Pembrolizumab (Keytruda) in combination with chemotherapy demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with chemotherapy alone as a first-line treatment for patients with metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1.
The results of the KEYNOTE-355 clinical trial in women with untreated locally recurrent inoperable or metastatic TNBC showed that among the patients with PD-L1 expression of combined positive score (CPS) ≥10, the median PFS was 9.7 months with pembrolizumab plus chemotherapy versus 5.6 months with chemotherapy alone (hazard ratio [HR], 0.65; P = .0012).
The 6-month PFS rates were 65% in the pembrolizumab plus chemotherapy arm versus 46.9% in the chemotherapy-alone arm. At 12 months, the PFS rates were 39.1% and 23.0%, respectively, said Javier Cortés, MD, PhD, Head, Breast Cancer Unit, IOB Institute of Oncology, Quiron Group, Madrid and Barcelona, Spain, at the ASCO 2020 annual meeting.
“These findings suggest a role for the addition of pembrolizumab to standard chemotherapy for the first-line treatment of metastatic TNBC,” said Dr Cortés.
The phase 2 KEYNOTE-086 trial had shown previously that pembrolizumab monotherapy had promising antitumor activity in patients with untreated PD-L1–positive metastatic TNBC.
In KEYNOTE-119, pembrolizumab monotherapy did not induce a significant improvement in survival compared with chemotherapy alone in treatment-naïve patients with metastatic TNBC, but a clear trend toward benefit with pembrolizumab was observed in patients with PD-L1 expression, and the response to pembrolizumab was more durable than the response to chemotherapy, he said.
The KEYNOTE-355 clinical trial included 847 patients (median age, 53 years) with untreated metastatic TNBC who had ≥6 months between treatment of curative intent and first disease recurrence. Patients were randomized in a 2:1 ratio to pembrolizumab plus chemotherapy (investigator’s choice of nab-paclitaxel, paclitaxel, or gemcitabine plus carboplatin) or to placebo plus chemotherapy. The patients were eligible to participate regardless of PD-L1 expression status. Crossover was not allowed.
In both arms, 75.1% of patients had a PD-L1 expression of ≥1, and 38.9% had a PD-L1 expression of ≥10. In both arms, 45% of patients received taxanes and 55% received gemcitabine plus carboplatin. At baseline, approximately 30% of the patients had de novo metastasis; approximately 50% had a disease-free interval of ≥12 months.
The median follow-up was approximately 26 months in each arm. In the intent-to-treat analysis of the entire cohort, regardless of PD-L1 status, the median PFS was 7.5 months in the pembrolizumab plus chemotherapy arm versus 5.6 months in the placebo plus chemotherapy arm (HR, 0.82). Statistical significance was not tested in the overall cohort. 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.
Although the addition of pembrolizumab resulted in a significant benefit in PFS in the subgroup of patients with CPS ≥10, the effect was less striking when the group was expanded to include patients with CPS ≥1. In this group, the median PFS was 7.6 months in the pembrolizumab plus chemotherapy arm and 5.6 months in the chemotherapy-alone arm, a difference that did not achieve a prespecified significance level of P = .001.
The 6-month PFS rates in this cohort were 56.4% and 46.6%, respectively, and the 12-month PFS rates were 31.7% and 19.4%, respectively.
Among patients with a PD-L1 expression of ≥10, the PFS advantage with pembrolizumab was preserved across most subgroups, with the exception of patients who had a previous disease-free interval of less than 12 months, although this group consisted of only 66 patients.
The overall survival data are not yet mature.
The rates of treatment-related adverse events of any grade were 96.3% in the pembrolizumab plus chemotherapy group and 95.0% in the placebo plus chemotherapy group.
Grades 3 to 5 treatment-related adverse events were reported in 68.1% and 66.9% of patients, respectively. Among patients receiving pembrolizumab, the rate of immune-mediated adverse events of any grade was 25.6%, and the rate of grades 3 to 5 was 5.2%.
“No patients died because of an immune-mediated event,” said Dr Cortés.
Catherine M. Kelly, MBBCh, BAO, MSc, FRCPI, Consultant, Medical Oncology, Mater Misericordiae University Hospital, Dublin, Ireland, discussed the study results. Similar to KEYNOTE-119, she said, as the PD-L1 expression, as measured by CPS, increases, so does the objective response rate as well as the duration of benefit with pembrolizumab in patients with metastatic TNBC, “and at a CPS ≥20, an exploratory analysis suggested an overall survival benefit.”
Regarding KEYNOTE-355, “What is clear in this study is that, again, we’re seeing the efficacy of pembrolizumab in combination with chemotherapy increases with increasing CPS,” Dr Kelly said.
She finished with some remaining questions arising from these data: What is the best antibody test to measure PD-L1 expression? What is the optimal PD-L1 cut point? Do patients with CPS between 1 and 10 benefit? What is the optimal chemotherapy partner? What is driving resistance and what is the difference between primary versus metastatic disease? If PD-1/PD-L1 inhibitors are approved in the neoadjuvant setting, what are the implications for their use in metastatic disease? These are questions that are awaiting responses.