Dabrafenib compassionate use?

A phase-II clinical trial with the longest follow-up to date confirmed that vemurafenib induces a clinical response in more than half of patients with advanced melanoma expressing BRAF^V600 mutations, according to a report in the Feb. 23 issue of the New England Journal of Medicine.

Median overall survival was 16 months in these patients, who had highly unfavorable characteristics at baseline. With follow-up as long as 20 months, this study “provides critical information on long-term survival” that was not available from previous studies of vemurafenib (Zelboraf) in metastatic melanoma, said Dr. Jeffrey A. Sosman of the Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, and his associates.

The U.S. Food and Drug Administration approved vemurafenib on Aug. 17, 2011 for patients with unresectable or metastatic melanoma with the BRAF^V600E mutation as detected by an FDA-approved test. The FDA acted after a pivotal phase-III trial showed vemurafenib improved overall survival compared with dacarbazine. When the phase-III data were analyzed, median follow-up was just 6.2 months in the experimental arm, and median overall survival had not been reached for patients treated with vemurafenib.

The FDA also considered the currently reported phase-II trial, which included 132 patients with stage-IV melanoma that had progressed despite at least one systemic treatment. Tumor tissue from 56% of patients screened for the trial had a BRAF^V600 mutation, which was required for study entry. Vemurafenib is a potent kinase inhibitor that was developed to target this mutation within cancer cells specifically.

Patients in the study were given oral vemurafenib (960 mg twice daily) and followed every 6 weeks for disease progression at 10 medical centers in the United States and 3 in Australia. Median follow-up for efficacy was 13 months (range, 0.6-20 months). Treatment response was assessed by both the investigative team and by a blinded independent review committee.

The committee found that 8 patients (6%) showed a complete response and 62 (47%) showed a partial response to vemurafenib, for an overall response rate of 53%. A total of 38 patients (29%) showed stable disease. Only 18 (14%) showed progressive disease; 6 patients could not be assessed.

Dr. Sosman and his colleagues found a 5% complete response rate and a 52% partial response rate, for an overall response rate of 57%, which generally accorded with the independent review committee’s findings.

Molecular sequencing showed 122 patients in the trial had BRAF^V600E mutations and 10 patients had BRAF^V600K mutations. Four of the 10 patients with the BRAF^V600K mutation had a partial response and 3 had stable disease.

These response rates are higher than those associated with any previous treatments for advanced melanoma, the researchers noted. The lowest response occurred in patients with an LDL level more than 1.5 times the upper limit of normal.

The median duration of response was 6.7 months, and one-fourth of the subjects remained progression free for more than a year. Median overall survival was 16 months. At the time of the data cut-off (July 1, 2011), 62 patients (47% of the study population) were alive.

“Most objective responses were evident at the time of the first set of scans (week 6), but in some patients, responses did not appear until the patient had been receiving the drug for more than 6 months,” the researchers said (N. Engl. J. Med. 2012;366:707-14).

The longer follow-up in this study thus permitted the investigators to observe these late responses.

Overall survival was 77% at 6 months and 58% at 12 months, and it was estimated to be 43% at 18 months, they noted.

Until now, median overall of metastatic melanoma has been 6-10 months, Dr. Sosman and his colleagues noted. In previously untreated patients who responded to ipilimumab (Yervoy) – an immunotherapy also approved last year – it reached 11 months.

Most patients had at least one adverse event related to vemurafenib, but most were not severe. Adverse effects chiefly were arthralgia, rash, photosensitivity, fatigue, and alopecia. Although many patients required dose interruptions (64%) or reductions (45%), “patients were able to receive most of their intended daily dose,” the investigators wrote.

Four patients discontinued the study drug altogether, including one who developed a retinal-vein occlusion. Another patient died from rapidly progressive melanoma and renal failure that may have been related to the study drug.

Vemurafenib is known to have the paradoxical effect of promoting cutaneous squamous cell carcinomas or keratoacanthomas, so the study subjects were closely monitored for these. Thirty-four patients (26%) developed such neoplasms, usually at the start of therapy. All were managed with resection and vemurafenib was not discontinued. Another eight patients were found to have basal cell carcinomas.

“As with most targeted therapies that block a driver oncogene,” vemurafenib will likely encounter resistance with long-term use, Dr. Sosman and his colleagues said. The mechanisms of resistance to vemurafenib are currently being investigated, so that strategies to prevent or overcome it can be devised.

This study was funded by Hoffman-LaRoche. Dr. Sosman and his associates reported ties to various companies, including Abraxis, Altor, Amgen, BMS, Celldex, Genentech, Genesis Biopharma, GlaxoSmithKline, Hoffman-La Roche, Merck, Novartis, Pfizer, Plexxikon, Prometheus, Roche, and Serametrix.

