2013 ASCO Annual Meeting

CHICAGO – Patients with advanced ovarian cancer may now have a less toxic but acceptably efficacious option when it comes to first-line chemotherapy, based on the final results of the Multicenter Italian Trials in Ovarian Cancer collaborative group’s trial 7 (MITO-7).

A total of 822 women were randomized to receive either the standard every-3-week regimen of chemotherapy – carboplatin with area under the curve (AUC 6) plus paclitaxel 175 mg/m² on day 1 every 21 days for six cycles – or to get a weekly regimen – carboplatin AUC 2 plus paclitaxel 60 mg/m² weekly for 18 administrations.

Trial results, reported at the annual meeting of the American Society of Clinical Oncology, showed that the weekly group did not have better progression-free or overall survival than did the group treated once every 3 weeks. But the weekly group did have lower rates of toxicities such as alopecia, neuropathy, and febrile neutropenia, as well as a better quality of life.

"Given the observed confidence intervals of progression-free survival, MITO-7 quality of life and toxicity data further support the use of a weekly schedule as first-line therapy for advanced ovarian cancer," commented lead investigator Dr. Sandro Pignata, a urogynecologist with Italy’s National Cancer Institute in Naples.

The patients studied by Dr. Pignata’s team had FIGO stage IC to IV ovarian, fallopian tube, or primary peritoneal cancer and had not previously received chemotherapy. Most were treated on the Italian MITO-7 trial, although some were treated on the Italian MANGO trial or the French ARCAGY GINECO trial.

The proportion receiving all planned cycles of chemotherapy was 85% in the weekly group and 91% in the 3-weekly group, he reported.

With a median follow-up of 19.9 months, the rate of progression-free survival was 18.8 months and 16.5 months, respectively, a nonsignificant difference. The findings were the same in subgroup analyses. There was also no significant difference in overall survival.

Quality of life measured with the FACT-O TOI (Functional Assessment of Cancer Therapy, for ovarian cancer, Trial Outcome Index) during the first 9 weeks of therapy (the trial’s other primary endpoint) was significantly better in the weekly treatment group.

With the weekly regimen, scores worsened slightly 1 week after the first administration but remained stable thereafter, according to Dr. Pignata. In contrast, with the 3-weekly regimen, scores worsened 1 week after each course of chemotherapy.

In terms of adverse events, the weekly group had significantly lower rates of grade 3 or worse neutropenia (39% vs. 50%), febrile neutropenia (less than 1% vs. 3%), thrombocytopenia (1% vs. 7%), and renal toxicity (0% vs. 2%); grade 2 alopecia (28% vs. 58%); and grade 2 or higher neuropathy (6% vs. 16%).

"The rate of severe allergic reaction or any-grade allergic reaction was not statistically significantly different," he pointed out. Also, "I want to underline that a significant proportion of patients treated with this weekly regimen...completed 18 weeks of therapy without losing their hair."

Dr. Pignata disclosed no relevant conflicts of interest.

CHICAGO – Patients with advanced ovarian cancer may now have a less toxic but acceptably efficacious option when it comes to first-line chemotherapy, based on the final results of the Multicenter Italian Trials in Ovarian Cancer collaborative group’s trial 7 (MITO-7).

A total of 822 women were randomized to receive either the standard every-3-week regimen of chemotherapy – carboplatin with area under the curve (AUC 6) plus paclitaxel 175 mg/m² on day 1 every 21 days for six cycles – or to get a weekly regimen – carboplatin AUC 2 plus paclitaxel 60 mg/m² weekly for 18 administrations.

Trial results, reported at the annual meeting of the American Society of Clinical Oncology, showed that the weekly group did not have better progression-free or overall survival than did the group treated once every 3 weeks. But the weekly group did have lower rates of toxicities such as alopecia, neuropathy, and febrile neutropenia, as well as a better quality of life.

"Given the observed confidence intervals of progression-free survival, MITO-7 quality of life and toxicity data further support the use of a weekly schedule as first-line therapy for advanced ovarian cancer," commented lead investigator Dr. Sandro Pignata, a urogynecologist with Italy’s National Cancer Institute in Naples.

The patients studied by Dr. Pignata’s team had FIGO stage IC to IV ovarian, fallopian tube, or primary peritoneal cancer and had not previously received chemotherapy. Most were treated on the Italian MITO-7 trial, although some were treated on the Italian MANGO trial or the French ARCAGY GINECO trial.

The proportion receiving all planned cycles of chemotherapy was 85% in the weekly group and 91% in the 3-weekly group, he reported.

With a median follow-up of 19.9 months, the rate of progression-free survival was 18.8 months and 16.5 months, respectively, a nonsignificant difference. The findings were the same in subgroup analyses. There was also no significant difference in overall survival.

Quality of life measured with the FACT-O TOI (Functional Assessment of Cancer Therapy, for ovarian cancer, Trial Outcome Index) during the first 9 weeks of therapy (the trial’s other primary endpoint) was significantly better in the weekly treatment group.

With the weekly regimen, scores worsened slightly 1 week after the first administration but remained stable thereafter, according to Dr. Pignata. In contrast, with the 3-weekly regimen, scores worsened 1 week after each course of chemotherapy.

In terms of adverse events, the weekly group had significantly lower rates of grade 3 or worse neutropenia (39% vs. 50%), febrile neutropenia (less than 1% vs. 3%), thrombocytopenia (1% vs. 7%), and renal toxicity (0% vs. 2%); grade 2 alopecia (28% vs. 58%); and grade 2 or higher neuropathy (6% vs. 16%).

"The rate of severe allergic reaction or any-grade allergic reaction was not statistically significantly different," he pointed out. Also, "I want to underline that a significant proportion of patients treated with this weekly regimen...completed 18 weeks of therapy without losing their hair."

Dr. Pignata disclosed no relevant conflicts of interest.

CHICAGO – Patients with advanced ovarian cancer may now have a less toxic but acceptably efficacious option when it comes to first-line chemotherapy, based on the final results of the Multicenter Italian Trials in Ovarian Cancer collaborative group’s trial 7 (MITO-7).

A total of 822 women were randomized to receive either the standard every-3-week regimen of chemotherapy – carboplatin with area under the curve (AUC 6) plus paclitaxel 175 mg/m² on day 1 every 21 days for six cycles – or to get a weekly regimen – carboplatin AUC 2 plus paclitaxel 60 mg/m² weekly for 18 administrations.

Trial results, reported at the annual meeting of the American Society of Clinical Oncology, showed that the weekly group did not have better progression-free or overall survival than did the group treated once every 3 weeks. But the weekly group did have lower rates of toxicities such as alopecia, neuropathy, and febrile neutropenia, as well as a better quality of life.

"Given the observed confidence intervals of progression-free survival, MITO-7 quality of life and toxicity data further support the use of a weekly schedule as first-line therapy for advanced ovarian cancer," commented lead investigator Dr. Sandro Pignata, a urogynecologist with Italy’s National Cancer Institute in Naples.

The patients studied by Dr. Pignata’s team had FIGO stage IC to IV ovarian, fallopian tube, or primary peritoneal cancer and had not previously received chemotherapy. Most were treated on the Italian MITO-7 trial, although some were treated on the Italian MANGO trial or the French ARCAGY GINECO trial.

The proportion receiving all planned cycles of chemotherapy was 85% in the weekly group and 91% in the 3-weekly group, he reported.

With a median follow-up of 19.9 months, the rate of progression-free survival was 18.8 months and 16.5 months, respectively, a nonsignificant difference. The findings were the same in subgroup analyses. There was also no significant difference in overall survival.

Quality of life measured with the FACT-O TOI (Functional Assessment of Cancer Therapy, for ovarian cancer, Trial Outcome Index) during the first 9 weeks of therapy (the trial’s other primary endpoint) was significantly better in the weekly treatment group.

With the weekly regimen, scores worsened slightly 1 week after the first administration but remained stable thereafter, according to Dr. Pignata. In contrast, with the 3-weekly regimen, scores worsened 1 week after each course of chemotherapy.

In terms of adverse events, the weekly group had significantly lower rates of grade 3 or worse neutropenia (39% vs. 50%), febrile neutropenia (less than 1% vs. 3%), thrombocytopenia (1% vs. 7%), and renal toxicity (0% vs. 2%); grade 2 alopecia (28% vs. 58%); and grade 2 or higher neuropathy (6% vs. 16%).

"The rate of severe allergic reaction or any-grade allergic reaction was not statistically significantly different," he pointed out. Also, "I want to underline that a significant proportion of patients treated with this weekly regimen...completed 18 weeks of therapy without losing their hair."

Dr. Pignata disclosed no relevant conflicts of interest.

CHICAGO – Long-term intensive blood and computed tomography follow-up offered no significant advantage over minimal follow-up for detecting colorectal cancer recurrences in the phase III FACS trial.

The proportion of patients with recurrence treated surgically with curative intent was 6.7% with intensive carcinoembryonic antigen (CEA) testing, 8% with monthly computed tomography imaging and 6.6% with combination CEA plus CT, compared with 2.3% with minimal follow-up involving a single CT scan.

After adjustment, it was about three times more likely that patients would have a recurrence with CEA (adjusted odds ratio, 2.70; P = .035), monthly CT imaging (OR, 3.45; P = .007) and CEA plus CT (OR, 2.95; P = .021) than with minimal follow-up.

"This result appeared to be quite robust" and was independent of cancer stage, co-primary investigator Dr. David Mant said at the annual meeting of the American Society of Clinical Oncology.

There was virtually no deviation in protocol by patients, however, the desire for unscheduled CT scans by surgeons meant that up to 30% in the minimal follow-up arm had 1 or more additional CTs, he noted. Still, in a per protocol analysis, the absolute differences in recurrence were 3.8- to 5.4-times higher with intensive follow-up. Again, there was no evidence of an additive effect of CEA plus CT.

Guidelines in the United States and Europe stress intensive follow-up including routine history and physical examination, CEA monitoring, yearly colonoscopy and repeated CT scans in those at high risk of recurrence.

The FACS (Follow-Up After Colorectal Surgery) trial looked at whether long-term intensive follow-up was worthwhile. Though commonplace after curative surgery, economic modeling suggests intensive followup may not be cost-effective and claims of a substantial overall survival benefit are inconsistent with the reported frequency and effectiveness of treatment for recurrence, explained Dr. David Mant, emeritus professor of general practice, Oxford University.

"As a long-term family physician, I’d seen many patients being followed-up for cancer and watched their cycle of deep anxiety, followed usually by relief, but sometimes with misery, as they waited for their follow-up appointments," he added. "It seemed to me that it was a very bad idea to carry on with this practice, unless it was to their benefit."

FACS involved 1,202 patients who were disease free on colonoscopy and CT imaging and had a blood CEA level of 10 mcg/L or less (Dukes’ stages A-C) after treatment for primary colorectal cancer. Their median age was 70 years.

Patients were randomly assigned to one of four follow-up regimens: "minimal" follow-up based mainly on symptoms and a single CT scan at 12-18 months; "CEA," which included minimal follow-up, plus 3 monthly blood CEA tests for 2 years then 6 monthly tests in years 3-5; "CT," which included minimal follow-up plus intensive CT imaging involving 6 monthly scans of the chest, abdomen, and pelvis for 2 years, and then annually for another 3 years; and "CEA plus CT," which included the CEA regimen in group 2 and the CT measures in group 3.

If during monitoring, a patient’s CEA level was 7 mcg/L or more above their baseline level at trial entry, the test was repeated as soon as possible. If the second test was also above the threshold, the patient’s physician was asked to refer the patient urgently to the local hospital.

Overall, 6% of patients (71/1,202) developed a recurrence treated surgically with curative intent. There was little difference between patients according to Duke’s staging (stage A, 5.1%; stage B, 6.1%; stage C, 6.2%), reported Dr. Mant and coprincipal investigator Dr. John Primrose of University of Southhampton, U.K.

"You actually do need rigorous initial staging to detect residual disease before you embark on any follow-up," Dr. Mant stressed. "I think both John and I are convinced that the reason why we have a 6% overall recurrence rate is because the people in this trial were appropriately staged. The survival curves don’t suggest they were any less sick than patients in other trials."

At the time of the analysis, 59% of patients with a recurrence treated with curative intent were still alive, but there was no statistical difference in colorectal cancer deaths (P = .66) or total deaths (P = .45) between the minimum and intensive follow-up arms, he said.

In a meta-analysis that integrated the FACS data with that from three previous trials, the overall effect of intensive follow-up was not significant (OR, 0.96; P = .56), Dr. Mant said. The number needed to treat to detect potentially curable recurrence with intensive follow-up is about 20 to 25 and that predicts a number-needed-to-treat of about 40 to 50 for 5-year post-recurrence survival.

Dr. Maughan said the disparity between the current meta-analysis and the Cochrane review may be because the latter included six studies, not three, and that the survival data from FACS may not be fully mature. A further analysis of the FACS data is planned in about 18 months.

Dr. Mant and his coauthors reported having no financial disclosures.

Mant, D., et al. "Effect of 3-5 years of scheduled CED and CT follow-up to detect recurrence of colorectal cancer: FACS randomized controlled trial." Ab. 3500.

