Immunotherapy for melanoma progresses with some interesting response patterns

HOLLYWOOD, FLA. – Tremendous progress has been made in recent years in the area of immunotherapy for the treatment of melanoma, and new agents and combinations continue to emerge, with some interesting response patterns, according to Dr. John A. Thompson.

Ipilimumab, for example, was added as a category 1 first-line systemic treatment option for melanoma to the 2012 National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Melanoma. The change was based largely on two trials showing prolonged survival in patients treated with the monoclonal antibody.

In one study (the MDX010-20 trial), 650 patients with previously treated metastatic melanoma were randomized to receive either ipilimumab and a gp100 vaccine, ipilimumab alone, or vaccine alone. Those who received ipilimumab had better overall survival (10 months, 10.1 months, and 6.4 months, respectively). The hazard ratios for death were 0.68 and 0.66 for ipilimumab plus gp100 vs. gp100 alone, and for ipilimumab alone vs. gp100 alone, respectively (N. Engl. J. Med. 2010;363:711-23).

A plateau on the survival curve after about 2.5 years out to about 5 years suggests that ipilimumab-treated patients may have prolonged survival, said Dr. Thompson, codirector of the Seattle Cancer Care Alliance Melanoma Clinic and a member of the NCCN Guidelines Panel on Melanoma.

The second trial (CA184-024) was a randomized controlled trial of ipilimumab as first-line therapy in about 500 patients with metastatic melanoma who were randomized to receive ipilimumab and dacarbazine or placebo and dacarbazine. The ipilimumab group had significantly better overall survival (11.2 vs. 9.1 months), and survival was higher among the ipilimumab-treated patients at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%, and 3 years (20.8% vs. 12.2%), with a hazard ratio for death of 0.72 (N. Engl. J. Med. 2011;364:2517-26).

It is important to keep in mind that ipilimumab can be associated with an "interesting" response pattern, and that response may be delayed, Dr. Thompson noted at the annual conference of the National Comprehensive Cancer Network.

He described one case involving a patient with extensive disease considered to be nonresectable. After 12 weeks, having received four doses, the patient’s disease appeared to progress with swelling and an increase in the size of tumors.

However, without further therapy, the disease began to regress by week 14, and by 2 years it was completely eliminated, Dr. Thompson said.

"So we have to be patient and wait for the generation of an immune response to ipilimumab," he said.

In a more recent study, ipilimumab was shown to be useful for the treatment of uveal melanoma. The response rate in 39 patients with metastatic uveal melanoma who were included in the multicenter, retrospective study and who were treated with either 3 mg/kg (34 patients) or 10 mg/kg (5 patients), was 2.6% at 12 weeks, and the response plus stable disease rate was 46% (Cancer 2013;119:3687).

At week 23, the response rate was 2.6% and the response plus stable disease rate was 28.2%. One patient had a complete response, and 1 had a partial response at 100 weeks, for an immune-related response rate of 5.1%. The median overall survival from first dose was 9.6 months.

Treatment in all three trials was associated with significant toxicity, Dr. Thompson said.

"We have to be very careful in managing the potential for immune-related adverse events. I think everyone using this agent or similar immune-checkpoint inhibitor drugs should educate themselves about the types of toxicities and how they should be handled," he said, noting that useful information about the risks of serious immune-mediated adverse reactions, along with algorithms for managing them, can be found at www.yervoy.com/hcp/rems.

He also said he routinely gives patients a "wallet card" that lists potential side effects, which can be helpful for identifying drug-related effects and for providing valuable information during doctor or emergency department visits.

Toxicities generally involve the skin (pruritus, rash), the gastrointestinal tract (diarrhea, abdominal pain, blood in stool, bowel perforation, peritoneal signs), the liver (elevated aspartate aminotransferase/alanine aminotransferase or bilirubin), the endocrine system (fatigue, headache, mental status changes, hypotension, abnormal thyroid function tests/serum chemistries), and the neurological system (unilateral or bilateral weakness, sensory alterations, paresthesias).

Toxicities affecting the skin typically appear around the time of the second dose, and GI effects tend to begin around the time of the third dose, he said. The GI toxicities affect up to 25% of patients, can progress rapidly, and require active intervention; patients should be advised not to ignore symptoms or write them off as a result of "something they ate."

Endocrine toxicities tend to occur toward the end of treatment, and some can be subtle in onset and difficult to diagnose without careful monitoring.

In general, mild toxicities should prompt evaluation for other causes of the symptoms, and can be managed with symptomatic therapy. Moderate toxicities (four to six stools per day over baseline, abdominal pain, blood in the stool, for example) should prompt withholding of ipilimumab, and treatment with prednisone or an equivalent at 0.5 mg/kg day if the symptoms persist for more than a week.

