Personalized Medicine Approaches Continue to Gain Steam in BRAF/NRAS+ Metastatic Melanoma

Meredith McKean, MD, MPH

The field of metastatic melanoma is continuing to develop novel targeted therapies that will further personalize treatment options to individuals based on the molecular characteristics of their disease, said Meredith McKean, MD, MPH, who highlighted that these developments further underscore the importance of broad molecular testing with next-generation sequencing (NGS).

“In oncology, we are continuing to evolve toward more personalization. That is in correlation with clinical trials that provide more opportunities for our patients. Trying to match the right patient to the right drug is really what we should be doing in oncology,” McKean said.

To that end, the ongoing phase 1 KN-8701 trial (NCT04913285) is evaluating KIN-2787, a novel small molecule pan-RAF inhibitor in patients with BRAF- and/or NRAS-mutated solid tumors, including melanoma and non–small cell lung cancer.1

Notably, patients with known class I, class II, or class III BRAF mutations are eligible for enrollment, which distinguishes the trial from others that include only patients with typical class I mutations like BRAF V600E.

In an interview with OncLive^®, McKean, associate director of the Melanoma and Skin Cancer Research Program at Sarah Cannon Research Institute of Tennessee Oncology, discussed how the presence of atypical BRAF mutations affects treatment selection in patients with metastatic melanoma, highlighted the ongoing KN-8701 trial, and explained why developments in this space further solidify the importance of broad molecular profiling.

OncLive^®:What are some of the unmet needs for systemic therapies for patients with class II and III BRAF mutations?

McKean: We have 3 different effective combination therapies for patients with classic BRAF V600E mutations, but there is a number of other patients with atypical BRAF mutations. Although there have been case reports and some examples of patients who may have some sensitivity to these classic BRAF/MEK inhibitor combinations, for the most part, these inhibitors are not very effective for patients with atypical mutations. Therefore, there is currently no FDA-approved treatment options for these patients and no standard-of-care targeted therapies.

If a patient with a class II or III BRAF mutation is identified, how does that affect how you approach treatment selection?

For standard of care, these patients are traditionally treated with immunotherapy. Then we start looking at clinical trials because there are so many options available. There are atypical BRAF inhibitors that have different binding [to BRAF] at high affinity and those that are more specific to these atypical mutations.

Several clinical trials are looking at different MEK inhibitors and ERK inhibitors that are trying to block just downstream of these active mutations.

What ongoing research has caught your eye in this space?

Several molecules are in development in phase 1 and 2 trials. The most important thing to know is that there are trial options out there. These patients and their providers should be seeking out these opportunities because there are molecules in development. Several different companies are [developing these] molecules. It will be exciting to see some of the results.

One such molecule is KIN-2787, which is now under study in the KN-8701 trial. The trial was expanded to include patients with NRAS-mutated melanoma. What could that mean for those patients?

Patients with NRAS mutations are another population with a high unmet need in metastatic melanoma. There are a couple different inhibitors and targeted therapies under development, but no therapies are approved for these patients. Some data have shown that these patients have worse outcomes compared with patients without NRAS mutations. Therefore, it is an important population for which we are looking to develop treatment options. [KIN-2787] is important because it may have some activity in targeting that patient population.

What do these advances signify regarding the importance of broad molecular profiling in patients with metastatic melanoma?

Number 1, for any oncologists or patients, is the importance of molecular profiling. The days of just looking for BRAF V600E mutations are over. We should be doing full comprehensive profiling for all our patients with metastatic melanoma to make sure we are identifying their driver mutations and available clinical trials for those with non–BRAF V600E mutations, NRAS mutations, or other mutations that might be seen on profiling. That is an important takeaway.

There is a lot of excitement about these clinical trial opportunities and trying to find new avenues of treatment for these patients.

What does the increasing emphasis on broad molecular testing mean for pathologists?

Our pathologists can have a difficult job because patients may have different resections of cutaneous tumors and in-transit metastases so they may not know where that patient is in their journey. It’s important for pathologists to [perform full molecular profiling]. [Pathologists should be] looking for mutations beyond just BRAF [V600E], NRAS, and KIT, which was the standard 3-gene panel test that had previously been done [in melanoma]. It’s important to recognize that it is worth checking with clinicians and asking: Has full profiling been completed? [It’s important to at least] have those results for the BRAF and NRAS mutations in that they could be game changers to open clinical trial opportunities for these patients.

Reference

1. A study to evaluate KIN-2787 in participants with BRAF and/or NRAS mutation positive solid tumors. Clinicaltrials.gov. Updated January 28, 2022. Accessed February 2, 2022. https://clinicaltrials.gov/ct2/show/NCT04913285