Addition of Navitoclax to Dabrafenib/Trametinib Aims to Improve Efficacy of Targeted Therapy in BRAF+ Metastatic Melanoma

Zeynep Eroglu, MD

With limited treatment options available for patients with metastatic melanoma who experience disease progression on or following immunotherapy, exploring ways to improve outcomes with the use of BRAF-targeted therapy in those with BRAF V600–mutant metastatic disease remains an area of interest, according to Zeynep Eroglu, MD.

The phase 2 CTEP-P9466 trial (NCT01989585) met one co-primary end point when the addition of navitoclax to the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) improved complete response (CR) rates vs historical controls in patients with BRAF V600–mutant metastatic melanoma. However, the study did not meet its other co-primary end point of maximal tumor shrinkage for patients treated with the triplet vs those given dabrafenib plus trametinib alone.

Findings from the phase 2 trial presented at the 2023 ASCO Annual Meeting revealed that patients treated with dabrafenib plus trametinib and navitoclax (n = 25) experienced an overall response rate (ORR) of 84% vs 80% in patients treated with dabrafenib plus trametinib alone (n = 25). Additionally, patients treated with the triplet achieved a CR rate of 20% and a partial response (PR) rate of 64%. The CR and PR rates for the doublet were 16% and 64%, respectively.

Patients treated with dabrafenib plus trametinib and navitoclax, experienced a median maximal tumor decrease of –68.8% (min, –2.1%; max, –100%) vs a median maximal tumor decrease of –63.1% (min, 6.7%; max, –100%) in patients treated on the doublet arm.

“Ultimately, we do still feel there is a role for BRAF-targeted therapy in melanoma. It is still valuable to explore these combinations to try to improve outcomes for our patients with metastatic disease,” Eroglu said in an interview with OncLive^®.

In the interview, Eroglu explained the rationale for adding navitoclax to dabrafenib plus trametinib in the treatment of patients with BRAF V600–mutant metastatic melanoma, highlighted the methodologies and results of the CTEP-P9466 trial, and described the implications of this research for this patient population.

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.

OncLive: What is known about the use of BRAF-targeted therapy in patients with metastatic melanoma?

Eroglu: Dabrafenib plus trametinib is a BRAF/MEK inhibitor combination therapy that was FDA approved in 2013 for the treatment of patients with advanced melanoma [who harbor] a BRAF V600 mutation. The combination has approximately a 70% objective response rate and a CR rate of approximately 10% to 15% [in the first-line setting], based on earlier studies, with a median progression-free survival [PFS] of about 11 to 12 months. However, increasingly, BRAF-targeted therapy drugs are used more in the second- or later-line setting after [progression following] first-line immunotherapy; targeted therapy may not be as effective in [the second-line] setting.

There was the [phase 3 DREAMseq trial (NCT02224781)] reporting lower tumor response rates and lower PFS when dabrafenib/trametinib was given after progression on prior immunotherapy. However, longer follow-up from targeted therapy studies have shown 5-year PFS rates of approximately 20%. Therefore, we believe there is a subset of patients who can have prolonged benefit from the BRAF-targeted therapy. Given the limited options in metastatic melanoma after [progression] on first-line immunotherapy, trying to improve outcomes with BRAF-targeted therapy may still be worthwhile.

What was the rationale for launching the CTEP-P9466 study?

Our hypothesis for this study was [that] targeting apoptosis in combination with BRAF-targeted therapy could lead to improved outcomes in patients with metastatic melanoma. We know from preclinical studies that the proapoptotic activity of BRAF/MEK inhibitors is modest overall, with residual antiapoptotic mechanisms that remain. We thought one way to enhance outcomes could be with drugs that lower the threshold for apoptosis induction by BRAF/MEK inhibitors.

One such drug may be navitoclax, which is a small-molecule inhibitor of the antiapoptotic BCL2 member proteins. Animal models have shown that adding navitoclax to BRAF/MEK inhibitors was associated with deeper tumor response, increased apoptosis of the tumor, and delayed progression compared with BRAF/MEK inhibitor therapy alone.

