Melanoma - Commentary on recent data from vemurafenib trials: Urban legends of BRAF inhibition
Jeffrey Weber M.D. Ph.D.
Moffitt Cancer Center
The first targeted drug for advanced melanoma -- vemurafenib (Zelboraf) -- has raised considerable hopes because many patients whose cancers have a specific mutation are responding to the drug. That mutation is in a gene called BRAF, and it seems to be a key driver of a subset of melanomas. Thanks to new data from an eagerly anticipated trial of the drug, there’s now more evidence that patients whose cancers have mutated BRAF can benefit from this treatment. Most important, data from this trial and an earlier study suggest the drug not only delays progression of the disease, but actually extends survival. As the review below points out, many important questions remain about how to best use this new therapy, including: Could even further gains come from using other types of drugs prior to vemurafenib therapy? Should vemurafenib be the very first drug patients with the mutant BRAF receive? We now have a lot more data about this important new treatment and many more trials are likely ongoing or to follow.
The recent data published in the New England Journal of Medicine describing the results of the BRIM2 phase II study of the selective BRAF inhibitor vemurafenib in previously treated melanoma patients provides a potent justification for the use of this drug in melanoma patients that have BRAF mutated melanoma1. While many in the oncology community have focused on the high response rates but short time to progression observed with the use of BRAF inhibitors, the excellent overall survival of 15.9 months in that trial of 132 second line melanoma patients suggests that real survival benefit can be gained from using BRAF inhibitors. The 53% overall response rate is excellent, but the proportion of complete responders (6%) is modest. Due to the early stopping of the randomized BRIM3 study2, and subsequent crossover of DTIC patients on the control arm to receive vemurafenib, there may never be a mature comparison in overall survival for that trial, but the front line BRIM3 vemurafenib data may be as favorable as the second line BRIM2 data in overall survival. Admittedly, in both studies, patients could be treated beyond progression, (which occurred in 24% of those on the BRIM2 trial) so the median progression-free survival data of 6.8 months may not reflect the true survival benefit obtained with this drug, which appears to be substantial.
The impressive survival data from the BRIM2 study will provoke further discussion of the notion that BRAF mutated patients without bulky disease or with slow growing melanoma should first go on an immune agent like ipilimumab, high dose IL-2, or even a PD-1 antibody trial in front line in preference to a BRAF inhibitor. While the immune agents may induce a modest proportion of patients to have long-term survival, representing the "tail on the curve 3,4," as we gain more long-term experience with vemurafenib, similar data may also be seen with that agent. Patients treated past progression, or who have isolated progressing lesions surgically resected, may derive considerable survival benefit from BRAF inhibition. For any patient with BRAF mutated melanoma, there may be a justification for treating with a BRAF inhibitor in front line.
An important question that remains is whether patients that progress after failing a BRAF inhibitor have explosive tumor growth and a rapid downhill course. While the post-progression survival in the BRIM2 and BRIM 3 studies was in the realm of 6-7 months, if the patients stayed on drug past progression, then survival after stopping vemurafenib indeed may have been quite short due to the prolonged time on treatment. The important question of which BRAF mutated patients to treat with a BRAF inhibitor, and whether immune agents should be used first is a critical question that needs an answer.
References:
1. Sosman, J.A, Kim, K.B., Schuchter, L.,Gonzalez, R. et al Survival in BRAF V600–Mutant Advanced Melanoma Treated with Vemurafenib N Engl J Med 2012;366:707-14.
2. Chapman PB, Hauschild A, Robert C, et al BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011 Jun 30;364(26):2507-16.
3. Hodi FS, O'Day SJ, McDermott DF, Weber RW,et al . Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug
19;363(8):711-23
4. Robert C, Thomas L, Bondarenko I, O'Day S,et al . Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-26
Moffitt Cancer Center
The first targeted drug for advanced melanoma -- vemurafenib (Zelboraf) -- has raised considerable hopes because many patients whose cancers have a specific mutation are responding to the drug. That mutation is in a gene called BRAF, and it seems to be a key driver of a subset of melanomas. Thanks to new data from an eagerly anticipated trial of the drug, there’s now more evidence that patients whose cancers have mutated BRAF can benefit from this treatment. Most important, data from this trial and an earlier study suggest the drug not only delays progression of the disease, but actually extends survival. As the review below points out, many important questions remain about how to best use this new therapy, including: Could even further gains come from using other types of drugs prior to vemurafenib therapy? Should vemurafenib be the very first drug patients with the mutant BRAF receive? We now have a lot more data about this important new treatment and many more trials are likely ongoing or to follow.
The recent data published in the New England Journal of Medicine describing the results of the BRIM2 phase II study of the selective BRAF inhibitor vemurafenib in previously treated melanoma patients provides a potent justification for the use of this drug in melanoma patients that have BRAF mutated melanoma1. While many in the oncology community have focused on the high response rates but short time to progression observed with the use of BRAF inhibitors, the excellent overall survival of 15.9 months in that trial of 132 second line melanoma patients suggests that real survival benefit can be gained from using BRAF inhibitors. The 53% overall response rate is excellent, but the proportion of complete responders (6%) is modest. Due to the early stopping of the randomized BRIM3 study2, and subsequent crossover of DTIC patients on the control arm to receive vemurafenib, there may never be a mature comparison in overall survival for that trial, but the front line BRIM3 vemurafenib data may be as favorable as the second line BRIM2 data in overall survival. Admittedly, in both studies, patients could be treated beyond progression, (which occurred in 24% of those on the BRIM2 trial) so the median progression-free survival data of 6.8 months may not reflect the true survival benefit obtained with this drug, which appears to be substantial.
The impressive survival data from the BRIM2 study will provoke further discussion of the notion that BRAF mutated patients without bulky disease or with slow growing melanoma should first go on an immune agent like ipilimumab, high dose IL-2, or even a PD-1 antibody trial in front line in preference to a BRAF inhibitor. While the immune agents may induce a modest proportion of patients to have long-term survival, representing the "tail on the curve 3,4," as we gain more long-term experience with vemurafenib, similar data may also be seen with that agent. Patients treated past progression, or who have isolated progressing lesions surgically resected, may derive considerable survival benefit from BRAF inhibition. For any patient with BRAF mutated melanoma, there may be a justification for treating with a BRAF inhibitor in front line.
An important question that remains is whether patients that progress after failing a BRAF inhibitor have explosive tumor growth and a rapid downhill course. While the post-progression survival in the BRIM2 and BRIM 3 studies was in the realm of 6-7 months, if the patients stayed on drug past progression, then survival after stopping vemurafenib indeed may have been quite short due to the prolonged time on treatment. The important question of which BRAF mutated patients to treat with a BRAF inhibitor, and whether immune agents should be used first is a critical question that needs an answer.
References:
1. Sosman, J.A, Kim, K.B., Schuchter, L.,Gonzalez, R. et al Survival in BRAF V600–Mutant Advanced Melanoma Treated with Vemurafenib N Engl J Med 2012;366:707-14.
2. Chapman PB, Hauschild A, Robert C, et al BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011 Jun 30;364(26):2507-16.
3. Hodi FS, O'Day SJ, McDermott DF, Weber RW,et al . Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug
19;363(8):711-23
4. Robert C, Thomas L, Bondarenko I, O'Day S,et al . Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-26
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