Dabrafenib and Trametinib Plus Navitoclax Meets CR End Point in BRAF V600–mutant Metastatic Melanoma

The combination of dabrafenib (Tafinlar) and trametinib (Mekinist) plus navitoclax generated responses and met the co-primary end point for complete response (CR) rate vs historical controls in patients with BRAF V600–mutant metastatic melanoma, according to data from the phase 2 CTEP-P9466 trial (NCT01989585) presented at the 2023 ASCO Annual Meeting.1

However, the study missed its other co-primary end point of maximal tumor shrinkage for patients treated with the combination of dabrafenib, trametinib, and navitoclax vs those given dabrafenib plus trametinib.

Findings showed that patients who received the triplet combination (n = 25) experienced an overall response rate (ORR) of 84%, consisting of a 20% CR rate and a 64% partial response (PR) rate. Within this group, 12% of patients had stable disease (SD) and 4% had progressive disease (PD). Patients who received dabrafenib plus trametinib alone (n = 25) had an ORR of 80%, including a CR rate of 16%, PR rate of 64%, and a SD rate of 8%. No patients experienced PD in this arm.

Patients in the triplet arm experienced a median maximal tumor decrease of –68.8% (min, –2.1%; max, –100%) compared with –63.1% (min, 6.7%; max, –100%) in the doublet arm. The mean maximal tumor regression was –63.6% (standard deviation, 27.1) for the triplet vs –63.9% (standard deviation, 28.6) for the doublet (P = .88).

AlthoughBRAF/MEK-inhibitors are a highly effective standard of care within BRAF-mutant melanoma, developed resistance to inhibition of the MAPK pathway could limit the durability of responses.

“There is a subset of patients who can have prolonged benefit from BRAF-targeted therapy,” lead study author Zeynep Eroglu, MD, said in a presentation of the data. “With the limited options in metastatic melanoma after failure of immunotherapy, attempting to improve outcomes with BRAF-targeted therapy may still be worthwhile.”

Eroglu is a medical oncologist in the Department of Cutaneous Oncology at Moffitt Cancer Center and an assistant professor in the Department of Oncologic Sciences at the University of South Florida Morsani College of Medicine in Tampa, Florida.

Investigators hypothesized that administering navitoclax before the dual BRAF inhibitor regimen, then continuously in combination, would improve responses and survival outcomes by inhibiting BCL-2. Prior data from the phase 1 dose-escalation portion of CTEP-P9466 showed that the triplet elicited clinical efficacy in 20 patients with BRAF-mutant solid tumors, including 10 with metastatic melanoma. The recommended phase 2 dose (RP2D) for the combination was established at 150 mg of dabrafenib twice per day, 2 mg of trametinib per day, and 225 mg of navitoclax per day.²

The trial enrolled patients 18 years of age or older who had histologically confirmed BRAF V600–mutant (E/K) advanced melanoma and measurable disease.³ Patients were allowed to have previously received treatment with ICIs, but they were ineligible if they had prior exposure to BRAF inhibitors. Patients with brain metastases were also able to enroll provided they had received treatment at a minimum of 3 months before enrollment. An ECOG performance status of 0 or 1 was also required.

Patients were enrolled on the trial from January 11th, 2019, to March 15th, 2022. Fifty patients were randomly assigned 1:1 to receive oral dabrafenib and trametinib with or without oral navitoclax at the RP2D. Dabrafenib was administered at a standard dose level of 150 mg twice daily alongside 2 mg of trametinib once per day for a 28-day cycle. The 25 patients in the triplet arm also received a lead-in dosing with 150 mg of navitoclax once per day for one week before receiving a once-daily 225 mg dose of navitoclax in combination with dabrafenib and trametinib.¹

Patients were then stratified by tumor burden (<100 mm vs ≥100 mm).

All study participants were required to undergo MRI or CT scans, biopsy, and blood sample collection throughout the trial. A blood BRAF circulating tumor cell (CTC) assay was also performed on serial blood samples at multiple time points, including both before and after the navitoclax lead-in.

