A phase I study of the PD-L1 inhibitor, durvalumab, in combination with a PARP inhibitor, olaparib, and a VEGFR1-3 inhibitor, cediranib, in recurrent women's cancers with biomarker analyses

Alexandra S Zimmer, Erin Nichols, Ashley Cimino-Mathews, Cody Peer, Liang Cao, Min-Jung Lee, Elise C Kohn, Christina M Annunziata, Stanley Lipkowitz, Jane B Trepel, Rajni Sharma, Lekha Mikkilineni, Margaret Gatti-Mays, William D Figg, Nicole D Houston, Jung-Min Lee, Alexandra S Zimmer, Erin Nichols, Ashley Cimino-Mathews, Cody Peer, Liang Cao, Min-Jung Lee, Elise C Kohn, Christina M Annunziata, Stanley Lipkowitz, Jane B Trepel, Rajni Sharma, Lekha Mikkilineni, Margaret Gatti-Mays, William D Figg, Nicole D Houston, Jung-Min Lee

Abstract

Background: Strategies to improve activity of immune checkpoint inhibitors are needed. We hypothesized enhanced DNA damage by olaparib, a PARP inhibitor, and reduced VEGF signaling by cediranib, a VEGFR1-3 inhibitor, would complement anti-tumor activity of durvalumab, a PD-L1 inhibitor, and the 3-drug combination would be tolerable.

Methods: This phase 1 study tested the 3-drug combination in a 3 + 3 dose escalation. Cediranib was taken intermittently (5 days on/2 days off) at 15 or 20 mg (dose levels 1 and 2, respectively) with durvalumab 1500 mg IV every 4 weeks, and olaparib tablets 300 mg twice daily. The primary end point was the recommended phase 2 dose (RP2D). Response rate, pharmacokinetic (PK), and correlative analyses were secondary endpoints.

Results: Nine patients (7 ovarian/1 endometrial/1 triple negative breast cancers, median 3 prior therapies [2-6]) were treated. Grade 3/4 adverse events include hypertension (1/9), anemia (1/9) and lymphopenia (3/9). No patients experienced dose limiting toxicities. The RP2D is cediranib, 20 mg (5 days on/2 days off) with full doses of durvalumab and olaparib. Four patients had partial responses (44%) and 3 had stable disease lasting ≥6 months, yielding a 67% clinical benefit rate. No significant effects on olaparib or cediranib PK parameters from the presence of durvalumab, or the co-administration of cediranib or olaparib were identified. Tumoral PD-L1 expression correlated with clinical benefit but cytokines and peripheral immune subsets did not.

Conclusions: The RP2D is tolerable and has preliminary activity in recurrent women's cancers. A phase 2 expansion study is now enrolling for recurrent ovarian cancer patients.

Trial registration: ClinicalTrials.gov identifier: NCT02484404. Registered June 29, 2015.

Keywords: Immune checkpoint inhibitor; Ovarian cancer; PARP inhibitor; VEGF inhibition.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Changes in tumor size and duration on the treatment. a Changes in tumor size on the study treatment. b Duration in the study. c Best response. One patient with TNBC had clinical progressive disease before first response evaluation imaging and is represented as zero (0) in a and b. Abbreviations: S: platinum-sensitive recurrent ovarian cancer, R: platinum-resistant recurrent ovarian cancer. OvCa: ovarian cancer. TNBC: triple negative breast cancer

