Ripretinib Demonstrates Impressive Efficacy, Durability in Heavily Pretreated KIT-Mutated Melanoma

Filip Janku, MD, PhD

The efficacy seen with ripretinib (Qinlock) in patients with KIT-mutated melanoma was higher than has been previously reported, according to Filip Janku, MD, PhD. Furthermore, the switch-control tyrosine kinase inhibitor (TKI) has elicited durable responses, even in patients who were heavily pretreated, making the drug a powerful tool for this patient population.

Investigators enrolled 26 patients with KIT-altered melanoma into this 2-part dose escalation/expansion study (NCT02571036). Patients were treated at the recommended phase 2 dose of 150 mg with daily ripretinib.

At the May 10, 2021, data cutoff, the confirmed overall response rate was 23% with 1 complete response and 5 partial responses. The median progression-free survival (PFS) was 7.3 months, with a median duration of response of 7.4 months.¹

“[Patients with KIT mutations] appear to be perhaps slightly less responsive to immune therapies, which are otherwise quite effective in many patients with melanoma,” Janku said. “That created unmet need, and the reason why we decided to test ripretinib in a cohort of patients with melanoma during the phase 1 study, followed by an expansion cohort study on the recommended phase 2 dose.”

In an interview with OncLive^®, Janku, an associate professor in the Department of Investigational Cancer Therapeutics (Phase I Program) at The University Of Texas MD Anderson Cancer Center, discussed the phase 1 study with ripretinib in patients with KIT-mutated or KIT-amplified melanoma.

OncLive^®: What was the rationale for this study?

Janku: The rationale was relatively simple. DCC-2618, or ripretinib, is a very effective KIT-kinase inhibitor, which has quite a unique mechanism of action by blocking the KIT function by its interaction with the switch pocket. That unique mechanism of action gives ripretinib better efficacy irrespective of the underlying subtype of the KIT mutations. When ripretinib was in the early stages of development, the main concern was gastrointestinal stromal tumor [GIST], which is a disease heavily driven by KIT or PDGFRAa [gene] mutations.

We also saw that [ripretinib] might have activity due to its unique mechanism of action. In other KIT-driven malignancies, such as melanoma, the existing KIT inhibitors have a mixed efficacy record with response rates, which are ranging between 16% and 30%, and the PFS is typically relatively short, [previously] reported somewhere from 3 to 6 months. We felt that with [ripretinib], we might have a shot [at improving response rates in] this population.

KIT mutations are not frequent in melanoma. They are present in only about 3% of all patients with melanoma, but [are more common in] certain subtypes of melanoma, such as mucosal, in which the prevalence of KIT mutations is about 30%, or acral, in which the prevalence is about 20%.

What was the design and methods used in phase 1 of the trial?

The phase 1 study was a classical dose-escalation study, which was fairly quick. Within a few dose levels, we reached the efficacious range and ultimately settled that 150 mg daily should be the recommended phase 2 dose. That was not a maximum tolerated dose, that was the recommended phase 2 dose.

This patient population was heavily represented by patients with GIST, but also some other solid tumors, [since] the dose escalation did not necessarily have requirements for molecular selection. The study enrolled additional multiple cohorts; most of the cohorts were focused on GIST with a certain level for pretreatment. We also had a cohort which specifically focused on melanoma, and the results, which we presented at ESMO, I personally find them quite exciting. I do believe that [ripretinib] might be the best-in-class KIT inhibitor for melanoma patients. The results are perhaps not as straightforward as they are [for patients with GIST], in which we treated the refractory population, who had no other therapeutic options. But the combination of direct and indirect evidence suggests that we might be dealing with a potentially very powerful tool in this patient population.

What did you see as far as efficacy?

The efficacy was intriguing and came up on a higher end than what has been presented so far. If we use a very stringent criteria and look at only confirmed responses, we've seen 1 complete response and 5 partial responses, which would account for total response rate in the intend-to-treat population of all 26 patients [of] about 23%. There were 2 original unconfirmed responses, so if these are included, that would bring up the response rate to 31%, which would be on the high end of what has been reported.

Even more importantly, the responses were durable. The median duration of response was more than 9 months. In addition to that, PFS in the entire population, which includes patients who did not necessarily achieve partial or complete response, was 7.3 months, which I think is probably [some] of the best data ever reported. It's also important to keep in mind that these patients were heavily pretreated. Nearly 40% of patients had 3 or more lines of prior therapies. Nearly all patients, 89%, had prior immunotherapy. About 35% of patients received prior KIT inhibitors.

