SDEF: FDA Approval Expected this Month for Ipilimumab

WAILEA, HAWAII – Expect a flood of patient inquiries regarding ipilimumab beginning in late March, when it is widely expected to receive Food and Drug Administration marketing approval as the first new drug for melanoma in 13 years.

"This is the first drug ever shown to increase survival in patients with metastatic melanoma in a randomized study," Dr. Richard D. Carvajal said at the annual Hawaii Dermatology Seminar, sponsored by Skin Disease Education Foundation (SDEF). "Every melanoma patient is going to want it. But it's not for everybody."

For example, patients with rapidly progressive advanced disease may not be good candidates for ipilimumab, because the survival curves in the pivotal phase III clinical trial didn’t start to separate until about month 3. Ipilimumab affects the immune system, rather than directly targeting the tumor as do chemotherapy drugs. It takes some time for the ipilimumab-enhanced immune system to recognize the cancer and exert an antitumor effect, explained Dr. Carvajal, a medical oncologist in the melanoma and sarcoma service at Memorial Sloan-Kettering Cancer Center, New York.

Melanoma accounts for nearly 9,000 deaths annually in the United States. There is a dearth of treatment options for patients with advanced melanoma; indeed, the only FDA-approved treatments are dacarbazine (granted approval in 1975) and interleukin-2 (approved in 1998).

When chemotherapy works in advanced melanoma, it works quickly: A scan obtained after 6-8 weeks of therapy will show stability or shrinkage. That sort of response can also be seen with ipilimumab – but in addition, two novel patterns of response have been observed. One involves an initial increase in total tumor volume at the beginning of therapy, followed by delayed onset of stabilization or shrinkage.

Even more strikingly, some patients develop entirely new sites of metastatic disease when ipilimumab is started, with stabilization or shrinkage of both the new lesions and the baseline lesions coming several months later, according to Dr. Carvajal.

Ipilimumab is a fully human monoclonal antibody that binds to cytotoxic T lymphocyte–associated antigen 4 located on T cells. Inhibition of that antigen enhances the antitumor T-cell response. The administration schedule used in the clinical trials was one intravenous dose given every 3 weeks, for a total of four doses. Maintenance dosing at 12-week intervals has been employed in some studies.

The multicenter pivotal trial included 676 metastatic melanoma patients who were randomized to ipilimumab, a glycoprotein 100 peptide vaccine serving as placebo, or both. The 12-month survival rate was 46% with ipilimumab alone, compared with 25% with vaccine only; the 24-month survival rates were 23% and 14%. Median overall survival was 10.0 months with ipilimumab plus vaccine, 10.1 months with ipilimumab alone, and 6.4 months with vaccine only (N. Engl. J. Med. 2010;363:711-23).

Grade 3/4 immune-related toxicities associated with ipilimumab include diarrhea in about 4% of patients, rash or pruritus in 1%, and hepatitis, adrenal insufficiency, thyroiditis, or hypophysitis in fewer than 1% each.

"We've found that, if detected early, most of the toxicities are easily treated and reversible," Dr. Carvajal said. "The severity of toxicity is inversely related to the vigilance of surveillance, so we’re going to have to educate our medical oncology colleagues that they have to watch these patients quite closely. At any sign of bowel dysfunction – even increased gas – you have to initiate therapy to keep the diarrhea under control."

Caught early, the diarrhea is typically resolved or controlled within 2 weeks via high-dose oral corticosteroids, he added.

Vitiligo occurs in about 3% of treated patients. Depigmentation of hair and eyelashes has also been seen.

It appears that the patients who develop some type of immune side effect are more likely to have a beneficial response to treatment, according to Dr. Carvajal.

Efforts are ongoing to identify biomarkers that predict outcome so that ipilimumab can be employed selectively.

Bristol-Myers Squibb is developing ipilimumab. Dr. Carvajal has no financial relationship with the company, although he does serve as a consultant to Novartis regarding imatinib (Gleevec), another drug that is being developed as a novel therapy for melanoma. SDEF and this publication are owned by Elsevier.

