1. Fuerst, Mark L.

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CHICAGO-New data on long-term disease control and extended survival continue to prove the success of immunotherapy and targeted therapy for the treatment of advanced melanoma, according to two new studies presented at the 2017 ASCO Annual Meeting, held June 2-6.

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Long-term outcomes show pembrolizumab treatment provides durable efficacy after stopping the protocol-specified duration of treatment in patients with ipilimumab-naive advanced melanoma, reported lead author Caroline Robert, MD, of Gustave Roussy, Villejuif, France (Abstract 9504).


Earlier results of the KEYNOTE-006 trial showed that pembrolizumab provided superior progression-free survival (PFS) and overall survival (OS) and improved overall response rate versus ipilimumab, with a lower rate of grade 3-5 treatment-related adverse events despite longer exposure.


The 834 patients, median age 62 years, 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 four doses. Treatment was continued for 2 years in the pembrolizumab arm or until disease progression, intolerable toxicity, or the patient or investigator decided to discontinue therapy. Tumor imaging was performed at week 12, then every 6 weeks up to week 48 and every 12 weeks thereafter.


Robert reported that 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).


Virtually all (98%) of the 104 patients who completed 2 years of pembrolizumab treatment are alive after a median follow-up of 9.7 months, noted Robert. Responses were durable in patients who completed pembrolizumab; the estimated PFS was 91 percent.


The safety profile with pembrolizumab continued to be favorable.


In conclusion, Robert said "the estimated risk for progression or death nearly 10 months after completing pembrolizumab is 9 percent and does not appear to differ by best response to pembrolizumab. The data further support the use of pembrolizumab as standard of care for patients with advanced melanoma."


Targeted Therapy

The longest follow-up for any randomized trial evaluating a BRAF inhibitor combined with a MEK inhibitor found that long-term survival is achievable with dabrafenib plus trametinib in patients with BRAF V600-mutant metastatic melanoma, particularly those with favorable baseline factors (Abstract 9505).


The combination of dabrafenib plus trametinib has been shown to improve outcomes versus a BRAF inhibitor alone in this patient population after 3 years of follow-up. Specific baseline factors, such as LDH level and number of organ sites with metastases, have been associated with long-term OS.


Study co-author Jeffery Weber, MD, of NYU Langone Medical Center, New York, N.Y., presented an updated 5-year landmark analysis to further characterize the impact of dabrafenib and trametinib in 162 patients with BRAF V600-mutant unresectable or metastatic melanoma. The patients were equally divided in three cohorts of dabrafenib 150 mg plus trametinib 2 mg, dabrafenib 150 mg plus trametinib 1 mg, or dabrafenib monotherapy 150 mg twice daily.


After a median follow-up of 66.5 months, the 5-year OS with the higher dose combination was 28 percent; for those with normal baseline LDH and less than three organ sites with metastasis, the OS was 51 percent.


No new safety signals were identified with the long-term combined therapy.


"These results demonstrate that some patients with metastatic melanoma can achieve durable benefit with dabrafenib plus trametinib therapy. These data support the use of the combination as a treatment option that can achieve long-term survival in BRAF V600E/K-mutated melanoma," said Weber.


ASCO discussant Alexander Menzies, MD, of Melanoma Institute Australia, The University of Sydney in Sydney, commented: "The introduction of ipilimumab changed the game for advanced melanoma. It cured patients, but most still do not respond." The 20 percent survival rate with ipilimumab is 10 percent higher than historical rates.


Now phase III studies show 5-year survival rates of 44 percent with dabrafenib plus trametinib, 37 percent with another targeted therapy combination, vemurafenib plus cobimetinib, and 35 percent with the checkpoint inhibitor nivolumab.


As for the pembrolizumab trial presented by Robert, "these are the most mature phase III PD-1 trial data to date, and is the first trial to end treatment at 2 years," stated Menzies.


He noted the difference in PFS rates were similar for patients with primary resistance, but for acquired resistance PFS was higher for those in the pembrolizumab group (31%) as compared to those in the ipilimumab group (14%). The 2-year duration of response was 71 percent in both groups.


Similarly, the data Weber presented are the most mature for a combination of a BRAF inhibitor and a MEK inhibitor to date, Menzies said. He noted the survival curve appears to plateau at about 3 years, adding that in the highest dose group, which is the commonly used dose, the PFS was 13 percent at 5 years even though only 4 percent of patients were still on treatment.


Menzies pointed out that none of patients with high LDH levels were progression-free at 2 years as compared to one-quarter of those with normal LDH levels.


Among advanced melanoma patients, "who are the survivors?" asked Menzies. Clinical features among survivors include normal LDH, less disease or volume of disease, ECOG 0 status, and complete response. Biomarkers in the tumor, blood, and imaging may help, but "no biomarkers are sufficiently robust to accurately predict outcome," he said.


In conclusion, Menzies noted: "Current drugs provide long-term survival for a subset of patients, but most progress and die. We need better treatments to raise the bar. We need better biomarkers to predict the clinical outcomes."


The goal, he said, "should not simply be to improved overall survival, but improved long-term control, preferably off therapy, and not just in melanoma but across cancer."


Mark L. Fuerst is a contributing writer.