[email protected]

CHICAGO – Long-term intensive blood and computed tomography follow-up offered no significant advantage over minimal follow-up for detecting colorectal cancer recurrences in the phase III FACS trial.

The proportion of patients with recurrence treated surgically with curative intent was 6.7% with intensive carcinoembryonic antigen (CEA) testing, 8% with monthly computed tomography imaging and 6.6% with combination CEA plus CT, compared with 2.3% with minimal follow-up involving a single CT scan.

After adjustment, it was about three times more likely that patients would have a recurrence with CEA (adjusted odds ratio, 2.70; P = .035), monthly CT imaging (OR, 3.45; P = .007) and CEA plus CT (OR, 2.95; P = .021) than with minimal follow-up.

"This result appeared to be quite robust" and was independent of cancer stage, co-primary investigator Dr. David Mant said at the annual meeting of the American Society of Clinical Oncology.

There was virtually no deviation in protocol by patients, however, the desire for unscheduled CT scans by surgeons meant that up to 30% in the minimal follow-up arm had 1 or more additional CTs, he noted. Still, in a per protocol analysis, the absolute differences in recurrence were 3.8- to 5.4-times higher with intensive follow-up. Again, there was no evidence of an additive effect of CEA plus CT.

Guidelines in the United States and Europe stress intensive follow-up including routine history and physical examination, CEA monitoring, yearly colonoscopy and repeated CT scans in those at high risk of recurrence.

The FACS (Follow-Up After Colorectal Surgery) trial looked at whether long-term intensive follow-up was worthwhile. Though commonplace after curative surgery, economic modeling suggests intensive followup may not be cost-effective and claims of a substantial overall survival benefit are inconsistent with the reported frequency and effectiveness of treatment for recurrence, explained Dr. David Mant, emeritus professor of general practice, Oxford University.

"As a long-term family physician, I’d seen many patients being followed-up for cancer and watched their cycle of deep anxiety, followed usually by relief, but sometimes with misery, as they waited for their follow-up appointments," he added. "It seemed to me that it was a very bad idea to carry on with this practice, unless it was to their benefit."

FACS involved 1,202 patients who were disease free on colonoscopy and CT imaging and had a blood CEA level of 10 mcg/L or less (Dukes’ stages A-C) after treatment for primary colorectal cancer. Their median age was 70 years.

Patients were randomly assigned to one of four follow-up regimens: "minimal" follow-up based mainly on symptoms and a single CT scan at 12-18 months; "CEA," which included minimal follow-up, plus 3 monthly blood CEA tests for 2 years then 6 monthly tests in years 3-5; "CT," which included minimal follow-up plus intensive CT imaging involving 6 monthly scans of the chest, abdomen, and pelvis for 2 years, and then annually for another 3 years; and "CEA plus CT," which included the CEA regimen in group 2 and the CT measures in group 3.

If during monitoring, a patient’s CEA level was 7 mcg/L or more above their baseline level at trial entry, the test was repeated as soon as possible. If the second test was also above the threshold, the patient’s physician was asked to refer the patient urgently to the local hospital.

Overall, 6% of patients (71/1,202) developed a recurrence treated surgically with curative intent. There was little difference between patients according to Duke’s staging (stage A, 5.1%; stage B, 6.1%; stage C, 6.2%), reported Dr. Mant and coprincipal investigator Dr. John Primrose of University of Southhampton, U.K.

"You actually do need rigorous initial staging to detect residual disease before you embark on any follow-up," Dr. Mant stressed. "I think both John and I are convinced that the reason why we have a 6% overall recurrence rate is because the people in this trial were appropriately staged. The survival curves don’t suggest they were any less sick than patients in other trials."

At the time of the analysis, 59% of patients with a recurrence treated with curative intent were still alive, but there was no statistical difference in colorectal cancer deaths (P = .66) or total deaths (P = .45) between the minimum and intensive follow-up arms, he said.

In a meta-analysis that integrated the FACS data with that from three previous trials, the overall effect of intensive follow-up was not significant (OR, 0.96; P = .56), Dr. Mant said. The number needed to treat to detect potentially curable recurrence with intensive follow-up is about 20 to 25 and that predicts a number-needed-to-treat of about 40 to 50 for 5-year post-recurrence survival.

Dr. Maughan said the disparity between the current meta-analysis and the Cochrane review may be because the latter included six studies, not three, and that the survival data from FACS may not be fully mature. A further analysis of the FACS data is planned in about 18 months.

Dr. Mant and his coauthors reported having no financial disclosures.

Mant, D., et al. "Effect of 3-5 years of scheduled CED and CT follow-up to detect recurrence of colorectal cancer: FACS randomized controlled trial." Ab. 3500.

[email protected]

CHICAGO – Long-term intensive blood and computed tomography follow-up offered no significant advantage over minimal follow-up for detecting colorectal cancer recurrences in the phase III FACS trial.

The proportion of patients with recurrence treated surgically with curative intent was 6.7% with intensive carcinoembryonic antigen (CEA) testing, 8% with monthly computed tomography imaging and 6.6% with combination CEA plus CT, compared with 2.3% with minimal follow-up involving a single CT scan.

After adjustment, it was about three times more likely that patients would have a recurrence with CEA (adjusted odds ratio, 2.70; P = .035), monthly CT imaging (OR, 3.45; P = .007) and CEA plus CT (OR, 2.95; P = .021) than with minimal follow-up.

"This result appeared to be quite robust" and was independent of cancer stage, co-primary investigator Dr. David Mant said at the annual meeting of the American Society of Clinical Oncology.

There was virtually no deviation in protocol by patients, however, the desire for unscheduled CT scans by surgeons meant that up to 30% in the minimal follow-up arm had 1 or more additional CTs, he noted. Still, in a per protocol analysis, the absolute differences in recurrence were 3.8- to 5.4-times higher with intensive follow-up. Again, there was no evidence of an additive effect of CEA plus CT.

Guidelines in the United States and Europe stress intensive follow-up including routine history and physical examination, CEA monitoring, yearly colonoscopy and repeated CT scans in those at high risk of recurrence.

The FACS (Follow-Up After Colorectal Surgery) trial looked at whether long-term intensive follow-up was worthwhile. Though commonplace after curative surgery, economic modeling suggests intensive followup may not be cost-effective and claims of a substantial overall survival benefit are inconsistent with the reported frequency and effectiveness of treatment for recurrence, explained Dr. David Mant, emeritus professor of general practice, Oxford University.

"As a long-term family physician, I’d seen many patients being followed-up for cancer and watched their cycle of deep anxiety, followed usually by relief, but sometimes with misery, as they waited for their follow-up appointments," he added. "It seemed to me that it was a very bad idea to carry on with this practice, unless it was to their benefit."

FACS involved 1,202 patients who were disease free on colonoscopy and CT imaging and had a blood CEA level of 10 mcg/L or less (Dukes’ stages A-C) after treatment for primary colorectal cancer. Their median age was 70 years.

Patients were randomly assigned to one of four follow-up regimens: "minimal" follow-up based mainly on symptoms and a single CT scan at 12-18 months; "CEA," which included minimal follow-up, plus 3 monthly blood CEA tests for 2 years then 6 monthly tests in years 3-5; "CT," which included minimal follow-up plus intensive CT imaging involving 6 monthly scans of the chest, abdomen, and pelvis for 2 years, and then annually for another 3 years; and "CEA plus CT," which included the CEA regimen in group 2 and the CT measures in group 3.

If during monitoring, a patient’s CEA level was 7 mcg/L or more above their baseline level at trial entry, the test was repeated as soon as possible. If the second test was also above the threshold, the patient’s physician was asked to refer the patient urgently to the local hospital.

Overall, 6% of patients (71/1,202) developed a recurrence treated surgically with curative intent. There was little difference between patients according to Duke’s staging (stage A, 5.1%; stage B, 6.1%; stage C, 6.2%), reported Dr. Mant and coprincipal investigator Dr. John Primrose of University of Southhampton, U.K.

"You actually do need rigorous initial staging to detect residual disease before you embark on any follow-up," Dr. Mant stressed. "I think both John and I are convinced that the reason why we have a 6% overall recurrence rate is because the people in this trial were appropriately staged. The survival curves don’t suggest they were any less sick than patients in other trials."

At the time of the analysis, 59% of patients with a recurrence treated with curative intent were still alive, but there was no statistical difference in colorectal cancer deaths (P = .66) or total deaths (P = .45) between the minimum and intensive follow-up arms, he said.

In a meta-analysis that integrated the FACS data with that from three previous trials, the overall effect of intensive follow-up was not significant (OR, 0.96; P = .56), Dr. Mant said. The number needed to treat to detect potentially curable recurrence with intensive follow-up is about 20 to 25 and that predicts a number-needed-to-treat of about 40 to 50 for 5-year post-recurrence survival.

Dr. Maughan said the disparity between the current meta-analysis and the Cochrane review may be because the latter included six studies, not three, and that the survival data from FACS may not be fully mature. A further analysis of the FACS data is planned in about 18 months.

Dr. Mant and his coauthors reported having no financial disclosures.

Mant, D., et al. "Effect of 3-5 years of scheduled CED and CT follow-up to detect recurrence of colorectal cancer: FACS randomized controlled trial." Ab. 3500.

[email protected]

CHICAGO – Dose-dense chemotherapy reduced the risk of progression or death by 34% compared with standard therapy in young patients who had poor-risk germ cell tumors with unfavorable tumor marker decline in the phase III GETUG 13 trial.

Neurotoxicity was increased, but manageable. There was no excess of second cancers, as observed in other trials. And the overall survival rate after 3 years now exceeds 75% in these patients with poor-prognosis disease.

"The dose-dense regimen should become the new standard treatment for these patients with poor-risk disease and slow tumor marker decline," Dr. Karim Fizazi, with the Institut Gustave Roussy, Villejuif, France, said at the meeting.

For patients with poor-prognosis germ cell tumors, the standard treatment – involving four cycles of bleomycin, etoposide and cisplatin (BEP) chemotherapy – was established in 1987. Over the last decade, the prognostic role of tumor marker decline has been demonstrated, but all of the phase III trials in the last 25 years have reported negative results and 48% of patients achieve a cure at 5 years, he said.

Patrice Wendling/IMNG Medical Media

The GETUG (Genitourinary Tumor Group) 13 investigators hypothesized that personalized treatment, including individualized cumulative doses of bleomycin, should be used only for patients with early unfavorable tumor marker decline; that paclitaxel, ifosfamide, and increased oxaliplatin dose intensity would have an incremental and small benefit in the first-line setting; and that toxic deaths from neutropenic fever and secondary leukemia could be prevented through the use of granulocyte colony-stimulating factor (G-CSF) and capping etoposide at 2 g/m².

In all, 263 patients with various poor-risk germ cell tumors were enrolled, and 254 underwent tumor marker analysis on day 21 after the first cycle of BEP. Of these, 51 patients with favorable tumor decline continued on BEP for a total of four courses, and 203 patients with unfavorable tumor decline were randomized to continue on BEP for a total of four courses (n = 105) or to receive a dose-dense regimen (n = 98) consisting of paclitaxel-BEP plus oxaliplatin 130 mg/m² on day 10 for two cycles, followed by two cycles of cisplatin 100 mg on day 1; ifosfamide 2 mg/m² on days 10, 12, and 14; and continuous-infusion bleomycin 25 U/d on days 10-14. The trial was amended so all patients received G-CSF support. Oxaliplatin was deleted from cycles 3-4 of the dose-dense regimen after excess neurotoxicity was observed in the first 10 patients, Dr. Fizazi said.

Tumor marker decline was calculated using a logarithmic formula (J. Clin. Oncol. 2004;22:3868-76).

At 3 years, the primary endpoint of progression-free survival was 59% in the dose-dense group and 48% in the unfavorable tumor decline group randomized to BEP (hazard ratio, 0.66; P = .05), Dr. Fizazi said. At last follow-up, 63 patients in the dose-dense group were alive and continuously free of progression, compared with 46 in the BEP unfavorable group.

Progression-free survival favored the dose-dense regimen in all subgroups tested, with patients with mediastinal primary or extrapulmonary visceral metastases tending to benefit more, he said.

There was a nonsignificant trend for overall survival in patients receiving the dose-dense regimen, with 3-year rates of 73% in the dose-dense group and 65% in the unfavorable BEP arm (HR 0.78; P = .34).

Toxicities in the dose-dense and BEP groups were comparable for neutropenic fever (17% in both), toxic deaths (1% in both), and second cancers (1% vs. 4%). Patients in the dose-dense arm experienced more neurotoxicities that were grade 2 or higher (23% vs. 4%), and they were significantly less likely to undergo salvage high-dose chemotherapy and transplant (6% vs. 16%; P = .01), Dr. Fizazi said.

The prognostic value of tumor marker decline was again demonstrated in outcome comparisons, he said. At 3 years, the favorable BEP group, as compared with the unfavorable BEP group, had significantly better rates of progression-free survival (70% vs. 48%; HR, 0.66; P = .01) and overall survival (84% vs. 65%; HR, 0.65; P = .02).

