Adjuvant Setting the Focus of Latest Advancements in Melanoma

Joseph Stiwil, MD

Joseph Stilwill, MD

Many of the melanoma data presented during the 2018 ASCO Annual Meeting were in the adjuvant setting, including promising results with BRAF/MEK inhibition, as well as anti—PD-1 therapies, said Joseph Stilwill, MD, a medical oncologist at the Sarah Cannon Research Institute.

In June 2018, the FDA approved the combination of the BRAF inhibitor encorafenib (Braftovi) and the MEK inhibitor binimetinib (Mektovi) for patients withBRAF-mutant unresectable or metastatic melanoma. The approval came following results of the phase III COLUMBUS trial, which were presented at ASCO.

Data from the trial showed a 39% reduction in the risk of death with the combination compared with vemurafenib (Zelboraf) at a median follow-up of 36.8 months.¹The 3-year overall survival (OS) rates were 47% with the combination versus 32% with single-agent vemurafenib.

In the same week, the FDA accepted a supplemental biologics license application for the use of adjuvant pembrolizumab (Keytruda) for patients with resected, high-risk stage III melanoma. The application was based on data from the phase III EORTC 1325-MG/KEYNOTE-054 trial, which demonstrated a 43% reduction in the risk of recurrence or death with adjuvant pembrolizumab versus placebo.²

Results also showed the 1-year recurrence-free survival rate was 75.4% (95% CI, 71.3%-78.9%) with pembrolizumab versus 61.0% (95% CI, 56.5%-65.1%) with placebo (HR, 0.57; 98.4% CI, 0.43-0.74;P<.0001).

The PD-1 inhibitor nivolumab (Opdivo) is also approved by the FDA in this setting, suggesting that anti—PD-1 therapies have a considerable role to play in the adjuvant space.

The unanswered question, said Stilwell, is whether BRAF/MEK inhibition in combination with immunotherapy is worth exploring. And in metastatic disease, the optimal sequence of therapies continues to be refined.

In an interview withTargeted Oncology, Stilwill addressed recent advances in melanoma and the focus of research moving forward.

TARGETED ONCOLOGY:What are some of the most recent advancements in melanoma?

Stilwill:The really exciting advances in melanoma over the last year [have been in the] adjuvant [setting], both in theBRAF-positive population as well as in the general population. BRAF and MEK inhibition, as well as anti—PD-1 therapy, have shown a significant benefit in the adjuvant setting and are less toxic than [previously approved] adjuvant therapy.

There were a couple of updates from the 2018 ASCO Annual Meeting that showed a continuation of what we probably knew to be true. [These studies] helped to confirm that complete lymph node dissection is probably not necessary for most patients with sentinel lymph node-positive disease. Additionally, the eighth edition of the American Joint Committee on Cancer (AJCC) Staging System holds up to external validation.

TARGETED ONCOLOGY:Is it likely that adjuvant pembrolizumab will get FDA approval for patients with stage III disease?

Stilwill:Knowing that nivolumab shows a clear improvement over high-dose ipilimumab (Yervoy) tells us that it is clearly an option. Pembrolizumab definitely showed an improvement in progression-free survival over observation. It may be an option moving forward that has less toxicity than prior standard therapy.

TARGETED ONCOLOGY:How have the results of the COLUMBUS trial and the subsequent FDA approval of binimetinib and encorafenib impacted practice?

Stilwill:It&rsquo;s potentially exciting. It's hard to know without a direct head-to-head comparison, but it seems to suggest that it's a pretty effective regimen. It's the first trial to show a greater than 30-month OS benefit. That may be quite significant. [The] side effects may be reduced a bit. It's hard to definitively say, but it's potentially a nice option for patients withBRAF-positive disease.

TARGETED ONCOLOGY:Is there any rationale for BRAF/MEK combinations with immunotherapy?

Stilwill:That's something we are definitely looking at, especially in the stage IV realm. [We&rsquo;re also looking at] how exactly to sequence therapy. InBRAF-positive patients, there is some suggestion that initial treatment with a BRAF/MEK inhibitor and then quickly changing to immunotherapy may be beneficial. Trials are underway looking at that. It will be really interesting to see the results of those trials.

TARGETED ONCOLOGY:What were some other exciting abstracts presented at the 2018 ASCO Annual Meeting?

Stilwill:The external validation of the eighth edition of the AJCC Staging System is interesting. Looking at the tumor burden and sentinel lymph node is also interesting. When patients with stage IIIA disease were stratified by tumor burden, you could see that patients with 1 mm or less showed substantially better prognosis. That will affect how we practice. In patients with low tumor burden in [their] sentinel lymph nodes, we'll have to consider adjuvant therapy. Adjuvant therapy may be something we want to strongly consider in those patients with a higher [tumor] burden.

TARGETED ONCOLOGY:What is the role of talimogene laherparepvec (T-VEC; Imlygic), and how do you decide which patients should receive it?

Stilwill:That's a great question, and I don't think we have the answer. We're going to have to wait on clinical trials to tell us. At this point, the upfront data with either BRAF/MEK inhibition or anti—PD-1 therapy is strong. T-VEC will be something we want to look at moving forward.

TARGETED ONCOLOGY:What factors determine the optimal sequence for patients?

Stilwill:The sequencing of treatment in unresectable disease will be important. I'm interested to see how those trials turn out.

A lot of it is based on toxicity. In patients with autoimmune conditions andBRAF-positive disease, you certainly want to think about BRAF/MEK inhibition as initial therapy. For patients who have a performance status that is a bit more borderline, therapy with an anti—PD-1 inhibitor alone probably makes sense. It's probably a little better tolerated. All things being equal, it&rsquo;s an interesting decision to have to make between the 2.

When we look at the stage IV setting, long-term data show that the responses to immunotherapy tend to be a little more durable, so [I] would probably side with that as initial therapy.

References:

1. Dummer R, Ascierto PA, Gogas H, et al. Overall survival in COLUMBUS: a phase 3 trial of encorafenib (ENCO) plus binimetinib (BINI) vs vemurafenib (VEM) or enco inBRAF-mutant melanoma.J Clin Oncol. 2018;36 (suppl; abstr 9504).
2. Egermont AMM, Blank CU, Mandala M, et al. Pembrolizumab vs. placebo after complete resection of high-risk stage iii melanoma: efficacy and safety results from the EORTC 1325-MG/KEYNOTE-054 double-blinded phase 3 trial. In: Proceedings from the 2018 AACR Annual Meeting; April 14-18, 2018; Chicago, Illinois. Abstract CT001.