The co-primary end points of the study were the estimated CR rate for the triplet compared with historical controls and the comparison of maximal tumor shrinkage between both groups. Notably, this study was not powered for a direct comparison of each regimen for CR rate. Instead, a single-stage statistical design was used to compare a null CR rate of 10% with an alternative CR rate of 30%. The end null hypothesis was rejected if 5 or more patients in the triplet arm had a CR. A 25% increase in maximal tumor regression was deemed clinically meaningful.

“The reason for these primary end points was the expectation that adding navitoclax wouldn't improve the already very high response rates seen with BRAF/MEKinhibitor therapy, but deepen the tumor responses,” Eroglu explained.

Key secondary end points included ORR, progression-free survival (PFS), and overall survival (OS). The data cut-off was March 2023.

The median age of patients in the overall population was 57 (range 31-71). Regarding biological sex, 54% of patients identified as female and 46% were male. The majority of patients had stage IV disease (64%), followed by stage II disease (32%) and disease stage unknown (4%). Sixty-eight percent of patients received prior immunotherapy, and 26% received prior oncolytic virus therapy, radiation therapy, or other. Patients had a mean of 1.9 prior lines of therapy. Half of patients had baseline lactate dehydrogenase levels below the upper limit of normal. In terms of baseline tumor burden, 74% of patients had tumors less than 100 mm, and 26% had tumors 100 mm or larger.

At a median follow-up of 27.4 months, the median PFS was 20.9 months (95% CI, 11.3–not reached [NR]) with the triplet and 21.7 months (95% CI, 9.6-NR) with the doublet (log-rank P = .7).

Further efficacy analysis showed a trend for improved OS in patients treated with navitoclax dabrafenib and trametinib vs dabrafenib and trametinib alone. The 2-year OS rate in the experimental arm was 74% (95% CI, 50%-87%) and 57% (95% CI, 34%-74%) in the doublet arm (P = .16). In patients with lower baseline tumor burden, 2-year OS rates were 80% (95% CI, 50%-93%) and 59% (95% CI, 32%-79%) with the doublet and triplet, respectively (P = .06). Median OS was 36 months (95% CI, 23-NR) in the overall population.

Regarding safety, 2 patients in each study arm discontinued treatment due to treatment-related adverse effects (TRAEs). On average, patients in the triplet arm underwent 12.9 cycles of treatment and 12.1 cycles in the doublet arm. The majority of TRAEs were grades 1 and 2.

Any-grade TRAEs observed in more than 50% of patients included nausea (n = 36), diarrhea (n = 32), fatigue (n = 31), and fever (n = 28).

All patients in the study will continue to be followed for survival. Correlative analyses on tumor and blood samples, including WES/RNA sequencing, immune panels, BCL-2 family member analyses, circulating tumor DNA analysis, and proteomics at baseline and early treatment stages are also ongoing.

“Targeting apoptosis in BRAF V600–mutant melanoma may be considered for future exploration in the post immunotherapy setting, and results of the correlative analyses may help to inform [these] future studies,” Eroglu concluded.

Disclosures: Dr Eroglu reports serving as a consultant or in an advisory role for Eisai, Elsevier, Genentech/Roche, OncoSec, Pfizer, and Regeneron; she received institutional research funding from Boehringer Ingelheim, Novartis, and Pfizer.

References

1. Eroglu Z, Mehner JM, Anita Giobbie-Hurder A, et al. Randomized phase II trial of dabrafenib and trametinib with or without navitoclax in patients (pts) with BRAF-mutant (MT) metastatic melanoma (MM) (CTEP P9466). J Clin Oncol. 2023;41(suppl 16):9511. doi:10.1200/JCO.2023.41.16_suppl.9511
2. Sullivan RJ, Mehnert J, Tawbi H, et al. First in human, dose escalation trial of the combination of dabrafenib, trametinib, and navitoclax in patients with BRAF mutant solid tumors. Mol Cancer Ther. 2018;17 (suppl 1):LB-B30. doi:10.1158/1535-7163.TARG-17-LB-B30
3. Testing the addition of navitoclax to the combination of dabrafenib and trametinib in people who have BRAF mutant melanoma. ClinicalTrials.gov. Updated May 26, 2023. Accessed June 5, 2023. https://clinicaltrials.gov/ct2/show/NCT01989585