Toxicities Hinder Potential Efficacy of Ceritinib/Trametinib in Pretreated Advanced Melanoma

Zeynep Eroglu, MD

Although dual suppression of the mTOR and MAPK pathways could be a viable therapy avenue for patients with pretreated advanced melanoma, overcoming overlapping toxicities when combining these types of therapies will be paramount, according to Zeynep Eroglu, MD.

A phase 1/2 trial (NCT03501368) evaluated ceritinib (Zykadia) alone and in combination with trametinib (Mekinist) in patients with advanced melanoma that progressed after prior treatment with anti–PD-1 therapy (and prior BRAF/MEK inhibitors, if eligible). Findings presented at the 2024 AACR Annual Meeting showed that no patients treated with single-agent ceritinib (n = 11) responded; 2 patients experienced stable disease (SD). In patients treated with the combination, 2 patients experienced a partial response, and 6 patients had SD.

Notably, dose-limiting toxicities of grade 3 rash and grade 2 glaucoma prompted investigators to de-escalate dosing from dose level 1 of 300 mg of ceritinib per day and 2 mg of trametinib per day to 300 mg and 1.5 mg, respectively. The subsequent dose level was established as the maximum tolerated dose.

“Our hope is that with further drug development, drug discovery, and newer agents being tested, we may be able to find more tolerable drugs that may then be easier to combine with less toxicity [to allow for escalation] to more clinically efficacious doses,” Zeynep Eroglu, MD, said in an interview with OncLive.

In the interview, Eroglu addressed unmet needs in patients with pretreated advanced melanoma, expanded on findings for the combination of ceritinib and trametinib derived from the phase 1/2 study, and explained how these data could help inform future research.

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, both located in Tampa.

OncLive: What unmet needs currently exist for patients with mutant melanoma? How did this research aim to address these needs?

Eroglu: In patients with advanced metastatic melanoma, after [progression on] first-line immunotherapy, which is how a majority of patients are treated, there is a lack of treatment options. There have been recent advances with the approval of [lifileucel (Amtagvi)], which is very exciting after primary therapy [with a checkpoint inhibitor and potentially a BRAF inhibitor]. However, there are also a lot of patients who are not eligible for those types of adoptive cellular therapies for various reasons. Especially patients whose melanoma does not have a BRAF V600 mutation, there is a need for better treatment options for [these patients] after [progression] on immunotherapy.

We know that there's been some data with the use of MEK inhibitors in patients with BRAF wild-type [disease] and, more specifically, with NRAS-mutated melanoma. The response rates have not been great. Typically from small studies, response rates have been approximately 10% to 15% with MEK inhibitors in [patients with] BRAF wild-type or NRAS-mutant melanoma. Our thought with this study was to see if we can improve upon some of the data with TKIs in [patients with] BRAF wild-type melanoma.

Ceritinib, specifically, is a TKI that's FDA approved for use in ALK-mutated lung cancers. There has [also] been data from the lab of Keiran Smalley, PhD, at Moffitt Cancer Center, looking at the use of ceritinib in both NRAS-mutant and wild-type, as well as BRAF-mutant and wild-type cell lines, and then subsequently animal models, showing some activity of ceritinib.

Mechanistically, it doesn't have anything to do with ALK inhibition in melanoma; it seems to inhibit kinases such as IGF1R, ACK1, or FAK, in terms of its efficacy. Furthermore, when ceritinib is combined with the MEK inhibitor trametinib, there is some synergistic benefit decreasing tumor growth in melanoma xenografts, and suppressing both the MAPK and mTOR signaling. Looking at animal models after prior anti–PD-1 immunotherapy, the combination of the ceritinib and trametinib [seems to be] even more effective when administered after prior anti-PD–1 therapy.

What patient population was enrolled onto this study?

In this small phase 1/2 trial, [we enrolled] patients with advanced metastatic melanoma. Most of the patients had stage IV disease, many of whom had N1c melanoma. A small number [of patients [n = 2] had a stage III, unresectable melanoma. All patients had to receive prior anti–PD-1–based immunotherapy for eligibility, and many of the patients received multiple prior lines of therapy. The median was 3 prior lines of therapy.

