Dual Kinase Therapy Slows BRAF-Mutated Metastatic Melanoma

VIENNA – Combination therapy with a BRAF inhibitor and a MEK inhibitor extended progression-free survival by more than 3 months in patients with BRAF V600 mutated metastatic melanoma, early clinical findings suggest.

"This is the first kinase-kinase combination to show enhanced antitumor activity over the single agent," and the first to show that specific oncogenic toxicities may be reduced with combination therapy, said Dr. Georgina Long of the Melanoma Institute Australia in Sydney.

In a phase II randomized trial, progression-free survival (PFS) was nearly 9 months when the BRAF inhibitor dabrafenib was given at the same time as the MEK inhibitor trametinib, as compared to about 6 months with dabrafenib monotherapy. Overall response rates (ORR) were significantly higher at 76% with the combination therapy and 54% with dabrafenib monotherapy; the duration of response also longer, at 10.5 months for combination therapy and 5.6 months for monotherapy. The proportion of patients with PFS at 12 months was 41%, 26%, and 9%, respectively. Overall survival at 12 months was 79%, 68%, and 70%, although 80% of patients from the monotherapy arm crossed over to the full-dose combination.

The findings were published online, Sept. 29, in the New England Journal of Medicine (doi:10.1056/NEJMoa1210093) to coincide with their release at the European Multidisciplinary Cancer Congress.

As single agents, BRAF inhibitors and MEK inhibitors have been shown to improve PFS vs. standard chemotherapy, but the results can be relatively short lived, Dr. Long said.

There is a strong rationale for combining the two classes of drugs, she said. "The MAPK [mitogen-activated protein kinase] pathway is constituently and aberrantly activated in the vast majority of melanomas." The BRAF protein is mutated in approximately 50% of melanoma cases.

Preclinical data have already shown that combining the two classes of drugs can possibly overcome drug resistance and may also decrease the incidence of some adverse events that have been seen with single-agent therapy.

In the phase II study, Dr. Long and her colleagues randomized 162 patients with BRAF V600-mutated metastatic melanoma to receive either dabrafenib monotherapy, 150 mg twice daily, or the same dose of dabrafenib plus either trametinib, 2 mg twice daily or 1 mg twice daily.

Baseline patient characteristics were broadly similar among the three treatment groups, although patients in the full-dose combination arm were about 8 years older on average than were those in the half-dose combination arm or monotherapy groups. The majority (83%-87%) of patients in each group had the V600E mutation, with the remainder having the V600K mutation.

After a median follow-up to 14 months, the primary end point of PFS was 5.8 months with dabrafenib monotherapy, as compared with 9.4 months (P less than .0001) with the higher dose of combination therapy and 9.2 months (P = .005) with the lower dose.

The ORR was 76% with the higher-dose combination as compared with 54% with dabrafenib monotherapy (P = .026); the duration of response also was longer, 10.5 months vs. 5.6 months, respectively.

Pyrexia, defined as a fever of more than 38.5 C, was significantly more likely to be associated with combination therapy. Pyrexia occurred in 67% and 63% of those on combination therapies and in 23% on monotherapy.

"In all three arms, the median time to first fever was less than 6 weeks," Dr. Long said. "Corticosteroids were an effective prophylactic to prevent fever in these patients."

Nausea and vomiting also were more common in the combination arms. Alopecia and skin-related events including squamous cell carcinoma, hyperkeratosis, and papilloma were less frequent with combination therapy.

Two phase III studies will now investigate the use of the 2-mg dose combination with dabrafenib (COMB-d) or vemurafenib (COMBI-v) versus monotherapy in the first line treatment of advanced melanoma.

Vemurafenib/GDC-0973 Combination Tested

In a separate open-label, phase IB study presented at ESMO, the safety and tolerability of a different BRAF/MEK inhibitor combination – vemurafenib (Zelboraf) and the investigational compound GDC-0973 – was investigated.

