Pembrolizumab/Chemo Approved in Europe for Select Locally Recurrent Unresectable or Metastatic TNBC

The European Commission has approved pembrolizumab (Keytruda) plus chemotherapy for the frontline treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors have a PD-L1 expression combined positive score (CPS) of 10 or higher and who have not previously received chemotherapy for metastatic disease.¹

The regulatory decision is based on the final analysis of the phase 3 KEYNOTE-355 trial (NCT02819518), results of which demonstrated that pembrolizumab plus nab-paclitaxel (Abraxane), paclitaxel, or gemcitabine plus carboplatin significantly improved overall survival (OS) and progression-free survival (PFS) over chemotherapy alone in this population.

The median OS in the investigative and control arms was 23.0 months and 16.1 months, respectively (HR, 0.73; 95% CI, 0.55-0.95; P = .0093).² The median PFS with pembrolizumab plus chemotherapy was 9.7 months vs 5.6 months with chemotherapy alone (HR, 0.66; 95% CI, 0.50-0.88; P = .0018).

“This approval is an important milestone for appropriate patients with metastatic TNBC who are in need of new treatment options,” Javier Cortés, MD, PhD, head of the International Breast Cancer Center, Quironsalud Group, stated in a press release. “With this approval, patients in Europe with metastatic TNBC whose tumors express PD-L1 CPS of 10 or higher have a new immunotherapy treatment option that can be used in combination with different chemotherapy agents.”

KEYNOTE-355 enrolled previously untreated patients with locally recurrent inoperable or metastatic disease with PD-L1 expression. To be eligible for enrollment, patients needed to be at least 18 years of age, an ECOG performance status of 0 or 1, a life expectancy of 12 weeks or more from randomization, acceptable organ function, and acceptable organ function.

Patients could not have received systemic steroids, nor could they have active central nervous system metastases and active autoimmune disease.

A total of 847 study participants were randomized 2:1 to receive chemotherapy alone (n = 281) or pembrolizumab at 200 mg every 3 weeks and chemotherapy in the form of nab-paclitaxel at 100 mg/m2 on days 1, 8, 15 every 28 days; paclitaxel 90 mg/m2 on days 1, 8, 15 every 28 days; or gemcitabine at 1000 mg/m2 and carboplatin area under the curve 2 on days 1 and 8 every 21 days (n = 566). Treatment was continued until disease progression or cessation.

Stratification factors comprised chemotherapy received on the trial (taxane or gemcitabine/carboplatin), PD-L1 expression (CPS of 1 or higher vs CPS or less than 1), and previous treatment with same class of chemotherapy in the neoadjuvant or adjuvant setting (yes vs no).

The primary end points of the trial were PFS and OS in the patients with PD-L1–positive tumors, both the CPS or 10 or higher and 1 or higher subgroups, and the ITT population. Key secondary end points included objective response rate (ORR), duration of response (DOR), disease control rate (DCR), and safety in all treated patients.

The median age across the treatment arms was 53 years, 39.7% had an ECOG performance status of 1, and most patients did not receive their prior same class of chemotherapy. Regarding CPS scores, 75.1% of those in the investigative arm had a CPS of 1 or higher and 38.9% had a CPS of 10 or higher; in the control arm, these rates were 75.1% and 36.7%, respectively. Moreover, 45.2% of patients across the arms received taxane chemotherapy and 54.9% received gemcitabine plus carboplatin.

Additional data from the trial presented during the 2021 ESMO Congress showed that the 18-month OS rates in the investigative and control arms within the subgroup of patients with a PD-L1 CPS or 10 or higher were 58.3% and 44.7%, respectively; at 24 months, these rates were 48.2% and 34.0%, respectively. The 12-month PFS rates in this subgroup were 39.1% and 23.0%, respectively.

In the subgroup of patients with a PD-L1 CPS of 1 or higher, the median OS was 17.6 months in those who received pembrolizumab plus chemotherapy (n = 425) vs 16.0 months in those given chemotherapy alone (n = 211; HR, 0.86; 95% CI, 0.72-1.04; P = .0563). The 18-month OS rates in this subgroup were 48.4% in the investigative arm and 41.4% in the control arm; the 24-month rates were 37.7% and 29.5%, respectively.

The median PFS was 7.6 months with the chemoimmunotherapy combination vs 5.6 months with chemotherapy alone (HR, 0.75; 95% CI, 0.62-0.91). The 12-month PFS rates in the investigative and control arms were 31.7% and 19.4%, respectively.

In the ITT population, the median OS was 17.2 months with the pembrolizumab combination (n = 566) vs 15.5 months with chemotherapy alone (n = 281; HR, 0.89; 95% CI, 0.76-1.05). The 18-month OS rates were 47.8% vs 41.8%, respectively, and the 24-month rates were 35.5% and 30.4%, respectively. The median PFS was 7.5 months in the investigative arm vs 5.6 months in the control arm (HR, 0.82; 95% CI, 0.70-0.98). The 12-month PFS rates were 29.3% and 20.8%, respectively.

In the subset of patients with a PD-L1 CPS of 10 or higher, the pembrolizumab combination elicited an ORR of 52.7% vs 40.8% with chemotherapy alone. In the subset of those with PD-L1 CPS of 1 or higher, the ORRs in the investigative and control arms were 44.9% and 38.9%, respectively. In the ITT population, pembrolizumab plus chemotherapy induced an ORR of 40.8% vs 37.0% with chemotherapy alone.

The median DORs in the investigative and control arms in patients with a CPS of 10 or higher were 12.8 months (range, 1.6+ to 45.9+) and 7.3 months (range, 1.5 to 46.6+), respectively. In the subset of patients with a PD-L1 CPS of 1 or higher, the median DOR was 10.1 months (range, 1.0+ to 45.9+) with pembrolizumab plus chemotherapy vs 6.8 months (range, 1.5 to 46.6+) with chemotherapy alone. In the ITT population, the median DORs in the investigative and control arms were 10.1 months (range, 1.0+ to 45.9+) and 6.5 months (range, 1.5 to 46.6+), respectively.

The DCR in the PD-L1 CPS of 10 or higher subset was 65.0% with the chemoimmunotherapy combination vs 54.4% with chemotherapy alone. In the PD-L1 CPS of 1 or higher subsets, these rates were 58.6% and 53.6%, respectively; in the ITT population, these rates were 56.0% and 51.2%, respectively.

Safety proved to be consistent with what is known with each regimen, and no new signals were observed.

References

1. European Commission approves Merck’s KEYTRUDA (pembrolizumab) plus chemotherapy as treatment for certain patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC). News release. Merck. October 22, 2021. Accessed October 22, 2021. https://bit.ly/3C1U2FH
2. Cortés J, Cescon DW, Rugo HS, et al. KEYNOTE-355: final results from a randomized, double-blind phase 3 study of first-line pembrolizumab + chemotherapy vs placebo + chemotherapy for metastatic TNBC. Ann Oncol. 2021;32(suppl 5):S1289-S1290. doi:10.1016/j.annonc.2021.08.2089