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MEDICAL FRONTIERS - 53rd Annual Meeting of the American Society of Clinical Oncology (ASCO)

Chicago, Illinois / June 2-6, 2017

Chicago - A growing proportion of patients with advanced metastatic melanoma are surviving for long periods due largely to two approaches. One involves combining therapies targeted at the BRAF and MEK pathways. The other involves immunotherapies. At the 2017 ASCO meeting, documentation of the success of these strategies included data on very long-term survival in a proportion of individuals treated with either. This benefit extended to patients with brain metastases. The combination of BRAF and MEK inhibitors is appropriate for patients with BRAF V600-mutant disease, while BRAF status is not relevant to use of immunotherapies. Vaccine combination therapies may play a role in selected patients.

The treatment of metastatic melanoma was transformed by the introduction of potent BRAF inhibitors, such as dabrafenib and vemurafenib, and checkpoint inhibitor immunotherapies, such as ipilimumab, nivolumab and pembrolizumab. These demonstrated unprecedented activity and improved overall survival (OS) relative to chemotherapy. Now even greater activity may be achieved when drugs are combined. In BRAF V600 metastatic melanoma, this involves adding a MEK inhibitor, such as trametinib, to prevent resistance that arises when BRAF inhibitors are used alone. For immunotherapy, checkpoint inhibitor combination may warrant the additional toxicity in some situations, such as the presence of brain metastases.

Long-term Data in Advanced Melanoma

According to a randomized trial which now has the longest follow-up of a BRAF inhibitor combined with a MEK inhibitor, the combination of dabrafenib plus trametinib in BRAF V600-mutant metastatic melanoma is demonstrating survival that is sometimes measured in years. In an updated 5-year landmark analysis of 162 patients with BRAF V600–mutant unresectable or metastatic melanoma, the 5-year OS with the highest dose combination was 28%. 

In this study, the patients were randomized to one of the three groups: 1) 150 mg twice-daily (BID) dabrafenib (D150BID) as a monotherapy; 2) D150BID plus 1 mg once-daily (QD) trametinib (T); or 3) D150BID plus 2 mg QD T. Most patients on monotherapy crossed over to one of the D/T arms, which were combined for the 5-year OS analyses.

While OS on D/T at 5 years was impressive for metastatic disease, it is also noteworthy that the combination of therapies targeted at BRAF and MEK were associated with a flattening of the tail of the OS curve over time. This flattening was particularly pronounced in the subgroup of those who entered the study with a low disease burden, defined as normal baseline LDH and metastases involving less than 3 organ sites. In low disease burden patients randomized to the arm receiving D150BID plus 2 mg T, survival at 4 years was 57% and declined only to 51% at 5 years, which was slower than that observed in those who received D150BID monotherapy (see Figure 1).

In the absence of any new safety signals in extended followup, these data re-confirm earlier evidence originally reported by lead author Dr. Georgina Long, University of Sydney, Sydney, Australia, at SMR 2015. In her retrospective analysis of patients with varying baseline factors, including LDH and number of disease sites, those presenting with lower burden of disease fared drastically better. In that analysis, patients with normal LDH and less than 3 disease sites had an OS of 70%. Conversely, those with LDH at ≥ ULN observed an OS of only 7%.

BRAF mutation remains the critical genetic feature in advanced melanoma that guides patients’ treatment options. These results confirm that long-term survival can be achieved with this combination and therefore should be an important consideration for patients with BRAF mutation-positive advanced melanoma, including those with low disease burden.

“These data support the use of dabrafenib plus trametinib as a treatment option that can achieve long-term survival in BRAF V600E/K-mutated melanoma,” reported co-author Dr. Jeffery Weber, NYU Langone Medical Center, New York, NY.

Combi-MB: Brain Metastases in Melanoma

The benefit of combining a BRAF and MEK inhibitor appears to extend to patients with brain metastases, according to another set of data presented at ASCO. In a phase II, open-label, multicenter study, called COMBI-MB, the combination of dabrafenib plus trametinib was evaluated in patients with BRAF mutation-positive melanoma that has metastasized to the brain. After a median follow-up of 9 months, the overall response rate was 58%, with a median duration of response of 6.5 months. Although this duration of response is shorter than that observed in melanoma patients without brain metastases, these are encouraging findings.

“These results support the use of dabrafenib plus trametinib as a treatment option for patients with brain metastases,” reported Dr. Michael Davis, The University of Texas MD Anderson Cancer Center, Houston, Texas.

