Study Results Champion Keytruda/Chemo as ‘New Standard of Care’ in TNBC Subset

Keytruda (pembrolizumab) plus chemotherapy improved survival outcomes in patients with previously untreated, locally recurrent, inoperable or metastatic triple-negative breast cancer (TNBC), with a PD-L1 combined positive score (CPS) of 10 or higher, according to findings from the phase 3 KEYNOTE-355 clinical trial.

Trial findings, which were presented at the 2021 San Antonio Breast Cancer Symposium, showed that the Keytruda/chemotherapy regimen led to an average overall survival of 23 months, which is higher than the average overall survival of 16.1 months in patients who received chemotherapy plus placebo. At 18 months, 58.3% of patients receiving the Keytruda combo were alive, compared with 44.7% in the chemotherapy group.

Progression-free survival, which is the time a patient lives before their disease gets worse, was longer in the immunotherapy group, too, at an average of 9.7 months compared with 5.6 months in the Keytruda and chemotherapy alone groups, respectively. At the 12-month mark, 39.1% of patients administered Keytruda/chemotherapy were still alive without disease progression, compared with 23% in the placebo/chemotherapy group.

Furthermore, a PD-L1 CPS of at least 10 was found to be a reasonable cut-off to define the population of patients expected to derive the most benefit from this regimen. PD-L1 CPS measures the amount of PD-L1 protein — which is targeted by checkpoint blockade drugs like Keytruda — that is present in an individual’s cancer. These findings showed that patients with PD-L1 scores of 10 or higher had enough of the protein for the therapy to work effectively.

“These results provide further support for pembrolizumab in combination with chemotherapy as the new standard-of-care treatment regimen for patients with locally recurrent, unresectable or metastatic TNBC whose tumors express a PD-L1 CPS of 10 or more,” lead study author Dr. Javier Cortés, the head of breast cancer and gynecological cancers at Hospital Universitario Ramón y Cajal, in Madrid said in a presentation of the data.

Keytruda is currently approved by the Food and Drug Administration (FDA) for use in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS 10 or greater) as determined by an FDA-approved test. The November 2020 approval was based on earlier findings of the KEYNOTE-355 trial.

In the KEYNOTE-355 trial, the addition of Keytruda to chemotherapy resulted in a statistically significant and clinically meaningful improvement in both progression-free survival and overall survival compared to chemotherapy alone as a first-line treatment for patients with metastatic TNBC with a PD-L1 CPS of 10 or more. However, no statistically significant benefit in progression-free survival or overall survival was previously observed in a subgroup of patients with PD-L1 CPS of 1 or higher, and the benefit of the regimen was not tested in the intent-to-treat (ITT) population due to the prespecified testing strategy.

In the trial, investigators enrolled patients 18 years or older with central determination of TNBC and PD-L1 expression. Moreover, patients had to have previously untreated, locally recurrent, inoperable or metastatic disease; de novo metastasis or completion of treatment with curative intent within six months of first disease recurrence; and an ECOG performance status — which measures how much the disease impacts or limits daily living — of 0 or 1. Patients’ life expectancy had to exceed 12 weeks, and adequate organ function was required.

Those with active central nervous system metastasis, active autoimmune disease or who had been previously treated with systemic steroids were not eligible for enrollment.

Patients were randomized to receive either intravenous (IV) Keytruda plus chemotherapy (two-thirds of the population) or placebo plus chemotherapy (one-third of the population). Keytruda was administered at a dose of 200 milligrams (mg) every three weeks. Chemotherapy regimens included:

• Abraxane (nab-paclitaxel)
• Paclitaxel
• Gemcitabine/carboplatin

Furthermore, patients were stratified by chemotherapy regimen (taxane vs gemcitabine/carboplatin), PD-L1 tumor expression (CPS of 1 or greater vs CPS less than 1), and prior treatment with the same class of chemotherapy in the neoadjuvant or adjuvant setting (yes vs no).

The main goals of the study were to assess progression-free survival and overall survival in the PD-L1 CPS of 10 or higher, PD-L1 CPS of 1 or higher, and in the ITT populations. Secondary endpoints included objective response rate, duration of response, disease control rate and safety in all treated patients.

In this analysis, researchers sought to assess outcomes in subgroups of patients by additional CPS cut-offs.

Of the 847 total patients enrolled on the study, 566 were randomized to the Keytruda group compared with 281 who were randomized to the placebo group.

