Point/Counterpoint: What is the first-line treatment of choice for metastatic BRAF-mutant melanoma?

Consider immunotherapy as first-line treatment.

Application of immunotherapy is becoming increasingly more sophisticated as we learn to control the many signals that activate and deactivate T cells. We now have two approved immunotherapies for metastatic melanoma – high-dose interleukin-2 (Proleukin) and ipilimumab (Yervoy) – and at least two investigational ones – adoptive T-cell therapy and a novel antibody to PD-1 (MDX-1106; ASCO 2010 annual meeting. Abstract 2506) – that are especially promising.

There is no question that if you give only a single agent and compare agents head to head, ipilimumab will lose to vemurafenib (Zelboraf), a targeted BRAF inhibitor, in terms of response rate, progression-free survival, and probably median survival. But our goal is the best overall outcome in this population, and in that regard, the sequencing of agents comes into play, and there may be advantages to giving immunotherapy first.

The first of several factors to consider when selecting initial therapy is that immunotherapy can produce long-term durable remissions; for example, about 5% of patients given high-dose interleukin-2 have a remission lasting more than 2 years, in some cases more than 10 years, often without maintenance therapy (Clin. Cancer Res. 2006;12:2353s-8s). In contrast, virtually all patients given targeted agents will require some sort of second therapy when they have progression.

Second, the actual treatment duration of immunotherapy is quite limited, and patients having a response may never need a second therapy. But for targeted therapy, as far as we can tell, patients will have to remain on that therapy forever.

A third factor is the speed of response. Reponses to immunotherapy are slow, in some cases taking at least 12 weeks, whereas responses to targeted agents often occur within days. So it may be difficult to give immunotherapy if you wait until a patient has progression on the targeted agent, whereas the targeted agent works so quickly that it may still be an option after failure of immunotherapy.

It is also noteworthy that targeted therapy can be associated with fulminant relapse. Our limited experience has been that a subset of patients has incredibly rapid progression when this therapy begins to fail and the targeted agent is discontinued, so there’s no opportunity to give immunotherapy at that point.

To be sure, patients with high tumor burden and very rapid tumor progression at initial metastatic presentation are generally not good candidates for receiving immunotherapy first. So you really have to look at the overall patient and consider potential predictive markers like low baseline lymphocyte count (which would disfavor immunotherapy) and preexisting autoimmune disease (which would exclude patients from some immunotherapies and favor targeted therapy).

Fourth, it has been proposed that giving immunotherapy first and targeted therapy second may be synergistic. Admittedly, this is purely theoretical. But the idea is that ipilimumab, for instance, remains in the body for up to 3 months, so if a patient starts to develop progression on this agent and a targeted agent is given at that time, you are essentially giving combination therapy.

Also, antitumor immunity may play an important role in the efficacy of targeted therapy. Very interesting preclinical data suggest that some of the activity of targeted agents requires existing immune responses (Cancer Cell. 2010;18:485-98), so inducing or expanding an immune response first may produce a better overall effect from the targeted agent. Clinically, evidence was presented that vemurafenib induces T-cell infiltrates in the tumor.

In conclusion, there are compelling reasons to consider immunotherapy as first-line therapy for melanoma. At present, we sometimes have to make difficult choices between initial therapies based on the individual patient, existing data, and our clinical judgment. But future treatment will likely entail use of these therapies in combination to optimize outcomes. Those trials are being planned. There are all sorts of possible combinations coming down the road that will likely improve outcomes.

Dr. Sznol is professor of medical oncology and codirector of the melanoma program at Yale Cancer Center, New Haven, Conn. He disclosed that he is a consultant to Bristol-Myers Squibb (manufacturer of ipilimumab) and Genesis Biopharma (a developer of adoptive cell therapies).

BRAF-targeted therapy has better overall survival.

About half of melanomas have a mutation of BRAF, providing a target for therapy that at the present time has demonstrated great promise. Vemurafenib achieves rapid, often dramatic responses in most patients. In BRIM-2, a phase II trial among patients who had had a failure of a prior therapy, nearly all had regression of disease on vemurafenib and more than 50% achieved a confirmed RECIST (Response Evaluation Criteria in Solid Tumors) clinical response (N. Engl. J. Med., in press). In BRIM-3, a phase III trial among patients with untreated disease, vemurafenib provided a dramatic improvement in both progression-free survival and overall survival over dacarbazine with hazard ratios of 0.26 and 0.37, respectively (N. Engl. J. Med. 2011;364:2507-16).

