LIO-1: Lucitanib + nivolumab in patients with advanced solid tumors—Updated phase 1b results and initial experience in phase 2 ovarian cancer cohort.
Authors: Hamilton Erika P. , Jackson Camille Catherine , Eskander Ramez Nassef , Backes Floor Jenniskens , Makker Vicky , Musa Fernanda , Olawaiye Alexander , Alldredge Jill , Pothuri Bhavana , Secord Angeles Alvarez , Concin Nicole , Gonzalez Martin Antonio , Go Jowell , Wride Kenton , Lepley Denise M. , Cameron Teresa , Patel Manish R. 
Published: June 2021

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Background: The phase (Ph) 1b part of LIO-1 (NCT04042116; ENGOT-GYN3/AGO/LIO) assessed the oral antiangiogenic, multikinase inhibitor lucitanib + immune checkpoint inhibitor nivolumab, confirming the recommended Ph2 dose (RP2D) of lucitanib as 6 mg QD + nivolumab (480 mg IV every 28 days). To maximize lucitanib exposure and potential clinical benefit of the combination, individualized lucitanib dose titration is being explored in a Ph2 part, across 4 recurrent gynecologic malignancies (endometrial, cervical, ovarian, and ovarian/endometrial clear-cell cancers) using a Simon 2-stage design. We present updated Ph1b data and describe initial experience for the first 24 patients (pts) enrolled in the Ph2 ovarian cancer (OC) cohort. Methods: In Ph1b, pts with advanced, metastatic solid tumors received lucitanib at 6, 8, and 10 mg QD + nivolumab (in a 4+3 dose escalation). In the Ph2 OC cohort, pts with recurrent high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer (excluding clear-cell histology) with ≥2 prior chemotherapy regimens (including ≥1 platinum doublet) received the combination at RP2D; lucitanib dose was escalated from 6 mg to 8 mg and then to 10 mg QD for pts who met safety-based titration criteria. Visit cutoff was Feb 1, 2021. Results: In the Ph1b part (N = 17), median treatment duration was 109 days (range 14–505+). There has been 1 confirmed complete response (CR; anal cancer) and 1 confirmed partial response (PR; cervical cancer) per RECIST v1.1 with durations of 7.1 and 12.8 months, respectively. Ten pts had stable disease (SD), 3 had progressive disease, and 2 were nonevaluable; 3 pts remain on treatment. Overall disease control rate (CR + PR + SD ≥16 wk) was 47.1%. One dose-limiting toxicity (DLT; grade [G] 3 proteinuria) was observed in a pt receiving lucitanib 6 mg, leading to lucitanib discontinuation; no DLTs were seen at 8 or 10 mg. G ≥3 treatment-emergent adverse events (TEAEs) reported in ≥2 pts included hypertension (HTN; n = 4), fatigue (n = 2), and proteinuria (n = 2). Of the first 24 pts enrolled in the Ph2 OC cohort, 13 (54%) remain on treatment (median duration 59 [2–167+] days). Most frequent any-grade TEAEs were HTN (n = 10), fatigue (n = 8), nausea (n = 7), and proteinuria (n = 6). The only G ≥3 TEAE experienced in ≥2 pts was HTN (n = 4); 1 pt discontinued due to G4 HTN/G2 angina pectoris and 1 pt to G2 colonic perforation. To date, 21 pts have completed ≥1 cycle; 11 met safety-based dose-titration criteria, 10 of whom escalated to the 8 mg lucitanib dose. Of these, 5 pts subsequently escalated to 10 mg. One pt required dose reduction from 6 mg to 4 mg lucitanib. Conclusions: Ph1b data suggest that lucitanib + nivolumab has promising signs of antitumor activity. A safety-based dose-titration strategy appears feasible with manageable toxicity, based on experience from the Ph2 OC cohort to date; efficacy data from this cohort will also be presented. Clinical trial information: NCT04042116.