Future of checkpoint blockade in triple-negative breast cancer: combination strategies to lead the way
Authors: M.L. Telli, S. Vinayak
Journal: Annals of Oncology (2019)

Increasing evidence points to an important role of the immune response in the prognosis and treatment of triple-negative breast cancer (TNBC) [1.Adams S. Gray R.J. Demaria S. et al.Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199.J Clin Oncol. 2014; 32: 2959-2966Crossref PubMed Scopus (897) Google Scholar, 2.Denkert C. von Minckwitz G. Brase J.C. et al.Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers.J Clin Oncol. 2015; 33: 983-991Crossref PubMed Scopus (725) Google Scholar, 3.Loi S. Sirtaine N. Piette F. et al.Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98.J Clin Oncol. 2013; 31: 860-867Crossref PubMed Scopus (1150) Google Scholar]. Following early successes of monoclonal antibody therapies targeting the programmed cell death (PD)-1/programmed cell death ligand-1 (PD-L1) axis in melanoma and lung cancer, among others, the field forged forward rapidly with evaluation of these drugs in the treatment of advanced TNBC. The phase I KEYNOTE-012 study of the anti-PD-1 antibody pembrolizumab in PD-L1-positive metastatic TNBC reported an objective response rate (ORR) of 18.5% and a median overall survival (OS) of 11.2 months in a primarily pre-treated cohort of 32 patients [4.Nanda R. Chow L.Q. Dees E.C. et al.Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study.J Clin Oncol. 2016; 34: 2460-2467Crossref PubMed Scopus (987) Google Scholar]. Notably, all responses were seen in patients with prior chemotherapy exposure in the advanced disease setting. A larger phase I study of the anti-PD-L1 antibody atezolizumab as monotherapy in advanced TNBC, irrespective of PD-L1 expression, reported an ORR of 9.6% and median OS of 8.9 months, with higher rates of response seen in patients treated in the first-line setting (ORR = 24%) and in those with PD-L1 expression in the immune cell compartment (ORR = 12%) [5.Emens L.A. Cruz C. Eder J.P. et al.Long-term clinical outcomes and biomarker analyses of atezolizumab therapy for patients with metastatic triple-negative breast cancer: a phase 1 study.JAMA Oncol. 2018; (Sep 13 [Epub ahead of print] doi 101001/jamaoncol20184224)Google Scholar]. While overall activity was modest in this unselected phase I population, this trial and others suggested the promise of more prolonged durability of response in the numerically small population of patients achieving an objective response. Based on this possibility, Genentech/Roche moved from their phase I program directly into a phase III randomized trial of nab-paclitaxel combined with atezolizumab or placebo in the first-line treatment of metastatic TNBC, after obtaining preliminary safety and efficacy data for the combination [6.Adams S. Diamond J.R. Hamilton E. et al.Atezolizumab plus nab-paclitaxel in the treatment of metastatic triple-negative breast cancer with 2-year survival follow-up: a phase 1b clinical trial.JAMA Oncol. 2018; (Oct 19 [Epub ahead of print] doi 101001/jamaoncol20185152)Crossref PubMed Scopus (181) Google Scholar]. The results of this trial, IMpassion 130 (NCT02425891), were recently reported and are significant in that they are the first randomized data from a phase III trial for this indication [7.Schmid P. Adams S. Rugo H.S. et al.Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer.N Engl J Med. 2018; 379: 2108-2121Crossref PubMed Scopus (2303) Google Scholar]. In this study, atezolizumab benefit was only seen in the 41% of the patient population whose tumors expressed PD-L1 in least 1% of the immune cell compartment. In this group, ORR was 58.9%, median progression-free survival (PFS) 7.5 months and preliminary interim OS 25 months with combined therapy, and this corresponded to a median PFS improvement of 2.5 months over nab-paclitaxel and placebo. Overall survival differences between arms are preliminary and non-significant at this first reported analysis. Follow-up of the overall survival results of IMpassion 130 is eagerly awaited, as are the results of the phase III KEYNOTE 355 study of chemotherapy plus pembrolizumab or placebo in the first-line treatment of advanced TNBC (NCT02819518). In this issue of Annals of Oncology, Adams et al. [8.Adams S. Loi S. Toppmeyer D. et al.Pembrolizumab monotherapy for previously untreated, PD-L1-positive, metastatic triple-negative breast cancer: cohort B of the phase II KEYNOTE-086 study.Ann Oncol. 