Longer Imatinib Therapy Improves Outcomes For High-Risk GIST

CHICAGO – In findings that are likely to change clinical practice, a randomized phase III trial has shown that extending the duration of adjuvant imatinib therapy markedly improves outcomes in patients with resected gastrointestinal stromal tumor who are at high risk for recurrence.

Compared with their counterparts given imatinib (Gleevec) for just 1 year after surgery, patients given the drug for 3 years were 54% less likely to have had a recurrence and 55% less likely to have died at the 5-year mark.

In addition, extended treatment with the drug, an oral agent that inhibits multiple tyrosine kinases, was generally well tolerated.

Lead author Dr. Heikki Joensuu presented the trial’s findings in a press briefing and later in a plenary session at the annual meeting of the American Society of Clinical Oncology.

"These data are pretty compelling," commented Dr. Joensuu, professor of oncology at Helsinki University Central Hospital. "I would not be surprised if the standard will be 3 years of adjuvant imatinib in the near future."

At present, there are no data from randomized trials to suggest that taking this therapy out further will yield even greater benefit, Dr. Joensuu said. Instead, he predicted, the strategy going forward will be to stop imatinib at 3 years but closely follow up patients to catch any recurrences early.

"There is evidence that when we restart imatinib, the patients will respond to imatinib again," he explained. "And those patients who have a small tumor volume will have a good chance of responding to imatinib rechallenge for many years, even after 10 years."

Dr. Mark G. Kris, moderator of the press briefing, commented, "I think the entire oncology community was extremely excited when we saw that survival curve and those numbers at 5 years, and I think that’s one of the reasons that this paper was chosen for the plenary session. It’s one of the amazing stories in oncology that ... patients who had a 50% death likelihood at 5 years, by taking four pills [of imatinib] a day, are alive at 5 years, and the vast majority alive are cancer free."

The data will likely be taken into consideration by professional oncology organizations as they update their practice guidelines, according to Dr. Kris, chief of the thoracic oncology service and the William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan-Kettering Cancer Center in New York. "This is the kind of data that does change guidelines, absolutely, and I believe that’s what we are going to see," he said.

Participants in the trial, formally known as the SSGXVIII/AIO trial, were 400 patients in Finland, Germany, Norway, and Sweden who underwent resection of stem cell growth factor (KIT)-positive gastrointestinal stromal tumor (GIST), and were at high risk for recurrence according to modified Consensus Criteria.

In the pre-imatinib era, such patients had at least 50% risks of recurrence and death in the first 5 years after resection, according to Dr. Joensuu.

The patients were assigned in equal numbers to treatment with imatinib 400 mg/day for either 1 year (shown to improve recurrence-free survival in a previous trial) or 3 years on an open-label basis. The drug targets the KIT and platelet-derived growth factor receptor (PDGFR)-alpha tyrosine kinases, the genes for which are mutated in most GISTs, as well as the BCR-ABL tyrosine kinase.

Safety results showed that "the treatment was generally well tolerated," Dr. Joensuu reported. The most common adverse events were anemia, periorbital edema, fatigue, nausea, and muscle cramps, all of which were generally mild.

Relative to their counterparts in the 1-year group, patients in the 3-year group were more likely to experience grade 3/4 adverse events (33% vs. 20%) and to stop treatment because of adverse events (14% vs. 8%), however.

Intention-to-treat efficacy results showed that after a 54-month median follow-up, the 5-year rate of recurrence-free survival was significantly better with 3 years of imatinib than with 1 year (65.6% vs. 47.9%; hazard ratio, 0.46; P less than .0001). "Resistance was not a big problem in the current study," Dr. Joensuu noted.

In addition, although the 5-year rate of overall survival was high in both groups, it was likewise superior with 3 years of imatinib (92.0% vs. 81.7%; HR, 0.45; P = .019). The majority of deaths were due to GIST.

There may be other pharmacotherapy options for patients at high risk for GIST recurrence, he acknowledged. "We need to have the next generation of trials, and we also may need to address sequential treatment and combinations. And we need to learn more about the biology of the disease."

Abstract discussant Dr. Charles D. Blanke, chief of medical oncology at the University of British Columbia, Vancouver, said, "If you have a patient who has a high-risk GIST – at least as defined by the study – giving him or her 3 years of imatinib represents the new gold standard. For now, the overall survival benefit demonstrated with immediate postoperative imatinib means it is no longer acceptable to withhold treatment in the adjuvant setting hoping to ‘catch up’ when a patient has recurrent metastatic disease."