A total of 219 patients treated with Keytruda had a PD-L1 CPS of 10 or higher; 421 were treated and had a PD-L1 CPS of 1 or higher; and 562 were treated in the ITT population. Twenty-seven patients with a PD-L1 CPS of 10 or higher completed treatment while 189 discontinued, 35 patients with a PD-L1 CPS of 1 or higher completed treatment and 379 discontinued, and 39 patients in the ITT population completed treatment and 514 discontinued.

Among the 281 patients randomized to placebo, 103 were treated with a PD-L1 CPS of 10 or higher, 211 were treated with a PD-L1 CPS of 1 or higher, and 281 were treated in the ITT population. Five patients with a PD-L1 CPS of 10 or higher completed treatment and 95 discontinued, eight patients with a PD-L1 CPS of 1 or higher completed treatment and 200 discontinued, and 12 patients in the ITT population completed treatment and 264 discontinued.

Baseline characteristics between the two treatment groups were well balanced. The median age was 53 years (range, 22 to 85), and 41% and 38.4% of patients adminstered Keytruda and placebo, respectively, had an ECOG performance status of 1, meaning that they were restricted in strenuous physical activity, but were still able to carry out light and sedentary tasks, such as housework and office work. Additionally, 75.1% of patients in each group had a PD-L1 CPS of 1 or more; 38.9% and 36.7% of Keytruda- and placebo-treated patients, respectively, had a CPS of 10 or higher.

Furthermore, more than half of patients in each group received gemcitabine/carboplatin at 54.9% vs 54.8%, respectively.

Additional data showed that, at a median follow-up of 44 months with Keytruda, the median overall survival among the PD-L1 CPS of 1 or higher group was 17.6 months with Keytruda vs 16 months with placebo, and 17.2 months vs 15.5 months, respectively, in the ITT population. The 18-month progression-free survival rates with Keytruda in the PD-L1 CPS of 1 or higher and ITT groups were 48.4% and 47.8%, respectively; in the placebo groups, these rates were 41.4% and 41.8%, respectively.

Further analyses showed that the median overall survival for Keytruda vs placebo was 16.2 months vs 14.7 months, respectively, in those with a PD-L1 CPS of less than 1; 13.9 months vs 15.5 months, respectively, in those with a CPS of 1 to 9; 20.3 months vs 17.6 months, respectively, in those with a CPS of 10 to 19; and 24.0 months vs 15.6 months, respectively in those with a CPS of 20 or higher.

At a data cutoff date of June 15, 2021, the median progression-free survival among those with a PD-L1 CPS of 1 or higher was 7.6 months in the Keytruda group vs 5.6 months in the placebo group; the one-year progression-free survival rates were 31.7% and 19.4%, respectively. In the ITT population, the median progression-free survival was 7.5 months vs 5.6 months, respectively, and the one-year PFS rates were 29.3% and 20.8%, respectively.

When broken down further, the average progression-free survival for Keytruda vs placebo was 6.3 months vs 6.2 months, respectively, in those with a PD-L1 CPS of less than 1; 5.7 months vs 5.6 months, respectively, in those with a CPS of 1 to 9; 9.9 months vs 7.6 months, respectively, in patients with a CPS between 10 and 19; and 9.2 months vs 5.4 months, respectively in those with a CPS of 20 or higher.

In terms of safety, 96.3% of patients receiving Keytruda vs 95% of patients administered placebo reported treatment-related side effects of any severity; 68.1% vs 66.9%, respectively, had side effects reported as severe, life-threating or fatal. Serious side effects occurred in 17.8% of patients receiving Keytruda vs 12.1% of those administered placebo, and 18.3% vs 11% of patients, respectively, experienced a side effects that led to discontinuation of either study drug. Moreover, 0.4% of patients in the Keytruda group experienced a side effect that led to death.

The most common side effects reported in the Keytruda and placebo groups were anemia (49.1% vs 45.9%, respectively), neutropenia (41.1% vs 38.1%) and nausea (39.3% vs 41.3%).

Keytruda works by activating the patient’s immune system to find and fight cancer, which could lead to immune-mediated side effects. Immune-mediated side effects were reported in 26.5% of patients in the Keytruda group vs 6.4% of those receiving placebo. Additionally, 5.3% of patients in the Keytruda group experienced an immune-mediated side effect that was severe, life-threatening or fatal, 3.4% reported serious immune-related side effects, and 2.8% had an immune-mediated side effect that led to treatment discontinuation; these rates were 0% in the placebo group.

This article was originally published on OncLive as, “Pembrolizumab Plus Chemotherapy Represents New Standard of Care for Metastatic TNBC With PD-L1 CPS ≥10.”

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