Passion for immune checkpoint blockade in triple negative breast cancer: Comment on the IMpassion130 study
Authors: M. Kok, E.P. Winer, S. Loi
Journal: Annals of Oncology (2018)

Phase I/II trials evaluating programmed cell death 1 protein (PD-1) blockade in metastatic triple negative breast cancer (TNBC) have shown low level antitumor activity (response rates 5%–10%) in unselected patient cohorts [1.Dirix L.Y. Takacs I. Jerusalem G. et al.Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1b JAVELIN Solid Tumor study.Breast Cancer Res Treat. 2018; 167: 671-686Crossref PubMed Scopus (438) Google Scholar, 2.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, 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: 1088Crossref Google Scholar]. Patients treated in the first-line setting or those with PD-L1-positive tumors appear to have a greater likelihood of response (18%–23%) [2.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, 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: 1088Crossref Google Scholar]. Importantly however, responses, when they occur, appear to be durable and can last for many years, illustrating the potential clinical benefit for patients with metastatic TNBC patients for whom the median overall survival is only 8–13 months [4.Metzger-Filho O. Tutt A. de Azambuja E. et al.Dissecting the heterogeneity of triple-negative breast cancer.J Clin Oncol. 2012; 30: 1879-1887Crossref PubMed Scopus (336) Google Scholar]. IMpassion130 is the first global phase III registration study to report results for the addition of atezolizumab, a PD-L1 inhibitor, to nab-paclitaxel in the first-line treatment of incurable, locally advanced or metastatic triple negative breast cancer [5.Schmid P. Adams S. Rugo H.S. et al.Atezolizumab and Nab-paclitaxel in advanced triple-negative breast cancer.New Engl J Med. 2018; (Oct 20 [Epub ahead of print] doi 101056/NEJMoa1809615)Crossref PubMed Scopus (2303) Google Scholar]. It randomized 902 patients from 41 countries around the world between 2015 and 2017. Notable inclusion criteria included a disease-free interval of 12 months or more from last day of adjuvant chemotherapy, no prior palliative systemic treatment and brain metastases, if present, needed to be treated and asymptomatic without corticosteroids. Patients were not required to have PD-L1-positive tumors, but PD-L1 status was used for stratification. PD-L1-positive (PD-L1+) was defined as expression of at least 1% on tumor-infiltrating immune cells (IC0 versus IC1/2/3) using the Ventana SP142 assay. Central laboratory confirmation of TNBC status was performed retrospectively. The statistical analytic plan was complex. The primary end point was progression-free survival (PFS) (by RECIST 1.1) [6.Eisenhauer E.A.1 Therasse P. Bogaerts J. et al.New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).Eur J Cancer. 2009; 45: 228-247Abstract Full Text Full Text PDF PubMed Scopus (18258) Google Scholar] in the intent-to treat (ITT) population tested after 600 PFS events. This end point, if meeting the pre-defined log rank P value (two-sided < 0.005), was followed by PFS testing in the PD-L1+ population (RECIST 1.1). If the first two analyses reached statistical significance, these analyses were followed by an interim overall survival (OS) look in the ITT, and then an interim OS look the PD-L1+ population. The final OS analysis is scheduled to occur 53 months after the first patient was entered on trial. The population enrolled had a median age of 55 years and 63% relapsed after prior adjuvant/neoadjuvant treatment (hence 37% were most likely de novo stage IV). Approximately 40% of the patients in the ITT population had PD-L1+ disease. Fifty percent had lung metastases. At a median follow-up of 12.9 months, median PFS in the ITT was significantly improved with the addition of atezolizumab [5.5–7.2 months; hazard ratio (HR) 0.80 (0.69–0.92); P = 0.0025). PFS benefit was also observed in the PD-L1+ subset [5.0–7.5 months; HR 0.62 (0.49–0.78); P < 0.001). Hence, an interim OS look was allowed and OS was observed to be trending positive in the ITT population [median 17.6–21.3 months; HR 0.84 (0.69–1.02); P = 0.08), with a numerically impressive median OS increase of 9.5 months in the PD-L1+ population [15.5–25 months; HR 0.62 (0.45–0.86)]. This improvement in survival represents one of the largest gains in trials of advanced TNBC to date, though it is noted that the OS data is still largely immature and will need to be confirmed with longer follow-up. There was minimal crossover to checkpoint agents by patients on the placebo arm, partially because this was intentionally prohibited by the study Sponsor. This study represents a significant milestone for the development of immune checkpoint blockade (ICB) in breast cancer. What is most impressive here, though perhaps not surprising, is the relatively larger increase in the interim OS results compared with the median PFS difference between the atezolizumab and placebo arms. This OS effect has been observed in other studies of ICB and prompted a study amendment to enlarge the sample size to provide the necessary power to look for a difference in OS. Overall, these results strongly suggest that the addition of atezolizumab does change the natural history of advanced TNBC, particularly for patients whose tumors are PD-L1 positive. We speculate that this OS effect could be due to the impact of atezolizumab on the local tumor microenvironment as well as on systemic immunity. As a consequence, treatment with atezolizumab