That said, the optimal duration of therapy remains unknown. "There are plenty of reasons to think giving imatinib for a longer period would be better, but that theory remains unproven," he said. "For now, if I were a patient with resected GIST and I had a compliant oncologist, I would request more. As a compliant oncologist, I personally will offer patients treatment to eternity, meaning indefinitely."

However, Dr. Blanke added, "I reserve the right to change my mind pending the longer-term overall survival results of SSGXVIII and the findings in PERSIST-5," a trial assessing 5 years of adjuvant imatinib. "But I don’t think GISTs are curable, even in the adjuvant setting, and I bet I won’t [change my mind]."

Oncologists must also decide for themselves which patients to treat, as the high-risk category used in the SSGXVIII trial included patients with possible recurrence risks ranging from 34% up to nearly 100%.

"But given the possibility that we need to treat for a very long time, coupled with the difficulty patients have taking long-duration drugs, I probably will recommend therapy for those with a 50% chance or greater of recurrence following surgery alone," he said. "I suspect many of you will choose a lower number."

Dr. Joensuu reported being a consultant to and receiving honoraria from Novartis. Novartis provided the drug and partly funded the trial. Dr. Kris reported being a consultant to GlaxoSmithKline, Merck, and Sanofi-Aventis. Dr. Blanke reported being a consultant to Novartis.

CHICAGO – In findings that are likely to change clinical practice, a randomized phase III trial has shown that extending the duration of adjuvant imatinib therapy markedly improves outcomes in patients with resected gastrointestinal stromal tumor who are at high risk for recurrence.

Compared with their counterparts given imatinib (Gleevec) for just 1 year after surgery, patients given the drug for 3 years were 54% less likely to have had a recurrence and 55% less likely to have died at the 5-year mark.

In addition, extended treatment with the drug, an oral agent that inhibits multiple tyrosine kinases, was generally well tolerated.

Lead author Dr. Heikki Joensuu presented the trial’s findings in a press briefing and later in a plenary session at the annual meeting of the American Society of Clinical Oncology.

"These data are pretty compelling," commented Dr. Joensuu, professor of oncology at Helsinki University Central Hospital. "I would not be surprised if the standard will be 3 years of adjuvant imatinib in the near future."

At present, there are no data from randomized trials to suggest that taking this therapy out further will yield even greater benefit, Dr. Joensuu said. Instead, he predicted, the strategy going forward will be to stop imatinib at 3 years but closely follow up patients to catch any recurrences early.

"There is evidence that when we restart imatinib, the patients will respond to imatinib again," he explained. "And those patients who have a small tumor volume will have a good chance of responding to imatinib rechallenge for many years, even after 10 years."

Dr. Mark G. Kris, moderator of the press briefing, commented, "I think the entire oncology community was extremely excited when we saw that survival curve and those numbers at 5 years, and I think that’s one of the reasons that this paper was chosen for the plenary session. It’s one of the amazing stories in oncology that ... patients who had a 50% death likelihood at 5 years, by taking four pills [of imatinib] a day, are alive at 5 years, and the vast majority alive are cancer free."

The data will likely be taken into consideration by professional oncology organizations as they update their practice guidelines, according to Dr. Kris, chief of the thoracic oncology service and the William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan-Kettering Cancer Center in New York. "This is the kind of data that does change guidelines, absolutely, and I believe that’s what we are going to see," he said.

Participants in the trial, formally known as the SSGXVIII/AIO trial, were 400 patients in Finland, Germany, Norway, and Sweden who underwent resection of stem cell growth factor (KIT)-positive gastrointestinal stromal tumor (GIST), and were at high risk for recurrence according to modified Consensus Criteria.

In the pre-imatinib era, such patients had at least 50% risks of recurrence and death in the first 5 years after resection, according to Dr. Joensuu.

The patients were assigned in equal numbers to treatment with imatinib 400 mg/day for either 1 year (shown to improve recurrence-free survival in a previous trial) or 3 years on an open-label basis. The drug targets the KIT and platelet-derived growth factor receptor (PDGFR)-alpha tyrosine kinases, the genes for which are mutated in most GISTs, as well as the BCR-ABL tyrosine kinase.