For severe toxicity (seven or more stools per day over baseline, peritoneal signs along with signs of perforation, ileus, and fever, for example), discontinue ipilimumab; evaluate for bowel perforation; consider endoscopy; and give steroids at 1-2 mg/kg per day until the patient improves, with tapering over a month, he said.

As for other emerging immunotherapy drugs, anti–programmed death-1 (anti-PD-1) antibodies now in development are showing great promise in melanoma. One recent study showed that combining an anti-PD-1 (nivolumab) and ipilimumab was effective for the treatment of advanced melanoma (N. Engl. J. Med. 2013;369:122-33). Concurrent treatment with both agents was associated with a "very encouraging" 53% objective response rate in 53 patients, "albeit with a high rate of grade III/IV toxicity," he said.

"The findings are quite striking in terms of the degree of suppression in tumor measurement," he added, noting that the studies are ongoing.

Compared with targeted therapy for melanoma, which tends to have early and dramatic results, with tumor shrinkage and delayed tumor progression early, but with a plateau over the long term ("the answer is still out" on long-term efficacy, Dr. Thompson noted), immunotherapy tends to have little effect early in the course of therapy but is associated with a "promising tail on the survival curve, where there’s a subset of patients who have very durable response and survival," he said.

A simplified treatment algorithm can be used to help select the appropriate treatment, he added.

For patients with low-volume BRAF wild-type disease (who thus are not thought to be eligible for BRAF-directed therapy), consider clinical trial enrollment or high-dose interleukin-2, ipilimumab, or an anti-PD1 (expected to be available soon, according to Dr. Thompson).

For those with BRAF wild-type and symptomatic bulky disease, the choice is more difficult given the delayed immune response with ipilimumab. Consider a clinical trial; combining cytotoxic agents with an immune checkpoint inhibitor may also be appropriate in these patients, he said.

The decision is also complicated for those with documented BRAF mutation and low-volume disease, as going straight to targeted therapy is an option, but trying an immune checkpoint drug first, and moving to targeted therapy if the patient fails to respond, is also an option.

Targeted therapy is recommended for those with BRAF mutation and bulky disease, he said.

As for patients who have undergone resection for stage 3 or certain high-risk stage 2 disease, the guidelines call for consideration of adjuvant therapy. Interferon is an approved therapy for these patients, but there has been a lot of disagreement among NCCN Melanoma Panel members regarding its use because of the side-effect profile.

A study looking at ipilimumab vs. placebo in these patients is underway, as is a trial comparing low- and high-dose ipilimumab and interferon.

"We are eagerly awaiting the results," he said, noting that other areas of interest with respect to immunotherapy include T-cell therapy (including cells with engineered immune receptors); lymphokines (such as IL-15 and IL-21), either alone or in combination with vaccines or immune checkpoint inhibitors; receptor-directed cytokines; and combinations of targeted agents with immunomodulators.

Dr. Thompson reported receiving grant or research support from Bristol-Myers Squibb, Exelixis, Genentech, and GlaxoSmithKline.

HOLLYWOOD, FLA. – Tremendous progress has been made in recent years in the area of immunotherapy for the treatment of melanoma, and new agents and combinations continue to emerge, with some interesting response patterns, according to Dr. John A. Thompson.

Ipilimumab, for example, was added as a category 1 first-line systemic treatment option for melanoma to the 2012 National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Melanoma. The change was based largely on two trials showing prolonged survival in patients treated with the monoclonal antibody.

In one study (the MDX010-20 trial), 650 patients with previously treated metastatic melanoma were randomized to receive either ipilimumab and a gp100 vaccine, ipilimumab alone, or vaccine alone. Those who received ipilimumab had better overall survival (10 months, 10.1 months, and 6.4 months, respectively). The hazard ratios for death were 0.68 and 0.66 for ipilimumab plus gp100 vs. gp100 alone, and for ipilimumab alone vs. gp100 alone, respectively (N. Engl. J. Med. 2010;363:711-23).

A plateau on the survival curve after about 2.5 years out to about 5 years suggests that ipilimumab-treated patients may have prolonged survival, said Dr. Thompson, codirector of the Seattle Cancer Care Alliance Melanoma Clinic and a member of the NCCN Guidelines Panel on Melanoma.

The second trial (CA184-024) was a randomized controlled trial of ipilimumab as first-line therapy in about 500 patients with metastatic melanoma who were randomized to receive ipilimumab and dacarbazine or placebo and dacarbazine. The ipilimumab group had significantly better overall survival (11.2 vs. 9.1 months), and survival was higher among the ipilimumab-treated patients at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%, and 3 years (20.8% vs. 12.2%), with a hazard ratio for death of 0.72 (N. Engl. J. Med. 2011;364:2517-26).

