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Immune Checkpoint Agents Advance in Breast Cancer

Silas Inman @silasinman
Published: Wednesday, Jul 26, 2017

Sylvia Adams, MD
Sylvia Adams, MD
With the prospect of phase III data that could confirm their efficacy, checkpoint inhibitors against PD-1 and PD-L1 have shown promise, both as monotherapies and in combination with chemotherapy for patients with triple-negative breast cancer (TNBC), Sylvia Adams, MD, said during a presentation at the 16th Annual International Congress on the Future of Breast Cancer East.

“We think there is definitely value for immune checkpoint blockade in triple-negative disease. When you look at the metastatic trials, while the response rates are relatively low, most of the responses are durable,” said Adams, from the NYU Langone Medical Center. “For patient selection, it is important to consider the line of therapy. The earlier the better.”

The presence of tumor infiltrating lymphocytes (TILs) is often associated with response to PD-1 or PD-L1. In breast cancer, PD-L1 expression is almost exclusively seen on TILs and not the tumor cells. Consequently, PD-L1 expression is highest in patients with TNBC, inflammatory breast cancer, and ductal carcinoma in situ. At present, the most promising results have been observed in the TNBC population, with early findings showing promise in the neoadjuvant space.

Active as Monotherapy

Reported findings from a few early phase studies show that the PD-1 inhibitor pembrolizumab (Keytruda) and the PD-L1 inhibitor atezolizumab (Tecentriq) have shown durable responses, with higher rates seen in the earlier settings for those with metastatic TNBC.

Researchers have explored atezolizumab monotherapy in a phase I study for women with metastatic TNBC in the frontline or pretreated setting.1 The objective response rate (ORR) in the frontline setting (n = 19) was 26%. In the second-line group (n = 28), the ORR was 4% and in the third-line and beyond (n = 65) the ORR was 8%.

In this study, which had the longest follow-up for a study of a checkpoint inhibitor in breast cancer, the 1- and 2-year overall survival (OS) rates in the frontline setting were 63% and 47%, respectively. For those who received 2 or more lines of prior therapy, OS rates were 37% and 18%, respectively.

In results from the phase II KEYNOTE-086 trial, researchers assessed pembrolizumab at 200 mg every 3 weeks in patients with metastatic TNBC as a first-line therapy in cohort B (n = 52) and heavily pretreated patients in cohort A (n = 170).2,3 Sixty percent of patients had PD-L1–positive tumors in cohort A and all patients tested positive in the cohort B.

ORR was 4.7% (95% CI, 2.3%-9.2%) with single-agent pembrolizumab in cohort A, including a complete response (CR) rate of 0.6%.2 PD-L1 status was not associated with response, with ORRs of 4.8% and 4.7% in the PD-L1–positive and –negative groups, respectively.

In cohort B of the study,3 the ORR was 23%, with a CR rate of 4%. The 3-month progression-free survival (PFS) rate was 41% and the 6-month rate was 28%. The median PFS was 2.1 months (95% CI, 2.0-3.9).

Encouraging Results in Combination

Building on the positive outcomes observed with monotherapy, researchers are now considering checkpoint inhibitors in combination with chemotherapy. Adams noted that there is preclinical evidence suggesting synergy between chemotherapy and immunotherapy, with other combination potentials on the horizon.

"It will be the future of breast cancer to combine immunotherapy with other targeted therapies, radiation therapy, and other agents," she added. "One of the unanswered questions is which is the best combination partner. Some of the chemotherapies are more immunogenic than others."

A phase Ib/II study explored pembrolizumab plus eribulin (Halaven) for patients with metastatic TNBC.4 Half of enrolled patients had not received prior chemotherapy and 43.6% were PD-L1–positive. In 39 evaluable patients at an interim analysis of the study, the ORR with the combination was 33.3% (95% CI, 19.5%-48.1%). The CR rate was 2.6% and 28.2% of patients had stable disease for ≥8 weeks, of which 7.7% was for ≥24 weeks.

The phase III KEYNOTE-355 study is currently exploring the safety and efficacy of pembrolizumab plus chemotherapy as a first-line therapy for patients with locally recurrent inoperable or metastatic TNBC. The trial plans to enroll 858 patients (NCT02819518).

Upfront treatment with atezolizumab plus nab-paclitaxel (Abraxane) showed a confirmed ORR of 46% in patients with metastatic TNBC (n = 13; 95% CI, 19-75) in one phase Ib trial.5 The complete response in the frontline setting was 8%. Across all lines of treatment (n = 32), the ORR was 38%, with a CR rate of 3%. The PFS and OS data were not yet mature.

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