Safety results showed that "the treatment was generally well tolerated," Dr. Joensuu reported. The most common adverse events were anemia, periorbital edema, fatigue, nausea, and muscle cramps, all of which were generally mild.

Relative to their counterparts in the 1-year group, patients in the 3-year group were more likely to experience grade 3/4 adverse events (33% vs. 20%) and to stop treatment because of adverse events (14% vs. 8%), however.

Intention-to-treat efficacy results showed that after a 54-month median follow-up, the 5-year rate of recurrence-free survival was significantly better with 3 years of imatinib than with 1 year (65.6% vs. 47.9%; hazard ratio, 0.46; P less than .0001). "Resistance was not a big problem in the current study," Dr. Joensuu noted.

In addition, although the 5-year rate of overall survival was high in both groups, it was likewise superior with 3 years of imatinib (92.0% vs. 81.7%; HR, 0.45; P = .019). The majority of deaths were due to GIST.

There may be other pharmacotherapy options for patients at high risk for GIST recurrence, he acknowledged. "We need to have the next generation of trials, and we also may need to address sequential treatment and combinations. And we need to learn more about the biology of the disease."

Abstract discussant Dr. Charles D. Blanke, chief of medical oncology at the University of British Columbia, Vancouver, said, "If you have a patient who has a high-risk GIST – at least as defined by the study – giving him or her 3 years of imatinib represents the new gold standard. For now, the overall survival benefit demonstrated with immediate postoperative imatinib means it is no longer acceptable to withhold treatment in the adjuvant setting hoping to ‘catch up’ when a patient has recurrent metastatic disease."

That said, the optimal duration of therapy remains unknown. "There are plenty of reasons to think giving imatinib for a longer period would be better, but that theory remains unproven," he said. "For now, if I were a patient with resected GIST and I had a compliant oncologist, I would request more. As a compliant oncologist, I personally will offer patients treatment to eternity, meaning indefinitely."

However, Dr. Blanke added, "I reserve the right to change my mind pending the longer-term overall survival results of SSGXVIII and the findings in PERSIST-5," a trial assessing 5 years of adjuvant imatinib. "But I don’t think GISTs are curable, even in the adjuvant setting, and I bet I won’t [change my mind]."

Oncologists must also decide for themselves which patients to treat, as the high-risk category used in the SSGXVIII trial included patients with possible recurrence risks ranging from 34% up to nearly 100%.

"But given the possibility that we need to treat for a very long time, coupled with the difficulty patients have taking long-duration drugs, I probably will recommend therapy for those with a 50% chance or greater of recurrence following surgery alone," he said. "I suspect many of you will choose a lower number."

Dr. Joensuu reported being a consultant to and receiving honoraria from Novartis. Novartis provided the drug and partly funded the trial. Dr. Kris reported being a consultant to GlaxoSmithKline, Merck, and Sanofi-Aventis. Dr. Blanke reported being a consultant to Novartis.

CHICAGO – In findings that are likely to change clinical practice, a randomized phase III trial has shown that extending the duration of adjuvant imatinib therapy markedly improves outcomes in patients with resected gastrointestinal stromal tumor who are at high risk for recurrence.

Compared with their counterparts given imatinib (Gleevec) for just 1 year after surgery, patients given the drug for 3 years were 54% less likely to have had a recurrence and 55% less likely to have died at the 5-year mark.

In addition, extended treatment with the drug, an oral agent that inhibits multiple tyrosine kinases, was generally well tolerated.

Lead author Dr. Heikki Joensuu presented the trial’s findings in a press briefing and later in a plenary session at the annual meeting of the American Society of Clinical Oncology.

"These data are pretty compelling," commented Dr. Joensuu, professor of oncology at Helsinki University Central Hospital. "I would not be surprised if the standard will be 3 years of adjuvant imatinib in the near future."

At present, there are no data from randomized trials to suggest that taking this therapy out further will yield even greater benefit, Dr. Joensuu said. Instead, he predicted, the strategy going forward will be to stop imatinib at 3 years but closely follow up patients to catch any recurrences early.

"There is evidence that when we restart imatinib, the patients will respond to imatinib again," he explained. "And those patients who have a small tumor volume will have a good chance of responding to imatinib rechallenge for many years, even after 10 years."