It is important to keep in mind that ipilimumab can be associated with an "interesting" response pattern, and that response may be delayed, Dr. Thompson noted at the annual conference of the National Comprehensive Cancer Network.

He described one case involving a patient with extensive disease considered to be nonresectable. After 12 weeks, having received four doses, the patient’s disease appeared to progress with swelling and an increase in the size of tumors.

However, without further therapy, the disease began to regress by week 14, and by 2 years it was completely eliminated, Dr. Thompson said.

"So we have to be patient and wait for the generation of an immune response to ipilimumab," he said.

In a more recent study, ipilimumab was shown to be useful for the treatment of uveal melanoma. The response rate in 39 patients with metastatic uveal melanoma who were included in the multicenter, retrospective study and who were treated with either 3 mg/kg (34 patients) or 10 mg/kg (5 patients), was 2.6% at 12 weeks, and the response plus stable disease rate was 46% (Cancer 2013;119:3687).

At week 23, the response rate was 2.6% and the response plus stable disease rate was 28.2%. One patient had a complete response, and 1 had a partial response at 100 weeks, for an immune-related response rate of 5.1%. The median overall survival from first dose was 9.6 months.

Treatment in all three trials was associated with significant toxicity, Dr. Thompson said.

"We have to be very careful in managing the potential for immune-related adverse events. I think everyone using this agent or similar immune-checkpoint inhibitor drugs should educate themselves about the types of toxicities and how they should be handled," he said, noting that useful information about the risks of serious immune-mediated adverse reactions, along with algorithms for managing them, can be found at www.yervoy.com/hcp/rems.

He also said he routinely gives patients a "wallet card" that lists potential side effects, which can be helpful for identifying drug-related effects and for providing valuable information during doctor or emergency department visits.

Toxicities generally involve the skin (pruritus, rash), the gastrointestinal tract (diarrhea, abdominal pain, blood in stool, bowel perforation, peritoneal signs), the liver (elevated aspartate aminotransferase/alanine aminotransferase or bilirubin), the endocrine system (fatigue, headache, mental status changes, hypotension, abnormal thyroid function tests/serum chemistries), and the neurological system (unilateral or bilateral weakness, sensory alterations, paresthesias).

Toxicities affecting the skin typically appear around the time of the second dose, and GI effects tend to begin around the time of the third dose, he said. The GI toxicities affect up to 25% of patients, can progress rapidly, and require active intervention; patients should be advised not to ignore symptoms or write them off as a result of "something they ate."

Endocrine toxicities tend to occur toward the end of treatment, and some can be subtle in onset and difficult to diagnose without careful monitoring.

In general, mild toxicities should prompt evaluation for other causes of the symptoms, and can be managed with symptomatic therapy. Moderate toxicities (four to six stools per day over baseline, abdominal pain, blood in the stool, for example) should prompt withholding of ipilimumab, and treatment with prednisone or an equivalent at 0.5 mg/kg day if the symptoms persist for more than a week.

For severe toxicity (seven or more stools per day over baseline, peritoneal signs along with signs of perforation, ileus, and fever, for example), discontinue ipilimumab; evaluate for bowel perforation; consider endoscopy; and give steroids at 1-2 mg/kg per day until the patient improves, with tapering over a month, he said.

As for other emerging immunotherapy drugs, anti–programmed death-1 (anti-PD-1) antibodies now in development are showing great promise in melanoma. One recent study showed that combining an anti-PD-1 (nivolumab) and ipilimumab was effective for the treatment of advanced melanoma (N. Engl. J. Med. 2013;369:122-33). Concurrent treatment with both agents was associated with a "very encouraging" 53% objective response rate in 53 patients, "albeit with a high rate of grade III/IV toxicity," he said.

"The findings are quite striking in terms of the degree of suppression in tumor measurement," he added, noting that the studies are ongoing.

Compared with targeted therapy for melanoma, which tends to have early and dramatic results, with tumor shrinkage and delayed tumor progression early, but with a plateau over the long term ("the answer is still out" on long-term efficacy, Dr. Thompson noted), immunotherapy tends to have little effect early in the course of therapy but is associated with a "promising tail on the survival curve, where there’s a subset of patients who have very durable response and survival," he said.

A simplified treatment algorithm can be used to help select the appropriate treatment, he added.

