Presurgical, Postsurgical Targeted Therapy Effective in Some Melanomas

Patients with stage 3 or 4 melanoma may benefit from receiving BRAF and MEK inhibitors if they are eligible for surgery.

Presurgical and postsurgical treatment with BRAF and MEK inhibitors was found to be a “safe and effective” option among some patients with resectable (removable by surgery) melanoma, according to recently published research.

A team of researchers from Poland, whose findings were published in Cancer, showed that among 47 patients with borderline resectable stage 3 or resectable stage 4 melanoma with BRAF V600 mutations, neoadjuvant (presurgical) BRAF and MEK inhibitor treatment, followed by surgery and adjuvant (postsurgical) BRAK and MEK inhibitors resulted in 26% of patients achieving a pathological complete response and 21% of patients achieving a near-complete-response.

Pathological complete response “is basically no viable melanoma cell seen on the surgical specimen,” while near pathological complete response describes less than 10% viable cells, Dr. Ankit Mangla explained during an interview with CURE®. “Anything more than that — if you see, say, 20% viable cells or, say, 15% viable cells, is called partial pathological response. And then no response is, of course, no death of melanoma cells.”

Mangla is an assistant professor in the Department of Medicine, School of Medicine at Case Western Reserve University School of Medicine and a member of the Developmental Therapeutics Program at the Case Comprehensive Cancer Center in Cleveland.

“This trial tells you if you really have a very bulky disease and if you have somebody who has a huge amount of very big [metastasis] sitting there, and surgery is really planned for that patient, maybe that's a patient [who] will benefit from this kind of an approach where you will use BRAF/MEK inhibitors to debulk the tumor,” Mangla said.

BRAF and MEK Inhibitors in Melanoma

BRAF and MEK inhibitors are forms of targeted therapy, as he explained.

“There is a pathway by which a signal is transduced from the environment to the cancer cell to divide,” Mangla said. “That pathway is called the RAF pathway. So, what happens is that the signal jumps from one enzyme to the other, and the BRAF is one of the enzymes in between, and then there is more enzyme downstream. So, a mutation in these enzymes can actually render the pathway independent of external stimuli, and it can start transmitting signals on its own to allow the cancer cells to divide.

“Researchers back in, I would say, the early 2000s, found a drug which was inhibiting the only the BRAF-mutated enzyme, that was blocking that enzyme from working and it helped control the disease, but only for a very short while, it was less than three months. So then, they found out that there was an escape pathway that was developing, that if you block the enzyme, [the] signal will escape to another enzyme called the MEK enzyme. So then, they developed another drug called a MEK inhibitor. … They blocked the two enzymes together, both the BRAF and the MEK, and that could actually prolong the disease control beyond nine months. So, that was very meaningful. That is why when we give BRAF and MEK inhibitors we give it always in a combination, we do not use single agents anymore, because we have to block the two enzymes together.”

Survival Outcomes After BRAF and MEK Inhibitors

Among the entire patient cohort, the median recurrence-free survival (how long a patient lives without their cancer returning) was 19.4 months and the median distant metastasis-free survival (how long a patient lives without cancer spreading to another part of the body) was 21.9 months, with researchers stating that those times were significantly longer among patients with a pathological complete response or a near-pathological complete response than among patients with a minor pathological response.

Researchers reported that after 48 months, relapse-free survival (how long a patient lives without any signs or symptoms of cancer) and overall survival (how long a patient lives, regardless of disease status) among patients with pathological complete response/near-pathological complete response were 36.3% and 64.8%, respectively. Patients with a pathological partial response/pathological nonresponse were 20% and 37.4%, respectively.

At a median follow-up of 52.5 months, the median progression-free survival (how long a patient lives without their disease spreading or worsening) since the start of BRAF and MEK inhibitor therapy was 25.1 months.

These findings, according to the study, confirmed that the combination of BRAF and MEK inhibitors “is an effective and safe regimen in the perioperative [before and after surgery] treatment of stage 3 or 4 melanoma. Major pathological response to neoadjuvant treatment is a surrogate marker of recurrence including [distant metastasis-free survival] in these patients.”

The objective response rate (patients who responded partially or completely to treatment) was 81%, with researchers noting that they found a “significant, moderate correlation between the change in largest dimension of target lesions during neoadjuvant treatment and the level of pathological response.”

The median overall survival from the start of presurgical treatment was 50.2 months, and the median time on systemic targeted therapy before and after surgery was 71 weeks, which included a week-long off period.

BRAF and MEK Inhibitor Treatments and Side Effects

Before surgery, 42 patients received treatment via Tafinlar (dabrafenib) and Mekinist (trametinib), while three patients were treated with Zelboraf (vemurafenib) and Cotellic (cobimetinib), and two patients received Braftovi (encorafenib) and Mektovi (binimetinib), with a median duration of presurgical treatment of 17 weeks. Researchers noted that all patients received surgery, with one patient progressing on presurgical therapy. Microscopically margin-negative (when no cancer cells are found at the edge of the surgically removed tissue, according to the National Cancer Institute) resections were achieved in 87% of patients, with researchers noting that presurgical BRAF and MEK inhibitor therapy “did not result in any new specific complications of surgery or postoperative complications.”

Researchers reported that one patient discontinued BRAF and MEK inhibitors before surgery due to grade 3 (severe) gross hematuria (blood in the urine) and one patient discontinued use of MEK inhibitors due to grade 2 (moderate) LVEF decrease (a reduction in the fraction of blood pumped from the left ventricle of the heart, according to National Library of Medicine), while dosage of Tafinlar was reduced in 10 patients due to toxicity and Zelboraf dosage was decreased in one patient.

Regarding surgical side effects, 14 patients reported seroma (a lump caused by a buildup of fluid, according to the National Cancer Institute), eight patients reported dehiscence (when a surgical wound reopens, according to the National Cancer Institute) and one patient was rehospitalized for more than 10 days, while 21 patients did not experience any surgery-related side effects, and no systemic therapy or surgery-related deaths were reported.

Forty-four patients received postsurgical targeted therapy with the same inhibitors they received before surgery, whereas one patient received only a BRAF inhibitor due to the MEK inhibitor being discontinued prior to surgery due to toxicity and two patients did not receive postsurgical targeted therapy.

The scheduled minimum year of postoperative treatment was completed by 25 patients, 13 patients stopped due to disease progression during postsurgical treatment, four patients withdrew their agreement to continue with BRAF/MEK inhibitor therapy and postsurgical therapy was stopped in one case due to toxicity, with two patients still on treatment at the time of analysis and the median time of postsurgical therapy being 54 weeks. Five patients also received postsurgical radiotherapy.

“The cohort is not very big … but it's a still impactful study because it shows you the power of using BRAF and MEK inhibitors upfront, that they can shrink the tumor. They make unresectable tumors resectable,” Mangla said.

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