Combination Regimens Inspire Hope for the Treatment of Melanoma

Michael A. Davies, MD, PhD

The treatment landscape for melanoma was bleak for many decades, but over the last 10 years, physicians have seen the approval of 11 new therapies for the treatment of patients with melanoma, which mostly have been either targeted therapies or immunotherapies. Outcomes for patients are promising more now than ever, but more research still needs to be done.

“The take-home message is the understanding and treatment of melanoma has been absolutely transformed, and with that, we now have a lot of reason for optimism that was missing for decades,” Michael A. Davies, MD, PhD, told Targeted Oncology. “However, there is a continued need to improve outcomes even further.”

While responses are promising with both outcomes in targeted therapies and immunotherapies, physicians still debate what the right treatment is for patients with advanced melanoma. The long-term outcomes observed with immunotherapies, such as immune checkpoint inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo), lead many to believe patients should be treated with immunotherapy upfront, regardless of their BRAF mutational status. However, targeted therapies may also be a suitable approach to select patients with a targetable mutation, such as BRAF or MEK.

Researchers are also looking at potential combination therapies, particularly the combination of targeted therapy and immunotherapy together. At the 2020 American Association for Cancer Research (AACR) Annual Meeting, data from the phase III IMspire150 trial demonstrated durable responses and significant improvement in progression-free survival (PFS) with the combination of atezolizumab (Tecentriq), an immunotherapy, plus vemurafenib (Zelboraf), and cobimetinib (Cotellic), the BRAF/MEK inhibitors.

The median PFS with the triplet regimen was 15.1 months (95% CI, 11.4-18.4) versus 10.6 months with the targeted therapy doublet alone (95% CI, 9.3-12.7; log-rank P =.0249). Interestingly, this benefit was observed across all prognostic subgroups. While these results are positive, the question of how the triplet regimen compares with immunotherapy alone remains unanswered.

In an interview with Targeted Oncology, Davies, professor and chairman, Department of Melanoma Medical Oncology, MD Anderson Cancer Center, discussed the current treatment landscape of melanoma and the recent advances that have provided a great level of optimism to what was known to be a very challenging cancer setting.

TARGETED ONCOLOGY: What does the prognosis of patients with melanoma look like today?

Davies: Melanoma is a disease that has truly been transformed over the last decade due to an improved understanding of the molecular drivers and the heterogeneity of the disease, and particularly, the factors that regulate the tumor response. This information has been translated into new and more effective therapies.

Before 2011, we had never had a positive phase III trial for patients with stage IV metastatic melanoma. The median survival for these patients was approximately 6 months, and when it affects patients who are often young and healthy, we have a very clear focus on achieving long-term survival, and the long-term survival for those patients was less than 10%.

Between 2011 and 2019, we saw the approval of 11 new treatments that were equally divided between immunotherapies with checkpoint inhibitors as single-agents or in combination and targeted therapies for patients who have a BRAF V600E mutation, which is present in approximately 50% of cutaneous melanoma patients. With those improvements, we think the median survival now is probably 2 years or greater, and we are seeing long-term survival in the range of 30% or higher when we look at the general population.

What is probably the most exciting has been recent updates from clinical trials where we now have 5-year survival data. In particular, the CheckMate-067 study showed a 5-year OS rate of 52% in treatment-naïve stage IV melanoma patients treated with combination therapy of ipilimumab and nivolumab. With single-agent nivolumab, the [5-year OS] was 44%, and there were very similar 5-year data for pembrolizumab as well. We have seen 5-year OS rates with targeted therapy with dabrafenib and trametinib, at approximately 34%. We are truly leaps and bounds ahead of where we were a decade ago.

In addition to that progress, we have now seen these agents being applied increasingly and now being approved for patients with earlier stages of disease. Nivolumab, pembrolizumab, dabrafenib, and trametinib have all been approved as adjuvant therapy for patients with stage III disease, but we don’t know yet how that is really impacting OS in this disease. However, we are quite optimistic and hopeful that this is going to result in further improvements in outcomes. This is a change in both the treatments and outcomes for patients with advanced melanoma.

TAREGETD ONCOLOGY: The role of immunotherapy and targeted therapies continue to expand in melanoma. Do you want to highlight any other research in this space?

