Combination treatment with PD-1 + CTLA-4 checkpoint inhibitors shows improvement in breadth, depth, and durability of response, coupled with a disproportionate increase in immune-related adverse events (irAE). CX-072, a Probody™ therapeutic (Pb-Tx) directed against PD-L1, is designed to be preferentially activated by tumor-associated proteases and not in healthy tissue. Preclinically, anti–PD-1 Pb-Tx + anti–CTLA-4 showed comparable efficacy with improved safety compared to the non–Pb-Tx combination control. This dose-escalation cohort examines safety and tolerability of CX-072 (anti-PD-L1 Pb-Tx) + the CTLA-4 inhibitor ipi in pts with advanced solid tumors.
In this ongoing phase 1/2 study (NCT03013491), PD-1, PD-L1, and CTLA-4 inhibitor-naive pts receive combination CX-072 + ipi (part B1). Planned doses of CX-072 (0.3, 1, 3, or 10 mg/kg) are administered in combination with ipi (3, 6, or 10 mg/kg) every 21 days for 4 cycles, followed by CX-072 monotherapy every 14 days.
As of April 20, 2018, part B1 enrolled 16 pts. Median age (range) and number of prior anticancer treatments was 60 years (28-70) and 3 (1-12), respectively. 6 pts were still on treatment at time of data cut. Median number (range) of CX-072 (0.3, 1, 3, or 10 mg/kg) and ipi (3 mg/kg) doses were 3 (1-20) and 3 (1-4), respectively. All cohorts through 10 mg/kg CX-072 (dose selected for monotherapy cohort expansion) are now enrolled without reaching the MTD. 1 DLT (grade 3 dyspnea, 0.3 mg/kg CX-072 + ipi) occurred. Grade 3 treatment-related (TR) irAEs occurred in 2 pts (12.5%; colitis and dyspnea/pneumonitis). No subject discontinued due to TR irAEs. Best response in 10 evaluable pts included 1 complete response (anal SCC, 0.3 mg/kg CX-072 + ipi), 2 partial response (non-seminoma testicular, 1 mg/kg CX-072 + ipi; small bowel, 3 mg/kg CX-072 + ipi), 1 stable disease, and 6 progressive disease.
Despite small pt numbers and limited follow up, early data suggest manageable safety profiles at all doses and antitumor activity with CX-072 + ipi in tumor types not approved for checkpoint inhibitors. The study is ongoing and escalation of ipi to 10 mg/kg is pending.
Clinical trial identification
Legal entity responsible for the study
CytomX Therapeutics, Inc.
CytomX Therapeutics, Inc.
Editorial support was provided by Andrew Occiano (ApotheCom, San Francisco, CA).
R.E. Sanborn: Research funding/grant: Merck; Investigator initiated Study: BMS, Medimmune; Institutional research support, honoraria: AstraZeneca; Advisory board: AstraZeneca, Seattle Genetics, Takeda, Genentech, Abbvie, Celldex; Travel, accommodations, investigator meeting: Janssen. E.G.E. de Vries: Research grant: Amgen, Genentech, Roche, Chugai, Synthon, CytomX, Nordic Nanovector, Regeneron, G1 Therapeutics, AstraZeneca, Radius Health (institution); Consulting: Pfizer, Sanofi (institution). P. Lorusso: Data safety monitoring board: Agios, FivePrime, Halozyme; Advisory board: Alexion, Ariad, CytomX, GenMab, Genentech, Glenmark, Ignyta, Menarini, Novartis, Omniox, Takeda, imCORE Alliance, Roche-Genentech. N. Uboha: Consulting: EMD Serono, Lilly, FlatIron, GLG. M.J. Fidler: Consulting: Genentech, AstraZeneca, Takeda, AbbVie; Speakers bureau: Merck, Celgene, Genentech, AbbVie. R. Humphrey, M. Will: Employment: CytomX Therapeutics. K.A. Autio: Research funding: CytomX, Pfizer, Lilly, GSK, Merck, ARMO Biosciences. F. Thistlethwaite: Research grant: Novartis; Consulting: Pfizer, BMS, Octimet, Achilles Therapeutics, Evelo Biosciences; Honorarium: Novartis; Speakers' bureau: BMS. All other authors have declared no conflicts of interest.