The BRIM7 study involved 70 patients with BRAF V600-mutated metastatic melanoma. Since one of the aims of the trial was to identify a dose that could move forward into phase II and III trials if no unforeseen toxicity occurred, several doses and schedules of vemurafenib and GDC-0973 were evaluated, according to study investigator Dr. Rene Gonzalez of the University of Colorado Cancer Center in Denver.

Nearly all – 67 of the 70 patients, experienced a possible treatment-related adverse event. However, the events were grade 3 or 4 in only 20 patients; the most common grade 3 or 4 adverse effects were non–acneiform rash (5 or 7.1% of patients) and diarrhea (4 or 5.7%). Fatigue occurred in one patient and nausea was seen in one patient (1.4% of patients).

Treatment was temporarily interrupted in 13 patients (18.5%) given the vemurafenib and GDC-0973 combination, and 2 patients (2.9%) required a dose reduction.

Preliminary antitumor activity in vemurafenib-naive patients (n = 25) was particularly encouraging, with all patients seemingly responding to varying degrees, with reductions in tumor size from baseline ranging from 30% to 60%.

The meeting was a joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

GSK provided research funding for both studies. Dr. Long has participated in advisory boards for GSK, Roche, and Bristol-Myers Squibb, and received honoraria and research funding from Roche. Dr. Gonzalez has received research support, advisory board, and consulting fees from Roche/Genentech and GSK. Dr. Dummer made no disclosures.

VIENNA – Combination therapy with a BRAF inhibitor and a MEK inhibitor extended progression-free survival by more than 3 months in patients with BRAF V600 mutated metastatic melanoma, early clinical findings suggest.

"This is the first kinase-kinase combination to show enhanced antitumor activity over the single agent," and the first to show that specific oncogenic toxicities may be reduced with combination therapy, said Dr. Georgina Long of the Melanoma Institute Australia in Sydney.

In a phase II randomized trial, progression-free survival (PFS) was nearly 9 months when the BRAF inhibitor dabrafenib was given at the same time as the MEK inhibitor trametinib, as compared to about 6 months with dabrafenib monotherapy. Overall response rates (ORR) were significantly higher at 76% with the combination therapy and 54% with dabrafenib monotherapy; the duration of response also longer, at 10.5 months for combination therapy and 5.6 months for monotherapy. The proportion of patients with PFS at 12 months was 41%, 26%, and 9%, respectively. Overall survival at 12 months was 79%, 68%, and 70%, although 80% of patients from the monotherapy arm crossed over to the full-dose combination.

The findings were published online, Sept. 29, in the New England Journal of Medicine (doi:10.1056/NEJMoa1210093) to coincide with their release at the European Multidisciplinary Cancer Congress.

As single agents, BRAF inhibitors and MEK inhibitors have been shown to improve PFS vs. standard chemotherapy, but the results can be relatively short lived, Dr. Long said.

There is a strong rationale for combining the two classes of drugs, she said. "The MAPK [mitogen-activated protein kinase] pathway is constituently and aberrantly activated in the vast majority of melanomas." The BRAF protein is mutated in approximately 50% of melanoma cases.

Preclinical data have already shown that combining the two classes of drugs can possibly overcome drug resistance and may also decrease the incidence of some adverse events that have been seen with single-agent therapy.

In the phase II study, Dr. Long and her colleagues randomized 162 patients with BRAF V600-mutated metastatic melanoma to receive either dabrafenib monotherapy, 150 mg twice daily, or the same dose of dabrafenib plus either trametinib, 2 mg twice daily or 1 mg twice daily.

Baseline patient characteristics were broadly similar among the three treatment groups, although patients in the full-dose combination arm were about 8 years older on average than were those in the half-dose combination arm or monotherapy groups. The majority (83%-87%) of patients in each group had the V600E mutation, with the remainder having the V600K mutation.

After a median follow-up to 14 months, the primary end point of PFS was 5.8 months with dabrafenib monotherapy, as compared with 9.4 months (P less than .0001) with the higher dose of combination therapy and 9.2 months (P = .005) with the lower dose.