2019; 30: 405-411Abstract Full Text Full Text PDF PubMed Scopus (332) Google Scholar, 9.Adams S. Schmid P. Rugo H.S. et al.Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study.Ann Oncol. 2019; 30: 397-404Abstract Full Text Full Text PDF PubMed Scopus (418) Google Scholar] report phase II data from the KEYNOTE-086 trial of pembrolizumab monotherapy in unselected previously treated (cohort A) and PD-L1-positive previously untreated (Cohort B) metastatic TNBC. KEYNOTE-086 cohort A included 170 women with metastatic TNBC, who were notably heavily pre-treated in the metastatic setting (43.5% with ≥3 prior lines of therapy) and included patients with both PD-L1 positive (61.8%) and negative tumors. The ORR was 5.3%, and there was no improvement in the biomarker selected PD-L1-positive population (ORR = 5.7%). Median OS was 9 months and the duration of response had not been reached at the time of data cut-off. Unfortunately, pembrolizumab monotherapy activity seen in cohort A was disappointing, far less than observed in KEYNOTE-012, which also included a similarly heavily pre-treated metastatic TNBC population (25% with ≥5 prior lines of therapy); however unlike cohort A, KEYNOTE-012 restricted eligibility to only PD-L1-positive patients. On the contrary, KEYNOTE-086 cohort B focused on pembrolizumab monotherapy in a selected population of 84 women with metastatic TNBC, with no prior systemic therapy for metastatic disease, and all patients had PD-L1-positive tumors. The ORR of 21.4% was numerically better when compared with cohort A, median duration of response was 10.4 months, and median OS was 18 months. These two cohorts of KEYNOTE-086 provide further evidence that the use of checkpoint inhibitor therapy early in the course of advanced disease is superior to later line treatment. Delving deeper into subgroups in these relatively small cohorts, both cohorts A and B showed non-significant but consistent enrichment of responses among patients that had less metastatic disease burden (<3 organ sites), non-visceral disease only, lymph node metastases only, and no liver metastases. Moreover, use of PD-L1 as an integral biomarker to select the eligible patient population in cohort B, but not in cohort A, adds to the heterogeneity of patients included, and is an important consideration when interpreting these results. Currently, there are several issues regarding the use of PD-L1 immunohistochemistry as a potential biomarker of checkpoint inhibitor therapy response. There is significant inconsistency among reported clinical trials in the use of various PD-L1 antibodies, staining of tumor versus immune cells, cut-offs for positive expression, and type of tissue used for testing (primary versus metastatic). Identification of a robust immunologic biomarker that can predict checkpoint inhibitor therapy response remains a challenge. While we await results of KEYNOTE-355 and, importantly, an additional phase III trial of pembrolizumab versus chemotherapy of physician's choice in the second- and third-line treatment of metastatic TNBC (KEYNOTE-119; NCT02555657), based on the available data in hand at this juncture, it seems doubtful that monotherapy will ever have a role in any line in the treatment of metastatic TNBC. Unlike in non-small-cell lung cancer where pembrolizumab monotherapy is a preferred approach for approximately 30% of the first-line patients with high-level PD-L1 expression on tumor cells (≥50%) based on major improvements in PFS and OS compared with combination chemotherapy [10.Reck M. Rodriguez-Abreu D. Robinson A.G. et al.Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.N Engl J Med. 2016; 375: 1823-1833Crossref PubMed Scopus (6288) Google Scholar], metastatic TNBC is simply a different disease. High-level PD-L1 expression is uncommon in this disease, and while important phase III data are outstanding, it appears at present that combined therapy earlier in the course of advanced disease is superior on all accounts. While there is considerable controversy around PD-L1 as the optimal biomarker for patient selection, it seems unlikely that another biomarker or biomarkers could identify a clinically important subset of patients where monotherapy would be a preferred approach. To realize the potential PD-1 and PD-L1 blockade in advanced TNBC, the future will belong to combinatorial strategies. It seems that the promise of monotherapy treatment as a viable strategy may be over before it started. None declared.