Melanoma
Curator: Larry H. Bernstein, MD, FCAP
Nab-Paclitaxel Shows Benefit in Advanced Melanoma
News | October 01, 2015 | Melanoma
By Leah Lawrence
Treatment with nab-paclitaxel resulted in significantly improved progression-free survival and a greater disease control rate in chemotherapy-naive patients with metastatic melanoma compared with dacarbazine, according to the results of a study published recently in Annals of Oncology.
Unacceptable
Treatment with “nab-paclitaxel demonstrated clinically meaningful superiority compared with dacarbazine,” wrote Evan M. Hersh, MD, of the University of Arizona Cancer Center, and colleagues, “with a near doubling of median progression-free survival and a 44% improvement in disease control rate (includes patients with stable disease for ≥ 16 weeks) in chemotherapy-naive patients with metastatic melanoma.”
Based on these results, they concluded that “nab-paclitaxel can be considered in the treatment armamentarium for chemotherapy-naive patients with metastatic melanoma.”
According to the study, the use of taxanes in metastatic melanoma has had limited success; however, nab-paclitaxel—paclitaxel formulated as albumin-bound nanoparticles—has shown some efficacy in chemotherapy-naive patients.
This phase III trial randomly assigned 529 chemotherapy-naive patients with stage IV melanoma to nab-paclitaxel (n = 264) on days 1, 8, and 15, every 4 weeks, or dacarbazine (n = 265) every 3 weeks.
In the final analysis, 58% of patients assigned nab-paclitaxel and 64% assigned dacarbazine progressed or died. There was a greater than 2-month improvement in progression-free survival among patients assigned to nab-paclitaxel compared with dacarbazine (4.8 vs 2.5 months; hazard ratio [HR], 0.792 [95% confidence interval (CI), 0.631–0.992]; P=.004).
“The robustness of the progression-free survival analysis was supported with various sensitivity analyses related to off-schedule response assessments or missed study visits,” the researchers noted.
“The robustness of the progression-free survival analysis was supported with various sensitivity analyses related to off-schedule response assessments or missed study visits,” the researchers noted.
No significant difference in overall survival was seen between the two groups (12.6 vs 10.5 months; P = .271).
“Although a significant difference in progression-free survival was observed with nab-paclitaxel vs dacarbazine, a significant treatment effect of nab-paclitaxel on overall survival may have been limited by the equivalent and high rate (75%) of use of post-study therapy, including newer agents, such as BRAF inhibitors and ipilimumab, by patients in both treatment arms,” Hersh and colleagues wrote.
There was no significant difference in the overall response rate seen in patients assigned nab-paclitaxel (15%) compared with dacarbazine (11%). However, patients treated with nab-paclitaxel had significant improvements in disease control rate (P = .004) and best overall response rate (P = .002) compared with dacarbazine.
Subgroup analyses also found that nab-paclitaxel resulted in improvements in progression-free survival regardless of BRAF mutation status. In addition, nab-paclitaxel treatment resulted in greater delays in progression compared with dacarbazine among those patients with the most advanced melanoma (HR, 0.734 [95% CI, 0.558–0.965]; P = .028).
According to the study, nab-paclitaxel is currently recommended by the National Comprehensive Cancer Network (NCCN) as single-agent treatment for advanced or metastatic melanoma.
“Results of ongoing trials of nab-paclitaxel in combination with targeted therapies or novel immunotherapies may help expand this recommendation in the future, as nab-paclitaxel may provide a good backbone regimen to build upon given its safety profile,” the researchers wrote.
– See more at: http://www.cancernetwork.com/melanoma/nab-paclitaxel-shows-benefit-advanced-melanoma#sthash.GkUDnwms.dpuf
Immunotherapy Combination Active in Advanced Melanoma
News | April 20, 2015 | Melanoma, AACR 2015
By Leah Lawrence
Melanoma
Nivolumab and ipilimumab was more effective than ipilimumab alone in a…
Combined treatment with the T-cell checkpoint pathway inhibitors nivolumab and ipilimumab produced significantly higher rates of response and progression-free survival among patients with advanced melanoma (regardless of BRAF mutation status) than did treatment with ipilimumab alone, according to the phase I results of a trial published in the New England Journal of Medicine and presented at the 2015 American Association for Cancer Research (AACR) Annual Meeting.
“On the basis of the high degree of tumor reduction in the current study, with a high rate of complete responses, a favorable clinical benefit can be anticipated with longer follow-up,” wrote study author F. Stephen Hodi, MD, of the Dana-Farber Cancer Institute, and colleagues.
The phase I dose-escalation study included 142 patients with treatment-naive metastatic melanoma. Patients were randomly assigned 2:1 to ipilimumab 3 mg/kg with nivolumab 1 mg/kg or placebo every 3 weeks for four doses, followed by nivolumab 3 mg/kg or placebo every 2 weeks.
