Expert Highlights Key Studies Revolutionizing the Melanoma Treatment Landscape

Shailender Bhatia, MD

Shailender Bhatia, MD

A number of abstracts were presented at the 2019 ASCO Annual Meeting demonstrating a therapeutic revolution for the treatment of patients with melanoma. Recently at the Best of ASCO Seattle meeting, Shailender Bhatia, MD, presented the top 5 abstracts from ASCO in the field of melanoma.

Bhatia noted the significance of combination therapy across a number of subsets of melanoma, including patients with brain metastases. Historically, patients with brain metastases from melanoma had a median survival of around 5 months, but recent data show that new agents and regimens can improve their survival. The phase II CheckMate 204 trial, in particular, demonstrated durable responses in these patients when treated with the combination of ipilimumab (Yervoy) plus nivolumab (Opdivo). At 1 year, around 60% of patients were alive and free of disease progression.

In a long-term analysis of thephase III EORTC 18071 trial, single-agent ipilimumab maintained its initial benefits by reducing the risk of recurrence long-term. These long-term follow-up data demonstrated that immunotherapy can improve survival in patients with advanced melanoma.

“That is reassuring for patients,” said Bhatia, an associate professor at the University of Washington, Seattle Cancer Care Alliance, “and also provides more proof that immunotherapy, when it works, can work durably, for long periods of time.”

Data from combination treatment with a BRAF and MEK inhibitor was also analyzed; in a pooled analysis from 2 clinical trials, long-term survivorship was looked at in patients treated with combination dabrafenib (Tafinlar) plus trametinib (Mekinist). Close to 20% of patients were still doing well after 5-year follow-up and had no evidence of disease progression. This is remarkable since the general belief is that most patients with melanoma treated with targeted therapy often do not have durable responses. However, most of these patients were still receiving therapy, while most long-term survivors with immunotherapy are treatment free.

TheInternational Neoadjuvant Melanoma Consortium (INMC)pooled data from several trials that used either immunotherapy or combination targeted therapy prior to surgical resection in patients with localized melanoma. The analysis demonstrated that neoadjuvant therapy in melanoma is feasible and likely to be used more commonly in the future. Bhatia said that testing a drug in the neoadjuvant setting could also allow physicians to select the appropriate agent for long-term treatment following surgery.

A final abstract that Bhatia highlighted compared whole-brain radiotherapy (WBRT) to observation in patients with 1 to 3 brain metastases from melanoma. However, these data demonstrated that WBRT did not add any meaningful improvement to outcomes for these patients.

“I think overtime, we will be moving more and more away from local therapies such as surgery or radiation therapy, especially WBRT,” said Bhatia.

In an interview withTargeted Oncology, Bhatia highlighted the key takeaways from the 5 abstracts he found most significant at the 2019 ASCO meeting for the treatment of patients with melanoma.

TARGETED ONCOLOGY: What are your thoughts on how much the field of melanoma has advanced over the last few years?

Bhatia:[The landscape] has changed in a very good way. As I like to say, there has been a therapy revolution in melanoma in the last 10 years or so in both the [immunotherapy and targeted chemotherapy] fronts.

We have had some amazing advances in immunotherapy, and melanoma has kind of led the way for immunotherapy in cancer. Now immunotherapy is being used in so many other cancers as well. We have also had significant advances on the chemotherapy front, such as BRAF or MEK inhibitors.

TARGETED ONCOLOGY: Could you discuss the significance of the CheckMate 204 trial for patients with symptomatic melanoma-related brain metastases?

Bhatia:This is quite a remarkable study. It gives us a long-term follow-up on patients who have brain metastases from melanoma, and instead of getting surgery or radiation, which we have been using all this time, these patients got systemic therapy, specifically in combination with immunotherapy with nivolumab plus ipilimumab. The findings were remarkable in that a very high proportion of patients responded to the treatment. From the follow-up so far, the responses look to be very durable, which is truly revolutionary for these patients in a highly challenging situation.

To put this into a historical perspective, patients who had brain metastases from melanoma, the survival used to be very poor. The median survival of these patients from historical data used to be close to 5 months, which is truly dismal. In this study, 60% of the patients were alive almost a year later and free of disease progression. Even at 2 years, it looked like we were close to more than 50% of the patients being alive and progression free, which is huge for these patients who have historically very, very poor survival.

I think this study has 2 main messages. First, patients with brain metastases do not necessarily need surgery, WBRT, or even gamma knife [radiosurgery]. If they are asymptomatic, they can actually be treated with systemic therapy; with systemic therapy, the combination therapy of ipilimumab and nivolumab has very high responses, leading to durable responses and long-term survivorship. Those 2 things are quite remarkable for this group of patients.