WAILEA, HAWAII – Expect a flood of patient inquiries regarding ipilimumab beginning in late March, when it is widely expected to receive Food and Drug Administration marketing approval as the first new drug for melanoma in 13 years.

"This is the first drug ever shown to increase survival in patients with metastatic melanoma in a randomized study," Dr. Richard D. Carvajal said at the annual Hawaii Dermatology Seminar, sponsored by Skin Disease Education Foundation (SDEF). "Every melanoma patient is going to want it. But it's not for everybody."

For example, patients with rapidly progressive advanced disease may not be good candidates for ipilimumab, because the survival curves in the pivotal phase III clinical trial didn’t start to separate until about month 3. Ipilimumab affects the immune system, rather than directly targeting the tumor as do chemotherapy drugs. It takes some time for the ipilimumab-enhanced immune system to recognize the cancer and exert an antitumor effect, explained Dr. Carvajal, a medical oncologist in the melanoma and sarcoma service at Memorial Sloan-Kettering Cancer Center, New York.

Melanoma accounts for nearly 9,000 deaths annually in the United States. There is a dearth of treatment options for patients with advanced melanoma; indeed, the only FDA-approved treatments are dacarbazine (granted approval in 1975) and interleukin-2 (approved in 1998).

When chemotherapy works in advanced melanoma, it works quickly: A scan obtained after 6-8 weeks of therapy will show stability or shrinkage. That sort of response can also be seen with ipilimumab – but in addition, two novel patterns of response have been observed. One involves an initial increase in total tumor volume at the beginning of therapy, followed by delayed onset of stabilization or shrinkage.

Even more strikingly, some patients develop entirely new sites of metastatic disease when ipilimumab is started, with stabilization or shrinkage of both the new lesions and the baseline lesions coming several months later, according to Dr. Carvajal.

Ipilimumab is a fully human monoclonal antibody that binds to cytotoxic T lymphocyte–associated antigen 4 located on T cells. Inhibition of that antigen enhances the antitumor T-cell response. The administration schedule used in the clinical trials was one intravenous dose given every 3 weeks, for a total of four doses. Maintenance dosing at 12-week intervals has been employed in some studies.

The multicenter pivotal trial included 676 metastatic melanoma patients who were randomized to ipilimumab, a glycoprotein 100 peptide vaccine serving as placebo, or both. The 12-month survival rate was 46% with ipilimumab alone, compared with 25% with vaccine only; the 24-month survival rates were 23% and 14%. Median overall survival was 10.0 months with ipilimumab plus vaccine, 10.1 months with ipilimumab alone, and 6.4 months with vaccine only (N. Engl. J. Med. 2010;363:711-23).

Grade 3/4 immune-related toxicities associated with ipilimumab include diarrhea in about 4% of patients, rash or pruritus in 1%, and hepatitis, adrenal insufficiency, thyroiditis, or hypophysitis in fewer than 1% each.

"We've found that, if detected early, most of the toxicities are easily treated and reversible," Dr. Carvajal said. "The severity of toxicity is inversely related to the vigilance of surveillance, so we’re going to have to educate our medical oncology colleagues that they have to watch these patients quite closely. At any sign of bowel dysfunction – even increased gas – you have to initiate therapy to keep the diarrhea under control."

Caught early, the diarrhea is typically resolved or controlled within 2 weeks via high-dose oral corticosteroids, he added.

Vitiligo occurs in about 3% of treated patients. Depigmentation of hair and eyelashes has also been seen.

It appears that the patients who develop some type of immune side effect are more likely to have a beneficial response to treatment, according to Dr. Carvajal.

Efforts are ongoing to identify biomarkers that predict outcome so that ipilimumab can be employed selectively.

Bristol-Myers Squibb is developing ipilimumab. Dr. Carvajal has no financial relationship with the company, although he does serve as a consultant to Novartis regarding imatinib (Gleevec), another drug that is being developed as a novel therapy for melanoma. SDEF and this publication are owned by Elsevier.