The ORR was 76% with the higher-dose combination as compared with 54% with dabrafenib monotherapy (P = .026); the duration of response also was longer, 10.5 months vs. 5.6 months, respectively.

Pyrexia, defined as a fever of more than 38.5 C, was significantly more likely to be associated with combination therapy. Pyrexia occurred in 67% and 63% of those on combination therapies and in 23% on monotherapy.

"In all three arms, the median time to first fever was less than 6 weeks," Dr. Long said. "Corticosteroids were an effective prophylactic to prevent fever in these patients."

Nausea and vomiting also were more common in the combination arms. Alopecia and skin-related events including squamous cell carcinoma, hyperkeratosis, and papilloma were less frequent with combination therapy.

Two phase III studies will now investigate the use of the 2-mg dose combination with dabrafenib (COMB-d) or vemurafenib (COMBI-v) versus monotherapy in the first line treatment of advanced melanoma.

Vemurafenib/GDC-0973 Combination Tested

In a separate open-label, phase IB study presented at ESMO, the safety and tolerability of a different BRAF/MEK inhibitor combination – vemurafenib (Zelboraf) and the investigational compound GDC-0973 – was investigated.

The BRIM7 study involved 70 patients with BRAF V600-mutated metastatic melanoma. Since one of the aims of the trial was to identify a dose that could move forward into phase II and III trials if no unforeseen toxicity occurred, several doses and schedules of vemurafenib and GDC-0973 were evaluated, according to study investigator Dr. Rene Gonzalez of the University of Colorado Cancer Center in Denver.

Nearly all – 67 of the 70 patients, experienced a possible treatment-related adverse event. However, the events were grade 3 or 4 in only 20 patients; the most common grade 3 or 4 adverse effects were non–acneiform rash (5 or 7.1% of patients) and diarrhea (4 or 5.7%). Fatigue occurred in one patient and nausea was seen in one patient (1.4% of patients).

Treatment was temporarily interrupted in 13 patients (18.5%) given the vemurafenib and GDC-0973 combination, and 2 patients (2.9%) required a dose reduction.

Preliminary antitumor activity in vemurafenib-naive patients (n = 25) was particularly encouraging, with all patients seemingly responding to varying degrees, with reductions in tumor size from baseline ranging from 30% to 60%.

The meeting was a joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

GSK provided research funding for both studies. Dr. Long has participated in advisory boards for GSK, Roche, and Bristol-Myers Squibb, and received honoraria and research funding from Roche. Dr. Gonzalez has received research support, advisory board, and consulting fees from Roche/Genentech and GSK. Dr. Dummer made no disclosures.

VIENNA – Combination therapy with a BRAF inhibitor and a MEK inhibitor extended progression-free survival by more than 3 months in patients with BRAF V600 mutated metastatic melanoma, early clinical findings suggest.

"This is the first kinase-kinase combination to show enhanced antitumor activity over the single agent," and the first to show that specific oncogenic toxicities may be reduced with combination therapy, said Dr. Georgina Long of the Melanoma Institute Australia in Sydney.

In a phase II randomized trial, progression-free survival (PFS) was nearly 9 months when the BRAF inhibitor dabrafenib was given at the same time as the MEK inhibitor trametinib, as compared to about 6 months with dabrafenib monotherapy. Overall response rates (ORR) were significantly higher at 76% with the combination therapy and 54% with dabrafenib monotherapy; the duration of response also longer, at 10.5 months for combination therapy and 5.6 months for monotherapy. The proportion of patients with PFS at 12 months was 41%, 26%, and 9%, respectively. Overall survival at 12 months was 79%, 68%, and 70%, although 80% of patients from the monotherapy arm crossed over to the full-dose combination.

The findings were published online, Sept. 29, in the New England Journal of Medicine (doi:10.1056/NEJMoa1210093) to coincide with their release at the European Multidisciplinary Cancer Congress.