undoubtedly influences response to subsequent lines of therapy. These results raise interesting questions for the development of immunotherapy in TNBC, and in breast cancer more generally. PD-L1 positivity (on the immune infiltrate) as measured by this particular assay seemed to predict greater magnitude of atezolizumab benefit. Further subgroup analyses did not show a great difference in the hazard ratio effect for a number of clinical factors, including prior adjuvant/neoadjuvant treatment, prior taxane use, and the presence of liver metastases. Objective response rate (per RECIST) was numerically higher with the addition of atezolizumab in the ITT (56% versus 46%) and PD-L1+ populations (59% versus 43%), with more complete responses observed (ITT 7% versus 2% and PD-L1+ group 10% versus 1%, respectively). The PD-L1+ population was smaller in this global phase III study (396/902 = 40.9%), compared with the early phase I study [2.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], despite the use of the same assay. This observation highlights the likely selection bias of patients enrolled onto early phase studies. Further studies will need to be performed to determine how the SP142 assay compares with other PD-L1 assays used with other PD-(L)1 agents. At least in advanced disease, preselection for features such as PD-L1 expression on immune cells seems necessary for identifying patients most likely to respond to the addition of atezolizumab. Other immune markers such as TIL counts [7.Salgado R. Denkert C. Demaria S. et al.The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014.Ann Oncol. 2015; 26: 259-271Abstract Full Text Full Text PDF PubMed Scopus (1653) Google Scholar] or CD8 levels [8.Kok M. Voorwerk L. Horlings H. et al.Adaptive phase II randomized trial of nivolumab after induction treatment in triple negative breast cancer (TONIC trial): final response data stage I and first translational data.J Clin Oncol. 2018; 36 (1012): 1012Crossref Google Scholar] may also prove useful for identification of patients with pre-existing antitumor immunity. Given the lower ORR observed with atezolizumab monotherapy in the phase I study (24% in PD-L1+; OS 17.6 months [2.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]), the role of cytotoxic chemotherapy in facilitating an antitumor immune response may be critical. In this study, nab-paclitaxel was chosen as the chemotherapy backbone due to the lack corticosteroid premedication requirement (theoretically detrimental to T-cell priming and increasing immune suppression) and because there is no absolute standard of care for treatment in this setting. Much has been previously published about the ability of cytotoxic chemotherapy to be immunogenic in preclinical models; one could also speculate that chemotherapy is also giving the immune system time to respond, debulking tumor burden to create a less hypoxic environment, lowering lactate dehydrogenase and allowing more glucose then allows T cells to do their job effectively. Replication stress and DNA damage induced may also enhance immune recognition. The optimal cytotoxic chemotherapy backbone (if there is one) is currently unknown. Concurrent nab-paclitaxel was shown not to change PD-L1 status in an earlier phase Ib trial and this is supported by the phase III data [9.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]. At present, we recognize that there are at least three main resistance mechanisms to atezolizumab. First, upfront or intrinsic resistance is present in many patients and likely reflects no pre-existing antitumor immunity. Why some patients retain some antitumor immunity and yet still relapse is unclear. Tumor growth is evidently occurring at time of RECIST progression, yet in some patients enhanced responses to subsequent therapies seems likely given the OS advantage but unlike other solid tumor types, we do not yet see a plateau on the tail of the curve suggest possible cures. This may appear with longer follow-up but it would seem that collecting data about the next PFS timepoint ("PFS2") is likely to be important. There is yet another time point after this that reflects complete host immune failure and rapid progressive disease. Hopefully serial tumor and plasma samples will be informative in the future in identifying these biological mechanisms. Optimal duration of checkpoint therapy in solid tumors is unknown. Recent data in the non-small-cell lung cancer setting suggest that longer duration is better in advanced disease and begs the question on the benefit of continuing atezolizumab in advanced TNBC post-RECIST progression. In this study, the median duration of atezolizumab treatment was only seven cycles. Given the chronic immunosuppression induced by tumor burden in the advanced setting, ongoing therapy may be particularly important. This question will need to be studied in a randomized trial. It is notable that the absolute median PFS increase was not large in either the ITT and PD-L1+ subset; both were less than 3 months, but the 1-year PFS difference in the ITT was 24% versus 18% and 29% versus 16% in the PD-L1+ subset for atezolizumab and placebo arms, respectively, a near-doubling for the PD-L1+ group. Similarly, in the PD-L1+ subset, 2-year OS was 54% versus 37% for atezolizumab and placebo arms, respectively, a 17% absolute difference in those alive at 2 years. These data highlight that median PFS and OS end points do not adequately capture the durability and clinical benefit of these immune treatments; the so-called 'tail on the