For patients with low-volume BRAF wild-type disease (who thus are not thought to be eligible for BRAF-directed therapy), consider clinical trial enrollment or high-dose interleukin-2, ipilimumab, or an anti-PD1 (expected to be available soon, according to Dr. Thompson).

For those with BRAF wild-type and symptomatic bulky disease, the choice is more difficult given the delayed immune response with ipilimumab. Consider a clinical trial; combining cytotoxic agents with an immune checkpoint inhibitor may also be appropriate in these patients, he said.

The decision is also complicated for those with documented BRAF mutation and low-volume disease, as going straight to targeted therapy is an option, but trying an immune checkpoint drug first, and moving to targeted therapy if the patient fails to respond, is also an option.

Targeted therapy is recommended for those with BRAF mutation and bulky disease, he said.

As for patients who have undergone resection for stage 3 or certain high-risk stage 2 disease, the guidelines call for consideration of adjuvant therapy. Interferon is an approved therapy for these patients, but there has been a lot of disagreement among NCCN Melanoma Panel members regarding its use because of the side-effect profile.

A study looking at ipilimumab vs. placebo in these patients is underway, as is a trial comparing low- and high-dose ipilimumab and interferon.

"We are eagerly awaiting the results," he said, noting that other areas of interest with respect to immunotherapy include T-cell therapy (including cells with engineered immune receptors); lymphokines (such as IL-15 and IL-21), either alone or in combination with vaccines or immune checkpoint inhibitors; receptor-directed cytokines; and combinations of targeted agents with immunomodulators.

Dr. Thompson reported receiving grant or research support from Bristol-Myers Squibb, Exelixis, Genentech, and GlaxoSmithKline.

HOLLYWOOD, FLA. – Tremendous progress has been made in recent years in the area of immunotherapy for the treatment of melanoma, and new agents and combinations continue to emerge, with some interesting response patterns, according to Dr. John A. Thompson.

Ipilimumab, for example, was added as a category 1 first-line systemic treatment option for melanoma to the 2012 National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Melanoma. The change was based largely on two trials showing prolonged survival in patients treated with the monoclonal antibody.

In one study (the MDX010-20 trial), 650 patients with previously treated metastatic melanoma were randomized to receive either ipilimumab and a gp100 vaccine, ipilimumab alone, or vaccine alone. Those who received ipilimumab had better overall survival (10 months, 10.1 months, and 6.4 months, respectively). The hazard ratios for death were 0.68 and 0.66 for ipilimumab plus gp100 vs. gp100 alone, and for ipilimumab alone vs. gp100 alone, respectively (N. Engl. J. Med. 2010;363:711-23).

A plateau on the survival curve after about 2.5 years out to about 5 years suggests that ipilimumab-treated patients may have prolonged survival, said Dr. Thompson, codirector of the Seattle Cancer Care Alliance Melanoma Clinic and a member of the NCCN Guidelines Panel on Melanoma.

The second trial (CA184-024) was a randomized controlled trial of ipilimumab as first-line therapy in about 500 patients with metastatic melanoma who were randomized to receive ipilimumab and dacarbazine or placebo and dacarbazine. The ipilimumab group had significantly better overall survival (11.2 vs. 9.1 months), and survival was higher among the ipilimumab-treated patients at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%, and 3 years (20.8% vs. 12.2%), with a hazard ratio for death of 0.72 (N. Engl. J. Med. 2011;364:2517-26).

It is important to keep in mind that ipilimumab can be associated with an "interesting" response pattern, and that response may be delayed, Dr. Thompson noted at the annual conference of the National Comprehensive Cancer Network.

He described one case involving a patient with extensive disease considered to be nonresectable. After 12 weeks, having received four doses, the patient’s disease appeared to progress with swelling and an increase in the size of tumors.

However, without further therapy, the disease began to regress by week 14, and by 2 years it was completely eliminated, Dr. Thompson said.

"So we have to be patient and wait for the generation of an immune response to ipilimumab," he said.

In a more recent study, ipilimumab was shown to be useful for the treatment of uveal melanoma. The response rate in 39 patients with metastatic uveal melanoma who were included in the multicenter, retrospective study and who were treated with either 3 mg/kg (34 patients) or 10 mg/kg (5 patients), was 2.6% at 12 weeks, and the response plus stable disease rate was 46% (Cancer 2013;119:3687).

At week 23, the response rate was 2.6% and the response plus stable disease rate was 28.2%. One patient had a complete response, and 1 had a partial response at 100 weeks, for an immune-related response rate of 5.1%. The median overall survival from first dose was 9.6 months.

Treatment in all three trials was associated with significant toxicity, Dr. Thompson said.