The study was sponsored by the University of Texas M.D. Anderson Cancer Center, Houston, and by Unicancer in Europe, with support from Institut National du Cancer, Ligue Nationale contre le Cancer, Sanofi-Aventis, Chugai, Baxter, and Faulding Pharmaceuticals. Dr. Fizazi and Dr. Bokemeyer reported no relevant disclosures.

[email protected]

CHICAGO – Dose-dense chemotherapy reduced the risk of progression or death by 34% compared with standard therapy in young patients who had poor-risk germ cell tumors with unfavorable tumor marker decline in the phase III GETUG 13 trial.

Neurotoxicity was increased, but manageable. There was no excess of second cancers, as observed in other trials. And the overall survival rate after 3 years now exceeds 75% in these patients with poor-prognosis disease.

"The dose-dense regimen should become the new standard treatment for these patients with poor-risk disease and slow tumor marker decline," Dr. Karim Fizazi, with the Institut Gustave Roussy, Villejuif, France, said at the meeting.

For patients with poor-prognosis germ cell tumors, the standard treatment – involving four cycles of bleomycin, etoposide and cisplatin (BEP) chemotherapy – was established in 1987. Over the last decade, the prognostic role of tumor marker decline has been demonstrated, but all of the phase III trials in the last 25 years have reported negative results and 48% of patients achieve a cure at 5 years, he said.

Patrice Wendling/IMNG Medical Media

The GETUG (Genitourinary Tumor Group) 13 investigators hypothesized that personalized treatment, including individualized cumulative doses of bleomycin, should be used only for patients with early unfavorable tumor marker decline; that paclitaxel, ifosfamide, and increased oxaliplatin dose intensity would have an incremental and small benefit in the first-line setting; and that toxic deaths from neutropenic fever and secondary leukemia could be prevented through the use of granulocyte colony-stimulating factor (G-CSF) and capping etoposide at 2 g/m².

In all, 263 patients with various poor-risk germ cell tumors were enrolled, and 254 underwent tumor marker analysis on day 21 after the first cycle of BEP. Of these, 51 patients with favorable tumor decline continued on BEP for a total of four courses, and 203 patients with unfavorable tumor decline were randomized to continue on BEP for a total of four courses (n = 105) or to receive a dose-dense regimen (n = 98) consisting of paclitaxel-BEP plus oxaliplatin 130 mg/m² on day 10 for two cycles, followed by two cycles of cisplatin 100 mg on day 1; ifosfamide 2 mg/m² on days 10, 12, and 14; and continuous-infusion bleomycin 25 U/d on days 10-14. The trial was amended so all patients received G-CSF support. Oxaliplatin was deleted from cycles 3-4 of the dose-dense regimen after excess neurotoxicity was observed in the first 10 patients, Dr. Fizazi said.

Tumor marker decline was calculated using a logarithmic formula (J. Clin. Oncol. 2004;22:3868-76).

At 3 years, the primary endpoint of progression-free survival was 59% in the dose-dense group and 48% in the unfavorable tumor decline group randomized to BEP (hazard ratio, 0.66; P = .05), Dr. Fizazi said. At last follow-up, 63 patients in the dose-dense group were alive and continuously free of progression, compared with 46 in the BEP unfavorable group.

Progression-free survival favored the dose-dense regimen in all subgroups tested, with patients with mediastinal primary or extrapulmonary visceral metastases tending to benefit more, he said.

There was a nonsignificant trend for overall survival in patients receiving the dose-dense regimen, with 3-year rates of 73% in the dose-dense group and 65% in the unfavorable BEP arm (HR 0.78; P = .34).

Toxicities in the dose-dense and BEP groups were comparable for neutropenic fever (17% in both), toxic deaths (1% in both), and second cancers (1% vs. 4%). Patients in the dose-dense arm experienced more neurotoxicities that were grade 2 or higher (23% vs. 4%), and they were significantly less likely to undergo salvage high-dose chemotherapy and transplant (6% vs. 16%; P = .01), Dr. Fizazi said.

The prognostic value of tumor marker decline was again demonstrated in outcome comparisons, he said. At 3 years, the favorable BEP group, as compared with the unfavorable BEP group, had significantly better rates of progression-free survival (70% vs. 48%; HR, 0.66; P = .01) and overall survival (84% vs. 65%; HR, 0.65; P = .02).

The study was sponsored by the University of Texas M.D. Anderson Cancer Center, Houston, and by Unicancer in Europe, with support from Institut National du Cancer, Ligue Nationale contre le Cancer, Sanofi-Aventis, Chugai, Baxter, and Faulding Pharmaceuticals. Dr. Fizazi and Dr. Bokemeyer reported no relevant disclosures.

[email protected]

CHICAGO – Dose-dense chemotherapy reduced the risk of progression or death by 34% compared with standard therapy in young patients who had poor-risk germ cell tumors with unfavorable tumor marker decline in the phase III GETUG 13 trial.

Neurotoxicity was increased, but manageable. There was no excess of second cancers, as observed in other trials. And the overall survival rate after 3 years now exceeds 75% in these patients with poor-prognosis disease.

"The dose-dense regimen should become the new standard treatment for these patients with poor-risk disease and slow tumor marker decline," Dr. Karim Fizazi, with the Institut Gustave Roussy, Villejuif, France, said at the meeting.

For patients with poor-prognosis germ cell tumors, the standard treatment – involving four cycles of bleomycin, etoposide and cisplatin (BEP) chemotherapy – was established in 1987. Over the last decade, the prognostic role of tumor marker decline has been demonstrated, but all of the phase III trials in the last 25 years have reported negative results and 48% of patients achieve a cure at 5 years, he said.

Patrice Wendling/IMNG Medical Media

The GETUG (Genitourinary Tumor Group) 13 investigators hypothesized that personalized treatment, including individualized cumulative doses of bleomycin, should be used only for patients with early unfavorable tumor marker decline; that paclitaxel, ifosfamide, and increased oxaliplatin dose intensity would have an incremental and small benefit in the first-line setting; and that toxic deaths from neutropenic fever and secondary leukemia could be prevented through the use of granulocyte colony-stimulating factor (G-CSF) and capping etoposide at 2 g/m².

In all, 263 patients with various poor-risk germ cell tumors were enrolled, and 254 underwent tumor marker analysis on day 21 after the first cycle of BEP. Of these, 51 patients with favorable tumor decline continued on BEP for a total of four courses, and 203 patients with unfavorable tumor decline were randomized to continue on BEP for a total of four courses (n = 105) or to receive a dose-dense regimen (n = 98) consisting of paclitaxel-BEP plus oxaliplatin 130 mg/m² on day 10 for two cycles, followed by two cycles of cisplatin 100 mg on day 1; ifosfamide 2 mg/m² on days 10, 12, and 14; and continuous-infusion bleomycin 25 U/d on days 10-14. The trial was amended so all patients received G-CSF support. Oxaliplatin was deleted from cycles 3-4 of the dose-dense regimen after excess neurotoxicity was observed in the first 10 patients, Dr. Fizazi said.

Tumor marker decline was calculated using a logarithmic formula (J. Clin. Oncol. 2004;22:3868-76).

At 3 years, the primary endpoint of progression-free survival was 59% in the dose-dense group and 48% in the unfavorable tumor decline group randomized to BEP (hazard ratio, 0.66; P = .05), Dr. Fizazi said. At last follow-up, 63 patients in the dose-dense group were alive and continuously free of progression, compared with 46 in the BEP unfavorable group.

Progression-free survival favored the dose-dense regimen in all subgroups tested, with patients with mediastinal primary or extrapulmonary visceral metastases tending to benefit more, he said.

There was a nonsignificant trend for overall survival in patients receiving the dose-dense regimen, with 3-year rates of 73% in the dose-dense group and 65% in the unfavorable BEP arm (HR 0.78; P = .34).

Toxicities in the dose-dense and BEP groups were comparable for neutropenic fever (17% in both), toxic deaths (1% in both), and second cancers (1% vs. 4%). Patients in the dose-dense arm experienced more neurotoxicities that were grade 2 or higher (23% vs. 4%), and they were significantly less likely to undergo salvage high-dose chemotherapy and transplant (6% vs. 16%; P = .01), Dr. Fizazi said.

The prognostic value of tumor marker decline was again demonstrated in outcome comparisons, he said. At 3 years, the favorable BEP group, as compared with the unfavorable BEP group, had significantly better rates of progression-free survival (70% vs. 48%; HR, 0.66; P = .01) and overall survival (84% vs. 65%; HR, 0.65; P = .02).

The study was sponsored by the University of Texas M.D. Anderson Cancer Center, Houston, and by Unicancer in Europe, with support from Institut National du Cancer, Ligue Nationale contre le Cancer, Sanofi-Aventis, Chugai, Baxter, and Faulding Pharmaceuticals. Dr. Fizazi and Dr. Bokemeyer reported no relevant disclosures.

[email protected]

CHICAGO – Cetuximab combined with radiotherapy was no better than conventional chemoradiotherapy for the treatment of locally advanced squamous cell carcinomas of the head and neck, based on data from a phase II/III study presented at the annual meeting of the American Society of Clinical Oncology.

"No differences in activity and efficacy were observed between the two treatments," said Dr. Maria Grazia Ghi, of Ospedale Civile Venezia in Venice, Italy. However, while the treatments did not significantly differ in severe toxicities, compliance was better with concomitant therapy than with chemoradiotherapy (CRT), with more patients completing treatment and fewer having unplanned treatment interruptions, she noted.

The phase II/III study compared concomitant CRT with cetuximab and radiotherapy (CET/RT) – with and without induction therapy – with docetaxel, cisplatin, and 5-fluorouracil (TPF) in treatment-naive patients with unresectable squamous cell carcinomas of the head and neck. In 2010, phase II results were reported indicating that TPF induction was feasible in this population and did not compromise subsequent CRT. In addition, TPF induction chemotherapy significantly increased the chance of complete response (P = .004). Preliminary in-field toxicity results were reported at the 2012 ASCO meeting.

At this year’s meeting, data were presented on overall survival with or without induction therapy, and on grade 3 or worse in-field toxicities with CRT vs. CET/RT.

A total of 420 patients with squamous cell cancers of the oral cavity, hypopharynx, or oropharynx with good performance status (Eastern Cooperative Oncology Group 0 or 1) were randomized in a 2 x 2 factorial design to receive either TPF induction every 3 weeks for three cycles, or no induction, with each group then further randomized to either two cycles of cisplatin and 5-fluorouracil (5-FU) delivered concomitantly with 70 Gy of radiation divided into 35 fractions, or 7 weeks of cetuximab and the same radiotherapy dose.

There were no significant differences in the primary endpoint, in-field toxicities, with grade 3 mucositis occurring in 35% of patients on CRT, compared with 34% on CET/RT. Grade 4 mucositis occurred in 3% and 2% of patients, respectively. Grade 3 or 4 skin toxicities were also similar between the groups, with grade 3 adverse events seen in 12% of patients on CRT, vs. 19% on CET/RT, and grade 4 events occurring in 1% and 0.6%, respectively.

However, treatment compliance was significantly better with CRT, with 91% of patients assigned to this therapy completing both cycles, compared with 81% of patients assigned to CET/RT (P = .005). In addition, 23% of patients on CRT required interruption of radiotherapy for more than 3 consecutive days, compared with 38% of patients on CET/RT (P less than .001).

Median progression-free survival rates were 20.9 months for CRT vs. 20.7 months for CET/RT, a difference that was not significant. At 2 years, 48% of patients on CRT and 43% on CET/RT were alive without progression.

Median overall survival durations were 39.5 vs. 38.2 months, and overall survival at 2 years’ follow-up was 65% and 59%, respectively; the differences were not statistically significant.

There was an evident trend toward better progression-free survival and overall survival on CRT for patients with oropharyngeal cancers, but these differences were not significant at most recent follow-up, Dr. Ghi said.

Response rates to therapy, regardless of induction status, did not differ significantly, with 34% on CRT and 38% on CET/RT having a complete response, 47% and 46% having partial responses, 5% and 6% having stable disease, and 14% and 11% experiencing disease progression.

Invited discussant Dr. Danny Rischin, professor of oncology at the Peter MacCallum Cancer Centre in Melbourne, noted that the study was limited by its inclusion of patients from the randomized phase II induction comparison who were not later randomized to cetuximab, thereby confounding results of the phase III portion of the study. He added that it is still unknown whether there is an interaction between induction chemotherapy and the type of subsequent concomitant treatment, since the phase II data on the induction phase have not yet been reported.

Additionally, it is uncertain whether cisplatin/5-FU with a lower dose of cisplatin as given in this study – 20 mg/m² on days 1-4 – is equivalent to three cycles of cisplatin when given with conventionally fractionated radiation, Dr. Rischin said.

"We really need to wait for the final study results, including outcomes with TPF, and HPV [human papillomavirus] analyses, particularly for understanding what was happening in oropharyngeal cancer patients, and we need to see interaction results before drawing any final conclusions," he added.

Dr. Ghi reported having no relevant disclosures. Dr. Rischin reported receiving research funding from Genentech and Serono.

CHICAGO – Cetuximab combined with radiotherapy was no better than conventional chemoradiotherapy for the treatment of locally advanced squamous cell carcinomas of the head and neck, based on data from a phase II/III study presented at the annual meeting of the American Society of Clinical Oncology.

