Phase 2 study of axitinib + nivolumab in mucosal melanoma with pilot addition of stereotactic body radiotherapy or ipilimumab in select progressors.

9555 Background: Mucosal melanoma (MM) is an aggressive subtype of melanoma with distinct biology, and outcomes in advanced disease are inferior compared with cutaneous melanoma. Frontline Chinese studies in MM have shown efficacy of combined VEGF/R and PD-1 blockade, but studies in more diverse populations and options in PD-1 resistance are lacking. Methods: We conducted a phase 2/1b single-center trial in patients (pts) with untreated, unresectable or advanced MM. Pts received standard nivolumab (nivo) plus axitinib (axi) 5mg PO twice daily. Primary endpoint of the phase 2 doublet arm was objective response rate (ORR) by RECIST 1.1 (H0=23%, Ha=48%). Clinical benefit rate (CBR) was defined as ORR or stable disease (SD) >6 months (mos). Upon progression with good tolerance, the phase 1b triplet arm pts received the addition of either stereotactic body radiotherapy (SBRT, 30Gy/5 fractions) or ipilimumab (ipi, 1mg/kg < 4 doses) to ongoing nivo + axi. The primary endpoint of the triplet was safety by CTCAE v5.0 and adverse events (AEs) of special interest (AESIs). Kaplan-Meier methods estimated time to event outcomes; ORR and AEs were reported as proportions with exact 95% confidence intervals. Results: N=21 pts were enrolled; N=20 were evaluable for efficacy. See Table for baseline population characteristics. Median follow up was 15 mos (IQR 6, 21), 45% of pts (95% CI: 23, 68) had an objective response; 3 complete and 6 partial responses. Median duration of response was 13 mos (8.6, not reached (NR)). SD persisted ≥ 6 mos in 2 of 7 pts; CBR was 55% (95% CI: 32,77). Median progression free survival (PFS) was 6.3 mos (3.5, NR), and 12-mos estimated PFS and overall survival was 37% (20,67) and 71% (52, 96), respectively. Rate of grade ≥3 treatment related AEs (TRAE) in the doublet arm (n=21) was 67% (95% CI: 43,85), most commonly hypertension & hepatitis, with two pt deaths; 1 nivo-related myasthenia gravis / myositis, and 1 nivo-related pancreatitis with steroid-related PJP pneumonia. 14 pts (70%) progressed on doublet therapy, of which 7 enrolled on the triplet arm. N=5 received ipi and N=2 SBRT (both to anorectal primaries and adjacent lymph nodes). There were 2 grade ≥3 TRAEs in the ipi triplet arm (hepatitis), 0 in the SBRT arm, no grade 5 events, and no AESIs. Zero of 4 evaluable pts in ipi triplet and 1 of 2 in the SBRT triplet responded (4+ mos, ongoing). Conclusions: The frontline combination of nivolumab and axitinib was effective in patients with unresectable or advanced outside of China, and a prospective global study randomized against immune checkpoint blockade is warranted. Adding either ipi or SBRT to nivo-axi appears safe in select pts with progressive disease and further studies are needed for pts with PD-1 resistant MM. Clinical trial information: NCT05384496 . Characteristic (n=21) N (%) Age (median) 73 years (IQR: 67, 82) Sex Female Male 13 (62%) 8 (38%) Race Caucasian Asian Black 16 (76%) 3 (14%) 2 (10%) Primary Site Anorectal Sinonasal Vulvovaginal 10 (48%) 8 (38%) 3 (14%) Stage Locoregionally advanced Metastatic 14 (67%) 7 (33%) LDH (median) 195 (IQR: 171,201)