In patients with BRAF wild-type tumors, combined treatment resulted in an objective response rate of 61% compared with 11% in those assigned ipilimumab alone (P < .001). Complete responses occurred in 22% of patients assigned to the combined immunotherapy treatment and none of the patients assigned to monotherapy.
Patients with BRAF-positive disease assigned to the combination therapy had an objective response rate of 52%, with 22% of patients achieving a complete response.
“In the combination group, the objective response rate was independent of tumor PD-L1 status: 58% (95% CI, 37 to 78) among patients with PD-L1–positive tumors and 55% (95% CI, 41 to 69) among patients with PD-L1–negative tumors,” the researchers wrote. “In the ipilimumab-monotherapy group, a numerically higher objective response rate was observed among patients with PD-L1–positive tumors than among patients with PD-L1–negative tumors (18% [95% CI, 2 to 52] vs 4% [95% CI, 0 to 19]).”
Additionally, patients assigned to combination therapy did not yet reach a median progression-free survival compared with 4.4 months for ipilimumab monotherapy. The median progression-free survival for combined treatment in BRAF-positive patients was 8.5 months compared with 2.7 months in the monotherapy group.
“In general, the spectrum of select adverse events that we observed was consistent with previous experience with the combination therapy,” the researchers wrote. “Three deaths related to the combination regimen were reported in this study; these deaths could be linked to preexisting conditions that were related to the cause of death or that required medical procedures that might have contributed to the death.”
Combined treatment was associated with a higher rate of drug-related grade 3 or 4 adverse events than was monotherapy (54% vs 24%).
– See more at: http://www.cancernetwork.com/melanoma/immunotherapy-combination-active-advanced-melanoma#sthash.fEVLSw6E.dpuf
FDA Approves Ipilimumab for Earlier Stage Melanoma
News | October 30, 2015 | Melanoma
By Anna Azvolinsky, PhD
Ipilimumab (Yervoy, Bristol Myers Squibb) is now approved by the US Food and Drug Administration (FDA) as an adjuvant therapy for stage III melanoma patients.1 In this setting, the immunotherapy is used following surgery to lower the risk of relapse. Ipilimumab is already FDA-approved for the treatment of metastatic, stage IV melanoma.
The monoclonal antibody, first approved in 2011, blocks the cytotoxic T-lymphocyte antigen 4 (CTLA-4) which can slow down the ability of a patient’s immune system to fight tumor cells. Ipilimumab blocks this antigen, facilitating the immune system’s ability to recognize melanoma cells as foreign and to mount an immune response against these tumor cells.
Ipilimumab was the first immune checkpoint antibody to be approved for melanoma.
“Today’s approval of Yervoy extends its use to patients who are at high risk of developing recurrence of melanoma after surgery,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research in a statement released by the FDA. “This new use of the drug in earlier stages of the disease builds on our understanding of the immune system’s interaction with cancer.”
According to a statement by the Melanoma Research Foundation, the approval is the first by the FDA in 20 years for an adjuvant melanoma therapy. Another available adjvuvant option for stage III patients is interferon.
The FDA approval is based on the EORTC 18071 phase III randomized, double blind clinical trial of 951 patients with high-risk stage III melanoma. All patients had complete lymph node dissection prior to starting the trial. Patients were randomized one to one to either 10 mg/kg ipilimumab or placebo infusions every 3 weeks for 4 doses, and then every 3 months for up to 3 years or to placebo.
The results were published online May 2015, in The Lancet Oncology.2
The most common reported side effects on trial were rash, diarrhea, fatigue, itching, headache, weight loss, and nausea. The most common high-grade immune-related adverse events in the ipilimumab treatment arm were gastrointestinal (16% of patients compared to <1% in the placebo arm), hepatic (11% compared to <1% in the placebo arm, and endocrine (8% compared to zero in the placebo arm).
Adverse events resulted in 52% (245 patients) of patients discontinuing treatment. Five patients (1%) died due to a drug-related adverse event in the ipilimumab treatment arm. Three patients died from colitis (two with gastrointestinal perforation), one patient because of myocarditis, and one patient because of multiorgan failure due to Guillain-Barré syndrome.
The median recurrence-free survival was 26.1 months in the ipilimumab study arm compared to 17.1 months in the placebo arm (hazard ratio of 0.75; P = .0013). The 3-year recurrence-free survival was 46.5% in the ipilimumab arm compared to 34.8% in the placebo arm.
“Adjuvant ipilimumab significantly improved recurrence-free survival for patients with completely resected high-risk stage III melanoma,” concluded the trial study authors. “The adverse event profile was consistent with that observed in advanced melanoma, but at higher incidences in particular for endocrinopathies. The risk-benefit ratio of adjuvant ipilimumab at this dose and schedule requires additional assessment based on distant metastasis-free survival and overall survival endpoints to define its definitive value.”
– See more at: http://www.cancernetwork.com/melanoma/fda-approves-ipilimumab-earlier-stage-melanoma#sthash.LRWc8XIn.dpuf
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