References

    1. J-m L, Ivy SP, Kohn EC. Challenges and opportunities for immunotherapies in gynecologic cancers. Oncology New York. 2016;30(1):67–69.
    1. Mouw KW, Goldberg MS, Konstantinopoulos PA, D'Andrea AD. DNA damage and repair biomarkers of immunotherapy response. Cancer Discov. 2017;7(7):675–693. doi: 10.1158/-17-0226.
    1. Hellmann MD, Nathanson T, Rizvi H, et al. Genomic features of response to combination immunotherapy in patients with advanced non-small-cell lung Cancer. Cancer Cell. 2018;33(5):843–84+. doi: 10.1016/j.ccell.2018.03.018.
    1. Jiao S, Xia W, Yamaguchi H, et al. PARP inhibitor upregulates PD-L1 expression and enhances Cancer-associated immunosuppression. Clin Cancer Res. 2017;23(14):3711–3720. doi: 10.1158/1078-0432.CCR-16-3215.
    1. Sun C, Fang Y, Yin J, et al. Rational combination therapy with PARP and MEK inhibitors capitalizes on therapeutic liabilities in RAS mutant cancers. Sci Transl Med. 2017;9(392).
    1. Hegan DC, Lu Y, Stachelek GC, Crosby ME, Bindra RS, Glazer PM. Inhibition of poly (ADP-ribose) polymerase down-regulates BRCA1 and RAD51 in a pathway mediated by E2F4 and p130. Proc Natl Acad Sci U S A. 2010;107(5):2201–2206. doi: 10.1073/pnas.0904783107.
    1. Kandalaft LE, Motz GT, Busch J, Coukos G. Angiogenesis and the tumor vasculature as antitumor immune modulators: the role of vascular endothelial growth factor and endothelin. Cancer Immunol Immunother. 2011;344:129–148. doi: 10.1007/82_2010_95.
    1. Liu JF, Barry WT, Birrer M, et al. Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study. Lancet Oncol. 2014;15(11):1207–1214. doi: 10.1016/S1470-2045(14)70391-2.
    1. Munoz-Unceta N, Burgueno I, Jimenez E, Paz-Ares L. Durvalumab in NSCLC: latest evidence and clinical potential. Ther Adv Med Oncol. 2018;10:1758835918804151. doi: 10.1177/1758835918804151.
    1. Lee J-M, Cimino-Mathews A, Peer CJ, et al. Safety and clinical activity of the programmed death-ligand 1 inhibitor Durvalumab in combination with poly (ADP-ribose) polymerase inhibitor Olaparib or vascular endothelial growth factor receptor 1-3 inhibitor Cediranib in Women’s cancers: a dose-escalation, phase I study. J Clin Oncol. 2017;35(19):2193–219+. doi: 10.1200/JCO.2016.72.1340.
    1. Roth Jeffrey, Peer Cody, Mannargudi Baskar, Swaisland Helen, Lee Jung-Min, Kohn Elise, Figg William. A Sensitive and Robust Ultra HPLC Assay with Tandem Mass Spectrometric Detection for the Quantitation of the PARP Inhibitor Olaparib (AZD2281) in Human Plasma for Pharmacokinetic Application. Chromatography. 2014;1(2):82–95. doi: 10.3390/chromatography1020082.
    1. Rajan A, Carter CA, Berman A, et al. Cixutumumab for patients with recurrent or refractory advanced thymic epithelial tumours: a multicentre, open-label, phase 2 trial. Lancet Oncol. 2014;15(2):191–200. doi: 10.1016/S1470-2045(13)70596-5.
    1. Tomita Y, Lee MJ, Lee S, et al. The interplay of epigenetic therapy and immunity in locally recurrent or metastatic estrogen receptor-positive breast cancer: correlative analysis of ENCORE 301, a randomized, placebo-controlled phase II trial of exemestane with or without entinostat. Oncoimmunology. 2016;5(11):e1219008. doi: 10.1080/2162402X.2016.1219008.
    1. Lee J-M, Trepel JB, Choyke P, et al. CECs and IL-8 have prognostic and predictive utility in patients with recurrent platinum-sensitive ovarian cancer: biomarker correlates from the randomized phase-2 trial of olaparib and cediranib compared with olaparib in recurrent platinum-sensitive ovarian cancer. Front Oncol. 2015;5:123. doi: 10.3389/fonc.2015.00123.
    1. Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol. 2011;12(9):852–861. doi: 10.1016/S1470-2045(11)70214-5.
    1. Matulonis UA, Berlin S, Ivy P, et al. Cediranib, an Oral inhibitor of vascular endothelial growth factor receptor kinases, is an active drug in recurrent epithelial ovarian, fallopian tube, and peritoneal Cancer. J Clin Oncol. 2009;27(33):5601–5606. doi: 10.1200/JCO.2009.23.2777.
    1. Konstantinopoulos P, Munster P, Forero-Torez A, et al. Topacio: preliminary activity and safety in patients (pts) with platinum-resistant ovarian cancer (PROC) in a phase 1/2 study of niraparib in combination with pembrolizumab. Gynecol Oncol. 2018;149:246. doi: 10.1016/j.ygyno.2018.04.554.
    1. Drew Y, de Jonge M, Hong S, et al. An open-label, phase II basket study of olaparib and durvalumab (MEDIOLA): results in germline BRCA-mutated (gBRCAm) platinum-sensitive relapsed (PSR) ovarian cancer (OC) Gynecol Oncol. 2018;149:246–247. doi: 10.1016/j.ygyno.2018.04.555.
    1. Lee J, Annunziata C, Houston N, et al. A phase 2 study of durvalumab, a PD-L1 inhibitor and olaparib in recurrent ovarian cancer (OvCa) Ann Oncol. 2018;29:332–358. doi: 10.1093/annonc/mdx768.
    1. Liu J, Herold C, Luo W, et al. A phase 2 trial of combination nivolumab and bevacizumab in recurrent ovarian cancer. Ann Oncol. 2018;29.
    1. Varga Andrea, Piha-Paul Sarina Anne, Ott Patrick Alexander, Mehnert Janice M., Berton-Rigaud Dominique, Morosky Anne, Zhao Guo Qing, Rangwala Reshma A., Matei Daniela. Pembrolizumab in patients (pts) with PD-L1–positive (PD-L1+) advanced ovarian cancer: Updated analysis of KEYNOTE-028. Journal of Clinical Oncology. 2017;35(15_suppl):5513–5513. doi: 10.1200/JCO.2017.35.15_suppl.5513.
    1. Schmid P, Adams S, Rugo HS, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast Cancer. N Engl J Med. 2018.
    1. Liu D, Wang S, Bindeman W. Clinical applications of PD-L1 bioassays for cancer immunotherapy. J Hematol Oncol. 2017;10:110. doi: 10.1186/s13045-017-0479-y.
    1. 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. 2017;12(2):208–222. doi: 10.1016/j.jtho.2016.11.2228.
    1. Vilain RE, Menzies AM, Wilmott JS, et al. Dynamic changes in PD-L1 expression and immune infiltrates early during treatment predict response to PD-1 blockade in melanoma. Clin Cancer Res. 2017;23(17):5024–5033. doi: 10.1158/1078-0432.CCR-16-0698.

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