Tebentafusp in combination with durvalumab and/or tremelimumab in patients with metastatic cutaneous melanoma: a phase 1 study

Abstract

Background: Immune checkpoint inhibitors have significantly improved outcomes in first line cutaneous melanoma. However, there is a high unmet need for patients who progress on these therapies and combination therapies are being explored to improve outcomes. Tebentafusp is a first-in-class gp100×CD3 ImmTAC bispecific that demonstrated overall survival (OS) benefit (HR 0.51) in metastatic uveal melanoma despite a modest overall response rate of 9%. This phase 1b trial evaluated the safety and initial efficacy of tebentafusp in combination with durvalumab (anti-programmed death ligand 1 (PDL1)) and/or tremelimumab (anti-cytotoxic T lymphocyte-associated antigen 4) in patients with metastatic cutaneous melanoma (mCM), the majority of whom progressed on prior checkpoint inhibitors.

Methods: In this open-label, multicenter, phase 1b, dose-escalation trial, HLA-A*02:01-positive patients with mCM received weekly intravenous tebentafusp with increasing monthly doses of durvalumab and/or tremelimumab starting day 15 of each cycle. The primary objective was to identify the maximum tolerated dose (MTD) or recommended phase 2 dose for each combination. Efficacy analyses were performed in all tebentafusp with durvalumab±tremelimumab treated patients with a sensitivity analysis in those who progressed on prior anti-PD(L)1 therapy.

Results: 85 patients were assigned to receive tebentafusp in combination with durvalumab (n=43), tremelimumab (n=13), or durvalumab and tremelimumab (n=29). Patients were heavily pretreated with a median of 3 prior lines of therapy, including 76 (89%) who received prior anti-PD(L)1. Maximum target doses of tebentafusp (68 mcg) alone or in combination with durvalumab (20 mg/kg) and tremelimumab (1 mg/kg) were tolerated; MTD was not formally identified for any arm. Adverse event profile was consistent with each individual therapy and there were no new safety signals nor treatment-related deaths. In the efficacy subset (n=72), the response rate was 14%, tumor shrinkage rate was 41% and 1-year OS rate was 76% (95% CI: 70% to 81%). The 1-year OS for triplet combination (79%; 95% CI: 71% to 86%) was similar to tebentafusp plus durvalumab (74%; 95% CI: 67% to 80%).

Conclusion: At maximum target doses, the safety of tebentafusp with checkpoint inhibitors was consistent with safety of each individual therapy. Tebentafusp with durvalumab demonstrated promising efficacy in heavily pretreated patients with mCM, including those who progressed on prior anti-PD(L)1.

Trial registration number: NCT02535078.

Keywords: Immune Checkpoint Inhibitors; Immunotherapy; Melanoma; T-Lymphocytes.

Figure 1

Flowchart for a phase 1b study of tebentafusp in combination with durvalumab and/or tremelimumab in patients with metastatic cutaneous melanoma. All patients who received at least one full or partial dose of study drug are in the safety analysis set. All patients assigned to Arm 1 (tebentafusp+durvalumab) and Arm 3 (tebentafusp+durvalumab+tremelimumab) who received at least one full or partial dose of study drug are in the efficacy analysis set (EAS). Patients in the EAS who discontinued prior anti-PD(L)1 therapy due to disease progression are in sensitivity analysis set.

Figure 2

Overall survival and best change in tumor size from baseline in patients receiving tebentafusp in combination with durvalumab±tremelimumab (A) Overall survival in months is plotted for each evaluable patient (n=63). + denotes censored. (A–B) Data are presented only for those patients for whom best overall response to previous anti- anti-PD(L)1 therapy was known and only patients with at least one evaluable post baseline target lesion scan were included. Nine patients overall were not included due to non-measurable disease at baseline or no evaluable post-baseline target lesion scans. Evaluable post-baseline scans must be on or prior to disease progression or starting subsequent alternative cancer therapy to be considered. (B) Waterfall plot showing the best change in tumor size (n=63). Forty-one per cent of patients had tumor reduction at any time. Tumor size was measured as the sum of longest diameters or short axis of the target lesions according to Response Evaluation Criteria In Solid Tumors V.1.1 by investigator assessment. Best percent change in target lesion size was the maximum percent reduction from baseline or the minimum percent increase from baseline (in the absence of a reduction), up until disease progression or starting subsequent alternative cancer therapy. Tumor shrinkage is shown regardless of whether new lesions identified. Reference lines at 20% and −30% mark target lesion response criteria for disease progression (PD), partial response (PR), respectively. CR, complete response; SD, stable disease.

Figure 3

Overall survival in patients who received tebentafusp and durvalumab±tremelimumab. (A) Kaplan-Meier estimates of overall survival (OS) for patients treated with tebentafusp in combination with durvalumab (Arm 1; n=43; blue) or durvalumab and tremelimumab (Arm 3; n=29; green). Events are deaths due to any cause. Patients not known to have died at the time of analysis are censored. For patients receiving combination tebentafusp and durvalumab (Arm 1), the median OS was 18.7 (95% CI: 15.4 to 22.3) months with a 1-year OS rate of 74% (95% CI: 67% to 80%). For patients receiving triplet therapy (Arm 3), the median OS was 19.9 (95% CI: 14.6 to 26.3) months with a 1-year OS rate of 79% (95% CI: 71% to 86%).

Figure 4

Overall survival in patients who progressed on prior anti-PD(L)1. (A) Kaplan-Meier estimates of overall survival (OS) for patients who progressed on prior anti-PD(L)1 therapy treated with tebentafusp in combination with durvalumab (Arm 1; n=34; blue) or durvalumab and tremelimumab (Arm 3; n=24; green). Events are deaths due to any cause. Patients not known to have died at the time of analysis are censored. For patients receiving combination tebentafusp and durvalumab (Arm 1), the median OS was 18.4 (95% CI: 13.1 to 22.3) months with a 1-year OS rate of 73% (95% CI: 65% to 80%). For patients receiving triplet therapy (Arm 3), the median OS was 17.8 (95% CI: 14.6 to 21.7) months with a 1-year OS rate of 78% (95% CI: 70% to 87%). (B) Kaplan-Meier estimates of OS for patients who had a best response of progressive disease while on prior anti-PD(L)1 (refractory; n=19; blue) or had a best response of either stable disease (n=17) or partial response/complete response (n=17) and then had disease progression on prior anti-PD(L)1 (relapsed n=34; red). For patients refractory to prior anti-PD(L)1, the median OS was 18.4 (95% CI: 7.2 to 28.6) months with a 1-year OS rate of 60% (95% CI: 49% to 72%). For patients relapsed on anti-PD(L)1, the median OS was 17.7 (95% CI: 15.4 to 21.7) months with a 1-year OS rate of 82% (95% CI: 75% to 89%).