TARGETED ONCOLOGY: How will the 5-year analysis of dabrafenib plus trametinib impact patients withBRAFV600—mutated unresectable or metastatic melanoma?

Bhatia:This study presents long-term follow-up with combination targeted chemotherapy with BRAF and MEK inhibitors, specifically dabrafenib plus trametinib. What the authors did here was pool data from 2 different trials which used this combination against other treatments. They pooled the group that got combination therapy with those 2 drugs together and analyzed how these people did in the long-term.

The interesting part of this study was that there was a proportion of patients who did really well, close to 20%, and at 5 years, those 20% of patients were still doing well. Their disease had not progressed, and they were continuing to receive therapy.The results are remarkable in that it goes against the conventional thinking that immunotherapy can result in long-term responses, but generally most patients who are treated with combination targeted chemotherapy, they typically do not have durable responses. This study provides some evidence against that dogma that patients can become long-term survivors only with immunotherapy.

The main take home from this study is that patients who are doing well on targeted chemotherapy can find some reassurance in that there is a possibility of long-term survivorship. Now, the other key question is for patients who have both immunotherapy and targeted chemotherapy as options for frontline treatment, what should we use? This study does not settle that question, but it does provide some reassurance to patients who are being treated with targeted chemotherapy.

TARGETED ONCOLOGY: What is the significance of the results from the EORTC 18071 trial in stage III melanoma?

Bhatia:This abstract is providing long-term follow-up data on a trial that was done several years back, and it compared ipilimumab to placebo for patients with stage III melanoma. These drugs were used in the adjuvant setting after surgery to prevent the chances of recurrence. What this study showed is that the initial observations from this trial suggesting we can have long-term benefit from ipilimumab in reducing the risk of recurrence are still maintained several years later. That is reassuring for patients and also provides more proof that immunotherapy, when it works, can work well for long periods of time.

These results are probably not as relevant to our current practice because most physicians would not be using ipilimumab for adjuvant therapy. Most physicians use PD-1—based therapies such as nivolumab or pembrolizumab (Keytruda) in the adjuvant setting. We have had trials that have proven that PD-1 drugs can be better than ipilimumab in both improving the relapse-free survival and also are associated with less toxicity. These long-term data for ipilimumab are reassuring, but they do not change our current practice.

TARGETED ONCOLOGY: What are your thoughts on the phase III trial investigating the role of WBRT in patients with at least 3 brain metastases?

Bhatia:This study compared WBRT versus observation in patients who had 3 or less brain metastases. What this trial showed was that WBRT did not meaningfully add to improving these outcomes in these patients. Also, keeping in mind the other study where systemic therapy worked so well for brain metastases, this study raises the question about the value of WBRT in this day and age when it comes to treating patients with melanoma.

My take on the various data that are coming out is that we are moving more and more towards systemic therapy for patients who have brain metastases because our systemic therapies seem to be working well intracranially as well as extracranially. I think overtime, we will be moving more and more away from local therapies such as surgery or radiation therapy, specifically WBRT.

TARGETED ONCOLOGY: How will the findings from the pooled analysis from the INMC impact the treatment landscape?

Bhatia:This is an interesting abstract. It is dealing with the outcomes from several trials that have been done in the neoadjuvant setting. These trials have used either immunotherapy or combination targeted therapy before surgery for patients who have localized melanoma. The results of those trials have mostly been presented previously, but this pooled analysis showed that neoadjuvant therapy is feasible, and the response rates are quite high. Patients who seem to respond well to these treatments out of surgery seem to do better in the long run. I think we still need to do more work in the neoadjuvant setting, but the big thing that comes from this analysis is that testing the drug in the neoadjuvant setting could allow us to select patients appropriately for long-term treatment with only those drugs that seem to be working effectively.

TARGETED ONCOLOGY: Looking forward, what other research do you anticipate will further impact the treatment landscape of melanoma?

Bhatia:At ASCO, there were a number of other studies which were early-phase studies looking at novel immunotherapies and combination strategies to find effective treatment options in patients who are not responding well to our commonly used regimens at this time. I think over the next few years, it’s going to be exciting to see more mature data from those studies.

I am quite confident we are moving in the right direction. Our patients are doing much better than they used to, and there are lots of promising treatments on the horizon. However, there is also a lot of activity happening right now, which is truly providing hope for long-term survivorship, even for patients in the advanced stages of melanoma.

Reference:

Bhatia S. Melanoma: Best of 2019 ASCO. Presented at: Best of ASCO Bellevue on Seattle’s Eastside; July 19-20, 2019; Seattle, WA.