One misconception about vemurafenib therapy is that everybody is going to have a relapse in 6-7 months and die. The progression-free survival has a median of 6.8 months, but we are seeing impressive median overall survival, with a 15.9-month median in BRIM-2, probably the longest in any similar trial. The 63% relative reduction in the risk of death in BRIM-3 with vemurafenib benefited nearly all subgroups but was most impressive in patients having high lactate dehydrogenase (LDH) levels or M1c disease. We are unlikely to get good long-term survival data from this trial because of the early favorable result and allowance of crossover.

Another misconception about vemurafenib therapy is that most patients will have aggressive disease at relapse, and there will not be an opportunity for a second therapy. In fact, many patients have a localized relapse, undergo resection, and can continue on the vemurafenib. My experience has been that the patients having an aggressive relapse are those who enrolled in the trial with aggressive disease, and would not have been appropriate for other treatments. They did have a great improvement in their quality of life, albeit not for as long as hoped.

With all the limitations of comparisons between trials, vemurafenib compared with ipilimumab has been associated with better rates of overall survival at 1 year (54%-58% vs. 46%) and 2 years (33% vs. 24%). And there is a huge improvement in the disease control rate (86% vs. 44%).

Unquestionably, some patients have highly durable remissions with immunotherapy, but a major frustration is our inability to pick out this small subset of patients up front – prior to therapy.

Vemurafenib is probably the only effective therapy we have ever had for symptomatic patients with a high LDH level, who need rapid improvement in their performance status. I honestly had never seen a patient with those characteristics respond to anything until vemurafenib.

Finally, there may be some science suggesting that giving vemurafenib after ipilimumab is better, but there is not one bit of data to show that you are not able to achieve a durable remission to ipilimumab after failure of a BRAF inhibitor. More research on the sequencing of therapies is needed. In BRIM-2, only about 5% of patients had previously received ipilimumab. And although an analysis is being done among the 24% who got ipilimumab after stopping vemurafenib, it is a post hoc analysis, and the goal is simply to ascertain any contribution to the overall survival result.

In conclusion, in this era of targeted agents, it is essential that all melanomas be genotyped. It is my view that patients with symptomatic bulky disease or an increased LDH level should get vemurafenib. Patients with indolent disease, asymptomatic M1a or M1b disease, could get either; I can’t make any passionate argument that they all should get vemurafenib. But if you’re trying to put a patient into remission for as long as you can with a good quality of life, then vemurafenib is much more likely to do that. Ultimately, we need trials evaluating the issues of sequencing and combination therapy.

Dr. Sosman is professor of medicine and director of the melanoma program at Vanderbilt-Ingram Cancer Center, Nashville, Tenn. He disclosed that he is a consultant to, and receives research support from, GlaxoSmithKline (manufacturer of investigational targeted therapies for melanoma) and Roche (manufacturer of vemurafenib).

Consider immunotherapy as first-line treatment.

Application of immunotherapy is becoming increasingly more sophisticated as we learn to control the many signals that activate and deactivate T cells. We now have two approved immunotherapies for metastatic melanoma – high-dose interleukin-2 (Proleukin) and ipilimumab (Yervoy) – and at least two investigational ones – adoptive T-cell therapy and a novel antibody to PD-1 (MDX-1106; ASCO 2010 annual meeting. Abstract 2506) – that are especially promising.

There is no question that if you give only a single agent and compare agents head to head, ipilimumab will lose to vemurafenib (Zelboraf), a targeted BRAF inhibitor, in terms of response rate, progression-free survival, and probably median survival. But our goal is the best overall outcome in this population, and in that regard, the sequencing of agents comes into play, and there may be advantages to giving immunotherapy first.

The first of several factors to consider when selecting initial therapy is that immunotherapy can produce long-term durable remissions; for example, about 5% of patients given high-dose interleukin-2 have a remission lasting more than 2 years, in some cases more than 10 years, often without maintenance therapy (Clin. Cancer Res. 2006;12:2353s-8s). In contrast, virtually all patients given targeted agents will require some sort of second therapy when they have progression.

Second, the actual treatment duration of immunotherapy is quite limited, and patients having a response may never need a second therapy. But for targeted therapy, as far as we can tell, patients will have to remain on that therapy forever.