As single agents, BRAF inhibitors and MEK inhibitors have been shown to improve PFS vs. standard chemotherapy, but the results can be relatively short lived, Dr. Long said.

There is a strong rationale for combining the two classes of drugs, she said. "The MAPK [mitogen-activated protein kinase] pathway is constituently and aberrantly activated in the vast majority of melanomas." The BRAF protein is mutated in approximately 50% of melanoma cases.

Preclinical data have already shown that combining the two classes of drugs can possibly overcome drug resistance and may also decrease the incidence of some adverse events that have been seen with single-agent therapy.

In the phase II study, Dr. Long and her colleagues randomized 162 patients with BRAF V600-mutated metastatic melanoma to receive either dabrafenib monotherapy, 150 mg twice daily, or the same dose of dabrafenib plus either trametinib, 2 mg twice daily or 1 mg twice daily.

Baseline patient characteristics were broadly similar among the three treatment groups, although patients in the full-dose combination arm were about 8 years older on average than were those in the half-dose combination arm or monotherapy groups. The majority (83%-87%) of patients in each group had the V600E mutation, with the remainder having the V600K mutation.

After a median follow-up to 14 months, the primary end point of PFS was 5.8 months with dabrafenib monotherapy, as compared with 9.4 months (P less than .0001) with the higher dose of combination therapy and 9.2 months (P = .005) with the lower dose.

The ORR was 76% with the higher-dose combination as compared with 54% with dabrafenib monotherapy (P = .026); the duration of response also was longer, 10.5 months vs. 5.6 months, respectively.

Pyrexia, defined as a fever of more than 38.5 C, was significantly more likely to be associated with combination therapy. Pyrexia occurred in 67% and 63% of those on combination therapies and in 23% on monotherapy.

"In all three arms, the median time to first fever was less than 6 weeks," Dr. Long said. "Corticosteroids were an effective prophylactic to prevent fever in these patients."

Nausea and vomiting also were more common in the combination arms. Alopecia and skin-related events including squamous cell carcinoma, hyperkeratosis, and papilloma were less frequent with combination therapy.

Two phase III studies will now investigate the use of the 2-mg dose combination with dabrafenib (COMB-d) or vemurafenib (COMBI-v) versus monotherapy in the first line treatment of advanced melanoma.

Vemurafenib/GDC-0973 Combination Tested

In a separate open-label, phase IB study presented at ESMO, the safety and tolerability of a different BRAF/MEK inhibitor combination – vemurafenib (Zelboraf) and the investigational compound GDC-0973 – was investigated.

The BRIM7 study involved 70 patients with BRAF V600-mutated metastatic melanoma. Since one of the aims of the trial was to identify a dose that could move forward into phase II and III trials if no unforeseen toxicity occurred, several doses and schedules of vemurafenib and GDC-0973 were evaluated, according to study investigator Dr. Rene Gonzalez of the University of Colorado Cancer Center in Denver.

Nearly all – 67 of the 70 patients, experienced a possible treatment-related adverse event. However, the events were grade 3 or 4 in only 20 patients; the most common grade 3 or 4 adverse effects were non–acneiform rash (5 or 7.1% of patients) and diarrhea (4 or 5.7%). Fatigue occurred in one patient and nausea was seen in one patient (1.4% of patients).

Treatment was temporarily interrupted in 13 patients (18.5%) given the vemurafenib and GDC-0973 combination, and 2 patients (2.9%) required a dose reduction.

Preliminary antitumor activity in vemurafenib-naive patients (n = 25) was particularly encouraging, with all patients seemingly responding to varying degrees, with reductions in tumor size from baseline ranging from 30% to 60%.

The meeting was a joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

GSK provided research funding for both studies. Dr. Long has participated in advisory boards for GSK, Roche, and Bristol-Myers Squibb, and received honoraria and research funding from Roche. Dr. Gonzalez has received research support, advisory board, and consulting fees from Roche/Genentech and GSK. Dr. Dummer made no disclosures.