Biochemotherapy Gets Mixed Results in High-Risk Melanoma

CHICAGO – Biochemotherapy is efficacious when used as adjuvant treatment for high-risk melanoma, but not enough to displace the current standard of care, suggests a randomized phase III trial of the Southwest Oncology Group.

The trial, known as S0008, pitted biochemotherapy (chemotherapy plus interleukin-2 and interferon) against high-dose interferon in 402 patients who had undergone wide local excision and lymphadenectomy for stage III melanoma that had features conferring a high risk of recurrence.

Biochemotherapy was associated with a 24% lower risk of relapse, compared with interferon, but there was no significant difference in overall survival, according to trial results reported at the annual meeting of the American Society of Clinical Oncology. Adverse event profiles differed somewhat.

"Biochemotherapy is the first and only therapy to demonstrate a significant improvement in relapse-free survival compared to high-dose interferon in stage III melanoma patients. Biochemotherapy, however, was not associated with an improvement in overall survival," said lead investigator Dr. Lawrence E. Flaherty of the Karmanos Cancer Institute in Detroit.

"Further follow-up will be done on the trial to provide additional insights on longer-term outcomes, but they are not expected to be statistically significant."

"Without an overall survival benefit, biochemotherapy does not replace interferon as the standard of care. However, this may be an attractive alternative to interferon for high-risk melanoma patients," he added, noting biochemotherapy’s advantages of a much shorter treatment duration (2 vs. 12 months) and higher rate of treatment completion.

"Probably more important for our research community is the ability to modify all of the elements that we see here – all of the chemotherapy and biotherapy – as newer elements enter into our field," Dr. Flaherty commented. "This is a template that we can move forward with much more easily and effectively, and efforts of that nature are already ongoing in the stage IV setting."

A session attendee asked, "Would you care to speculate why there was no impact on survival? The disease-free survival impact is very reasonable ... [but] the [overall survival] curves never separated. Any thoughts?"

Dr. Flaherty proposed that it may be related to salvage therapies received after progression, which have improved since the trial. "Certainly, [with] these patients’ having progressed on biochemotherapy, the question would be, what other agents are available then to treat them at progression? I think that that would be less of an issue today with newer agents out, [such as] vemurafenib [and] ipilimumab. It might look differently today than it did with data in the 2000s," he said.

Another attendee questioned whether the short duration of biochemotherapy in the study compromised its efficacy. "Maybe one of the issues here is, by doing 2 months of treatment, you are not really fully exploiting the value of biochemotherapy," he said. "But I know that in community settings, it’s very hard to go beyond this, so it’s a tricky situation."

"We agree," Dr. Flaherty replied. "We had to look for a regimen that could be done throughout the United States with the potential of safety as well as efficacy. And that may be different than what can be done in specialty comprehensive cancer centers."

Discussant Dr. Lynn Schuchter of the Abramson Cancer Center at the University of Pennsylvania, Philadelphia, said, "It’s reasonable to consider biochemotherapy in the adjuvant setting in highly selected patients with melanoma. When I’ve used it, it’s been in young patients with multiple positive lymph nodes."

"I would say that the study results that we heard today do not change the standard of care for our patients with stage III melanoma," she agreed. "And importantly, I would say that further tweaking of the interferon dose, schedule, or route, or type of interferon is not going to move the field forward. ... It’s time that we really look at the new phase III adjuvant trials," such as those involving ipilimumab, vemurafenib, and dabrafenib, and vaccines.

Patients in the S0008 trial were randomized in balanced fashion to biochemotherapy (a 2-month course involving cisplatin, vinblastine, dacarbazine, IL-2, and interferon) or high-dose interferon (4-week induction followed by 48-week maintenance).

Results showed that patients in the biochemotherapy arm were significantly more likely to complete treatment (80% vs. 43%; P less than .001).

With a median 6.25-year follow-up, "the relapse-free survival is strikingly in favor of the biochemotherapy arm" over the high-dose interferon arm, Dr. Flaherty reported (median, 4.3 vs. 1.9 years; hazard ratio, 0.76; P = .03). The 5-year rate of relapse-free survival was 47% and 39%, respectively.

Findings were generally similar across subgroups, although "the more favorable groups appear to be younger individuals, females, those with one to three positive nodes, macroscopic nodes, and those without ulceration," he noted.

There was no significant difference between groups in overall survival. The median duration was 8.4 years with high-dose interferon and was not reached with biochemotherapy. The 5-year rate was 56% in both groups. And findings again were generally similar across patient subgroups.

The two treatments had differing grade 3/4 adverse event profiles: Biochemotherapy was associated with higher rates of gastrointestinal, hematologic, and metabolic toxicities, but lower rates of hepatic and neuropsychiatric toxicities.

Dr. Flaherty disclosed that he is a consultant to and receives honoraria and research funding from Merck and Novartis. Dr. Schuchter disclosed that she receives research funding from Genentech, GlaxoSmithKline, Merck, and Roche.

