6.0% of those who were given chemotherapy alone; grade 3 to 5 immune-mediated AEs were experienced by 5.2% and 0% of patients, respectively. None of these effects resulted in death, but 3.9% of those on the investigative arm and 1.1% of those on the control arm discontinued treatment because of these toxicities.

Immune-mediated AEs reported in the investigative and control arms, respectively, included hypothyroidism (15.5% vs 3.2%), hyperthyroidism (4.8% vs 1.1%), pneumonitis (2.5% vs 0%), colitis (1.8% vs 0.4%), and severe skin reactions (1.8% vs 0.4%).

References

1. Merck receives positive EU CHMP opinion for KEYTRUDA (pembrolizumab) in combination with chemotherapy for certain patients with locally recurrent unresectable or metastatic triple-negative breast cancer whose tumors express PD-L1 (CPS ≥ 10). News release. Merck. September 17, 2021. Accessed September 17, 2021. https://bit.ly/3nI3z0g
2. Cortes J, Cescon DW, Rugo HS, et al. KEYNOTE-355: randomized, double-blind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer. J Clin Oncol. 2020;38(suppl 15):1000. doi:10.1200/JCO.2020.38.15_suppl.1000