DREAMseq (Doublet, Randomized Evaluation in Advanced Melanoma Sequencing): A phase III trial—ECOG-ACRIN EA6134.

Abstract

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.

Prescription Patterns, Recurrence, and Toxicity Rates of Adjuvant Treatment for Stage III/IV Melanoma—A Real World Single-Center Analysis

“…This striking difference in prescription rate of BRAFi/MEKi between our center and the German centers suggests significant regional disparities in clinical practice possibly influenced by physicians' preferences, local guidelines, and patient's perceptions. It is conceivable that physicians at our center favor adjuvant ICI because ICI treatment was shown to be less efficacious in the metastatic setting if given after progression on BRAFi/MEKi [11,12]. This has been related to the changes in the tumor microenvironment and the lower CD8 T cell infiltrate in tumor tissues of patients progressing on BRAFi/MEKi [13].…”

“…However, a prospective evaluation of the response of patients relapsing on/after adjuvant treatment to first-line treatment is currently not available. Given the clear survival advantage in the metastatic setting of first-line ipilimumab/nivolumab over BRAFi/MEKi as reported by the SECOMBIT [12] and DREAMSeq [11] trials, a randomized clinical trial comparing ICI versus BRAFi/MEKi in patients relapsing on or after adjuvant treatment is required.…”

Computational Model of Heterogeneity in Melanoma: Designing Therapies and Predicting Outcomes

“…Although this treatment does not act directly on melanoma cells, it can have a differential indirect effect on melanoma sub-populations, and acts more generally than targeted treatments. Very recent Phase III trials combining kinase inhibitors and ICIs show that starting a first line treatment with ICIs leads to better results in terms of survival time and duration of response than starting with kinase inhibitors ( 17 ). This is explained if checkpoint inhibitors induce effective prior elimination of resistant stage sub-populations.…”

The Use of ctDNA for BRAF Mutation Testing in Routine Clinical Practice in Patients with Advanced Melanoma

“…In comparison, 5-year OS rates in patients treated in phase III trials with dabrafenib plus trametinib and vemurafenib plus cobimetinib were 34% and 31%, respectively [27,28]. Recently published data from two randomized trials (SECOMBIT and DREAMseq) evaluating the optimal sequencing of BRAF-targeted therapy and immune checkpoint inhibitor therapy showed a survival advantage of the combination of nivolumab plus ipilimumab over first-line targeted therapy [29,30]. However, in cases where the disease is symptomatic and rapidly progressing, and the patient's condition appears to be deteriorating, BRAF-targeted therapy is still the preferred frontline treatment.…”