curve'. The IMpassion130 data will change the treatment landscape for a sizeable proportion of metastatic TNBC patients though it is unclear how these data may apply to those TNBC patients who relapse <12 months from their adjuvant therapy. Still, for the majority of breast cancer patients, we need to combine checkpoint agents with other therapies if we hope to see significant tumor response. For the relative immunological 'cold' breast tumors, identifying treatment strategies that can attract CD8+ T cells into tumors by altering the immune-suppressive tumor microenvironment are of high importance. In contrast to more immunogenic solid tumor types, such as melanoma and lung cancer, breast cancer is typically not characterized by a high number of mutations [10.Luen S. Virassamy B. Savas P. et al.The genomic landscape of breast cancer and its interaction with host immunity.Breast. 2016; 29: 241-250Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar]. While in-depth analysis of a breast cancer patient responding to immunotherapy indicated that tumor-infiltrating lymphocytes (TIL) can be reactive against mutated proteins [11.Zacharakis N. Chinnasamy H. Black M. et al.Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer.Nat Med. 2018; 24: 724-730Crossref PubMed Scopus (442) Google Scholar], preliminary data suggest that tumor mutational burden is not associated with outcome after anti-PD-L1 therapy in metastatic TNBC. With the exception of metastatic breast carcinoma with an exceptional high tumor mutational burden, such as those with microsatellite instability [12.Le D.T. Durham J.N. Smith K.N. et al.Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.Science. 2017; 357: 409-413Crossref PubMed Scopus (3822) Google Scholar], the relative contribution of single nucleotide variant mutations to the anti-breast cancer T-cell response remains to be determined. Breast cancer is characterized by few mutations but extensive somatic copy number alterations (CNAs) such as indels or structural variants. Whether CNAs could contribute in theory to immunological foreignness whether they are subsequently able to trigger immune responses or are largely immunosuppressive [13.Davoli T. Uno H. Wooten E.C. Elledge SJ. Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy.Science. 2017; 355Crossref PubMed Scopus (689) Google Scholar, 14.Roh W. Chen P.L. Reuben A. et al.Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance.Sci Transl Med. 2017; 9Crossref Scopus (487) Google Scholar] remains to be determined. In parallel, analyses of well-known immunosuppressive features such as regulatory T cells, myeloid cells, and stromal features resulting in the immune-exclusion phenotype, will yield crucial information on barriers that needs to be targeted before or together with PD-1 blocking treatment. Many clinical trials are ongoing that aim to assess the capacity of chemotherapy regimens, irradiation and other anti-cancer drugs to turn a 'cold' tumor into an 'inflamed' tumor, i.e. with a more favorable tumor microenvironment. Another issue to consider in the future is that immune escape is a much more dominant phenomenon in the metastatic setting compared with primary breast tumors [15.Luen S.J. Salgado R. Fox S. et al.Tumour-infiltrating lymphocytes in advanced HER2-positive breast cancer treated with pertuzumab or placebo in addition to trastuzumab and docetaxel: a retrospective analysis of the CLEOPATRA study.Lancet Oncol. 2017; 18: 52-62Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar, 16.Savas P. Virassamy B. Ye C. et al.Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis.Nat Med. 2018; 24: 986-993Crossref PubMed Scopus (478) Google Scholar]. Consequently, priming a metastatic lesion for ICB might be more difficult than a primary lesion. The extremely low response rate in patients with advanced TNBC after the first-line treatment suggests that the disease context may also play a role in the likelihood that an effective anticancer T-cell response can be elicited [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: 1088Crossref Google Scholar]. It is possible that certain immunotherapeutic approaches are simply not effective in the end-stage metastatic disease setting; in contrast, testing the same approaches in the primary disease setting could result in clinically relevant responses. A recent small study in stage III melanoma suggested that the neoadjuvant setting might be better suitable to expand tumor-resident T-cell clones compared with the adjuvant setting [17.Blank C.U. Rozeman E.A. Fanchi L.F. et al.Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma.Nat Med. 2018; (Oct 8 [Epub ahead of print] doi 101038/s41591-018-0198-0)Crossref Scopus (419) Google Scholar]. Neoadjuvant studies in breast cancer are currently ongoing. Although breast cancer was far from the first tumor type to show benefit from immunotherapy, the first steps have been taken. There is great hope that translational and clinical research will rationally expand the use of immunotherapy in patients with breast cancer in the years ahead. Close collaborations between investigators and pharma-partners will be necessary to study synergy between standard treatment modalities, novel immunomodulatory agents and ICB, to develop future ways of subgrouping breast cancers according to biomarkers of relevant immune molecules—high TIL, CD8, PD-L1, IFNγ, for example, with the ultimate aim to achieve the 'plateau' on the curve as well as to attain large OS effects in the PD-L1-negative population. None declared.