Anti-tumor activity of durvalumab (D), a programmed death ligand (PDL1) blocking antibody, may be enhanced by overcoming intratumoral immune suppression. The selective Generation 2.5 antisense oligonucleotide STAT3 inhibitor AZD9150 (STATi), a small molecule CXCR2 inhibitor AZD5069 (CX2i), and CTLA4 inhibitor tremelimumab (T) are in evaluation.
Part A, dose escalation in solid tumors, evaluated STATi + (D or D+T) and CX2i + (D or D+T) for safety, pharmacokinetics, pharmacodynamics and maximum tolerated dose. Part B, dose expansion in SCCHN, tested STATi (3 mg/kg)+D and CX2i (40 mg BID)+D in PDL1 pretreated/naive pts and as monotherapy for Objective Response Rate (ORR) and Disease Control Rate (DCR).
Part A showed STATi+D and CX2i+D as safe and tolerable combinations with confirmed partial responses (cPR) in multiple tumor types and 2 confirmed complete responses (cCR) in breast and prostate cancer (>64 weeks [wks] on treatment). STATi+DT had a cPR in sarcoma at 12 wks. In Part B (STATi+D reported here), the PDL1 naive arm had 25% ORR (4 cPR, 1 unconfirmed PR (uPR); 3 Human Papilloma Virus negative and 2 unknown), 45% DCR (9/20) was observed at 12 wks, and 30% of pts (6/20) remain on treatment at 25 wks. One cPR pt is unconfirmed CR at data cut off. In the PDL1 pretreated arm, 1 pt had complete metabolic response and 1 pt had uPR; 20% DCR (3/15) was observed at 12 wks. Safety and tolerability were confirmed for STATi+D in SCCHN pts, with manageable and reversible adverse events of thrombocytopenia and liver enzyme increases (for each, Grade 3/4 in 3.4% of 58 pts dosed); 2 STATi+D related discontinuations occurred.
Initial ORR and DCR data suggest enhanced antitumor activity results from combining a PDL1 antagonist (D) with an agent targeting immunosuppression in the tumor microenviornment (STATi) compared to PDL1 monotherapy. The combination may prove to provide a tolerable and effective option for patients with recurrent/metastatic SCCHN in the naive and PDL1-pretreated setting and other solid tumor types being studied.
Clinical trial identification
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E.E. Cohen: Consulted for AstraZeneca, Bristol-Myers Squibb, Human Longevity, Merck, Merck Serrano, and Pfizer. Received expenses for travel or accommodation from AstraZeneca, Merck, and Pfizer. Holds stock in Human Longevity, Inc. D.S. Hong: Received grants from Bayer, Lilly, Genentech, LOXO, Pfizer, Amgen, Mirati, Ignyta, Merck, Daichi-Sanko, and Eisai. Travel expenses were provided by MiRNA and LOXO. Consulted for Bayer, Baxter, and Guidepoint Global. He founded Oncoresponse. T. Wise Draper: Received funding for investigator-initiated studies from Bristol-Myers Squibb and Merck. D. Schrijvers: Participated in studies sponsored by Cougar, Janssen, and Bayer. Served on the advisory board of Janssen and Bayer Belgium. Spoken at events organized by Janssen and Bayer Belgium. R. Mesia Nin: Served an advisory role for AstraZeneca, Merck SL, Bayer, and Bristol. Received conference honoraria from Bristol and Merck SL. M.L. Scott, P. Lyne, P. McCoon, C.E. Cook: Employee of, and owns stock in, AstraZeneca. G. Mugundu: Employee of AstraZeneca and owns stock in AstraZeneca and Pfizer. M.M. Mehta: Employed by AstraZeneca. U. Keilholz: Received speaker honoraria, and served on advisory boards, for AstraZeneca, Merck, MSD, Pfizer, Novartis, and Innate. Participates in research sponsored by AstraZeneca and Merck. All other authors have declared no conflicts of interest.