Purpose: Tebentafusp is a first-in-class bispecific fusion protein designed to target gp100 (a melanoma-associated antigen) through a high affinity T-cell receptor (TCR) binding domain and an anti-CD3 T-cell engaging domain, which redirects T cells to kill gp100expressing tumor cells. Here, we report a multicenter phase I/II trial of tebentafusp in metastatic melanoma (NCT01211262) focusing on the mechanism of action of tebentafusp. Patients and Methods: Eighty-four patients with advanced melanoma received tebentafusp. Treatment efficacy, treatmentrelated adverse events, and biomarker assessments were performed for blood-derived and tumor biopsy samples obtained at baseline and on-treatment. Results: Tebentafusp was generally well-tolerated and active in both patients with metastatic uveal melanoma and patients with metastatic cutaneous melanoma. A 1-year overall survival rate of 65% was achieved for both patient cohorts. On-treatment cytokine measurements were consistent with the induction of IFNg pathway-related markers in the periphery and tumor. Notably, tebentafusp induced an increase in serum CXCL10 (a T-cell attractant) and a reduction in circulating CXCR3 þ CD8 þ T cells together with an increase in cytotoxic T cells in the tumor microenvironment. Furthermore, increased serum CXCL10 or the appearance of rash (likely due to cytotoxic T cells targeting gp100-expressing skin melanocytes) showed a positive association with patient survival. Conclusions: These data suggest that redirecting T cells using a gp100-targeting TCR/anti-CD3 bispecific fusion protein may provide benefit to patients with metastatic melanoma. Furthermore, the activity observed in these two molecularly disparate melanoma classes hints at the broad therapeutic potential of tebentafusp.

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Affinity-optimized T cell receptors can enhance the potency of adoptive T cell therapy. Afamitresgene autoleucel (afami-cel) is a human leukocyte antigen-restricted autologous T cell therapy targeting melanoma-associated antigen A4 (MAGE-A4), a cancer/testis antigen expressed at varying levels in multiple solid tumors. We conducted a multicenter, dose-escalation, phase 1 trial in patients with relapsed/refractory metastatic solid tumors expressing MAGE-A4, including synovial sarcoma (SS), ovarian cancer and head and neck cancer (NCT03132922). The primary endpoint was safety, and the secondary efficacy endpoints included overall response rate (ORR) and duration of response. All patients (N = 38, nine tumor types) experienced Grade ≥3 hematologic toxicities; 55% of patients (90% Grade ≤2) experienced cytokine release syndrome. ORR (all partial response) was 24% (9/38), 7/16 (44%) for SS and 2/22 (9%) for all other cancers. Median duration of response was 25.6 weeks (95% confidence interval (CI): 12.286, not reached) and 28.1 weeks (95% CI: 12.286, not reached) overall and for SS, respectively. Exploratory analyses showed that afami-cel infiltrates tumors, has an interferon-γ-driven mechanism of action and triggers adaptive immune responses. In addition, afami-cel has an acceptable benefit–risk profile, with early and durable responses, especially in patients with metastatic SS. Although the small trial size limits conclusions that can be drawn, the results warrant further testing in larger studies.

PURPOSE This phase I study aimed to define the recommended phase II dose (RP2D) of tebentafusp, a first-in-class T-cell receptor/anti-CD3 bispecific protein, using a three-week step-up dosing regimen, and to assess its safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity in patients with metastatic uveal melanoma (mUM). METHODS In this open-label, international, phase I/II study, HLA-A*02 or HLA-A*02:01+ patients with mUM received tebentafusp 20 μg once in week 1 and 30 μg once in week 2. Dose escalation (starting at 54 μg) began at week 3 in a standard 3 + 3 design to define RP2D. Expansion-phase patients were treated at the RP2D (20-30-68 μg). Blood and tumor samples were collected for pharmacokinetics/pharmacodynamics assessment, and treatment efficacy was evaluated for all patients with baseline efficacy data as of December 2017. RESULTS Between March 2016 and December 2017, 42 eligible patients who failed a median of two previous treatments were enrolled: 19 in the dose escalation cohort and 23 in an initial dose expansion cohort. Of the dose levels investigated, 68 μg was identified as the RP2D. Most frequent treatment-emergent adverse events regardless of attribution were pyrexia (91%), rash (83%), pruritus (83%), nausea (74%), fatigue (71%), and chills (69%). Toxicity attenuated following the first three doses. The overall response rate was 11.9% (95% CI, 4.0 to 25.6). With a median follow-up of 32.4 months, median overall survival was 25.5 months (range, 0.89-31.1 months) and 1-year overall survival rate was 67%. Treatment was associated with increased tumor T-cell infiltration and transient increases in serum inflammatory mediators. CONCLUSION Using a step-up dosing regimen of tebentafusp allowed a 36% increase in the RP2D compared with weekly fixed dosing, with a manageable side-effect profile and a signal of efficacy in mUM.

9531 Background: IMCgp100 is a bispecific biologic capable of redirecting T cells against the melanocyte-associated antigen gp100. In the first-in-human (FIH) clinical trial, preliminary efficacy of IMCgp100 in advanced uveal melanoma (UM) was observed; however, cases of severe T cell-mediated toxicities with the first 2 doses limited dosing to 50 mcg QW. This phase 1 study was designed to implement intra-patient escalation to mitigate toxicity and maximize exposure of IMCgp100. Methods: Using a 3+3 design, HLA-A2+ pts with metastatic UM were treated with low weekly (QW) dosing of IMCgp100 iv at Cycle 1, Day 1 (C1D1) (20 mcg) and C1D8 (30 mcg), followed by the escalated cohort dose administered at C1D15 and beyond. Results: Nineteen metastatic UM pts with a median of 3 prior lines of therapy (range 0 - 8) were treated across 4 target dose cohorts (60, 70, 80, and 75 mcg). Fifteen of 19 pts remain on treatment at the data cutoff (25Nov16). Enrollment completed 15Sep16. DLT was observed in 1 of 6 pts in the 70-mcg cohort (LFT elevation), and 2 of 4 pts treated at 80 mcg QW (LFT and bilirubin elevation). The 80 mcg dose level was not tolerated and a 75 mcg cohort was enrolled. Six pts were treated at 75 mcg without DLT; this dose was identified as the MTD and RP2D. All 3 DLT resolved without corticosteroids and all pts resumed IMCgp100. Frequent related AE included pruritus (84%), pyrexia (84%), fatigue (74%), hypotension (74%) and peripheral edema (63%). Gr 3/4 drug-related AE include AST increased (15%), erythema (15%) and hypotension (15%). Preliminary efficacy data (RECIST v1.1) from 17 evaluable pts (2 pts had insufficient follow-up) showed no objective responses; 12 pts had a BOR of SD (63%) including 4 pts (24%) with a ≥10% reduction in target lesions. With median follow-up of 1.8 mo, the disease control rate (16 wks) was 32%. Conclusions: The intra-patient escalation regimen of IMCgp100 results in a 50% increase in dose above the FIH Phase 1, acceptable safety profile, and preliminary efficacy in UM pts. Considering the dismal prognosis of metastatic UM, the PFS observed in this study is encouraging. A Phase 2 expansion cohort and separate pivotal trial of IMCgp100 in advanced UM are ongoing. Clinical trial information: NCT02570308.