"We have to be very careful in managing the potential for immune-related adverse events. I think everyone using this agent or similar immune-checkpoint inhibitor drugs should educate themselves about the types of toxicities and how they should be handled," he said, noting that useful information about the risks of serious immune-mediated adverse reactions, along with algorithms for managing them, can be found at www.yervoy.com/hcp/rems.

He also said he routinely gives patients a "wallet card" that lists potential side effects, which can be helpful for identifying drug-related effects and for providing valuable information during doctor or emergency department visits.

Toxicities generally involve the skin (pruritus, rash), the gastrointestinal tract (diarrhea, abdominal pain, blood in stool, bowel perforation, peritoneal signs), the liver (elevated aspartate aminotransferase/alanine aminotransferase or bilirubin), the endocrine system (fatigue, headache, mental status changes, hypotension, abnormal thyroid function tests/serum chemistries), and the neurological system (unilateral or bilateral weakness, sensory alterations, paresthesias).

Toxicities affecting the skin typically appear around the time of the second dose, and GI effects tend to begin around the time of the third dose, he said. The GI toxicities affect up to 25% of patients, can progress rapidly, and require active intervention; patients should be advised not to ignore symptoms or write them off as a result of "something they ate."

Endocrine toxicities tend to occur toward the end of treatment, and some can be subtle in onset and difficult to diagnose without careful monitoring.

In general, mild toxicities should prompt evaluation for other causes of the symptoms, and can be managed with symptomatic therapy. Moderate toxicities (four to six stools per day over baseline, abdominal pain, blood in the stool, for example) should prompt withholding of ipilimumab, and treatment with prednisone or an equivalent at 0.5 mg/kg day if the symptoms persist for more than a week.

For severe toxicity (seven or more stools per day over baseline, peritoneal signs along with signs of perforation, ileus, and fever, for example), discontinue ipilimumab; evaluate for bowel perforation; consider endoscopy; and give steroids at 1-2 mg/kg per day until the patient improves, with tapering over a month, he said.

As for other emerging immunotherapy drugs, anti–programmed death-1 (anti-PD-1) antibodies now in development are showing great promise in melanoma. One recent study showed that combining an anti-PD-1 (nivolumab) and ipilimumab was effective for the treatment of advanced melanoma (N. Engl. J. Med. 2013;369:122-33). Concurrent treatment with both agents was associated with a "very encouraging" 53% objective response rate in 53 patients, "albeit with a high rate of grade III/IV toxicity," he said.

"The findings are quite striking in terms of the degree of suppression in tumor measurement," he added, noting that the studies are ongoing.

Compared with targeted therapy for melanoma, which tends to have early and dramatic results, with tumor shrinkage and delayed tumor progression early, but with a plateau over the long term ("the answer is still out" on long-term efficacy, Dr. Thompson noted), immunotherapy tends to have little effect early in the course of therapy but is associated with a "promising tail on the survival curve, where there’s a subset of patients who have very durable response and survival," he said.

A simplified treatment algorithm can be used to help select the appropriate treatment, he added.

For patients with low-volume BRAF wild-type disease (who thus are not thought to be eligible for BRAF-directed therapy), consider clinical trial enrollment or high-dose interleukin-2, ipilimumab, or an anti-PD1 (expected to be available soon, according to Dr. Thompson).

For those with BRAF wild-type and symptomatic bulky disease, the choice is more difficult given the delayed immune response with ipilimumab. Consider a clinical trial; combining cytotoxic agents with an immune checkpoint inhibitor may also be appropriate in these patients, he said.

The decision is also complicated for those with documented BRAF mutation and low-volume disease, as going straight to targeted therapy is an option, but trying an immune checkpoint drug first, and moving to targeted therapy if the patient fails to respond, is also an option.

Targeted therapy is recommended for those with BRAF mutation and bulky disease, he said.

As for patients who have undergone resection for stage 3 or certain high-risk stage 2 disease, the guidelines call for consideration of adjuvant therapy. Interferon is an approved therapy for these patients, but there has been a lot of disagreement among NCCN Melanoma Panel members regarding its use because of the side-effect profile.

A study looking at ipilimumab vs. placebo in these patients is underway, as is a trial comparing low- and high-dose ipilimumab and interferon.

"We are eagerly awaiting the results," he said, noting that other areas of interest with respect to immunotherapy include T-cell therapy (including cells with engineered immune receptors); lymphokines (such as IL-15 and IL-21), either alone or in combination with vaccines or immune checkpoint inhibitors; receptor-directed cytokines; and combinations of targeted agents with immunomodulators.

Dr. Thompson reported receiving grant or research support from Bristol-Myers Squibb, Exelixis, Genentech, and GlaxoSmithKline.