CHICAGO – Biochemotherapy is efficacious when used as adjuvant treatment for high-risk melanoma, but not enough to displace the current standard of care, suggests a randomized phase III trial of the Southwest Oncology Group.

The trial, known as S0008, pitted biochemotherapy (chemotherapy plus interleukin-2 and interferon) against high-dose interferon in 402 patients who had undergone wide local excision and lymphadenectomy for stage III melanoma that had features conferring a high risk of recurrence.

Biochemotherapy was associated with a 24% lower risk of relapse, compared with interferon, but there was no significant difference in overall survival, according to trial results reported at the annual meeting of the American Society of Clinical Oncology. Adverse event profiles differed somewhat.

"Biochemotherapy is the first and only therapy to demonstrate a significant improvement in relapse-free survival compared to high-dose interferon in stage III melanoma patients. Biochemotherapy, however, was not associated with an improvement in overall survival," said lead investigator Dr. Lawrence E. Flaherty of the Karmanos Cancer Institute in Detroit.

"Further follow-up will be done on the trial to provide additional insights on longer-term outcomes, but they are not expected to be statistically significant."

"Without an overall survival benefit, biochemotherapy does not replace interferon as the standard of care. However, this may be an attractive alternative to interferon for high-risk melanoma patients," he added, noting biochemotherapy’s advantages of a much shorter treatment duration (2 vs. 12 months) and higher rate of treatment completion.

"Probably more important for our research community is the ability to modify all of the elements that we see here – all of the chemotherapy and biotherapy – as newer elements enter into our field," Dr. Flaherty commented. "This is a template that we can move forward with much more easily and effectively, and efforts of that nature are already ongoing in the stage IV setting."

A session attendee asked, "Would you care to speculate why there was no impact on survival? The disease-free survival impact is very reasonable ... [but] the [overall survival] curves never separated. Any thoughts?"

Dr. Flaherty proposed that it may be related to salvage therapies received after progression, which have improved since the trial. "Certainly, [with] these patients’ having progressed on biochemotherapy, the question would be, what other agents are available then to treat them at progression? I think that that would be less of an issue today with newer agents out, [such as] vemurafenib [and] ipilimumab. It might look differently today than it did with data in the 2000s," he said.

Another attendee questioned whether the short duration of biochemotherapy in the study compromised its efficacy. "Maybe one of the issues here is, by doing 2 months of treatment, you are not really fully exploiting the value of biochemotherapy," he said. "But I know that in community settings, it’s very hard to go beyond this, so it’s a tricky situation."

"We agree," Dr. Flaherty replied. "We had to look for a regimen that could be done throughout the United States with the potential of safety as well as efficacy. And that may be different than what can be done in specialty comprehensive cancer centers."

Discussant Dr. Lynn Schuchter of the Abramson Cancer Center at the University of Pennsylvania, Philadelphia, said, "It’s reasonable to consider biochemotherapy in the adjuvant setting in highly selected patients with melanoma. When I’ve used it, it’s been in young patients with multiple positive lymph nodes."

"I would say that the study results that we heard today do not change the standard of care for our patients with stage III melanoma," she agreed. "And importantly, I would say that further tweaking of the interferon dose, schedule, or route, or type of interferon is not going to move the field forward. ... It’s time that we really look at the new phase III adjuvant trials," such as those involving ipilimumab, vemurafenib, and dabrafenib, and vaccines.

Patients in the S0008 trial were randomized in balanced fashion to biochemotherapy (a 2-month course involving cisplatin, vinblastine, dacarbazine, IL-2, and interferon) or high-dose interferon (4-week induction followed by 48-week maintenance).

Results showed that patients in the biochemotherapy arm were significantly more likely to complete treatment (80% vs. 43%; P less than .001).

With a median 6.25-year follow-up, "the relapse-free survival is strikingly in favor of the biochemotherapy arm" over the high-dose interferon arm, Dr. Flaherty reported (median, 4.3 vs. 1.9 years; hazard ratio, 0.76; P = .03). The 5-year rate of relapse-free survival was 47% and 39%, respectively.

Findings were generally similar across subgroups, although "the more favorable groups appear to be younger individuals, females, those with one to three positive nodes, macroscopic nodes, and those without ulceration," he noted.

There was no significant difference between groups in overall survival. The median duration was 8.4 years with high-dose interferon and was not reached with biochemotherapy. The 5-year rate was 56% in both groups. And findings again were generally similar across patient subgroups.

The two treatments had differing grade 3/4 adverse event profiles: Biochemotherapy was associated with higher rates of gastrointestinal, hematologic, and metabolic toxicities, but lower rates of hepatic and neuropsychiatric toxicities.

Dr. Flaherty disclosed that he is a consultant to and receives honoraria and research funding from Merck and Novartis. Dr. Schuchter disclosed that she receives research funding from Genentech, GlaxoSmithKline, Merck, and Roche.