A phase-II clinical trial with the longest follow-up to date confirmed that vemurafenib induces a clinical response in more than half of patients with advanced melanoma expressing BRAF^V600 mutations, according to a report in the Feb. 23 issue of the New England Journal of Medicine.

Median overall survival was 16 months in these patients, who had highly unfavorable characteristics at baseline. With follow-up as long as 20 months, this study “provides critical information on long-term survival” that was not available from previous studies of vemurafenib (Zelboraf) in metastatic melanoma, said Dr. Jeffrey A. Sosman of the Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, and his associates.

The U.S. Food and Drug Administration approved vemurafenib on Aug. 17, 2011 for patients with unresectable or metastatic melanoma with the BRAF^V600E mutation as detected by an FDA-approved test. The FDA acted after a pivotal phase-III trial showed vemurafenib improved overall survival compared with dacarbazine. When the phase-III data were analyzed, median follow-up was just 6.2 months in the experimental arm, and median overall survival had not been reached for patients treated with vemurafenib.

The FDA also considered the currently reported phase-II trial, which included 132 patients with stage-IV melanoma that had progressed despite at least one systemic treatment. Tumor tissue from 56% of patients screened for the trial had a BRAF^V600 mutation, which was required for study entry. Vemurafenib is a potent kinase inhibitor that was developed to target this mutation within cancer cells specifically.

Patients in the study were given oral vemurafenib (960 mg twice daily) and followed every 6 weeks for disease progression at 10 medical centers in the United States and 3 in Australia. Median follow-up for efficacy was 13 months (range, 0.6-20 months). Treatment response was assessed by both the investigative team and by a blinded independent review committee.

The committee found that 8 patients (6%) showed a complete response and 62 (47%) showed a partial response to vemurafenib, for an overall response rate of 53%. A total of 38 patients (29%) showed stable disease. Only 18 (14%) showed progressive disease; 6 patients could not be assessed.

Dr. Sosman and his colleagues found a 5% complete response rate and a 52% partial response rate, for an overall response rate of 57%, which generally accorded with the independent review committee’s findings.

Molecular sequencing showed 122 patients in the trial had BRAF^V600E mutations and 10 patients had BRAF^V600K mutations. Four of the 10 patients with the BRAF^V600K mutation had a partial response and 3 had stable disease.

These response rates are higher than those associated with any previous treatments for advanced melanoma, the researchers noted. The lowest response occurred in patients with an LDL level more than 1.5 times the upper limit of normal.

The median duration of response was 6.7 months, and one-fourth of the subjects remained progression free for more than a year. Median overall survival was 16 months. At the time of the data cut-off (July 1, 2011), 62 patients (47% of the study population) were alive.

“Most objective responses were evident at the time of the first set of scans (week 6), but in some patients, responses did not appear until the patient had been receiving the drug for more than 6 months,” the researchers said (N. Engl. J. Med. 2012;366:707-14).

The longer follow-up in this study thus permitted the investigators to observe these late responses.

Overall survival was 77% at 6 months and 58% at 12 months, and it was estimated to be 43% at 18 months, they noted.

Until now, median overall of metastatic melanoma has been 6-10 months, Dr. Sosman and his colleagues noted. In previously untreated patients who responded to ipilimumab (Yervoy) – an immunotherapy also approved last year – it reached 11 months.

Most patients had at least one adverse event related to vemurafenib, but most were not severe. Adverse effects chiefly were arthralgia, rash, photosensitivity, fatigue, and alopecia. Although many patients required dose interruptions (64%) or reductions (45%), “patients were able to receive most of their intended daily dose,” the investigators wrote.

Four patients discontinued the study drug altogether, including one who developed a retinal-vein occlusion. Another patient died from rapidly progressive melanoma and renal failure that may have been related to the study drug.

Vemurafenib is known to have the paradoxical effect of promoting cutaneous squamous cell carcinomas or keratoacanthomas, so the study subjects were closely monitored for these. Thirty-four patients (26%) developed such neoplasms, usually at the start of therapy. All were managed with resection and vemurafenib was not discontinued. Another eight patients were found to have basal cell carcinomas.

“As with most targeted therapies that block a driver oncogene,” vemurafenib will likely encounter resistance with long-term use, Dr. Sosman and his colleagues said. The mechanisms of resistance to vemurafenib are currently being investigated, so that strategies to prevent or overcome it can be devised.

This study was funded by Hoffman-LaRoche. Dr. Sosman and his associates reported ties to various companies, including Abraxis, Altor, Amgen, BMS, Celldex, Genentech, Genesis Biopharma, GlaxoSmithKline, Hoffman-La Roche, Merck, Novartis, Pfizer, Plexxikon, Prometheus, Roche, and Serametrix.