The phase 1 [portion of CTEP-P9466 evaluated] dabrafenib plus trametinib and navitoclax in patients with the BRAF-mutant solid tumors. This was led by Ryan Sullivan, MD, at Massachusetts General Hospital, and was conducted through the National Cancer Institute's Experimental Therapeutic Clinical Trials Network [ETCTN]. There were 25 patients in that phase 1 study, and the recommended phase 2 dose [RP2D] was determined. It was the standard dosing of dabrafenib and trametinib with 225 mg a day of navitoclax with a 1-week lead in of navitoclax alone. Subsequently, in 2019, the phase 2 portion of the study was launched through the ETCTN, opening up at 14 centers. The data from that phase 2 study were presented at the 2023 ASCO Annual Meeting.

Could you expand on the design of the phase 2 portion of the trial?

[It included] patients with BRAF V600–mutant unresectable or metastatic melanoma who could have had any prior treatment except prior BRAF inhibitors. Fifty patients were randomly assigned 1:1 to the triplet of dabrafenib and trametinib plus navitoclax [at the RP2D] vs standard dabrafenib plus trametinib. Patients were stratified by tumor burden [<100 mm vs ≥100 mm]. From the 50 patients who were enrolled, 64% had stage IV melanoma, 68% had received prior immunotherapy, and 50% had elevated lactate dehydrogenase at baseline.

What efficacy findings from CTEP-P9466 were presented at the 2023 ASCO Annual Meeting?

The phase 2 study had 2 co-primary end points. The first was to estimate the CR rates in patients receiving the triplet regimen compared with historical controls. Ultimately, the CR rate was 20% in the triplet arm. Therefore, the study met this primary end point. Overall, the ORR was also quite high at 84% [with the triplet]. The CR rate was 16% with dabrafenib and trametinib alone.

The second co-primary end point compared maximal tumor shrinkage between the 2 study arms. The [median] maximal tumor shrinkage was [–68.8%] with the triplet and [–63.1%] with dabrafenib and trametinib alone. That was not a significant difference, so that end point was not met.

Looking at some of the secondary end points, there was a median follow-up of [27.4] months, and the PFS was similar with the triplet vs the doublet at 20.9 months [95% CI, 11.3-not reached (NR)] vs 21.7 months [95% CI, 9.6-NR]. The median overall survival [OS] for the entire cohort of 50 patients—keeping in mind that [68%] of patients had received prior anti–PD-1 immunotherapy—was 36 months [95% CI, 23-NR]. The 2-year OS rate was 74% [95% CI, 50%-87%] with the triplet vs 57% [95% CI, 34%-74%] with the doublet.

For the subgroup that was stratified by lower tumor burden, the 2-year OS was 80% [95% CI, 50%-93%] with the triplet vs 59% [95% CI, 32%-79%] with the doublet. We are going to be following patients longer for survival.

What safety findings were reported?

We saw the usual, well-known adverse effects [AEs] that have been reported with the dabrafenib and trametinib therapy in melanoma. As expected, hematologic toxicities such as thrombocytopenia and neutropenia were more frequent with the triplet because those are known AEs of navitoclax; however, grade 3 AEs were rare.

Overall, the study regimens, including the triplet, were fairly well tolerated. Of the 50 patients total, only 2 patients in each study arm had to discontinue treatment [due to] AEs.

What are next steps and potential implications of this research?

We'll be following patients longer for survival to [how] some of the differences we’re observing with the 2-year OS rates will look with longer follow-up. We're also beginning to analyze the correlatives from the study, including the blood, tissue, and tumor samples collected from the patients, [looking at] whole exome and RNA sequencing, immune panels, and markers of apoptosis. Based on what we see with longer survival follow-up and some data from the correlative analyses, we may then potentially pursue a larger randomized study [in patients] post-immunotherapy with this [triplet] combination, looking at a survival end point.

Reference

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