In COMBI-MB trial, 125 patients received dabrafenib 150 mg twice daily plus trametinib 2 mg daily in 4 cohorts: (A) BRAFV600E, asymptomatic melanoma with brain metastases and no prior local treatment (76 patients); (B) BRAFV600E, asymptomatic disease with prior local therapy (16 patients); (C) BRAFV600D/K/R, asymptomatic disease with or without prior local therapy (16 patients); and (D) BRAFV600D/E/K/R, symptomatic disease with or without prior local therapy (17 patients).

Median progression–free survival (PFS) was 5.6 months and the preliminary OS was 10.8 months. No unexpected safety issues were observed with this combination (see Table 1).

Historically, management of brain metastases focused on local treatments such as surgery, stereotactic radiosurgery, or whole brain radiotherapy, depending on the clinical presentation, according to Dr. Davis. New clinical trials suggest that about half of melanoma patients with brain metastases respond to systemic therapies, meeting a critical unmet medical need. Although Dr. Davis called for continued research to improve outcomes in this advanced melanoma population, he indicated that the recent data support targeted BRAF and MEK inhibitors in patients with BRAF V600-positive brain metastases.

Anti-PD1 Options in Melanoma

Combinations of checkpoint inhibitors are also being evaluated in metastatic melanoma, but single agent therapy, which is typically better tolerated than combination immunotherapy, is still being pursued. In one set of data presented at ASCO, the checkpoint PD-1 inhibitor pembrolizumab treatment provided durable efficacy after stopping the protocol-specified duration of treatment in patients with advanced melanoma naïve to immunotherapy.

In the KEYNOTE-006 trial, presented by Dr. Jacob Schachter, Elia Institute for Research and Treatment of Melanoma, Sheba Medical Center Israel, 834 patients were randomized to pembrolizumab 10 mg/kg every 2 weeks, pembrolizumab 10 mg/kg every 3 weeks, or ipilimumab 3 mg/kg every 3 weeks for 4 doses. Treatment was continued for 2 years in the pembrolizumab arm. Patients discontinued therapy as a result of disease progression, intolerable toxicity, or the patient or investigator decided to discontinue therapy.

After a median follow-up of nearly 3 years, pembrolizumab superiority over ipilimumab was confirmed, with nearly a doubling of median OS (32.3 vs 15.9 months). Median PFS was higher with pembrolizumab (8.3 months) than with ipilimumab (3.3 months). Of the 104/556 patients (19%) who completed 2 years of pembrolizumab treatment, 91% are progression-free after a median follow-up of 9.7 months. The safety profile with pembrolizumab continued to be favorable.

Checkpoint Combinations in Brain Mets

In advanced melanoma with brain metastases, improved activity was observed when the PD1 checkpoint inhibitor nivolumab was combined with the CTLA-4 inhibitor ipilimumab, according to a randomized phase II trial conducted by the Anti-PD1 Brain Collaboration. In this study, 67 patients with asymptomatic melanoma brain metastases with no prior local brain therapy were randomized to a combination of nivolumab and ipilimumab or nivolumab alone. Although there were three cohorts, cohort C was smaller, consisted of patients who had failed previous local therapy, were neurologically impaired, or had leptomeningeal disease.

When the two larger cohorts were compared, rates of intracranial response were 44% for the combination versus 20% for single-agent nivolumab. In addition, both the six-month PFS (50% vs. 29%) and OS (76% vs. 59%) were higher on the combination.

“The combination has high activity in melanoma brain metastases and may be considered for upfront therapy,” said Dr. Long. Plans are underway for a clinical trial to add radiotherapy for patients treated with nivolumab and ipililumab.

In the phase 2 CheckMate 204 trial, melanoma patients with measurable metastases but not neurologic symptoms were also treated with nivolumab plus ipilimumab, The objective response rate was 56%, including a complete response rate of 19%. Based on acceptable tolerability, Dr. Hussein Abdul-Hassan Tawbi, University of Texas MD Anderson Cancer Center, speculated that this combination might be a strategy for avoiding whole brain radiotherapy

In a smaller, retrospective observational study that included patients with brain metastases, patients with BRAF mutations were treated with either dabrafenib plus trametinib (86 patients) or ipilimumab plus nivolumab (61 patients) as first-line therapy. About one-third of the patients had brain metastases. Among those with brain metastasis, the 3- and 6-month discontinuation rates were 3% and 20% for targeted therapy and 33% and 50% for immunotherapy. The higher discontinuation rates with immunotherapy were attributed to toxicity. Outcome data are still being evaluated.