WAILEA, HAWAII – Expect a flood of patient inquiries regarding ipilimumab beginning in late March, when it is widely expected to receive Food and Drug Administration marketing approval as the first new drug for melanoma in 13 years.

"This is the first drug ever shown to increase survival in patients with metastatic melanoma in a randomized study," Dr. Richard D. Carvajal said at the annual Hawaii Dermatology Seminar, sponsored by Skin Disease Education Foundation (SDEF). "Every melanoma patient is going to want it. But it's not for everybody."

For example, patients with rapidly progressive advanced disease may not be good candidates for ipilimumab, because the survival curves in the pivotal phase III clinical trial didn’t start to separate until about month 3. Ipilimumab affects the immune system, rather than directly targeting the tumor as do chemotherapy drugs. It takes some time for the ipilimumab-enhanced immune system to recognize the cancer and exert an antitumor effect, explained Dr. Carvajal, a medical oncologist in the melanoma and sarcoma service at Memorial Sloan-Kettering Cancer Center, New York.

Melanoma accounts for nearly 9,000 deaths annually in the United States. There is a dearth of treatment options for patients with advanced melanoma; indeed, the only FDA-approved treatments are dacarbazine (granted approval in 1975) and interleukin-2 (approved in 1998).

When chemotherapy works in advanced melanoma, it works quickly: A scan obtained after 6-8 weeks of therapy will show stability or shrinkage. That sort of response can also be seen with ipilimumab – but in addition, two novel patterns of response have been observed. One involves an initial increase in total tumor volume at the beginning of therapy, followed by delayed onset of stabilization or shrinkage.

Even more strikingly, some patients develop entirely new sites of metastatic disease when ipilimumab is started, with stabilization or shrinkage of both the new lesions and the baseline lesions coming several months later, according to Dr. Carvajal.

Ipilimumab is a fully human monoclonal antibody that binds to cytotoxic T lymphocyte–associated antigen 4 located on T cells. Inhibition of that antigen enhances the antitumor T-cell response. The administration schedule used in the clinical trials was one intravenous dose given every 3 weeks, for a total of four doses. Maintenance dosing at 12-week intervals has been employed in some studies.

The multicenter pivotal trial included 676 metastatic melanoma patients who were randomized to ipilimumab, a glycoprotein 100 peptide vaccine serving as placebo, or both. The 12-month survival rate was 46% with ipilimumab alone, compared with 25% with vaccine only; the 24-month survival rates were 23% and 14%. Median overall survival was 10.0 months with ipilimumab plus vaccine, 10.1 months with ipilimumab alone, and 6.4 months with vaccine only (N. Engl. J. Med. 2010;363:711-23).

Grade 3/4 immune-related toxicities associated with ipilimumab include diarrhea in about 4% of patients, rash or pruritus in 1%, and hepatitis, adrenal insufficiency, thyroiditis, or hypophysitis in fewer than 1% each.

"We've found that, if detected early, most of the toxicities are easily treated and reversible," Dr. Carvajal said. "The severity of toxicity is inversely related to the vigilance of surveillance, so we’re going to have to educate our medical oncology colleagues that they have to watch these patients quite closely. At any sign of bowel dysfunction – even increased gas – you have to initiate therapy to keep the diarrhea under control."

Caught early, the diarrhea is typically resolved or controlled within 2 weeks via high-dose oral corticosteroids, he added.

Vitiligo occurs in about 3% of treated patients. Depigmentation of hair and eyelashes has also been seen.

It appears that the patients who develop some type of immune side effect are more likely to have a beneficial response to treatment, according to Dr. Carvajal.

Efforts are ongoing to identify biomarkers that predict outcome so that ipilimumab can be employed selectively.

Bristol-Myers Squibb is developing ipilimumab. Dr. Carvajal has no financial relationship with the company, although he does serve as a consultant to Novartis regarding imatinib (Gleevec), another drug that is being developed as a novel therapy for melanoma. SDEF and this publication are owned by Elsevier.