LIO-1: Initial phase 2 experience of lucitanib + nivolumab in patients with metastatic or recurrent cervical cancer (NCT04042116; ENGOT-GYN3/AGO/LIO) (034)

Objectives: Lucitanib is a potent, selective inhibitor of the tyrosine kinases VEGFR1-3, PDGFRα/ß, and FGFR1-3 that is being investigated in combination with the programmed cell death receptor 1 (PD-1) inhibitor nivolumab in four recurrent gynecologic malignancies (cervical, endometrial, ovarian, and ovarian/endometrial clear-cell cancers) in an ongoing phase II study, using a Simon’s two-stage design. To maximize lucitanib exposure and potential clinical benefit of the combination, individualized lucitanib dose titration is utilized. We presented initial data from the cervical cancer cohort. Methods: Patients with metastatic or recurrent cervical cancer of squamous carcinoma, adenocarcinoma, or adenosquamous carcinoma histology, who received ≥1 prior platinum-based chemotherapy regimen, with or without bevacizumab, were enrolled. Prior treatment with a PD-1 or programmed cell death ligand-1 (PD-L1) inhibitor was prohibited. All patients-initiated treatment with lucitanib 6 mg orally once daily (QD) + nivolumab 480 mg intravenously every 28 days. Lucitanib dose was escalated from 6 mg to 8 mg and up to 10 mg QD in patients who met safety-based titration criteria. Tumor response was assessed by investigators per RECIST v1.1. Data cut-off was September 1, 2021. Results: Twenty patients have been treated to date (median treatment duration: 85 days, range: 1-343+); 15 (75%) remain on treatment (13 remain on the combination and two on nivolumab monotherapy). Eleven (55%) patients received ≥2 prior anticancer regimens; nine (45%) had prior bevacizumab. To date, 17 (85%) patients have completed ≥1 cycle; two patients have escalated lucitanib to a dose of 8 mg, and three to the maximum dose of 10 mg. The most frequent anygrade treatment-emergent adverse events (TEAEs) have been hypertension (n=13, 65%), decreased appetite (n=11, 55%), asthenia/fatigue (n=10, 50%), and nausea (n=10, 50%). The most frequent grade ≥3 TEAE has been hypertension (n=4, 20%). Three (15%) patients discontinued lucitanib due to a related TEAE (colonic fistula, hypertension, and proteinuria). As of the data cut-off, 17 patients had at least one post-baseline tumor assessment, with four confirmed partial responses (PRs), eight patients with stable disease (7 remain ongoing), and five patients with the best response of progressive disease reported. The durations of PR range from 1.8+ to 9.3+ months. Of the four responding patients, three had received prior bevacizumab. Conclusions: Promising signs of antitumor activity in patients with metastatic or recurrent cervical cancer were noted in this initial analysis. Toxicity has been manageable and is consistent with that previously reported for lucitanib and nivolumab, and other agents of both classes. Having met Simon’s two-stage stage I requirements (≥3 confirmed responses), study accrual continues in stage II of the cervical cancer cohort. Additional and more mature data, including biomarker analyses, will be presented at the meeting. Objectives: Lucitanib is a potent, selective inhibitor of the tyrosine kinases VEGFR1-3, PDGFRα/ß, and FGFR1-3 that is being investigated in combination with the programmed cell death receptor 1 (PD-1) inhibitor nivolumab in four recurrent gynecologic malignancies (cervical, endometrial, ovarian, and ovarian/endometrial clear-cell cancers) in an ongoing phase II study, using a Simon’s two-stage design. To maximize lucitanib exposure and potential clinical benefit of the combination, individualized lucitanib dose titration is utilized. We presented initial data from the cervical cancer cohort. Methods: Patients with metastatic or recurrent cervical cancer of squamous carcinoma, adenocarcinoma, or adenosquamous carcinoma histology, who received ≥1 prior platinum-based chemotherapy regimen, with or without bevacizumab, were enrolled. Prior treatment with a PD-1 or programmed cell death ligand-1 (PD-L1) inhibitor was prohibited. All patients-initiated treatment with lucitanib 6 mg orally once daily (QD) + nivolumab 480 mg intravenously every 28 days. Lucitanib dose was escalated from 6 mg to 8 mg and up to 10 mg QD in patients who met safety-based titration criteria. Tumor response was assessed by investigators per RECIST v1.1. Data cut-off was September 1, 2021. Results: Twenty patients have been treated to date (median treatment duration: 85 days, range: 1-343+); 15 (75%) remain on treatment (13 remain on the combination and two on nivolumab monotherapy). Eleven (55%) patients received ≥2 prior anticancer regimens; nine (45%) had prior bevacizumab. To date, 17 (85%) patients have completed ≥1 cycle; two patients have escalated lucitanib to a dose of 8 mg, and three to the maximum dose of 10 mg. The most frequent anygrade treatment-emergent adverse events (TEAEs) have been hypertension (n=13, 65%), decreased appetite (n=11, 55%), asthenia/fatigue (n=10, 50%), and nausea (n=10, 50%). The most frequent grade ≥3 TEAE has been hypertension (n=4, 20%). Three (15%) patients discontinued lucitanib due to a related TEAE (colonic fistula, hypertension, and proteinuria). As of the data cut-off, 17 patients had at least one post-baseline tumor assessment, with four confirmed partial responses (PRs), eight patients with stable disease (7 remain ongoing), and five patients with the best response of progressive disease reported. The durations of PR range from 1.8+ to 9.3+ months. Of the four responding patients, three had received prior bevacizumab. Conclusions: Promising signs of antitumor activity in patients with metastatic or recurrent cervical cancer were noted in this initial analysis. Toxicity has been manageable and is consistent with that previously reported for lucitanib and nivolumab, and other agents of both classes. Having met Simon’s two-stage stage I requirements (≥3 confirmed responses), study accrual continues in stage II of the cervical cancer cohort. Additional and more mature data, including biomarker analyses, will be presented at the meeting.