"No differences in activity and efficacy were observed between the two treatments," said Dr. Maria Grazia Ghi, of Ospedale Civile Venezia in Venice, Italy. However, while the treatments did not significantly differ in severe toxicities, compliance was better with concomitant therapy than with chemoradiotherapy (CRT), with more patients completing treatment and fewer having unplanned treatment interruptions, she noted.

The phase II/III study compared concomitant CRT with cetuximab and radiotherapy (CET/RT) – with and without induction therapy – with docetaxel, cisplatin, and 5-fluorouracil (TPF) in treatment-naive patients with unresectable squamous cell carcinomas of the head and neck. In 2010, phase II results were reported indicating that TPF induction was feasible in this population and did not compromise subsequent CRT. In addition, TPF induction chemotherapy significantly increased the chance of complete response (P = .004). Preliminary in-field toxicity results were reported at the 2012 ASCO meeting.

At this year’s meeting, data were presented on overall survival with or without induction therapy, and on grade 3 or worse in-field toxicities with CRT vs. CET/RT.

A total of 420 patients with squamous cell cancers of the oral cavity, hypopharynx, or oropharynx with good performance status (Eastern Cooperative Oncology Group 0 or 1) were randomized in a 2 x 2 factorial design to receive either TPF induction every 3 weeks for three cycles, or no induction, with each group then further randomized to either two cycles of cisplatin and 5-fluorouracil (5-FU) delivered concomitantly with 70 Gy of radiation divided into 35 fractions, or 7 weeks of cetuximab and the same radiotherapy dose.

There were no significant differences in the primary endpoint, in-field toxicities, with grade 3 mucositis occurring in 35% of patients on CRT, compared with 34% on CET/RT. Grade 4 mucositis occurred in 3% and 2% of patients, respectively. Grade 3 or 4 skin toxicities were also similar between the groups, with grade 3 adverse events seen in 12% of patients on CRT, vs. 19% on CET/RT, and grade 4 events occurring in 1% and 0.6%, respectively.

However, treatment compliance was significantly better with CRT, with 91% of patients assigned to this therapy completing both cycles, compared with 81% of patients assigned to CET/RT (P = .005). In addition, 23% of patients on CRT required interruption of radiotherapy for more than 3 consecutive days, compared with 38% of patients on CET/RT (P less than .001).

Median progression-free survival rates were 20.9 months for CRT vs. 20.7 months for CET/RT, a difference that was not significant. At 2 years, 48% of patients on CRT and 43% on CET/RT were alive without progression.

Median overall survival durations were 39.5 vs. 38.2 months, and overall survival at 2 years’ follow-up was 65% and 59%, respectively; the differences were not statistically significant.

There was an evident trend toward better progression-free survival and overall survival on CRT for patients with oropharyngeal cancers, but these differences were not significant at most recent follow-up, Dr. Ghi said.

Response rates to therapy, regardless of induction status, did not differ significantly, with 34% on CRT and 38% on CET/RT having a complete response, 47% and 46% having partial responses, 5% and 6% having stable disease, and 14% and 11% experiencing disease progression.

Invited discussant Dr. Danny Rischin, professor of oncology at the Peter MacCallum Cancer Centre in Melbourne, noted that the study was limited by its inclusion of patients from the randomized phase II induction comparison who were not later randomized to cetuximab, thereby confounding results of the phase III portion of the study. He added that it is still unknown whether there is an interaction between induction chemotherapy and the type of subsequent concomitant treatment, since the phase II data on the induction phase have not yet been reported.

Additionally, it is uncertain whether cisplatin/5-FU with a lower dose of cisplatin as given in this study – 20 mg/m² on days 1-4 – is equivalent to three cycles of cisplatin when given with conventionally fractionated radiation, Dr. Rischin said.

"We really need to wait for the final study results, including outcomes with TPF, and HPV [human papillomavirus] analyses, particularly for understanding what was happening in oropharyngeal cancer patients, and we need to see interaction results before drawing any final conclusions," he added.

Dr. Ghi reported having no relevant disclosures. Dr. Rischin reported receiving research funding from Genentech and Serono.

CHICAGO – Cetuximab combined with radiotherapy was no better than conventional chemoradiotherapy for the treatment of locally advanced squamous cell carcinomas of the head and neck, based on data from a phase II/III study presented at the annual meeting of the American Society of Clinical Oncology.

"No differences in activity and efficacy were observed between the two treatments," said Dr. Maria Grazia Ghi, of Ospedale Civile Venezia in Venice, Italy. However, while the treatments did not significantly differ in severe toxicities, compliance was better with concomitant therapy than with chemoradiotherapy (CRT), with more patients completing treatment and fewer having unplanned treatment interruptions, she noted.

The phase II/III study compared concomitant CRT with cetuximab and radiotherapy (CET/RT) – with and without induction therapy – with docetaxel, cisplatin, and 5-fluorouracil (TPF) in treatment-naive patients with unresectable squamous cell carcinomas of the head and neck. In 2010, phase II results were reported indicating that TPF induction was feasible in this population and did not compromise subsequent CRT. In addition, TPF induction chemotherapy significantly increased the chance of complete response (P = .004). Preliminary in-field toxicity results were reported at the 2012 ASCO meeting.

At this year’s meeting, data were presented on overall survival with or without induction therapy, and on grade 3 or worse in-field toxicities with CRT vs. CET/RT.

A total of 420 patients with squamous cell cancers of the oral cavity, hypopharynx, or oropharynx with good performance status (Eastern Cooperative Oncology Group 0 or 1) were randomized in a 2 x 2 factorial design to receive either TPF induction every 3 weeks for three cycles, or no induction, with each group then further randomized to either two cycles of cisplatin and 5-fluorouracil (5-FU) delivered concomitantly with 70 Gy of radiation divided into 35 fractions, or 7 weeks of cetuximab and the same radiotherapy dose.

There were no significant differences in the primary endpoint, in-field toxicities, with grade 3 mucositis occurring in 35% of patients on CRT, compared with 34% on CET/RT. Grade 4 mucositis occurred in 3% and 2% of patients, respectively. Grade 3 or 4 skin toxicities were also similar between the groups, with grade 3 adverse events seen in 12% of patients on CRT, vs. 19% on CET/RT, and grade 4 events occurring in 1% and 0.6%, respectively.

However, treatment compliance was significantly better with CRT, with 91% of patients assigned to this therapy completing both cycles, compared with 81% of patients assigned to CET/RT (P = .005). In addition, 23% of patients on CRT required interruption of radiotherapy for more than 3 consecutive days, compared with 38% of patients on CET/RT (P less than .001).

Median progression-free survival rates were 20.9 months for CRT vs. 20.7 months for CET/RT, a difference that was not significant. At 2 years, 48% of patients on CRT and 43% on CET/RT were alive without progression.

Median overall survival durations were 39.5 vs. 38.2 months, and overall survival at 2 years’ follow-up was 65% and 59%, respectively; the differences were not statistically significant.

There was an evident trend toward better progression-free survival and overall survival on CRT for patients with oropharyngeal cancers, but these differences were not significant at most recent follow-up, Dr. Ghi said.

Response rates to therapy, regardless of induction status, did not differ significantly, with 34% on CRT and 38% on CET/RT having a complete response, 47% and 46% having partial responses, 5% and 6% having stable disease, and 14% and 11% experiencing disease progression.

Invited discussant Dr. Danny Rischin, professor of oncology at the Peter MacCallum Cancer Centre in Melbourne, noted that the study was limited by its inclusion of patients from the randomized phase II induction comparison who were not later randomized to cetuximab, thereby confounding results of the phase III portion of the study. He added that it is still unknown whether there is an interaction between induction chemotherapy and the type of subsequent concomitant treatment, since the phase II data on the induction phase have not yet been reported.

Additionally, it is uncertain whether cisplatin/5-FU with a lower dose of cisplatin as given in this study – 20 mg/m² on days 1-4 – is equivalent to three cycles of cisplatin when given with conventionally fractionated radiation, Dr. Rischin said.

"We really need to wait for the final study results, including outcomes with TPF, and HPV [human papillomavirus] analyses, particularly for understanding what was happening in oropharyngeal cancer patients, and we need to see interaction results before drawing any final conclusions," he added.

Dr. Ghi reported having no relevant disclosures. Dr. Rischin reported receiving research funding from Genentech and Serono.

CHICAGO – Maintenance therapy with the investigational immunotherapy L-BLP25 offered no significant overall survival advantage in stage III unresectable non-small cell lung cancer in the phase III START trial.

In a modified intention-to-treat population of 1,239 patients, median overall survival was 25.6 months with L-BLP25 and 22.3 months with placebo (adjusted hazard ratio, 0.88; P = .123). Median follow-up was 39.9 months and 37.7 months, respectively.

Although the trial failed to meet its primary endpoint, the results were encouraging in patients receiving initial concurrent chemoradiotherapy, the largest subset of patients in the trial, Dr. Charles Butts said at the annual meeting of the American Society of Clinical Oncology.

Median survival in these 806 patients was 10.2 months longer with L-BLP25 (now known as Tecemotide) at 30.8 months vs. 20.6 months with placebo (HR, 0.78; P = .016).

Patients in all subgroups in the preplanned analysis appeared to benefit from maintenance L-BLP25, except those who had initial sequential chemotherapy/radiation therapy (19.4 vs. 24.6 months; HR, 1.12; P .38).

The secondary endpoints also significantly favored L-BLP25 over placebo for time to symptomatic progression (14.2 vs. 11.4 months; HR, 0.85; P = .023) and time to progression (10.0 vs. 8.4 months; HR, 0.87; P = .053), said Dr. Butts of the Cross Cancer Institute, University of Alberta, Edmonton.

"The treatment was well tolerated, and, certainly, further study is required to confirm these results," he said.

In a statement released by the study sponsor, Merck KGaA, Dr. Butts observed that concurrent chemoradiotherapy is the standard of care recommended for unresectable stage III NSCLC in U.S. and European guidelines, and said, "This is the first time that an antigen-specific cancer immunotherapy has shown this effect in a substantial subgroup of NSCLC patients who are usually only observed following chemoradiotherapy."

L-BLP25, formerly known as Stimuvax, targets the mucin1 (MUC1) cell surface–associated antigen, which is overexpressed and aberrantly glycolated in many epithelial tumors, particularly NSCLC. L-BLP25 appeared to confer a survival benefit to patients with localized stage III NSCLC in two earlier phase II trials.

Treatment in the phase III START (Stimulating Targeted Antigenic Responses to NSCLC) trial, however, was suspended for a median of 135 days in 531 patients after the Food and Drug Administration placed a clinical hold in 2010 on all L-BLP25 trials after a case of fatal encephalitis was reported in a patient with multiple myeloma in a phase II study and immune-related causality could not be excluded, Dr. Butts explained.

The primary analysis population was modified to exclude 274 patients randomized within 6 months of the clinical hold – the time period the investigators hypothesized would be needed to receive enough injections to stimulate an immune response. To maintain the power of the trial, these patients were replaced with additional accrual, for a final sample size of 1,513 patients and a modified intention-to-treat population of 1,239, "making it by far, the largest trial in stage III non-small cell lung cancer ever conducted," he said.

As for whether the massive trial brings the promise of vaccine therapy for NSCLC to reality, invited discussant Dr. Johan Vansteenkiste, who is with University Hospitals Leuven, Belgium, said, "I think it starts in START because, yes, START delivers clinically relevant results."

He agreed there is room for a confirmatory trial and said further work is also needed to address the timing of injections, radiotherapy and immunotherapy links, the role inflammation plays in immunotherapy, and the use of biomarkers with MUC1 vaccinations and PD-1 antibodies.

START investigators in 33 countries enrolled patients with unresectable, locally advanced stage III NSCLC who had a response or stable disease after at least two cycles of platinum-based chemoradiotherapy (concurrent or sequential). Patients were randomized within 4-12 weeks of completing initial treatment to a single dose of cyclophosphamide on day 3 followed by weekly injections of L-BLP25 for 8 weeks and then six weekly maintenance injections, or a single dose of saline followed by placebo injections using the same schedule.

One-third of patients had stable disease, 65% had received concurrent chemoradiotherapy, 25% were current smokers, and the median duration of NSCLC from diagnosis was 6 months.

An overall survival analysis of the 274 patients whose treatment was interrupted showed absolutely no treatment effect of L-BLP25 vs. placebo (26.4 vs. 29.1 months; HR, 1.09; P = .66), "suggesting that uninterrupted therapy, particularly in the initial phases of immune therapy, is absolutely critical for any efficacy," Dr. Butts said.

Injection-site reactions occurred in 17.3% of patients given L-BLP25 and in 12% of the placebo group, and grade 3/4 flulike symptoms occurred in less than 2% of each arm. The most frequent adverse events with L-BLP25 and placebo were cough (33% vs. 28%), dyspnea (23.2% vs. 23.5%), fatigue (19.2% vs. 21.4%), back pain (14.3% vs. 11.1%), nausea (13.7% vs. 8.2%), and chest pain (13.2% vs. 9.4%).