Did you find anything that didn’t meet expectations?

So far, I have been giving a glowing review of this study. One thing which disappointed me was that I was hoping for a little bit more activity even in the patient population which received prior KIT inhibitors. The rationale for that was because of the unique mechanism of action of ripretinib, which I described initially. I was hoping that we might potentially have activity even in patients who might have built up mechanisms of adaptive resistance.

One possible explanation is that maybe the mechanisms of adaptive resistance might be distinctly different compared to GIST. The efficacy in patients with a prior exposure to KIT inhibitors was somewhat less, as represented by a PFS of 2.9 months in these patients compared with 10.2 months in patients who were naive to KIT inhibitors. That's perhaps 1 thing which I would comment as a possible slight disappointment. But when I say disappointment, I don't mean it as a really harsh term. Overall, this study produced quite exciting results and I was certainly very pleased to enter all my patients on it.

Did you record any new safety signals?

Ripretinib is overall well tolerated. And that's been known from [patients with GIST], I don't think the side effect profile in melanoma patients is necessarily any surprisingly different. The side effect profile is overall very bearable. Although we had 5 patients who discontinued therapy for adverse effects, if you look at the patients who have good effective therapy, [tolerability] is reflected by the long time on therapy or even response. These patients typically continued therapy. We even had 2 patients, who, at the time of analysis, were on therapy for more than 2 years; this is not surprising in [with disease], although ripretinib is already approved in GIST. There are still some patients who are on the initial phase 1 study, which is quite extraordinary for the protocol, which started enrolling in 2015/2016.

The side effect lipase was the only grade 3 toxicity, [however, that is] more a laboratory toxicity than a real problem. These patients, in a vast majority of cases, don't have any symptomatic issues which would be remotely resembling any pancreatic inflammation, let alone pancreatitis.

I think alopecia is a frequent adverse effect. It's not alopecia like from chemotherapy, it's more kind of like a grade 1 alopecia, mainly, in which the hair becomes thinner. Especially female patients often actually do use hair pieces because the hair also becomes a little bit fuzzy, which makes it harder to maintain the style. But it's not a complete loss of hair which would require just shaving it off, as we might with chemotherapy.

Actinic keratosis is a known side effect from GIST, as well. That might be due to some off-target effects, which actually might result in some additional stimulation of the MEK kinase pathway, which actually might ultimately result in actinic keratosis. And in the GIST study, we’ve even seen patients with a squamous skin cancer, which obviously was in all cases amenable to a relatively simple procedure in the dermatologist office, or minor surgery in the worst-case scenario.

Some of the typical side effects of ripretinib would include palmar-plantar erythrodysesthesia. We call it hand-foot syndrome, but it's mostly feet, you see it very seldomly in hands, which can be anything from peeling to edema to sensitivity. This is a side effect which is noticeable. It can be annoying, but [it is] typically manageable and not very often a reason for treatment discontinuation. Overall, very consistent with what we have observed before in our pre-extensive experience from phase 1 with expansion in GIST, as well as from the randomized registration study in GIST.

As the study is only in phase 1, what are the next steps for the trial that you'd like to see?

Well, that's being debated. Deciphera, which is the biotech [company] owning ripretinib, is probably thinking about it quite intensely. If it’s in my world, I would like to bring it forward. We haven't seen as much activity in [pretreated patients with KIT-alterations] as we would have wished. I still think that the activity compared to other KIT inhibitors might be superior [with ripretinib]. I would like to see a plan for further development, and I hope the company will go in that direction. Ripretinib has been commercially available because of approval for previously treated metastatic GIST. Therefore, it's not unreasonable to consider presenting the data on KIT-altered melanoma to groups in charge of treatment guidelines such as the National Comprehensive Cancer Network.

Is there anything I didn't ask about that you'd perhaps want to add?

It would be nice to understand the mechanisms of adaptive resistance to KIT inhibitors because that ultimately might help us to get some additional grounds and see some additional activity in patients who were previously treated with KIT inhibitors. That would be a good thing to do in the future. I would like to see this treatment moving forward in melanoma because I think it can have its role. The selling point, which is obvious from what was presented in the poster, is that these patients have benefits, and this benefit is often very durable.

Reference

1. Janku F, Bauer S, Shoumariyeh K, et al. Phase I study of ripretinib, a broad-spectrum KIT and PDGFRA inhibitor, in patients with KIT-mutated or KIT-amplified melanoma. Ann Oncol. 2021;32(suppl 5):S896-S897. doi:10.1016/j.annonc.2021.08.1467