PURPOSE: Agents targeting programmed death receptor 1 (PD-1) or its ligand (PD-L1) have shown antitumor activity in the treatment of metastatic breast cancer (MBC). The aim of this study was to assess the activity of avelumab, a PD-L1 inhibitor, in patients with MBC. METHODS: In a phase 1 trial (JAVELIN Solid Tumor; NCT01772004), patients with MBC refractory to or progressing after standard-of-care therapy received avelumab intravenously 10 mg/kg every 2 weeks. Tumors were assessed every 6 weeks by RECIST v1.1. Adverse events (AEs) were graded by NCI-CTCAE v4.0. Membrane PD-L1 expression was assessed by immunohistochemistry (Dako PD-L1 IHC 73-10 pharmDx). RESULTS: A total of 168 patients with MBC, including 58 patients with triple-negative breast cancer (TNBC), were treated with avelumab for 2-50 weeks and followed for 6-15 months. Patients were heavily pretreated with a median of three prior therapies for metastatic or locally advanced disease. Grade ≥ 3 treatment-related AEs occurred in 13.7% of patients, including two treatment-related deaths. The confirmed objective response rate (ORR) was 3.0% overall (one complete response and four partial responses) and 5.2% in patients with TNBC. A trend toward a higher ORR was seen in patients with PD-L1+ versus PD-L1- tumor-associated immune cells in the overall population (16.7% vs. 1.6%) and in the TNBC subgroup (22.2% vs. 2.6%). CONCLUSION: Avelumab showed an acceptable safety profile and clinical activity in a subset of patients with MBC. PD-L1 expression in tumor-associated immune cells may be associated with a higher probability of clinical response to avelumab in MBC.

Center for Cancer and Blood Disorders Bethesda MD USA

CHU Sart Tilman Liege and Liege University Liege Belgium

Cooper Hospital University Medical Center Camden NJ USA

EMD Serono Billerica MA USA

Greenville Hospital System Greenville SC USA

Merck KGaA Darmstadt Germany

Metairie Oncologist LLC Metairie LA USA

Michigan State University East Lansing MI USA

Nemocnice Horovice Onkologicke Oddelení Horovice Czech Republic

Sarah Cannon Research Institute London UK

Sarah Cannon Research Institute Nashville TN USA

Semmelweis University Budapest Hungary

Sint Augustinus University of Antwerp Antwerp Belgium

The John Hopkins University School of Medicine Baltimore MD USA

University Cancer and Blood Center LLC Athens GA USA

University College London Cancer Institute London UK

University of Alabama Birmingham AL USA

University of Miami Miller School of Medicine Miami FL USA

Zobrazit více v PubMed

O’Shaughnessy J. Extending survival with chemotherapy in metastatic breast cancer. Oncologist. 2005;10(Suppl 3):20–29. doi: 10.1634/theoncologist.10-90003-20. PubMed DOI

National Cancer Institute . SEER cancer stat facts: female breast cancer. Bethesda: National Cancer Institute; 2016. p. 2016.

National Comprehensive Cancer Network (V2 2017) NCCN clinical practice guidelines in oncology: breast cancer. Orlando: National Comprehensive Cancer Network; 2017. PubMed

Dent R, Trudeau M, Pritchard KI, et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res. 2007;13:4429–4434. doi: 10.1158/1078-0432.CCR-06-3045. PubMed DOI

Anders CK, Abramson V, Tan T, et al. The evolution of triple-negative breast cancer: from biology to novel therapeutics. Am Soc Clin Oncol Educ Book. 2016;35:34–42. doi: 10.14694/EDBK_159135. PubMed DOI

Andre F, Zielinski CC. Optimal strategies for the treatment of metastatic triple-negative breast cancer with currently approved agents. Ann Oncol. 2012;23:46–51. doi: 10.1093/annonc/mdr047. PubMed DOI

Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol. 2015;33:1974–1982. doi: 10.1200/JCO.2014.59.4358. PubMed DOI PMC

Mittendorf EA, Philips AV, Meric-Bernstam F, et al. PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res. 2014;2:361–370. doi: 10.1158/2326-6066.CIR-13-0127. PubMed DOI PMC

Schalper KA, Velcheti V, Carvajal D, et al. In situ tumor PD-L1 mRNA expression is associated with increased TILs and better outcome in breast carcinomas. Clin Cancer Res. 2014;20:2773–2782. doi: 10.1158/1078-0432.CCR-13-2702. PubMed DOI

Wimberly H, Brown JR, Schalper K, et al. PD-L1 expression correlates with tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy in breast cancer. Cancer Immunol Res. 2015;3:326–332. doi: 10.1158/2326-6066.CIR-14-0133. PubMed DOI PMC

Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8:793–800. doi: 10.1038/nm730. PubMed DOI

Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192:1027–1034. doi: 10.1084/jem.192.7.1027. PubMed DOI PMC