Rates of any adverse event leading to death were similar at 4.5% of L-BLP25-treated patients and 7.3% of placebo-treated patients, Dr. Butts said. Grade 3 or 4 potentially immune-related adverse events were low, at just two patients in both groups (0.2% vs. 0.4%).

"There really were no safety concerns seen in the trial," he said.

L-BLP25 is currently being investigated in the similarly designed phase III INSPIRE (L-BLP25 Liposome Vaccine Trial in Asian NSCLC Patients: Stimulating Immune Response) trial in 420 unresectable, locally advanced stage III NSCLC patients in Hong Kong, China, Korea, Singapore, and Taiwan.

START was supported by Merck KGaA. Dr. Butts reported a consultant/advisory role and honoraria from Merck KGaA and Merck Serono. Dr. Vansteenkiste reported a consultant/advisory role with Merck Serono and GlaxoSmithKline, and research support from Eli Lilly and AstraZeneca.

[email protected]

CHICAGO – Maintenance therapy with the investigational immunotherapy L-BLP25 offered no significant overall survival advantage in stage III unresectable non-small cell lung cancer in the phase III START trial.

In a modified intention-to-treat population of 1,239 patients, median overall survival was 25.6 months with L-BLP25 and 22.3 months with placebo (adjusted hazard ratio, 0.88; P = .123). Median follow-up was 39.9 months and 37.7 months, respectively.

Although the trial failed to meet its primary endpoint, the results were encouraging in patients receiving initial concurrent chemoradiotherapy, the largest subset of patients in the trial, Dr. Charles Butts said at the annual meeting of the American Society of Clinical Oncology.

Median survival in these 806 patients was 10.2 months longer with L-BLP25 (now known as Tecemotide) at 30.8 months vs. 20.6 months with placebo (HR, 0.78; P = .016).

Patients in all subgroups in the preplanned analysis appeared to benefit from maintenance L-BLP25, except those who had initial sequential chemotherapy/radiation therapy (19.4 vs. 24.6 months; HR, 1.12; P .38).

The secondary endpoints also significantly favored L-BLP25 over placebo for time to symptomatic progression (14.2 vs. 11.4 months; HR, 0.85; P = .023) and time to progression (10.0 vs. 8.4 months; HR, 0.87; P = .053), said Dr. Butts of the Cross Cancer Institute, University of Alberta, Edmonton.

"The treatment was well tolerated, and, certainly, further study is required to confirm these results," he said.

In a statement released by the study sponsor, Merck KGaA, Dr. Butts observed that concurrent chemoradiotherapy is the standard of care recommended for unresectable stage III NSCLC in U.S. and European guidelines, and said, "This is the first time that an antigen-specific cancer immunotherapy has shown this effect in a substantial subgroup of NSCLC patients who are usually only observed following chemoradiotherapy."

L-BLP25, formerly known as Stimuvax, targets the mucin1 (MUC1) cell surface–associated antigen, which is overexpressed and aberrantly glycolated in many epithelial tumors, particularly NSCLC. L-BLP25 appeared to confer a survival benefit to patients with localized stage III NSCLC in two earlier phase II trials.

Treatment in the phase III START (Stimulating Targeted Antigenic Responses to NSCLC) trial, however, was suspended for a median of 135 days in 531 patients after the Food and Drug Administration placed a clinical hold in 2010 on all L-BLP25 trials after a case of fatal encephalitis was reported in a patient with multiple myeloma in a phase II study and immune-related causality could not be excluded, Dr. Butts explained.

The primary analysis population was modified to exclude 274 patients randomized within 6 months of the clinical hold – the time period the investigators hypothesized would be needed to receive enough injections to stimulate an immune response. To maintain the power of the trial, these patients were replaced with additional accrual, for a final sample size of 1,513 patients and a modified intention-to-treat population of 1,239, "making it by far, the largest trial in stage III non-small cell lung cancer ever conducted," he said.

As for whether the massive trial brings the promise of vaccine therapy for NSCLC to reality, invited discussant Dr. Johan Vansteenkiste, who is with University Hospitals Leuven, Belgium, said, "I think it starts in START because, yes, START delivers clinically relevant results."

He agreed there is room for a confirmatory trial and said further work is also needed to address the timing of injections, radiotherapy and immunotherapy links, the role inflammation plays in immunotherapy, and the use of biomarkers with MUC1 vaccinations and PD-1 antibodies.

START investigators in 33 countries enrolled patients with unresectable, locally advanced stage III NSCLC who had a response or stable disease after at least two cycles of platinum-based chemoradiotherapy (concurrent or sequential). Patients were randomized within 4-12 weeks of completing initial treatment to a single dose of cyclophosphamide on day 3 followed by weekly injections of L-BLP25 for 8 weeks and then six weekly maintenance injections, or a single dose of saline followed by placebo injections using the same schedule.

One-third of patients had stable disease, 65% had received concurrent chemoradiotherapy, 25% were current smokers, and the median duration of NSCLC from diagnosis was 6 months.

An overall survival analysis of the 274 patients whose treatment was interrupted showed absolutely no treatment effect of L-BLP25 vs. placebo (26.4 vs. 29.1 months; HR, 1.09; P = .66), "suggesting that uninterrupted therapy, particularly in the initial phases of immune therapy, is absolutely critical for any efficacy," Dr. Butts said.

Injection-site reactions occurred in 17.3% of patients given L-BLP25 and in 12% of the placebo group, and grade 3/4 flulike symptoms occurred in less than 2% of each arm. The most frequent adverse events with L-BLP25 and placebo were cough (33% vs. 28%), dyspnea (23.2% vs. 23.5%), fatigue (19.2% vs. 21.4%), back pain (14.3% vs. 11.1%), nausea (13.7% vs. 8.2%), and chest pain (13.2% vs. 9.4%).

Rates of any adverse event leading to death were similar at 4.5% of L-BLP25-treated patients and 7.3% of placebo-treated patients, Dr. Butts said. Grade 3 or 4 potentially immune-related adverse events were low, at just two patients in both groups (0.2% vs. 0.4%).

"There really were no safety concerns seen in the trial," he said.

L-BLP25 is currently being investigated in the similarly designed phase III INSPIRE (L-BLP25 Liposome Vaccine Trial in Asian NSCLC Patients: Stimulating Immune Response) trial in 420 unresectable, locally advanced stage III NSCLC patients in Hong Kong, China, Korea, Singapore, and Taiwan.

START was supported by Merck KGaA. Dr. Butts reported a consultant/advisory role and honoraria from Merck KGaA and Merck Serono. Dr. Vansteenkiste reported a consultant/advisory role with Merck Serono and GlaxoSmithKline, and research support from Eli Lilly and AstraZeneca.

[email protected]

CHICAGO – Maintenance therapy with the investigational immunotherapy L-BLP25 offered no significant overall survival advantage in stage III unresectable non-small cell lung cancer in the phase III START trial.

In a modified intention-to-treat population of 1,239 patients, median overall survival was 25.6 months with L-BLP25 and 22.3 months with placebo (adjusted hazard ratio, 0.88; P = .123). Median follow-up was 39.9 months and 37.7 months, respectively.

Although the trial failed to meet its primary endpoint, the results were encouraging in patients receiving initial concurrent chemoradiotherapy, the largest subset of patients in the trial, Dr. Charles Butts said at the annual meeting of the American Society of Clinical Oncology.

Median survival in these 806 patients was 10.2 months longer with L-BLP25 (now known as Tecemotide) at 30.8 months vs. 20.6 months with placebo (HR, 0.78; P = .016).

Patients in all subgroups in the preplanned analysis appeared to benefit from maintenance L-BLP25, except those who had initial sequential chemotherapy/radiation therapy (19.4 vs. 24.6 months; HR, 1.12; P .38).

The secondary endpoints also significantly favored L-BLP25 over placebo for time to symptomatic progression (14.2 vs. 11.4 months; HR, 0.85; P = .023) and time to progression (10.0 vs. 8.4 months; HR, 0.87; P = .053), said Dr. Butts of the Cross Cancer Institute, University of Alberta, Edmonton.

"The treatment was well tolerated, and, certainly, further study is required to confirm these results," he said.

In a statement released by the study sponsor, Merck KGaA, Dr. Butts observed that concurrent chemoradiotherapy is the standard of care recommended for unresectable stage III NSCLC in U.S. and European guidelines, and said, "This is the first time that an antigen-specific cancer immunotherapy has shown this effect in a substantial subgroup of NSCLC patients who are usually only observed following chemoradiotherapy."

L-BLP25, formerly known as Stimuvax, targets the mucin1 (MUC1) cell surface–associated antigen, which is overexpressed and aberrantly glycolated in many epithelial tumors, particularly NSCLC. L-BLP25 appeared to confer a survival benefit to patients with localized stage III NSCLC in two earlier phase II trials.

Treatment in the phase III START (Stimulating Targeted Antigenic Responses to NSCLC) trial, however, was suspended for a median of 135 days in 531 patients after the Food and Drug Administration placed a clinical hold in 2010 on all L-BLP25 trials after a case of fatal encephalitis was reported in a patient with multiple myeloma in a phase II study and immune-related causality could not be excluded, Dr. Butts explained.

The primary analysis population was modified to exclude 274 patients randomized within 6 months of the clinical hold – the time period the investigators hypothesized would be needed to receive enough injections to stimulate an immune response. To maintain the power of the trial, these patients were replaced with additional accrual, for a final sample size of 1,513 patients and a modified intention-to-treat population of 1,239, "making it by far, the largest trial in stage III non-small cell lung cancer ever conducted," he said.

As for whether the massive trial brings the promise of vaccine therapy for NSCLC to reality, invited discussant Dr. Johan Vansteenkiste, who is with University Hospitals Leuven, Belgium, said, "I think it starts in START because, yes, START delivers clinically relevant results."

He agreed there is room for a confirmatory trial and said further work is also needed to address the timing of injections, radiotherapy and immunotherapy links, the role inflammation plays in immunotherapy, and the use of biomarkers with MUC1 vaccinations and PD-1 antibodies.

START investigators in 33 countries enrolled patients with unresectable, locally advanced stage III NSCLC who had a response or stable disease after at least two cycles of platinum-based chemoradiotherapy (concurrent or sequential). Patients were randomized within 4-12 weeks of completing initial treatment to a single dose of cyclophosphamide on day 3 followed by weekly injections of L-BLP25 for 8 weeks and then six weekly maintenance injections, or a single dose of saline followed by placebo injections using the same schedule.

One-third of patients had stable disease, 65% had received concurrent chemoradiotherapy, 25% were current smokers, and the median duration of NSCLC from diagnosis was 6 months.

An overall survival analysis of the 274 patients whose treatment was interrupted showed absolutely no treatment effect of L-BLP25 vs. placebo (26.4 vs. 29.1 months; HR, 1.09; P = .66), "suggesting that uninterrupted therapy, particularly in the initial phases of immune therapy, is absolutely critical for any efficacy," Dr. Butts said.

Injection-site reactions occurred in 17.3% of patients given L-BLP25 and in 12% of the placebo group, and grade 3/4 flulike symptoms occurred in less than 2% of each arm. The most frequent adverse events with L-BLP25 and placebo were cough (33% vs. 28%), dyspnea (23.2% vs. 23.5%), fatigue (19.2% vs. 21.4%), back pain (14.3% vs. 11.1%), nausea (13.7% vs. 8.2%), and chest pain (13.2% vs. 9.4%).

Rates of any adverse event leading to death were similar at 4.5% of L-BLP25-treated patients and 7.3% of placebo-treated patients, Dr. Butts said. Grade 3 or 4 potentially immune-related adverse events were low, at just two patients in both groups (0.2% vs. 0.4%).

"There really were no safety concerns seen in the trial," he said.

L-BLP25 is currently being investigated in the similarly designed phase III INSPIRE (L-BLP25 Liposome Vaccine Trial in Asian NSCLC Patients: Stimulating Immune Response) trial in 420 unresectable, locally advanced stage III NSCLC patients in Hong Kong, China, Korea, Singapore, and Taiwan.

START was supported by Merck KGaA. Dr. Butts reported a consultant/advisory role and honoraria from Merck KGaA and Merck Serono. Dr. Vansteenkiste reported a consultant/advisory role with Merck Serono and GlaxoSmithKline, and research support from Eli Lilly and AstraZeneca.

[email protected]

CHICAGO – In platinum-sensitive relapsed serous ovarian cancer patients, maintenance olaparib therapy was of most benefit among women with a BRCA mutation, based on results from a randomized phase II trial reported at the annual meeting of the American Society of Clinical Oncology.

The 265 women enrolled in the study had responded to platinum chemotherapy and were assigned evenly to olaparib – an investigational inhibitor of poly(ADP-ribose) polymerase (PARP) – or placebo for maintenance therapy.

Relative to placebo, olaparib reduced the risk of progression or death by a significant 82% (hazard ratio, 0.18) among patients with BRCA mutations and by a lesser but still significant 47% (HR, 0.53) in patients without BRCA mutations, reported first author Dr. Jonathan Ledermann, a professor of medical oncology in the UCL Cancer Institute, University College London.

There was also a greater carryover benefit of olaparib in the BRCA mutation–positive subset, in that they had a longer time to progression or death after the next therapy they received.

"As a result of these compelling data, phase III confirmatory trials are now starting in patients with BRCA mutations later this year," Dr. Lederman said.