Vaccine plus Immunotherapy

Combinations of intralesional immunotherapy with an oncolytic virus plus another immunotherapy have shown early promise and could provide another tool for oncologists to treat melanoma. Oncolytic viruses used as single agents play a role in older patients with multiple comorbidities and primarily injectable disease, or in patients who predominantly have injectable disease and prefer a more local therapy approach. Adding in a checkpoint inhibitor could lead to even more efficacy and expand therapy to more metastatic melanoma patients.

Primary results from a randomized, open-label phase II study of talimogene laherparepvec (TVEC) and ipilimumab versus ipilimumab alone in unresected stage IIIB- IV melanoma shows the combination more than doubled response rates. TVEC is a herpes simplex virus (HSV)-1-based oncolytic virus designed to selectively replicate in tumors and produce granulocyte macrophage colony-stimulating factor to stimulate antitumor immune responses. Among the 198 patients, the overall response rate after 68 weeks of the combination was 38.8% and after 58 weeks of ipilimumab was 18%. Notably, responses were not limited to injected lesions, indicating an abscopal effect. Toxicity of the TVEC plus ipilimumab combination was tolerable with no unexpected adverse events.

Conclusion

For advanced melanoma patients, the question of how to best sequence targeted and immunotherapy therapies remains unanswered. Targeted therapies appear to work well and quickly for patients with BRAF-positive mutations, with mild, transient, early-onset side effects. Immunotherapies appear to work best in combinations, but the majority of patients still do not respond within the first 2 years, and side effects can be substantial.

Ongoing clinical trials are expected to answer this question, looking at the sequence of BRAF/MEK inhibitor therapy followed by immunotherapy after progression in patients with Stage III-IV BRAFV600 melanoma, and vice versa.  Other studies are looking to identify, through the use of biomarkers, which patients may be more likely to respond to immunotherapy and conversely, which would be innate non-responders

Systemic therapy as initial treatment for patients with asymptomatic CNS melanoma metastases is an important new option for patients. Current studies show no unexpected toxicities and, in general, concordant responses between the brain and extra-CNS disease. These early results will likely change practice and lead to a new era in melanoma therapy for brain metastases. 

Questions and Answers

Questions and answers with Dr. Marcus Butler, Cancer Clinical Research Unit (CCRU), Princess Margaret Cancer Centre, Toronto, Ontario.

Q: Could you characterize the stabilization of the survival curve in the phase II trial with dabrafenib and trametinib in metastatic melanoma? Does this predict long-term survival on targeted therapy in at least some patients?

A: It appears that long term survival is possible in patients with limited disease (3 or less sites) and normal LDH.  Given the high response rate and tolerability of targeted therapy, this is a very reasonable option for this population.

Q: A combination of dabrafenib and trametinib showed clinical benefit and was tolerable in patients with BRAF V600–mutant melanoma that had metastasized to the brain. Does this suggest a clinical role for this strategy or it is still best considered experimental?

A: Yes, given the response rate that has been demonstrated, the presence of brain metastasis should not be
a contraindication for giving patients targeted therapy.  The best way to combine all the tools at our disposal
(i.e. surgery, stereotactic radiation, whole brain radiation and immunotherapy) is not yet defined.  Further research will be needed to define how these modalities can be combined to the optimal benefit of our patients.

Q: The combination of nivolumab with ipilimumab showed significant activity in melanoma brain metastases. When would you consider using this immunotherapy combination as upfront therapy in these patients?

A:  This is a very important question since these patients were not randomized between treatment approaches nor was the impact of a combined approach tested.  Often in clinical practice we are faced with small lesions that are asymptomatic or are not definitively metastases.  Certainly in these patients combined immunotherapy is a reasonable option.  Further research is needed to define the best approach for these patients with larger lesions

Q: How do you envision targeted therapies and immunotherapies developing into complementary options for advanced melanoma based on patient characteristics?

A: I am very optimistic about the future treatment of melanoma.  Our first task is to look at combination approaches to determine if synergistic benefit can be achieved.  Additionally, biomarker assessment to determine who benefits most from a particular treatment modality will be crucial.  We are already identifying clinical factors and genetic alterations that may help to guide treatment decisions.