Purpose Combination PD-1/CTLA-4 blockade and dual BRAF/MEK inhibition have each shown significant clinical benefit in patients with BRAFV600 mutant metastatic melanoma, leading to broad regulatory approval. Little prospective data exist to guide the choice of either initial therapy or treatment sequence in this population. This study was conducted to determine which initial treatment or treatment sequence produced the best efficacy. Methods In a phase III trial, patients with treatment-naïve BRAFV600-mutant metastatic melanoma were randomized to receive either combination nivolumab/ipilimumab (Arm A) or dabrafenib/trametinib (Arm B) in Step 1, and at disease progression were enrolled in Step 2 receiving the alternate therapy, dabrafenib/trametinib (Arm C) or nivolumab/ipilimumab (Arm D). The primary endpoint was 2-year overall survival. Secondary endpoints were 3-year overall survival, objective response rate, response duration, progression-free survival, crossover feasibility and safety. Results 265 patients were enrolled with 73 going onto Step 2 (27 Arm C, 46 Arm D). The study was stopped early by the independent DSMC due to a clinically significant endpoint being achieved. The 2-year overall survival for those starting on Arm A was 71.8% (62.5, 79.1%) and Arm B 51.5% (41.7, 60.4%) (log-rank p=0.010). Step 1 progression-free survival favored Arm A (p=0.054). Objective response rates were: Arm A:46.0%; Arm B:43.0%; Arm C:47.8%; Arm D:29.6%. Median duration of response was not reached for Arm A and 12.7 months for Arm B (p<0.001). Crossover occurred in 52% of patients with documented disease progression. Grade >3 toxicities occurred with similar frequency between arms and regimen toxicity profiles were as anticipated. Conclusion Combination nivolumab/ipilimumab followed by BRAF and MEK inhibitor therapy, if necessary, should be the preferred treatment sequence for a large majority of patients.

356154 Background: Combinations of immune checkpoint inhibitors (CPI) blocking PD-1 and CTLA-4 or BRAF/MEK inhibitors have both shown significant antitumor efficacy and overall survival (OS) benefit in patients (pts) with BRAFV600-mutant metastatic melanoma (MM), leading to broad regulatory approval. Little prospective data exists to guide the choice of one over the other as initial therapy or the preferred treatment sequence in this population. The DREAMseq Trial was designed to compare the efficacy and toxicity of the sequence of nivolumab/ipilimumab (N/I) followed by dabrafenib/trametinib (D/T) to the converse sequence. Methods: Eligible pts with treatment-naive BRAFV600-mutant MM were stratified by ECOG Performance Status (PS) 0 or 1 and LDH level and randomized 1:1 to receive Step 1 with either N/I (Arm A) or D/T (Arm B) and at disease progression (PD) were enrolled in Step 2 receiving the alternate therapy, D/T (Arm C) or N/I (Arm D), respectively. Pts received N (1mg/kg)/I (3 mg/kg) q3 wks x 4 doses followed by N 240 IV q2 wks for up to 72 wks (Arms A and D) or D 150 mg po BID and T 2 mg po qD until PD (Arms B and C). In 2019, investigators were given the option to use alternate induction dosing of N (3mg/kg)/I (1 mg/kg) q3 wks x 4 doses for Arms A and D. Cycles were every 6 wks and imaging was obtained at baseline and q12 wks on each arm. Primary endpoint was 2-year OS. At the 4th Interim Analysis with 59% of pts being 2 yrs from enrollment, the DSMC and NCI CTEP recommended halting accrual and releasing the data. Results: Beginning 7/2015, 265 out of a proposed 300 pts were enrolled (133 Arm A and 132 Arm B). Median age was 61 (25-85) and 63% were male. Demographics for Arm A and B were balanced with 67% PS 0 and 60% with normal LDH. As of 7/16/21, at a median follow-up of 27.7 mos, 27 pts had switched to Arm C and 46 to Arm D. Overall Grade 3+ toxicity was 60% in Arm A and 52% in Arm B. Grade 5 treatment-related AEs included 2 on Arm A and 1 on Arm C. ORR to date is: Arm A 46% (52/113), Arm B 43% (49/114), Arm C 48% (11/23) and Arm D 30% (8/27). 37/42 assessed pts in Arm A and 19/37 in Arm B remain in response. Median DOR: Arm A- Not reached; Arm B-12.7 mos (95% CI: 8.2, -) (p <0.001). There were 100 deaths (Arm A to C- 38/Arm B to D- 62). 2-yr OS rate for those starting with Arm A was 72% (95% CI: 62-81%) and for Arm B 52% (95% CI: 42-62%) (log-rank p= 0.0095). PFS showed a trend in favor of Arm A (log-rank p=0.054). Both the PFS and OS curves show a biphasic pattern with Arm B being above Arm A until 6 and 10 mos, respectively. For the 115 pts with documented progression on Step 1 (Arm A-44/Arm B-71), 60 (52%) had registered for Step 2. The principal reason for not enrolling on Step 2 was death from PD within 6 mos (Arm A:15/23; Arm B: 25/32). Conclusions: For pts with advanced BRAFV600-mutant MM, the treatment sequence beginning with the CPI combination of N/I resulted in superior OS, which became evident at 10 mos, with longer Step 1 DOR and more ongoing responses than the treatment sequence beginning with D/T. Clinical trial information: NCT02224781.

No abstract

In patients with previously treated metastatic uveal melanoma, the historical 1 year overall survival rate is 37% with a median overall survival of 7.8 months. We conducted a multicenter, single-arm, open-label phase 2 study of tebentafusp, a soluble T cell receptor bispecific (gp100×CD3), in 127 patients with treatment-refractory metastatic uveal melanoma (NCT02570308). The primary endpoint was the estimation of objective response rate based on RECIST (Response Evaluation Criteria in Solid Tumours) v1.1. Secondary objectives included safety, overall survival, progression-free survival and disease control rate. All patients had at least one treatment-related adverse event, with rash (87%), pyrexia (80%) and pruritus (67%) being the most common. Toxicity was mostly mild to moderate in severity but was greatly reduced in incidence and intensity after the initial three doses. Despite a low overall response rate of 5% (95% CI: 2–10%), the 1 year overall survival rate was 62% (95% CI: 53–70%) with a median overall survival of 16.8 months (95% CI: 12.9–21.3), suggesting benefit beyond traditional radiographic-based response criteria. In an exploratory analysis, early on-treatment reduction in circulating tumour DNA was strongly associated with overall survival, even in patients with radiographic progression. Our findings indicate that tebentafusp has promising clinical activity with an acceptable safety profile in patients with previously treated metastatic uveal melanoma, and data suggesting ctDNA as an early indicator of clinical benefit from tebentafusp need confirmation in a randomized trial.