Overall, 51% of patients enrolled in the trial, formally known as Study 19 and sponsored by AstraZeneca (the manufacturer of olaparib), had a known deleterious BRCA germline mutation or a BRCA mutation in their tumor.

The main results, previously published, showed that maintenance olaparib prolonged progression-free survival in the trial population overall, with a hazard ratio of 0.35 (N. Engl. J. Med. 2012;366:1382-92). There was no significant gain in overall survival as of an interim analysis, but there was a suggestion of benefit for patients with a BRCA mutation.

Among the BRCA mutation–positive subset, median progression-free survival was 11.2 months with olaparib versus 4.3 months with placebo (HR, 0.18; P less than .00001). Among the BRCA mutation–negative group, median progression-free survival was 5.6 months with olaparib versus 5.5 months with placebo (HR, 0.53; P less than .007).

There was still no overall survival advantage of olaparib in the trial population as a whole, but 23% of patients in the placebo group were switched to a PARP inhibitor. "This may be sufficient ... to actually have a confounding effect on the overall survival of these patients," Dr. Ledermann commented. There was a trend toward better overall survival with olaparib in the BRCA mutation–positive subset.

In addition, olaparib was superior to placebo in terms of the time from randomization to progression after a second, subsequent therapy, both among the BRCA mutation–positive subset (23.8 vs. 15.3 months; HR, 0.46; P less than .0003) and among the BRCA mutation–negative subset (17.1 vs. 14.7 months; HR, 0.64; P = .03).

"This I think translates into a clinically meaningful benefit, in that the effect if you like of olaparib is carried over beyond progression, to the time that they fail a second subsequent therapy," Dr. Ledermann said.

There was no significant difference in quality of life between the olaparib and placebo groups among women having a BRCA mutation.

Tolerability of olaparib did not differ significantly between women with the BRCA mutation–positive subset and the overall trial population. The leading adverse events in the former were low-grade nausea (seen in 73%) and fatigue (seen in 54%).

Dr. Ledermann disclosed that he receives travel grants from AstraZeneca. The trial was sponsored by AstraZeneca.

CHICAGO – In platinum-sensitive relapsed serous ovarian cancer patients, maintenance olaparib therapy was of most benefit among women with a BRCA mutation, based on results from a randomized phase II trial reported at the annual meeting of the American Society of Clinical Oncology.

The 265 women enrolled in the study had responded to platinum chemotherapy and were assigned evenly to olaparib – an investigational inhibitor of poly(ADP-ribose) polymerase (PARP) – or placebo for maintenance therapy.

Relative to placebo, olaparib reduced the risk of progression or death by a significant 82% (hazard ratio, 0.18) among patients with BRCA mutations and by a lesser but still significant 47% (HR, 0.53) in patients without BRCA mutations, reported first author Dr. Jonathan Ledermann, a professor of medical oncology in the UCL Cancer Institute, University College London.

There was also a greater carryover benefit of olaparib in the BRCA mutation–positive subset, in that they had a longer time to progression or death after the next therapy they received.

"As a result of these compelling data, phase III confirmatory trials are now starting in patients with BRCA mutations later this year," Dr. Lederman said.

Overall, 51% of patients enrolled in the trial, formally known as Study 19 and sponsored by AstraZeneca (the manufacturer of olaparib), had a known deleterious BRCA germline mutation or a BRCA mutation in their tumor.

The main results, previously published, showed that maintenance olaparib prolonged progression-free survival in the trial population overall, with a hazard ratio of 0.35 (N. Engl. J. Med. 2012;366:1382-92). There was no significant gain in overall survival as of an interim analysis, but there was a suggestion of benefit for patients with a BRCA mutation.

Among the BRCA mutation–positive subset, median progression-free survival was 11.2 months with olaparib versus 4.3 months with placebo (HR, 0.18; P less than .00001). Among the BRCA mutation–negative group, median progression-free survival was 5.6 months with olaparib versus 5.5 months with placebo (HR, 0.53; P less than .007).

There was still no overall survival advantage of olaparib in the trial population as a whole, but 23% of patients in the placebo group were switched to a PARP inhibitor. "This may be sufficient ... to actually have a confounding effect on the overall survival of these patients," Dr. Ledermann commented. There was a trend toward better overall survival with olaparib in the BRCA mutation–positive subset.

In addition, olaparib was superior to placebo in terms of the time from randomization to progression after a second, subsequent therapy, both among the BRCA mutation–positive subset (23.8 vs. 15.3 months; HR, 0.46; P less than .0003) and among the BRCA mutation–negative subset (17.1 vs. 14.7 months; HR, 0.64; P = .03).

"This I think translates into a clinically meaningful benefit, in that the effect if you like of olaparib is carried over beyond progression, to the time that they fail a second subsequent therapy," Dr. Ledermann said.

There was no significant difference in quality of life between the olaparib and placebo groups among women having a BRCA mutation.

Tolerability of olaparib did not differ significantly between women with the BRCA mutation–positive subset and the overall trial population. The leading adverse events in the former were low-grade nausea (seen in 73%) and fatigue (seen in 54%).

Dr. Ledermann disclosed that he receives travel grants from AstraZeneca. The trial was sponsored by AstraZeneca.

CHICAGO – In platinum-sensitive relapsed serous ovarian cancer patients, maintenance olaparib therapy was of most benefit among women with a BRCA mutation, based on results from a randomized phase II trial reported at the annual meeting of the American Society of Clinical Oncology.

The 265 women enrolled in the study had responded to platinum chemotherapy and were assigned evenly to olaparib – an investigational inhibitor of poly(ADP-ribose) polymerase (PARP) – or placebo for maintenance therapy.

Relative to placebo, olaparib reduced the risk of progression or death by a significant 82% (hazard ratio, 0.18) among patients with BRCA mutations and by a lesser but still significant 47% (HR, 0.53) in patients without BRCA mutations, reported first author Dr. Jonathan Ledermann, a professor of medical oncology in the UCL Cancer Institute, University College London.

There was also a greater carryover benefit of olaparib in the BRCA mutation–positive subset, in that they had a longer time to progression or death after the next therapy they received.

"As a result of these compelling data, phase III confirmatory trials are now starting in patients with BRCA mutations later this year," Dr. Lederman said.

Overall, 51% of patients enrolled in the trial, formally known as Study 19 and sponsored by AstraZeneca (the manufacturer of olaparib), had a known deleterious BRCA germline mutation or a BRCA mutation in their tumor.

The main results, previously published, showed that maintenance olaparib prolonged progression-free survival in the trial population overall, with a hazard ratio of 0.35 (N. Engl. J. Med. 2012;366:1382-92). There was no significant gain in overall survival as of an interim analysis, but there was a suggestion of benefit for patients with a BRCA mutation.

Among the BRCA mutation–positive subset, median progression-free survival was 11.2 months with olaparib versus 4.3 months with placebo (HR, 0.18; P less than .00001). Among the BRCA mutation–negative group, median progression-free survival was 5.6 months with olaparib versus 5.5 months with placebo (HR, 0.53; P less than .007).

There was still no overall survival advantage of olaparib in the trial population as a whole, but 23% of patients in the placebo group were switched to a PARP inhibitor. "This may be sufficient ... to actually have a confounding effect on the overall survival of these patients," Dr. Ledermann commented. There was a trend toward better overall survival with olaparib in the BRCA mutation–positive subset.

In addition, olaparib was superior to placebo in terms of the time from randomization to progression after a second, subsequent therapy, both among the BRCA mutation–positive subset (23.8 vs. 15.3 months; HR, 0.46; P less than .0003) and among the BRCA mutation–negative subset (17.1 vs. 14.7 months; HR, 0.64; P = .03).

"This I think translates into a clinically meaningful benefit, in that the effect if you like of olaparib is carried over beyond progression, to the time that they fail a second subsequent therapy," Dr. Ledermann said.

There was no significant difference in quality of life between the olaparib and placebo groups among women having a BRCA mutation.

Tolerability of olaparib did not differ significantly between women with the BRCA mutation–positive subset and the overall trial population. The leading adverse events in the former were low-grade nausea (seen in 73%) and fatigue (seen in 54%).

Dr. Ledermann disclosed that he receives travel grants from AstraZeneca. The trial was sponsored by AstraZeneca.

CHICAGO – For patients undergoing allogeneic bone marrow transplantation, conditioning with busulfan and fludarabine followed by post-transplant graft-vs.-host disease prophylaxis with single-agent cyclophosphamide is safe and is associated with good event-free and overall survival, said investigators at the annual meeting of the American Society of Clinical Oncology.

In a study of 92 patients with high-risk leukemias or myeloid malignancies, 2-year overall survival was 67%, and the rate of grade 3 or 4 acute graft-vs.-host disease (GVHD) was 15%, comparable to that seen with busulfan-cyclophosphamide conditioning regimens, said Dr. Christopher G. Kanakry, a medical oncologist at the Sidney Kimmel Cancer Center at John Hopkins Medical Center in Baltimore.

Neil Osterweil/IMNG Medical Media

Chronic GVHD was seen in 14% of all patients, occurring in only 7% of patients with related donors, and 22% of those with unrelated donors (P = .041). Event-free survival at 2 years was 62% and did not differ by donor type, Dr. Kanakry said.

"Post-transplant single-agent GVHD prophylaxis can be safely and effectively combined with busulfan/fludarabine myeloablative conditioning and is associated with an acceptable incidence of grade 2-4 acute graft-vs.-host disease, a low incidence of grade 3-4 acute graft-vs.-host disease and chronic graft-vs.-host disease, low treatment-related mortality, and effective disease control with favorable event-free and overall survival," he said.

Dr. Kanakry and his colleagues at Johns Hopkins, the Fred Hutchinson Cancer Center in Seattle and the University of Texas MD Anderson Cancer Center in Houston combined efforts to see whether the clinical efficacy seen in single-center studies with busulfan/fludarabine conditioning and cyclophosphamide GVHD prophylaxis could be safely combined.

They enrolled patients with high-risk hematologic malignancies, including patients with acute myeloid leukemia (AML) or acute lymphocytic leukemia in first complete remission with high-risk features, acute leukemias in second or greater remission, refractory or relapsed AML with 10% or fewer bone marrow blasts, myelodysplastic syndrome with high-risk features, chronic myeloid leukemia beyond the first chronic phase or resistant to tyrosine kinase inhibitors, Philadelphia chromosome–negative myeloproliferative disorders, relapsed chemotherapy-sensitive Hodgkin or non-Hodgkin lymphoma, or stage III multiple myeloma.

Of the 92 patients enrolled, 45 had related donors and 47 had unrelated donors.

Grade 2-4 acute GVHD occurred in 51% of patients, 42% of those with related donors, and 60% with unrelated donors (P = .027). Chronic GVHD occurred in six patients (14%), three of whom had bronchiolitis obliterans syndrome. The incidence of chronic GVHD also was significantly higher among patients with unrelated donors (P = .041).

Among all patients, 9% died from nonrelapse causes within the first 100 days of transplant, and 16% died within 1 year. There was no difference in the incidence of nonrelapse mortality between related and unrelated donors.

Not surprisingly, patients with complete remissions had significantly better 2-year event-free survival, at 80%, compared with 50% for patients with minimal residual disease, and 33% for patients with active disease (P = .0005).

Overall 2-year survival for all patients was 67% and did not differ by donor type. Overall survival was significantly better for patients with complete remissions, 79% of whom were alive at 2 years, compared with 50% of those with minimal residual disease, and 54% of those with active disease (P = .019).

Invited discussant Dr. Marcos J.G. De Lima, a hematologist-oncologist at University Hospitals Case Western Medical Center in Cleveland noted that the regimen is relatively simple, comparatively inexpensive, and reproducible.

"Could a cynic say that less chronic GVHD was due to the fact that you were using bone marrow only? I don’t think so, but certainly there is a bone marrow component [to the GVHD results]," he said.

The investigators also did not determine whether patients had ever taken other immunosuppressants, such as calcineurin inhibitors, Dr. De Lima said,

"I want to remind you folks that one of the most frustrating things in our business is that even when we reduce the incidence of acute GVHD, very few strategies have translated into less chronic [GVHD]; it’s like there is a different life between acute and chronic GVHD, and here it’s almost the opposite, which is very intriguing," he said.

The study was supported by Otsuka Pharmaceuticals. Dr. Kanakry reported having no relevant disclosures. Dr. De Lima was a coauthor of the study. He disclosed receiving research funding from Celgene.

CHICAGO – For patients undergoing allogeneic bone marrow transplantation, conditioning with busulfan and fludarabine followed by post-transplant graft-vs.-host disease prophylaxis with single-agent cyclophosphamide is safe and is associated with good event-free and overall survival, said investigators at the annual meeting of the American Society of Clinical Oncology.

In a study of 92 patients with high-risk leukemias or myeloid malignancies, 2-year overall survival was 67%, and the rate of grade 3 or 4 acute graft-vs.-host disease (GVHD) was 15%, comparable to that seen with busulfan-cyclophosphamide conditioning regimens, said Dr. Christopher G. Kanakry, a medical oncologist at the Sidney Kimmel Cancer Center at John Hopkins Medical Center in Baltimore.