Dr. Mark G. Kris, moderator of the press briefing, commented, "I think the entire oncology community was extremely excited when we saw that survival curve and those numbers at 5 years, and I think that’s one of the reasons that this paper was chosen for the plenary session. It’s one of the amazing stories in oncology that ... patients who had a 50% death likelihood at 5 years, by taking four pills [of imatinib] a day, are alive at 5 years, and the vast majority alive are cancer free."

The data will likely be taken into consideration by professional oncology organizations as they update their practice guidelines, according to Dr. Kris, chief of the thoracic oncology service and the William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan-Kettering Cancer Center in New York. "This is the kind of data that does change guidelines, absolutely, and I believe that’s what we are going to see," he said.

Participants in the trial, formally known as the SSGXVIII/AIO trial, were 400 patients in Finland, Germany, Norway, and Sweden who underwent resection of stem cell growth factor (KIT)-positive gastrointestinal stromal tumor (GIST), and were at high risk for recurrence according to modified Consensus Criteria.

In the pre-imatinib era, such patients had at least 50% risks of recurrence and death in the first 5 years after resection, according to Dr. Joensuu.

The patients were assigned in equal numbers to treatment with imatinib 400 mg/day for either 1 year (shown to improve recurrence-free survival in a previous trial) or 3 years on an open-label basis. The drug targets the KIT and platelet-derived growth factor receptor (PDGFR)-alpha tyrosine kinases, the genes for which are mutated in most GISTs, as well as the BCR-ABL tyrosine kinase.

Safety results showed that "the treatment was generally well tolerated," Dr. Joensuu reported. The most common adverse events were anemia, periorbital edema, fatigue, nausea, and muscle cramps, all of which were generally mild.

Relative to their counterparts in the 1-year group, patients in the 3-year group were more likely to experience grade 3/4 adverse events (33% vs. 20%) and to stop treatment because of adverse events (14% vs. 8%), however.

Intention-to-treat efficacy results showed that after a 54-month median follow-up, the 5-year rate of recurrence-free survival was significantly better with 3 years of imatinib than with 1 year (65.6% vs. 47.9%; hazard ratio, 0.46; P less than .0001). "Resistance was not a big problem in the current study," Dr. Joensuu noted.

In addition, although the 5-year rate of overall survival was high in both groups, it was likewise superior with 3 years of imatinib (92.0% vs. 81.7%; HR, 0.45; P = .019). The majority of deaths were due to GIST.

There may be other pharmacotherapy options for patients at high risk for GIST recurrence, he acknowledged. "We need to have the next generation of trials, and we also may need to address sequential treatment and combinations. And we need to learn more about the biology of the disease."

Abstract discussant Dr. Charles D. Blanke, chief of medical oncology at the University of British Columbia, Vancouver, said, "If you have a patient who has a high-risk GIST – at least as defined by the study – giving him or her 3 years of imatinib represents the new gold standard. For now, the overall survival benefit demonstrated with immediate postoperative imatinib means it is no longer acceptable to withhold treatment in the adjuvant setting hoping to ‘catch up’ when a patient has recurrent metastatic disease."

That said, the optimal duration of therapy remains unknown. "There are plenty of reasons to think giving imatinib for a longer period would be better, but that theory remains unproven," he said. "For now, if I were a patient with resected GIST and I had a compliant oncologist, I would request more. As a compliant oncologist, I personally will offer patients treatment to eternity, meaning indefinitely."

However, Dr. Blanke added, "I reserve the right to change my mind pending the longer-term overall survival results of SSGXVIII and the findings in PERSIST-5," a trial assessing 5 years of adjuvant imatinib. "But I don’t think GISTs are curable, even in the adjuvant setting, and I bet I won’t [change my mind]."

Oncologists must also decide for themselves which patients to treat, as the high-risk category used in the SSGXVIII trial included patients with possible recurrence risks ranging from 34% up to nearly 100%.

"But given the possibility that we need to treat for a very long time, coupled with the difficulty patients have taking long-duration drugs, I probably will recommend therapy for those with a 50% chance or greater of recurrence following surgery alone," he said. "I suspect many of you will choose a lower number."

Dr. Joensuu reported being a consultant to and receiving honoraria from Novartis. Novartis provided the drug and partly funded the trial. Dr. Kris reported being a consultant to GlaxoSmithKline, Merck, and Sanofi-Aventis. Dr. Blanke reported being a consultant to Novartis.