A third factor is the speed of response. Reponses to immunotherapy are slow, in some cases taking at least 12 weeks, whereas responses to targeted agents often occur within days. So it may be difficult to give immunotherapy if you wait until a patient has progression on the targeted agent, whereas the targeted agent works so quickly that it may still be an option after failure of immunotherapy.

It is also noteworthy that targeted therapy can be associated with fulminant relapse. Our limited experience has been that a subset of patients has incredibly rapid progression when this therapy begins to fail and the targeted agent is discontinued, so there’s no opportunity to give immunotherapy at that point.

To be sure, patients with high tumor burden and very rapid tumor progression at initial metastatic presentation are generally not good candidates for receiving immunotherapy first. So you really have to look at the overall patient and consider potential predictive markers like low baseline lymphocyte count (which would disfavor immunotherapy) and preexisting autoimmune disease (which would exclude patients from some immunotherapies and favor targeted therapy).

Fourth, it has been proposed that giving immunotherapy first and targeted therapy second may be synergistic. Admittedly, this is purely theoretical. But the idea is that ipilimumab, for instance, remains in the body for up to 3 months, so if a patient starts to develop progression on this agent and a targeted agent is given at that time, you are essentially giving combination therapy.

Also, antitumor immunity may play an important role in the efficacy of targeted therapy. Very interesting preclinical data suggest that some of the activity of targeted agents requires existing immune responses (Cancer Cell. 2010;18:485-98), so inducing or expanding an immune response first may produce a better overall effect from the targeted agent. Clinically, evidence was presented that vemurafenib induces T-cell infiltrates in the tumor.

In conclusion, there are compelling reasons to consider immunotherapy as first-line therapy for melanoma. At present, we sometimes have to make difficult choices between initial therapies based on the individual patient, existing data, and our clinical judgment. But future treatment will likely entail use of these therapies in combination to optimize outcomes. Those trials are being planned. There are all sorts of possible combinations coming down the road that will likely improve outcomes.

Dr. Sznol is professor of medical oncology and codirector of the melanoma program at Yale Cancer Center, New Haven, Conn. He disclosed that he is a consultant to Bristol-Myers Squibb (manufacturer of ipilimumab) and Genesis Biopharma (a developer of adoptive cell therapies).

BRAF-targeted therapy has better overall survival.

About half of melanomas have a mutation of BRAF, providing a target for therapy that at the present time has demonstrated great promise. Vemurafenib achieves rapid, often dramatic responses in most patients. In BRIM-2, a phase II trial among patients who had had a failure of a prior therapy, nearly all had regression of disease on vemurafenib and more than 50% achieved a confirmed RECIST (Response Evaluation Criteria in Solid Tumors) clinical response (N. Engl. J. Med., in press). In BRIM-3, a phase III trial among patients with untreated disease, vemurafenib provided a dramatic improvement in both progression-free survival and overall survival over dacarbazine with hazard ratios of 0.26 and 0.37, respectively (N. Engl. J. Med. 2011;364:2507-16).

One misconception about vemurafenib therapy is that everybody is going to have a relapse in 6-7 months and die. The progression-free survival has a median of 6.8 months, but we are seeing impressive median overall survival, with a 15.9-month median in BRIM-2, probably the longest in any similar trial. The 63% relative reduction in the risk of death in BRIM-3 with vemurafenib benefited nearly all subgroups but was most impressive in patients having high lactate dehydrogenase (LDH) levels or M1c disease. We are unlikely to get good long-term survival data from this trial because of the early favorable result and allowance of crossover.

Another misconception about vemurafenib therapy is that most patients will have aggressive disease at relapse, and there will not be an opportunity for a second therapy. In fact, many patients have a localized relapse, undergo resection, and can continue on the vemurafenib. My experience has been that the patients having an aggressive relapse are those who enrolled in the trial with aggressive disease, and would not have been appropriate for other treatments. They did have a great improvement in their quality of life, albeit not for as long as hoped.

With all the limitations of comparisons between trials, vemurafenib compared with ipilimumab has been associated with better rates of overall survival at 1 year (54%-58% vs. 46%) and 2 years (33% vs. 24%). And there is a huge improvement in the disease control rate (86% vs. 44%).

Unquestionably, some patients have highly durable remissions with immunotherapy, but a major frustration is our inability to pick out this small subset of patients up front – prior to therapy.