Davies: It remains a debate in patients with newly diagnosed metastatic melanoma what the right treatment is. This is because we now have multiple effective therapies, and so we consider immunotherapy for patients even though they have a targetable mutation because of the long-term outcomes we have seen with immunotherapy, including durable disease control and survival years after we stop treatment. For BRAF-mutant patients, it is completely reasonable to treat initially with single-agent anti-PD-1 therapy or a combination immunotherapy of nivolumab and ipilimumab.

There are some patients where we do believe targeted therapy is the right approach, and again with targeted therapies, we now have 3 different FDA-approved BRAF/MEK combinations. They each have clinical response rates that are quite high and actually higher than what we see in the range of immunotherapy in the range of 80% but less of a track record in terms of long-term survival, particularly after stopping treatment.

While we have had debates on whether we should use immunotherapy or targeted therapy, there have been a lot of preclinical studies to suggest that combining targeted therapy and immunotherapy together may be a very effective strategy. Recently, we have seen the results of 2 randomized clinical trials in BRAF-mutant patients who were treated either with targeted therapy alone or targeted therapy plus PD-1. Most notably, we saw at the 2020 AACR Annual Meeting the results from the first phase III trial to compare BRAF and MEK alone versus BRAF/MEK plus PD-1. This was a phase III trial called IMspire150, and this was a large trial that compared treatment with targeted therapy of vemurafenib and cobimetinib versus those same drugs combined with the anti-PD-1 agent, atezolizumab. The results showed that actually using the 3 medications instead of 2 did not improve response rate, but it did reach its primary end point, which was to improve PFS. That meant that adding PD-1 to targeted therapy extended the duration of responses, which is a very positive result.

What is unclear is whether this is superior to treating with immunotherapy alone because that was not a comparator arm. We are still left in some ways with the question of whether it is appropriate to use targeted therapy or immunotherapy in a BRAF-mutant patient, but data suggests that you would use targeted therapy and perhaps we should be using a combination of targeted therapy with anti-PD-1.

TAREGETD ONCOLOGY: Are there any other combinations or treatments that are promising on the horizon now?

Davies: There is a lot of ongoing research because although we are very excited about the results we have seen, we still have many patients that do not respond to immunotherapy. There is a subset of patients who respond initially but then develop resistance, and at this point we have not found an effective immunotherapy approach that has shown dramatic benefit in patients who either did not respond to frontline immunotherapy or who responded and then progressed. We do know in those patients that targeted therapy can be effective, but we also know that can come with significant toxicity and overall worse outcomes than what has been seen in patients treated with targeted therapy upfront. Multiple investigations at this point, although nothing specifically approved in that area, are evaluating a number of different strategies. There has been some promising data for using autologous T-cell therapy or tumor-infiltrating lymphocytes (TIL) therapy. In a non-randomized study, we have seen responses in approximately 30% of patients who have previously progressed on PD-1 who were treated with TIL therapy. Many of those responses appear quite durable, so this is very promising data that I believe is under review.

In terms of other combination strategies, there is a lot of interest in adding other cytokines targeting Roll-like receptor 9, and there are trials looking at combining targeted therapy with immunotherapy in the second-line setting to potentially be an effective strategy as well. Those are some of the leading candidates at this point.

TAREGETD ONCOLOGY: What message would you like to share in honor of Melanoma Monday with other physicians?

Davies: The take-home message is the understanding and treatment of melanoma has been absolutely transformed, and with that, we now have a lot of reason for optimism that was missing for decades. For patients with metastatic melanoma, it is important to convey that these patients can be cured, even in their most advanced stages. However, there is a continued need to improve outcomes even further.

TAREGETD ONCOLOGY: Are there any other remaining challenges in this space?

Davies: One of the biggest challenges that we have had in melanoma is a very high risk of the cancer spreading to the brain and central nervous system (CNS). Melanoma has among the highest rates of CNS metastases among all solid cancers, and patients with CNS metastases historically have not only had very poor outcomes but have also been excluded from clinical trials. Over the last several years we have shown in several post-registration studies that both targeted therapy and immunotherapy can have very high rates of response and even durable responses in these patients. Whereas brain metastases were previously a death sentence, that is really not the case anymore. Even for patients who present with CNS disease, there is reason for hope and aggressive treatment in appropriately selected patients.