Melanoma Field Continues to Shift With Targeted Therapy, Immunotherapy Approvals

Joseph Stilwill, MD, associate professor of oncology and urology at Johns Hopkins Medicine

Joseph Stilwill, MD

A number of the findings in melanoma presented at the 2018 ASCO Annual Meeting were in the adjuvant setting, reporting benefits 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 with BRAF-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.¹ The 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.

OncLive: What did you focus on in your presentation on melanoma?

In an interview during the 2018 OncLive^® State of the Science Summit™, A Summer of Progress: Updates from ASCO 2018, Stilwill addressed recent advances in melanoma and the focus of research moving forward.Stilwill: The really exciting advances in melanoma over the last year [have been in the] adjuvant [setting], both in the BRAF-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.

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

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

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

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

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

What factors determine the optimal sequence for patients?

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.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.It’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 with BRAF-positive disease.That's something we are definitely looking at, especially in the stage IV realm. [We’re also looking at] how exactly to sequence therapy. In BRAF-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.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.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.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 and BRAF-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’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 in BRAF-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.