Vemurafenib is probably the only effective therapy we have ever had for symptomatic patients with a high LDH level, who need rapid improvement in their performance status. I honestly had never seen a patient with those characteristics respond to anything until vemurafenib.

Finally, there may be some science suggesting that giving vemurafenib after ipilimumab is better, but there is not one bit of data to show that you are not able to achieve a durable remission to ipilimumab after failure of a BRAF inhibitor. More research on the sequencing of therapies is needed. In BRIM-2, only about 5% of patients had previously received ipilimumab. And although an analysis is being done among the 24% who got ipilimumab after stopping vemurafenib, it is a post hoc analysis, and the goal is simply to ascertain any contribution to the overall survival result.

In conclusion, in this era of targeted agents, it is essential that all melanomas be genotyped. It is my view that patients with symptomatic bulky disease or an increased LDH level should get vemurafenib. Patients with indolent disease, asymptomatic M1a or M1b disease, could get either; I can’t make any passionate argument that they all should get vemurafenib. But if you’re trying to put a patient into remission for as long as you can with a good quality of life, then vemurafenib is much more likely to do that. Ultimately, we need trials evaluating the issues of sequencing and combination therapy.

Dr. Sosman is professor of medicine and director of the melanoma program at Vanderbilt-Ingram Cancer Center, Nashville, Tenn. He disclosed that he is a consultant to, and receives research support from, GlaxoSmithKline (manufacturer of investigational targeted therapies for melanoma) and Roche (manufacturer of vemurafenib).

Consider immunotherapy as first-line treatment.

Application of immunotherapy is becoming increasingly more sophisticated as we learn to control the many signals that activate and deactivate T cells. We now have two approved immunotherapies for metastatic melanoma – high-dose interleukin-2 (Proleukin) and ipilimumab (Yervoy) – and at least two investigational ones – adoptive T-cell therapy and a novel antibody to PD-1 (MDX-1106; ASCO 2010 annual meeting. Abstract 2506) – that are especially promising.

There is no question that if you give only a single agent and compare agents head to head, ipilimumab will lose to vemurafenib (Zelboraf), a targeted BRAF inhibitor, in terms of response rate, progression-free survival, and probably median survival. But our goal is the best overall outcome in this population, and in that regard, the sequencing of agents comes into play, and there may be advantages to giving immunotherapy first.

The first of several factors to consider when selecting initial therapy is that immunotherapy can produce long-term durable remissions; for example, about 5% of patients given high-dose interleukin-2 have a remission lasting more than 2 years, in some cases more than 10 years, often without maintenance therapy (Clin. Cancer Res. 2006;12:2353s-8s). In contrast, virtually all patients given targeted agents will require some sort of second therapy when they have progression.

Second, the actual treatment duration of immunotherapy is quite limited, and patients having a response may never need a second therapy. But for targeted therapy, as far as we can tell, patients will have to remain on that therapy forever.

A third factor is the speed of response. Reponses to immunotherapy are slow, in some cases taking at least 12 weeks, whereas responses to targeted agents often occur within days. So it may be difficult to give immunotherapy if you wait until a patient has progression on the targeted agent, whereas the targeted agent works so quickly that it may still be an option after failure of immunotherapy.

It is also noteworthy that targeted therapy can be associated with fulminant relapse. Our limited experience has been that a subset of patients has incredibly rapid progression when this therapy begins to fail and the targeted agent is discontinued, so there’s no opportunity to give immunotherapy at that point.

To be sure, patients with high tumor burden and very rapid tumor progression at initial metastatic presentation are generally not good candidates for receiving immunotherapy first. So you really have to look at the overall patient and consider potential predictive markers like low baseline lymphocyte count (which would disfavor immunotherapy) and preexisting autoimmune disease (which would exclude patients from some immunotherapies and favor targeted therapy).

Fourth, it has been proposed that giving immunotherapy first and targeted therapy second may be synergistic. Admittedly, this is purely theoretical. But the idea is that ipilimumab, for instance, remains in the body for up to 3 months, so if a patient starts to develop progression on this agent and a targeted agent is given at that time, you are essentially giving combination therapy.

Also, antitumor immunity may play an important role in the efficacy of targeted therapy. Very interesting preclinical data suggest that some of the activity of targeted agents requires existing immune responses (Cancer Cell. 2010;18:485-98), so inducing or expanding an immune response first may produce a better overall effect from the targeted agent. Clinically, evidence was presented that vemurafenib induces T-cell infiltrates in the tumor.