CHICAGO – Biochemotherapy is efficacious when used as adjuvant treatment for high-risk melanoma, but not enough to displace the current standard of care, suggests a randomized phase III trial of the Southwest Oncology Group.

The trial, known as S0008, pitted biochemotherapy (chemotherapy plus interleukin-2 and interferon) against high-dose interferon in 402 patients who had undergone wide local excision and lymphadenectomy for stage III melanoma that had features conferring a high risk of recurrence.

Biochemotherapy was associated with a 24% lower risk of relapse, compared with interferon, but there was no significant difference in overall survival, according to trial results reported at the annual meeting of the American Society of Clinical Oncology. Adverse event profiles differed somewhat.

"Biochemotherapy is the first and only therapy to demonstrate a significant improvement in relapse-free survival compared to high-dose interferon in stage III melanoma patients. Biochemotherapy, however, was not associated with an improvement in overall survival," said lead investigator Dr. Lawrence E. Flaherty of the Karmanos Cancer Institute in Detroit.

"Further follow-up will be done on the trial to provide additional insights on longer-term outcomes, but they are not expected to be statistically significant."

"Without an overall survival benefit, biochemotherapy does not replace interferon as the standard of care. However, this may be an attractive alternative to interferon for high-risk melanoma patients," he added, noting biochemotherapy’s advantages of a much shorter treatment duration (2 vs. 12 months) and higher rate of treatment completion.

"Probably more important for our research community is the ability to modify all of the elements that we see here – all of the chemotherapy and biotherapy – as newer elements enter into our field," Dr. Flaherty commented. "This is a template that we can move forward with much more easily and effectively, and efforts of that nature are already ongoing in the stage IV setting."

A session attendee asked, "Would you care to speculate why there was no impact on survival? The disease-free survival impact is very reasonable ... [but] the [overall survival] curves never separated. Any thoughts?"

Dr. Flaherty proposed that it may be related to salvage therapies received after progression, which have improved since the trial. "Certainly, [with] these patients’ having progressed on biochemotherapy, the question would be, what other agents are available then to treat them at progression? I think that that would be less of an issue today with newer agents out, [such as] vemurafenib [and] ipilimumab. It might look differently today than it did with data in the 2000s," he said.

Another attendee questioned whether the short duration of biochemotherapy in the study compromised its efficacy. "Maybe one of the issues here is, by doing 2 months of treatment, you are not really fully exploiting the value of biochemotherapy," he said. "But I know that in community settings, it’s very hard to go beyond this, so it’s a tricky situation."

"We agree," Dr. Flaherty replied. "We had to look for a regimen that could be done throughout the United States with the potential of safety as well as efficacy. And that may be different than what can be done in specialty comprehensive cancer centers."

Discussant Dr. Lynn Schuchter of the Abramson Cancer Center at the University of Pennsylvania, Philadelphia, said, "It’s reasonable to consider biochemotherapy in the adjuvant setting in highly selected patients with melanoma. When I’ve used it, it’s been in young patients with multiple positive lymph nodes."

"I would say that the study results that we heard today do not change the standard of care for our patients with stage III melanoma," she agreed. "And importantly, I would say that further tweaking of the interferon dose, schedule, or route, or type of interferon is not going to move the field forward. ... It’s time that we really look at the new phase III adjuvant trials," such as those involving ipilimumab, vemurafenib, and dabrafenib, and vaccines.

Patients in the S0008 trial were randomized in balanced fashion to biochemotherapy (a 2-month course involving cisplatin, vinblastine, dacarbazine, IL-2, and interferon) or high-dose interferon (4-week induction followed by 48-week maintenance).

Results showed that patients in the biochemotherapy arm were significantly more likely to complete treatment (80% vs. 43%; P less than .001).

With a median 6.25-year follow-up, "the relapse-free survival is strikingly in favor of the biochemotherapy arm" over the high-dose interferon arm, Dr. Flaherty reported (median, 4.3 vs. 1.9 years; hazard ratio, 0.76; P = .03). The 5-year rate of relapse-free survival was 47% and 39%, respectively.

Findings were generally similar across subgroups, although "the more favorable groups appear to be younger individuals, females, those with one to three positive nodes, macroscopic nodes, and those without ulceration," he noted.

There was no significant difference between groups in overall survival. The median duration was 8.4 years with high-dose interferon and was not reached with biochemotherapy. The 5-year rate was 56% in both groups. And findings again were generally similar across patient subgroups.

The two treatments had differing grade 3/4 adverse event profiles: Biochemotherapy was associated with higher rates of gastrointestinal, hematologic, and metabolic toxicities, but lower rates of hepatic and neuropsychiatric toxicities.

Dr. Flaherty disclosed that he is a consultant to and receives honoraria and research funding from Merck and Novartis. Dr. Schuchter disclosed that she receives research funding from Genentech, GlaxoSmithKline, Merck, and Roche.