Immune Checkpoint Agents Advance in Breast Cancer

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.”

Active as Monotherapy

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.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.

Encouraging Results in Combination

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).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.

Following on these results, the phase III IMpassion130 study randomized 900 patients with untreated metastatic TNBC to atezolizumab plus nab-paclitaxel or placebo plus nab-paclitaxel. The coprimary endpoints of the study are PFS and OS, and the trial reached full accrual in the first half of 2017, according to Adams (NCT02425891).

Along with demonstrating efficacy in the metastatic setting, the checkpoint inhibitors also appear to be beneficial prior to surgery for patients with early stage breast cancer. In the phase II I-SPY 2 trial,⁶ 249 patients with invasive disease were adaptively randomized to receive weekly paclitaxel alone (n = 180) or in combination with pembrolizumab (n = 69) followed by doxorubicin plus cyclophosphamide for 4 cycles.

Potential Shown in Rare Subtype

The pathologic CR (pCR) rate with pembrolizumab was 34.2% versus 13.6% in the control arm for women with HR+/HER- disease. In the TNBC group, the pCR was 62.4% with the pembrolizumab combination and 22.3% in the control arm, representing >99.9% probability of superiority and 99.3% probability of success in a phase III study.Most subtypes of breast cancer express PD-L1 on TILs, but metaplastic breast cancer (MPBC) frequently has the ligand directly on the tumor cells. In a study of 75 MPBC samples, 46% expressed PD-L1 on the tumor cells. In anecdotal findings, researchers observed a dramatic response in a patient with recurrent MPBC treated with pembrolizumab. In this experience, Adams said, there was eradication of a large tumor mass and visceral metastases.

Adams mentioned the DART trial exploring anti—CTLA-4 inhibition with ipilimumab (Yervoy) in combination with nivolumab (Opdivo) across a variety of rare tumors, including MPBC. The study was previously linked with the MATCH trial and is currently enrolling at more than 600 sites. Given the promising results seen with that combination, she encouraged patients with MPBC to enroll in the study (NCT02834013).

References

1. Schmid P, Cruz C, Braiteh FS, et al. Atezolizumab in metastatic triple-negative breast cancer: long-term clinical outcomes and biomarker analyses. Abstract presented at: AACR Annual Meeting 2017; April 1-5, 2017; Washington DC. Abstract 2986.
2. Adams S, Schmid P, Rugo HS, et al. Phase 2 study of pembrolizumab (pembro) monotherapy for previously treated metastatic triple-negative breast cancer (mTNBC): KEYNOTE-086 cohort A. J Clin Oncol. 2017;35 (suppl; abstr 1008).
3. Adams S, Loi S, Toppmeyer D, et al. Phase 2 study of pembrolizumab as first-line therapy for PD-L1—positive metastatic triple-negative breast cancer (mTNBC): Preliminary data from KEYNOTE-086 cohort B. J Clin Oncol. 2017;35 (suppl; abstr 1088).
4. Nanda R, Liu MC, Yau C, et al. Pembrolizumab plus standard neoadjuvant therapy for high-risk breast cancer (BC): Results from I-SPY 2. J Clin Oncol. 2017; 35 (suppl; abstr 506).
5. Tolaney S, Savulsky C, Aktan G, et al. Phase 1b/2 study to evaluate eribulin mesylate in combination with pembrolizumab in patients with metastatic triple-negative breast cancer. Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Abstract P5-15-02.
6. Adams S, Diamond JR, Hamilton EP, et al. Phase Ib trial of atezolizumab in combination with nab-paclitaxel in patients with metastatic triple-negative breast cancer (mTNBC). J Clin Oncol. 2016;34 (suppl; abstr 1009).