Neil Osterweil/IMNG Medical Media

Chronic GVHD was seen in 14% of all patients, occurring in only 7% of patients with related donors, and 22% of those with unrelated donors (P = .041). Event-free survival at 2 years was 62% and did not differ by donor type, Dr. Kanakry said.

"Post-transplant single-agent GVHD prophylaxis can be safely and effectively combined with busulfan/fludarabine myeloablative conditioning and is associated with an acceptable incidence of grade 2-4 acute graft-vs.-host disease, a low incidence of grade 3-4 acute graft-vs.-host disease and chronic graft-vs.-host disease, low treatment-related mortality, and effective disease control with favorable event-free and overall survival," he said.

Dr. Kanakry and his colleagues at Johns Hopkins, the Fred Hutchinson Cancer Center in Seattle and the University of Texas MD Anderson Cancer Center in Houston combined efforts to see whether the clinical efficacy seen in single-center studies with busulfan/fludarabine conditioning and cyclophosphamide GVHD prophylaxis could be safely combined.

They enrolled patients with high-risk hematologic malignancies, including patients with acute myeloid leukemia (AML) or acute lymphocytic leukemia in first complete remission with high-risk features, acute leukemias in second or greater remission, refractory or relapsed AML with 10% or fewer bone marrow blasts, myelodysplastic syndrome with high-risk features, chronic myeloid leukemia beyond the first chronic phase or resistant to tyrosine kinase inhibitors, Philadelphia chromosome–negative myeloproliferative disorders, relapsed chemotherapy-sensitive Hodgkin or non-Hodgkin lymphoma, or stage III multiple myeloma.

Of the 92 patients enrolled, 45 had related donors and 47 had unrelated donors.

Grade 2-4 acute GVHD occurred in 51% of patients, 42% of those with related donors, and 60% with unrelated donors (P = .027). Chronic GVHD occurred in six patients (14%), three of whom had bronchiolitis obliterans syndrome. The incidence of chronic GVHD also was significantly higher among patients with unrelated donors (P = .041).

Among all patients, 9% died from nonrelapse causes within the first 100 days of transplant, and 16% died within 1 year. There was no difference in the incidence of nonrelapse mortality between related and unrelated donors.

Not surprisingly, patients with complete remissions had significantly better 2-year event-free survival, at 80%, compared with 50% for patients with minimal residual disease, and 33% for patients with active disease (P = .0005).

Overall 2-year survival for all patients was 67% and did not differ by donor type. Overall survival was significantly better for patients with complete remissions, 79% of whom were alive at 2 years, compared with 50% of those with minimal residual disease, and 54% of those with active disease (P = .019).

Invited discussant Dr. Marcos J.G. De Lima, a hematologist-oncologist at University Hospitals Case Western Medical Center in Cleveland noted that the regimen is relatively simple, comparatively inexpensive, and reproducible.

"Could a cynic say that less chronic GVHD was due to the fact that you were using bone marrow only? I don’t think so, but certainly there is a bone marrow component [to the GVHD results]," he said.

The investigators also did not determine whether patients had ever taken other immunosuppressants, such as calcineurin inhibitors, Dr. De Lima said,

"I want to remind you folks that one of the most frustrating things in our business is that even when we reduce the incidence of acute GVHD, very few strategies have translated into less chronic [GVHD]; it’s like there is a different life between acute and chronic GVHD, and here it’s almost the opposite, which is very intriguing," he said.

The study was supported by Otsuka Pharmaceuticals. Dr. Kanakry reported having no relevant disclosures. Dr. De Lima was a coauthor of the study. He disclosed receiving research funding from Celgene.

CHICAGO – For patients undergoing allogeneic bone marrow transplantation, conditioning with busulfan and fludarabine followed by post-transplant graft-vs.-host disease prophylaxis with single-agent cyclophosphamide is safe and is associated with good event-free and overall survival, said investigators at the annual meeting of the American Society of Clinical Oncology.

In a study of 92 patients with high-risk leukemias or myeloid malignancies, 2-year overall survival was 67%, and the rate of grade 3 or 4 acute graft-vs.-host disease (GVHD) was 15%, comparable to that seen with busulfan-cyclophosphamide conditioning regimens, said Dr. Christopher G. Kanakry, a medical oncologist at the Sidney Kimmel Cancer Center at John Hopkins Medical Center in Baltimore.

Neil Osterweil/IMNG Medical Media

Chronic GVHD was seen in 14% of all patients, occurring in only 7% of patients with related donors, and 22% of those with unrelated donors (P = .041). Event-free survival at 2 years was 62% and did not differ by donor type, Dr. Kanakry said.

"Post-transplant single-agent GVHD prophylaxis can be safely and effectively combined with busulfan/fludarabine myeloablative conditioning and is associated with an acceptable incidence of grade 2-4 acute graft-vs.-host disease, a low incidence of grade 3-4 acute graft-vs.-host disease and chronic graft-vs.-host disease, low treatment-related mortality, and effective disease control with favorable event-free and overall survival," he said.

Dr. Kanakry and his colleagues at Johns Hopkins, the Fred Hutchinson Cancer Center in Seattle and the University of Texas MD Anderson Cancer Center in Houston combined efforts to see whether the clinical efficacy seen in single-center studies with busulfan/fludarabine conditioning and cyclophosphamide GVHD prophylaxis could be safely combined.

They enrolled patients with high-risk hematologic malignancies, including patients with acute myeloid leukemia (AML) or acute lymphocytic leukemia in first complete remission with high-risk features, acute leukemias in second or greater remission, refractory or relapsed AML with 10% or fewer bone marrow blasts, myelodysplastic syndrome with high-risk features, chronic myeloid leukemia beyond the first chronic phase or resistant to tyrosine kinase inhibitors, Philadelphia chromosome–negative myeloproliferative disorders, relapsed chemotherapy-sensitive Hodgkin or non-Hodgkin lymphoma, or stage III multiple myeloma.

Of the 92 patients enrolled, 45 had related donors and 47 had unrelated donors.

Grade 2-4 acute GVHD occurred in 51% of patients, 42% of those with related donors, and 60% with unrelated donors (P = .027). Chronic GVHD occurred in six patients (14%), three of whom had bronchiolitis obliterans syndrome. The incidence of chronic GVHD also was significantly higher among patients with unrelated donors (P = .041).

Among all patients, 9% died from nonrelapse causes within the first 100 days of transplant, and 16% died within 1 year. There was no difference in the incidence of nonrelapse mortality between related and unrelated donors.

Not surprisingly, patients with complete remissions had significantly better 2-year event-free survival, at 80%, compared with 50% for patients with minimal residual disease, and 33% for patients with active disease (P = .0005).

Overall 2-year survival for all patients was 67% and did not differ by donor type. Overall survival was significantly better for patients with complete remissions, 79% of whom were alive at 2 years, compared with 50% of those with minimal residual disease, and 54% of those with active disease (P = .019).

Invited discussant Dr. Marcos J.G. De Lima, a hematologist-oncologist at University Hospitals Case Western Medical Center in Cleveland noted that the regimen is relatively simple, comparatively inexpensive, and reproducible.

"Could a cynic say that less chronic GVHD was due to the fact that you were using bone marrow only? I don’t think so, but certainly there is a bone marrow component [to the GVHD results]," he said.

The investigators also did not determine whether patients had ever taken other immunosuppressants, such as calcineurin inhibitors, Dr. De Lima said,

"I want to remind you folks that one of the most frustrating things in our business is that even when we reduce the incidence of acute GVHD, very few strategies have translated into less chronic [GVHD]; it’s like there is a different life between acute and chronic GVHD, and here it’s almost the opposite, which is very intriguing," he said.

The study was supported by Otsuka Pharmaceuticals. Dr. Kanakry reported having no relevant disclosures. Dr. De Lima was a coauthor of the study. He disclosed receiving research funding from Celgene.

CHICAGO – The salvage chemotherapy regimen of paclitaxel, ifosfamide, and cisplatin was active in the first-line treatment of intermediate- and poor-risk germ cell tumors in a small multicenter phase II study.

Overall, 28 of 41 evaluable patients achieved a complete response (68%), including 57% of intermediate risk (8/14) and 74% of poor-risk (20/27) patients.

"TIP demonstrated promising efficacy and met its prespecified endpoint as worthy of further study," Dr. Darren Feldman said at the annual meeting of the American Society of Clinical Oncology.

Paclitaxel (Taxol), ifosfamide (Ifex) and cisplatin (Platinol), or TIP, has become a standard regimen for germ cell tumor patients requiring salvage chemotherapy, demonstrating an approximately 70% complete response rate and 63% progression-free survival after a median of 6 years in relapsed patients.

As a result of the findings, a multicenter, randomized phase II trial has been initiated comparing TIP with standard BEP (bleomycin, etoposide, and cisplatin) as first-line therapy in intermediate- and poor-risk patients, said Dr. Feldman, with Memorial Sloan-Kettering Cancer Center in New York.

The current trial enrolled 44 men with germ cell tumors that were International Germ Cell Cancer Collaborative Group (IGCCCG) poor-risk (66%) or modified intermediate-risk, defined by serum lactate dehydrogenase (LDH) three times the upper limit of normal, if LDH was the only intermediate-risk criterion.

Histology was non-seminoma in 86% and the testis was the primary tumor site in 68%. Median patient age was 27 years.

Four cycles of TIP every 21 days was given, as planned, in 89% of patients. The regimen contained paclitaxel 120 mg/m² daily on days 1-2; ifosfamide 1,200 mg/m² mixed 1:1 with Mesna 1,200 mg/m², both daily on days 1-5; and cisplatin 20 mg/m² daily on days 1-5. Peg-filgrastim 6 mg was given subcutaneously as neutropenic fever prophylaxis on day 6 or 7.

An additional one to two cycles of adjuvant TIP could be administered if viable germ cell tumor was found at postchemotherapy surgery. Paclitaxel was initially dosed at 240 mg/m² over 5 days, but the dosing was changed to 2 days because of allergic infusion reactions.

In all, 27 of the 41 patients achieved a complete response to chemotherapy, defined by marker and radiographic normalization or marker normalization with full resection of all tumor masses and pathology revealing teratoma or necrosis, Dr. Feldman said.

One patient achieved a complete response to chemotherapy plus surgery, defined by marker normalization plus full resection with viable germ cell tumor in the specimen, but negative margins.

Partial responses, lasting 4 weeks with negative markers, were observed in 36% of intermediate-risk (5/14) and 4% of poor-risk patients (1/27). Favorable responses (CR plus PR) were seen in 93% and 78%, and incomplete responses in 7% and 22%.

After a median follow-up of 3.1 years, the estimated progression-free survival was 79% overall, 87% among intermediate-risk patients and 76% among poor-risk patients, Dr. Feldman said.

"These results compare favorably to historic results and, in fact, look similar to what would be expected in IGCCCG good- or intermediate-risk patients," he added.

At the time of the analysis, 80% of patients remained progression free and only two had died, resulting in an estimated 3-year overall survival rate of 95%.

TIP had an acceptable safety profile, with no treatment-related deaths and grade 3/4 events limited to hematologic or electrolyte abnormalities, Dr. Feldman said.

Dr. Feldman reported having no financial disclosures. A coauthor reported a consultant/advisory role with Bristol-Myers Squibb.

[email protected]

CHICAGO – The salvage chemotherapy regimen of paclitaxel, ifosfamide, and cisplatin was active in the first-line treatment of intermediate- and poor-risk germ cell tumors in a small multicenter phase II study.

Overall, 28 of 41 evaluable patients achieved a complete response (68%), including 57% of intermediate risk (8/14) and 74% of poor-risk (20/27) patients.

"TIP demonstrated promising efficacy and met its prespecified endpoint as worthy of further study," Dr. Darren Feldman said at the annual meeting of the American Society of Clinical Oncology.

Paclitaxel (Taxol), ifosfamide (Ifex) and cisplatin (Platinol), or TIP, has become a standard regimen for germ cell tumor patients requiring salvage chemotherapy, demonstrating an approximately 70% complete response rate and 63% progression-free survival after a median of 6 years in relapsed patients.

As a result of the findings, a multicenter, randomized phase II trial has been initiated comparing TIP with standard BEP (bleomycin, etoposide, and cisplatin) as first-line therapy in intermediate- and poor-risk patients, said Dr. Feldman, with Memorial Sloan-Kettering Cancer Center in New York.

The current trial enrolled 44 men with germ cell tumors that were International Germ Cell Cancer Collaborative Group (IGCCCG) poor-risk (66%) or modified intermediate-risk, defined by serum lactate dehydrogenase (LDH) three times the upper limit of normal, if LDH was the only intermediate-risk criterion.

Histology was non-seminoma in 86% and the testis was the primary tumor site in 68%. Median patient age was 27 years.

Four cycles of TIP every 21 days was given, as planned, in 89% of patients. The regimen contained paclitaxel 120 mg/m² daily on days 1-2; ifosfamide 1,200 mg/m² mixed 1:1 with Mesna 1,200 mg/m², both daily on days 1-5; and cisplatin 20 mg/m² daily on days 1-5. Peg-filgrastim 6 mg was given subcutaneously as neutropenic fever prophylaxis on day 6 or 7.