Many of patients [previously received] other investigational agents, tumor-infiltrating lymphocyte therapy, other targeted agents, or chemotherapy, so this was a heavily pretreated population. In 46.2% of patients, the tumor mutation status that was NRAS and BRAF wild-type, [Additionally, 39.3% of patients had an NRAS mutation, and [14.3%] of patients had a BRAF V600 mutation.

What safety findings were derived when evaluating treatment with ceritinib and trametinib in mutant melanoma? Additionally, could you highlight what methods were utilized in the trial?

The initial portion of this study started with phase 2 because we looked at ceritinib as monotherapy at the standard FDA-approved dose of 450 mg per day to see if there was any single-agent activity with ceritinib in [patients] metastatic melanoma. We had 11 patients treated with ceritinib alone in the phase 2 portion. The safety was standard toxicity, and the most common grade 3/4 toxicity was liver enzyme elevation, which was tolerable.

Then, we switched to the phase 1 portion, which was the combination of ceritinib and trametinib, once the trametinib became available; 17 patients enrolled into the phase 1 portion. There, we did a dose escalation; we started with a lower dose of ceritinib at 300 mg per day with the standard dose of 2 mg per day of trametinib. That was our dose level 1, and then we had a level –1 to de-escalate to and a level 2 to escalate to.

We enrolled in groups of 3, and 12 patients were [treated] with the level 1 [regimen]. There were some concerns with toxicity. We had several patients who had grade 3 rash, which I would say was the most challenging [toxicity]. Subsequently, we had to de-escalate to dose level –1, which was 300 mg per day of ceritinib [plus] 1.5 mg per day of trametinib, and then we finished the study by enrolling five additional patients at the level 1 dose.

With the combination of ceritinib/trametinib, that was more challenging for patients in terms of several patients [requiring] dose holds or dose reductions because of rash and some of the other adverse effects seen with the combination of TKIs.

What efficacy was observed with ceritinib monotherapy and in combination with trametinib?

With ceritinib alone, we didn't see tumor responses. Two patients [experienced] prolonged stable disease [SD]. In the 17 patients [who received] ceritinib plus trametinib, we did have 2 patients with an objective response. In 3 of the 6 patients who had SD, it lasted for 6 months or longer.

Some of the patients did have prolonged duration of stable disease, and a couple with treatment response. However, if we were to compare [these data] with what we see with MEK inhibitors in melanoma, [ceritinib plus trametinib elicited] similar response rates. The median PFS ranged from 2.1 months [with ceritinib monotherapy] to 3.1 months [with the combination], and the median OS overall survival ranged from 7.3 months [with ceritinib alone] to 7.8 months [with the combination]. [It is important to] keep in mind that this was a heavily pretreated patient population.

We did try to see if we could identify any markers for improved benefit; however, we didn't see that. If the melanoma NRAS-mutated or wild-type, or BRAF-mutated or wild-type, that didn't seem to impact outcomes. We did note that if the patients had anti–PD-1 therapy as the last line of treatment that they progressed on before [receiving ceritinib plus trametinib], those patients seemed to do best. This was in line with what was seen in the animal models. The median OS for those patients who had a last line of anti–PD-1 therapy before going on the study was 10.2 months compared with 5.1 months for those [who did not receive] anti–PD-1 therapy [as their most recent treatment].

What are the potential next steps for this study?

We collected tumor biopsy specimens and blood samples from all the patients. We have day 1 and 15 biopsies, and some were obtained at the time of tumor progression. We are doing some analyses on those, such as flow cytometry and single-cell RNA sequencing, to see if there are any markers we can identify in the few patients who did have better responses, including in those patients who had immunotherapy as the last prior line of the therapy, to try to determine if there is any path forward with this type of signaling, even if it's not with these specific drugs. [We could potentially] focus on the targets from these 2 drugs in patients who had immunotherapy as their last line of therapy. Our hope is that the biopsy data, once analyzed, will give us a path forward.

The challenge, as I think has been seen in other studies in combining multiple TKIs, is some of the overlapping toxicities. That was the challenge with trametinib plus ceritinib. There may still be a role for targeted therapy in patients with metastatic melanoma after progression on prior anti–PD-1 or adoptive cellular therapy, [which could address] an unmet need for these patients.

Reference

Eroglu Z, Yin V, Markowitz J, et al. Phase 1/2 trial of trametinib + ceritinib in patients with unresectable melanoma. Presented at: 2024 AACR Annual Meeting; April 5-10, 2024; San Diego, CA. Abstract CT057.