Resensitization of uveal melanoma (UM) to immune checkpoint inhibition (ICI) by IMCgp100 (IMC).

Abstract

9592 Background: ICI responses in UM are rare (~5% with anti-CTLA4/PD1 monotherapy; 10-12% with combination ICI). IMC is a bispecific agent composed of a high affinity T cell receptor targeting the gp100 melanoma antigen fused to an anti-CD3 scFv that increases intratumoral CD8+ T cell infiltration and PD1/PDL1 expression, and may enhance response to post-IMCgp100 ICI. Methods: We previously reported on 19 UM pts treated in the phase I dose escalation cohort of IMC (IMCgp100-102). We performed a retrospective analysis of clinical features and response to pre- and post-IMC ICI for the 12 pts in this cohort as well as 17 other pts (n = 29) treated with post-IMC ICI at 7 centers from 8/2016 to 1/2019. 21/29 pts (including 10/12 pts from IMCgp100-102) are evaluable for response and/or survival and are included in the analysis. Results: Baseline characteristics (n = 21): median age 56 (range 45-69); 57% female; median number of prior therapies 2 (range 1-4). Pre- and post-IMC ICI included: IPI+NIVO (3 pre; 8 post), anti-PD1 monotherapy (7 pre; 8 post), and anti-CTLA4 monotherapy (4 pre; 5 post). 20 pts were evaluable for post-IMC ICI response (1 died before restaging): 3/20 (15%) had partial responses (53-78% regression); 5/20 (25%) had stable disease (SD) > 16 weeks; 1/20 had SD of unknown duration. Median PFS and OS from the initiation of post-IMC ICI were 4.9 (95% CI 2.7-10.7) and 10.1 (95% CI 5.7-NR) months, respectively. 13 pts received pre-IMC ICI, all with eventual disease progression. 3 pts had treatment duration or SD lasting > 6 months. Of these 3 pts, 2 had clinical benefit (defined as objective response or SD > 16 weeks) with post-IMC ICI. There was no clear association between rates of Gr ≥ 2 irAE with pre- or post-IMC ICI and response. For the 10 evaluable pts treated on IMCgp100-102, no marked difference in prior response to IMC (3 SD among 5 ICI responders vs 2 SD among 4 ICI non-responders) or mean tumor shrinkage with IMC (-14.0% vs -18.0%) was observed, but rates of Gr ≥ 2 fever, rash, and/or hypotension with IMC were higher among ICI responders (80% vs 50%). Conclusions: Survival outcomes with post-IMC ICI compare favorably to historical figures in pretreated UM pts. IMC may re-sensitize pts who had prior clinical benefit with ICI to subsequent ICI.

Phase I Study of Safety, Tolerability, and Efficacy of Tebentafusp Using a Step-Up Dosing Regimen and Expansion in Patients With Metastatic Uveal Melanoma

“…Consistent with this hypothesis, we observed that, of 24 patients treated with immune checkpoint inhibitors posttebentafusp, one achieved a complete response and three achieved a PR, for an ORR of 16.7%. 28 Notably, posttreatment biopsy specimens demonstrated increased expression of PD-L1 and programmed cell death protein-1.…”

“…Consistent with this hypothesis, we observed that, of 24 patients treated with immune checkpoint inhibitors post-tebentafusp, one achieved a complete response and three achieved a PR, for an ORR of 16.7%. 28 Notably, post-treatment biopsy specimens demonstrated increased expression of PD-L1 and programmed cell death protein-1. In this regard, combination of tebentafusp with anti–programmed cell death protein-1/PD-L1 antibody may potentially increase the efficacy of tebentafusp, and further investigation on this combination is warranted.…”

Successful treatment of metastatic uveal melanoma with ipilimumab and nivolumab after severe progression under tebentafusp: a case report

“…Furthermore, a subgroup of patients from the first phase I trial, who were progressive on ICIs and then also progressive on tebentafusp, in some cases responded to a re-challenge of ICIs after all ( 21 ).…”

The Latest on Uveal Melanoma Research and Clinical Trials: Updates from the Cure Ocular Melanoma (CURE OM) Science Meeting (2019)

“…ORR was 18% in Phase 1 (6). In the Phase 2 expansion cohort studying patients with prior treatment, a major area of focus is whether tebentafusp can restore sensitivity to the immune checkpoint inhibitors in metastatic UM (7). A separate trial of tebentafusp compared to investigator's choice treatment in previously untreated patients is ongoing.…”