In conclusion, there are compelling reasons to consider immunotherapy as first-line therapy for melanoma. At present, we sometimes have to make difficult choices between initial therapies based on the individual patient, existing data, and our clinical judgment. But future treatment will likely entail use of these therapies in combination to optimize outcomes. Those trials are being planned. There are all sorts of possible combinations coming down the road that will likely improve outcomes.

Dr. Sznol is professor of medical oncology and codirector of the melanoma program at Yale Cancer Center, New Haven, Conn. He disclosed that he is a consultant to Bristol-Myers Squibb (manufacturer of ipilimumab) and Genesis Biopharma (a developer of adoptive cell therapies).

BRAF-targeted therapy has better overall survival.

About half of melanomas have a mutation of BRAF, providing a target for therapy that at the present time has demonstrated great promise. Vemurafenib achieves rapid, often dramatic responses in most patients. In BRIM-2, a phase II trial among patients who had had a failure of a prior therapy, nearly all had regression of disease on vemurafenib and more than 50% achieved a confirmed RECIST (Response Evaluation Criteria in Solid Tumors) clinical response (N. Engl. J. Med., in press). In BRIM-3, a phase III trial among patients with untreated disease, vemurafenib provided a dramatic improvement in both progression-free survival and overall survival over dacarbazine with hazard ratios of 0.26 and 0.37, respectively (N. Engl. J. Med. 2011;364:2507-16).

One misconception about vemurafenib therapy is that everybody is going to have a relapse in 6-7 months and die. The progression-free survival has a median of 6.8 months, but we are seeing impressive median overall survival, with a 15.9-month median in BRIM-2, probably the longest in any similar trial. The 63% relative reduction in the risk of death in BRIM-3 with vemurafenib benefited nearly all subgroups but was most impressive in patients having high lactate dehydrogenase (LDH) levels or M1c disease. We are unlikely to get good long-term survival data from this trial because of the early favorable result and allowance of crossover.

Another misconception about vemurafenib therapy is that most patients will have aggressive disease at relapse, and there will not be an opportunity for a second therapy. In fact, many patients have a localized relapse, undergo resection, and can continue on the vemurafenib. My experience has been that the patients having an aggressive relapse are those who enrolled in the trial with aggressive disease, and would not have been appropriate for other treatments. They did have a great improvement in their quality of life, albeit not for as long as hoped.

With all the limitations of comparisons between trials, vemurafenib compared with ipilimumab has been associated with better rates of overall survival at 1 year (54%-58% vs. 46%) and 2 years (33% vs. 24%). And there is a huge improvement in the disease control rate (86% vs. 44%).

Unquestionably, some patients have highly durable remissions with immunotherapy, but a major frustration is our inability to pick out this small subset of patients up front – prior to therapy.

Vemurafenib is probably the only effective therapy we have ever had for symptomatic patients with a high LDH level, who need rapid improvement in their performance status. I honestly had never seen a patient with those characteristics respond to anything until vemurafenib.

Finally, there may be some science suggesting that giving vemurafenib after ipilimumab is better, but there is not one bit of data to show that you are not able to achieve a durable remission to ipilimumab after failure of a BRAF inhibitor. More research on the sequencing of therapies is needed. In BRIM-2, only about 5% of patients had previously received ipilimumab. And although an analysis is being done among the 24% who got ipilimumab after stopping vemurafenib, it is a post hoc analysis, and the goal is simply to ascertain any contribution to the overall survival result.

In conclusion, in this era of targeted agents, it is essential that all melanomas be genotyped. It is my view that patients with symptomatic bulky disease or an increased LDH level should get vemurafenib. Patients with indolent disease, asymptomatic M1a or M1b disease, could get either; I can’t make any passionate argument that they all should get vemurafenib. But if you’re trying to put a patient into remission for as long as you can with a good quality of life, then vemurafenib is much more likely to do that. Ultimately, we need trials evaluating the issues of sequencing and combination therapy.

Dr. Sosman is professor of medicine and director of the melanoma program at Vanderbilt-Ingram Cancer Center, Nashville, Tenn. He disclosed that he is a consultant to, and receives research support from, GlaxoSmithKline (manufacturer of investigational targeted therapies for melanoma) and Roche (manufacturer of vemurafenib).