A phase-II clinical trial with the longest follow-up to date confirmed that vemurafenib induces a clinical response in more than half of patients with advanced melanoma expressing BRAF^V600 mutations, according to a report in the Feb. 23 issue of the New England Journal of Medicine.

Median overall survival was 16 months in these patients, who had highly unfavorable characteristics at baseline. With follow-up as long as 20 months, this study “provides critical information on long-term survival” that was not available from previous studies of vemurafenib (Zelboraf) in metastatic melanoma, said Dr. Jeffrey A. Sosman of the Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, and his associates.

The U.S. Food and Drug Administration approved vemurafenib on Aug. 17, 2011 for patients with unresectable or metastatic melanoma with the BRAF^V600E mutation as detected by an FDA-approved test. The FDA acted after a pivotal phase-III trial showed vemurafenib improved overall survival compared with dacarbazine. When the phase-III data were analyzed, median follow-up was just 6.2 months in the experimental arm, and median overall survival had not been reached for patients treated with vemurafenib.

The FDA also considered the currently reported phase-II trial, which included 132 patients with stage-IV melanoma that had progressed despite at least one systemic treatment. Tumor tissue from 56% of patients screened for the trial had a BRAF^V600 mutation, which was required for study entry. Vemurafenib is a potent kinase inhibitor that was developed to target this mutation within cancer cells specifically.

Patients in the study were given oral vemurafenib (960 mg twice daily) and followed every 6 weeks for disease progression at 10 medical centers in the United States and 3 in Australia. Median follow-up for efficacy was 13 months (range, 0.6-20 months). Treatment response was assessed by both the investigative team and by a blinded independent review committee.

The committee found that 8 patients (6%) showed a complete response and 62 (47%) showed a partial response to vemurafenib, for an overall response rate of 53%. A total of 38 patients (29%) showed stable disease. Only 18 (14%) showed progressive disease; 6 patients could not be assessed.

Dr. Sosman and his colleagues found a 5% complete response rate and a 52% partial response rate, for an overall response rate of 57%, which generally accorded with the independent review committee’s findings.

Molecular sequencing showed 122 patients in the trial had BRAF^V600E mutations and 10 patients had BRAF^V600K mutations. Four of the 10 patients with the BRAF^V600K mutation had a partial response and 3 had stable disease.

These response rates are higher than those associated with any previous treatments for advanced melanoma, the researchers noted. The lowest response occurred in patients with an LDL level more than 1.5 times the upper limit of normal.

The median duration of response was 6.7 months, and one-fourth of the subjects remained progression free for more than a year. Median overall survival was 16 months. At the time of the data cut-off (July 1, 2011), 62 patients (47% of the study population) were alive.

“Most objective responses were evident at the time of the first set of scans (week 6), but in some patients, responses did not appear until the patient had been receiving the drug for more than 6 months,” the researchers said (N. Engl. J. Med. 2012;366:707-14).

The longer follow-up in this study thus permitted the investigators to observe these late responses.

Overall survival was 77% at 6 months and 58% at 12 months, and it was estimated to be 43% at 18 months, they noted.

Until now, median overall of metastatic melanoma has been 6-10 months, Dr. Sosman and his colleagues noted. In previously untreated patients who responded to ipilimumab (Yervoy) – an immunotherapy also approved last year – it reached 11 months.

Most patients had at least one adverse event related to vemurafenib, but most were not severe. Adverse effects chiefly were arthralgia, rash, photosensitivity, fatigue, and alopecia. Although many patients required dose interruptions (64%) or reductions (45%), “patients were able to receive most of their intended daily dose,” the investigators wrote.

Four patients discontinued the study drug altogether, including one who developed a retinal-vein occlusion. Another patient died from rapidly progressive melanoma and renal failure that may have been related to the study drug.

Vemurafenib is known to have the paradoxical effect of promoting cutaneous squamous cell carcinomas or keratoacanthomas, so the study subjects were closely monitored for these. Thirty-four patients (26%) developed such neoplasms, usually at the start of therapy. All were managed with resection and vemurafenib was not discontinued. Another eight patients were found to have basal cell carcinomas.

“As with most targeted therapies that block a driver oncogene,” vemurafenib will likely encounter resistance with long-term use, Dr. Sosman and his colleagues said. The mechanisms of resistance to vemurafenib are currently being investigated, so that strategies to prevent or overcome it can be devised.

This study was funded by Hoffman-LaRoche. Dr. Sosman and his associates reported ties to various companies, including Abraxis, Altor, Amgen, BMS, Celldex, Genentech, Genesis Biopharma, GlaxoSmithKline, Hoffman-La Roche, Merck, Novartis, Pfizer, Plexxikon, Prometheus, Roche, and Serametrix.