Combination pembrolizumab/chemo improves PFS in metastatic TNBC

Combining pembrolizumab with chemotherapy yielded a significant improvement in progression-free survival (PFS) compared with chemotherapy and placebo in patients with previously untreated, locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) that was PD-L1–positive, according to a randomized, phase III trial presented during the ASCO20 Virtual Scientific Program [1].

“Pembrolizumab monotherapy has shown antitumor activity and a manageable safety profile in patients with metastatic TNBC,” said Javier Cortés, MD, PhD, of the Vall d’Hebron Institute of Oncology, in Barcelona, who presented results of the KEYNOTE-355 trial. “The immunomodulatory properties of chemotherapy suggest that combining pembrolizumab with chemotherapy might enhance antitumor activity.”

The new study included 847 patients randomly assigned to receive either pembrolizumab plus chemotherapy (investigator’s choice of nab-paclitaxel, paclitaxel, or gemcitabine plus carboplatin; 566 patients) or placebo plus chemotherapy (281 patients).

The median age in both the pembrolizumab and placebo groups was 53 years. In both groups, 75.1% of patients had a PD-L1 combined positive score (CPS) ≥ 1. In the pembrolizumab group, 38.9% of patients had a CPS ≥ 10, compared with 36.7% in the placebo group. Chemotherapy was relatively evenly split between taxanes and the gemcitabine/carboplatin combination.

Among patients with a PD-L1 CPS ≥ 10, the median PFS was 9.7 months with pembrolizumab and 5.6 months with chemotherapy alone (HR 0.65, 95% CI [0.49, 0.86]; p = 0.0012). At 6 months, the PFS rate with pembrolizumab was 65.0%, compared with 46.9% without it. At 12 months, those rates were 39.1% and 23.0%, respectively.

Pembrolizumab was also better in the group with CPS ≥ 1, although this result did not meet the prespecified requirements for statistical significance. The median PFS in these patients was 7.6 months with pembrolizumab and 5.6 months without (HR 0.74, 95% CI [0.61, 0.90]; p = 0.0014, not meeting prespecified value of p = 0.00111). At 6 months, the groups had PFS rates of 56.4% and 46.6%, respectively; at 12 months, PFS was 31.7% and 19.4%, respectively.

In the intention-to-treat analysis of the full cohort, regardless of PD-L1 status, the median PFS was 7.5 months with pembrolizumab and 5.6 months with placebo (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.

Among patients with a PD-L1 CPS ≥ 10, the PFS benefit with pembrolizumab was preserved across most subgroups. The one exception was in patients with a prior disease-free interval of less than 12 months, although Dr. Cortés noted the small number of patients in this group (66 in total).

The rate of treatment-related adverse events (TRAEs) was similar between the groups, with 96.3% of patients experiencing any-grade TRAEs in the pembrolizumab group and 95.0% in the placebo group. Grades 3 to 5 TRAEs occurred in 68.1% and 66.9% of patients, respectively; events leading to discontinuation of any drug occurred in 18.1% of patients in the pembrolizumab group and in 11.0% in the chemotherapy-alone group.

“These findings suggest a role for the addition of pembrolizumab to standard chemotherapy for the first-line treatment of metastatic TNBC,” Dr. Cortés concluded.

Catherine M. Kelly, FRCPI, of Mater Misericordiae University Hospital, in Dublin, was the discussant for the study. She said that the lack of benefit seen in patients with CPS < 1 is consistent with the previously reported IMpassion130 trial, but not with KEYNOTE-522, suggesting the importance of higher PD-L1 expression, specifically, in the metastatic setting [2,3].

Dr. Kelly noted several remaining questions, including whether the specific chemotherapy partner matters, and whether those patients with PD-L1 CPS between 1 and 10 do derive benefit from the combination.

“Overall survival results are eagerly awaited, and needed, to fully establish the clinical utility of this combination,” Dr. Kelly said.

1. Cortes J, et al. ASCO Virtual Meeting, 29-31 May 2020, Abstract 1000.
2. Schmid P, et al. N Engl J Med. 2018;379(22):2108‐2121.
3. Schmid P, et al. N Engl J Med. 2020;382(9):810‐821.

Posted on 8 September 202022 February 2024