Iwai Y, Ishida M, Tanaka Y, et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci USA. 2002;99:12293–12297. doi: 10.1073/pnas.192461099. PubMed DOI PMC

Stanton SE, Disis ML. Clinical significance of tumor-infiltrating lymphocytes in breast cancer. J Immunother Cancer. 2016;4:59. doi: 10.1186/s40425-016-0165-6. PubMed DOI PMC

Cimino-Mathews A, Thompson E, Taube JM, et al. PD-L1 (B7-H1) expression and the immune tumor microenvironment in primary and metastatic breast carcinomas. Hum Pathol. 2016;47:52–63. doi: 10.1016/j.humpath.2015.09.003. PubMed DOI PMC

Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015;27:450–461. doi: 10.1016/j.ccell.2015.03.001. PubMed DOI PMC

Nanda R, Chow LQ, Dees EC, et al. Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study. J Clin Oncol. 2016;34:2460–2467. doi: 10.1200/JCO.2015.64.8931. PubMed DOI PMC

Emens L, Braiteh F, Cassier P, et al. Inhibition of PD-L1 by MPDL3280A leads to clinical activity in patients with metastatic triple-negative breast cancer (TNBC) Cancer Res. 2015;75:2859. doi: 10.1158/1538-7445.AM2015-2859. DOI

Schmid P, Cruz C, Braiteh FS, et al. Atezolizumab in metastatic TNBC (mTNBC): long-term clinical outcomes and biomarker analysis. Cancer Res. 2017;77:2986. doi: 10.1158/1538-7445.AM2017-2986. DOI

Heery CR, O’Sullivan-Coyne G, Madan RA, et al. Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial. Lancet Oncol. 2017;18:587–597. doi: 10.1016/S1470-2045(17)30239-5. PubMed DOI PMC

Boyerinas B, Jochems C, Fantini M, et al. Antibody-dependent cellular cytotoxicity activity of a novel anti-PD-L1 antibody avelumab (MSB0010718C) on human tumor cells. Cancer Immunol Res. 2015;3:1148–1157. doi: 10.1158/2326-6066.CIR-15-0059. PubMed DOI PMC

Fujii R, Friedman ER, Richards J, et al. Enhanced killing of chordoma cells by antibody-dependent cell-mediated cytotoxicity employing the novel anti-PD-L1 antibody avelumab. Oncotarget. 2016;7:33498–33511. PubMed PMC

Grenga I, Donahue RN, Lepone LM, et al. A fully human IgG1 anti-PD-L1 MAb in an in vitro assay enhances antigen-specific T-cell responses. Clin Transl Immunol. 2016;5:e83. doi: 10.1038/cti.2016.27. PubMed DOI PMC

Kaufman HL, Russell J, Hamid O, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol. 2016;17:1374–1385. doi: 10.1016/S1470-2045(16)30364-3. PubMed DOI PMC

Gulley JL, Rajan A, Spigel DR, et al. Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): dose-expansion cohort of a multicentre, open-label, phase 1b trial. Lancet Oncol. 2017;18:599–610. doi: 10.1016/S1470-2045(17)30240-1. PubMed DOI PMC

Apolo AB, Infante JR, Balmanoukian A, et al. Avelumab, an anti-programmed death-ligand 1 antibody, in patients with refractory metastatic urothelial carcinoma: results from a multicenter, phase Ib study. J Clin Oncol. 2017;35:2117–2124. doi: 10.1200/JCO.2016.71.6795. PubMed DOI PMC

Bavencio (avelumab) injection [package insert] Darmstadt. Darmstadt: Merck KGaA; 2017.

Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer. 2009;45:228–247. doi: 10.1016/j.ejca.2008.10.026. PubMed DOI

Donahue RN, Lepone LM, Grenga I, et al. Analyses of the peripheral immunome following multiple administrations of avelumab, a human IgG1 anti-PD-L1 monoclonal antibody. J Immunother Cancer. 2017;5:13. doi: 10.1186/s40425-017-0220-y. PubMed DOI PMC

Patel SP, Kurzrock R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther. 2015;14:847–856. doi: 10.1158/1535-7163.MCT-14-0983. PubMed DOI

Wang X, Teng F, Kong L, et al. PD-L1 expression in human cancers and its association with clinical outcomes. Onco Targets Ther. 2016;9:5023–5039. doi: 10.2147/OTT.S105862. PubMed DOI PMC

Hirsch FR, McElhinny A, Stanforth D, et al. PD-L1 Immunohistochemistry assays for lung cancer: results from phase 1 of the “blueprint PD-L1 IHC assay comparison project”. J Thorac Oncol. 2016;12:208–222. doi: 10.1016/j.jtho.2016.11.2228. PubMed DOI

Adams S, Diamond J, Hamiton E, 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;34:1009.

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. Eur J Cancer. 2017;72:S16. doi: 10.1016/S0959-8049(17)30131-4. DOI