An additional one to two cycles of adjuvant TIP could be administered if viable germ cell tumor was found at postchemotherapy surgery. Paclitaxel was initially dosed at 240 mg/m² over 5 days, but the dosing was changed to 2 days because of allergic infusion reactions.

In all, 27 of the 41 patients achieved a complete response to chemotherapy, defined by marker and radiographic normalization or marker normalization with full resection of all tumor masses and pathology revealing teratoma or necrosis, Dr. Feldman said.

One patient achieved a complete response to chemotherapy plus surgery, defined by marker normalization plus full resection with viable germ cell tumor in the specimen, but negative margins.

Partial responses, lasting 4 weeks with negative markers, were observed in 36% of intermediate-risk (5/14) and 4% of poor-risk patients (1/27). Favorable responses (CR plus PR) were seen in 93% and 78%, and incomplete responses in 7% and 22%.

After a median follow-up of 3.1 years, the estimated progression-free survival was 79% overall, 87% among intermediate-risk patients and 76% among poor-risk patients, Dr. Feldman said.

"These results compare favorably to historic results and, in fact, look similar to what would be expected in IGCCCG good- or intermediate-risk patients," he added.

At the time of the analysis, 80% of patients remained progression free and only two had died, resulting in an estimated 3-year overall survival rate of 95%.

TIP had an acceptable safety profile, with no treatment-related deaths and grade 3/4 events limited to hematologic or electrolyte abnormalities, Dr. Feldman said.

Dr. Feldman reported having no financial disclosures. A coauthor reported a consultant/advisory role with Bristol-Myers Squibb.

[email protected]

CHICAGO – The salvage chemotherapy regimen of paclitaxel, ifosfamide, and cisplatin was active in the first-line treatment of intermediate- and poor-risk germ cell tumors in a small multicenter phase II study.

Overall, 28 of 41 evaluable patients achieved a complete response (68%), including 57% of intermediate risk (8/14) and 74% of poor-risk (20/27) patients.

"TIP demonstrated promising efficacy and met its prespecified endpoint as worthy of further study," Dr. Darren Feldman said at the annual meeting of the American Society of Clinical Oncology.

Paclitaxel (Taxol), ifosfamide (Ifex) and cisplatin (Platinol), or TIP, has become a standard regimen for germ cell tumor patients requiring salvage chemotherapy, demonstrating an approximately 70% complete response rate and 63% progression-free survival after a median of 6 years in relapsed patients.

As a result of the findings, a multicenter, randomized phase II trial has been initiated comparing TIP with standard BEP (bleomycin, etoposide, and cisplatin) as first-line therapy in intermediate- and poor-risk patients, said Dr. Feldman, with Memorial Sloan-Kettering Cancer Center in New York.

The current trial enrolled 44 men with germ cell tumors that were International Germ Cell Cancer Collaborative Group (IGCCCG) poor-risk (66%) or modified intermediate-risk, defined by serum lactate dehydrogenase (LDH) three times the upper limit of normal, if LDH was the only intermediate-risk criterion.

Histology was non-seminoma in 86% and the testis was the primary tumor site in 68%. Median patient age was 27 years.

Four cycles of TIP every 21 days was given, as planned, in 89% of patients. The regimen contained paclitaxel 120 mg/m² daily on days 1-2; ifosfamide 1,200 mg/m² mixed 1:1 with Mesna 1,200 mg/m², both daily on days 1-5; and cisplatin 20 mg/m² daily on days 1-5. Peg-filgrastim 6 mg was given subcutaneously as neutropenic fever prophylaxis on day 6 or 7.

An additional one to two cycles of adjuvant TIP could be administered if viable germ cell tumor was found at postchemotherapy surgery. Paclitaxel was initially dosed at 240 mg/m² over 5 days, but the dosing was changed to 2 days because of allergic infusion reactions.

In all, 27 of the 41 patients achieved a complete response to chemotherapy, defined by marker and radiographic normalization or marker normalization with full resection of all tumor masses and pathology revealing teratoma or necrosis, Dr. Feldman said.

One patient achieved a complete response to chemotherapy plus surgery, defined by marker normalization plus full resection with viable germ cell tumor in the specimen, but negative margins.

Partial responses, lasting 4 weeks with negative markers, were observed in 36% of intermediate-risk (5/14) and 4% of poor-risk patients (1/27). Favorable responses (CR plus PR) were seen in 93% and 78%, and incomplete responses in 7% and 22%.

After a median follow-up of 3.1 years, the estimated progression-free survival was 79% overall, 87% among intermediate-risk patients and 76% among poor-risk patients, Dr. Feldman said.

"These results compare favorably to historic results and, in fact, look similar to what would be expected in IGCCCG good- or intermediate-risk patients," he added.

At the time of the analysis, 80% of patients remained progression free and only two had died, resulting in an estimated 3-year overall survival rate of 95%.

TIP had an acceptable safety profile, with no treatment-related deaths and grade 3/4 events limited to hematologic or electrolyte abnormalities, Dr. Feldman said.

Dr. Feldman reported having no financial disclosures. A coauthor reported a consultant/advisory role with Bristol-Myers Squibb.

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CHICAGO – Retreating unresectable gastrointestinal stromal tumors with imatinib after disease progression can improve both progression-free survival and disease control rates, but the benefits of rechallenge are short lived, investigators reported at the annual meeting of the American Society of Clinical Oncology.

Imatinib rechallenge is commonly tried in patients with gastrointestinal stromal tumors (GIST) that have progressed after an initial response to imatinib (Gleevec) in the first line and sunitinib (Sutent) or another tyrosine kinase inhibitor (TKI) in the second line, but without empirical evidence to support the practice, said Dr. Yoon-Koo Kang, professor of oncology at Seoul National University in Seoul, South Korea.

In the phase III RIGHT (Rechallenge of imatinib in GIST having no effective treatment) trial, patients who were randomized to imatinib rechallenge had a small but significant benefit in progression-free survival (PFS), with a median of 1.8 months compared with 0.9 months for patients assigned to placebo (hazard ratio [HR] 0.45, P = .00075).

In addition, significantly more patients retreated with imatinib had stable disease lasting at least 4 weeks (30 vs. 17 patients, P = .005), 8 weeks (17 vs.6, P = .008), or 12 weeks (13 vs. 2, P = .003).

"Rechallenge of imatinib significantly improves progression-free survival and disease-control rate in patients with advanced GIST after failure of at least imatinib and sunitinib, likely by continuous kinase inhibition of the bulk of disease clones which retain imatinib sensitivity. However, TKI-resistant clones continue to progress, leading to relatively brief duration of benefit," said Dr. Kang.

The investigators enrolled patients with metastatic and/or unresectable GIST who had previously had either disease control with first-line imatinib for longer than 6 months, or who experienced disease progression on both first-line imatinib and second-line sunitinib. The patients had Eastern Cooperative Oncology Group (ECOG) performance status scores from 0 to 3.

A total of 41 patients were randomized in a double-blinded fashion to imatinib until disease progression, at which point they could stop or continue on imatinib, and 40 were randomized to placebo until disease progression, after which they could be crossed over to receive imatinib. In each group, 16 patients had previously received treatment with three or more TKIs, including nilotinib (Tasigna), sorafenib (Nexavar), regorafenib (Stivarga), or dovitinib.

Of the 40 patients in the placebo arm, 37 crossed over to imatinib after disease progression. Median PFS after crossover in these patients approached that of patients initially assigned to imatinib at 1.7 months.

Grade 3 or 4 fatigue occurred in four patients on imatinib vs. none on placebo, and grade 3 or 4 hyperbilirubinemia occurred in three patients and one patient, respectively. Grade 3 or 4 anemias were detected in 12 patients on imatinib vs. 3 on placebo.

The trial demonstrates the wisdom of the adage "if at first you don’t succeed, try, try again," said invited discussant Dr. Shreyaskumar Patel, professor of sarcoma oncology at the University of Texas MD Anderson Cancer Center in Houston.

If patients have "run out of all sorts of options, randomizing them to imatinib instead of placebo certainly slows down the rate of progression, even in the absence of a response, and certainly can [have an] impact on their overall quality of life and their natural history," he said.

The results also support the use of a kinase inhibitor rather than placebo in the control arm of future trials for novel anti-GIST agents, he added.

Dr. Kang and Dr. Patel disclosed ties to Novartis. Dr. Kang disclosed ties with Novartis and Bayer Schering Pharma. The RIGHT trial was sponsored in part by Novartis.

CHICAGO – Retreating unresectable gastrointestinal stromal tumors with imatinib after disease progression can improve both progression-free survival and disease control rates, but the benefits of rechallenge are short lived, investigators reported at the annual meeting of the American Society of Clinical Oncology.

Imatinib rechallenge is commonly tried in patients with gastrointestinal stromal tumors (GIST) that have progressed after an initial response to imatinib (Gleevec) in the first line and sunitinib (Sutent) or another tyrosine kinase inhibitor (TKI) in the second line, but without empirical evidence to support the practice, said Dr. Yoon-Koo Kang, professor of oncology at Seoul National University in Seoul, South Korea.

In the phase III RIGHT (Rechallenge of imatinib in GIST having no effective treatment) trial, patients who were randomized to imatinib rechallenge had a small but significant benefit in progression-free survival (PFS), with a median of 1.8 months compared with 0.9 months for patients assigned to placebo (hazard ratio [HR] 0.45, P = .00075).

In addition, significantly more patients retreated with imatinib had stable disease lasting at least 4 weeks (30 vs. 17 patients, P = .005), 8 weeks (17 vs.6, P = .008), or 12 weeks (13 vs. 2, P = .003).

"Rechallenge of imatinib significantly improves progression-free survival and disease-control rate in patients with advanced GIST after failure of at least imatinib and sunitinib, likely by continuous kinase inhibition of the bulk of disease clones which retain imatinib sensitivity. However, TKI-resistant clones continue to progress, leading to relatively brief duration of benefit," said Dr. Kang.

The investigators enrolled patients with metastatic and/or unresectable GIST who had previously had either disease control with first-line imatinib for longer than 6 months, or who experienced disease progression on both first-line imatinib and second-line sunitinib. The patients had Eastern Cooperative Oncology Group (ECOG) performance status scores from 0 to 3.

A total of 41 patients were randomized in a double-blinded fashion to imatinib until disease progression, at which point they could stop or continue on imatinib, and 40 were randomized to placebo until disease progression, after which they could be crossed over to receive imatinib. In each group, 16 patients had previously received treatment with three or more TKIs, including nilotinib (Tasigna), sorafenib (Nexavar), regorafenib (Stivarga), or dovitinib.

Of the 40 patients in the placebo arm, 37 crossed over to imatinib after disease progression. Median PFS after crossover in these patients approached that of patients initially assigned to imatinib at 1.7 months.

Grade 3 or 4 fatigue occurred in four patients on imatinib vs. none on placebo, and grade 3 or 4 hyperbilirubinemia occurred in three patients and one patient, respectively. Grade 3 or 4 anemias were detected in 12 patients on imatinib vs. 3 on placebo.

The trial demonstrates the wisdom of the adage "if at first you don’t succeed, try, try again," said invited discussant Dr. Shreyaskumar Patel, professor of sarcoma oncology at the University of Texas MD Anderson Cancer Center in Houston.

If patients have "run out of all sorts of options, randomizing them to imatinib instead of placebo certainly slows down the rate of progression, even in the absence of a response, and certainly can [have an] impact on their overall quality of life and their natural history," he said.

The results also support the use of a kinase inhibitor rather than placebo in the control arm of future trials for novel anti-GIST agents, he added.

Dr. Kang and Dr. Patel disclosed ties to Novartis. Dr. Kang disclosed ties with Novartis and Bayer Schering Pharma. The RIGHT trial was sponsored in part by Novartis.

CHICAGO – Retreating unresectable gastrointestinal stromal tumors with imatinib after disease progression can improve both progression-free survival and disease control rates, but the benefits of rechallenge are short lived, investigators reported at the annual meeting of the American Society of Clinical Oncology.

Imatinib rechallenge is commonly tried in patients with gastrointestinal stromal tumors (GIST) that have progressed after an initial response to imatinib (Gleevec) in the first line and sunitinib (Sutent) or another tyrosine kinase inhibitor (TKI) in the second line, but without empirical evidence to support the practice, said Dr. Yoon-Koo Kang, professor of oncology at Seoul National University in Seoul, South Korea.

In the phase III RIGHT (Rechallenge of imatinib in GIST having no effective treatment) trial, patients who were randomized to imatinib rechallenge had a small but significant benefit in progression-free survival (PFS), with a median of 1.8 months compared with 0.9 months for patients assigned to placebo (hazard ratio [HR] 0.45, P = .00075).

In addition, significantly more patients retreated with imatinib had stable disease lasting at least 4 weeks (30 vs. 17 patients, P = .005), 8 weeks (17 vs.6, P = .008), or 12 weeks (13 vs. 2, P = .003).

"Rechallenge of imatinib significantly improves progression-free survival and disease-control rate in patients with advanced GIST after failure of at least imatinib and sunitinib, likely by continuous kinase inhibition of the bulk of disease clones which retain imatinib sensitivity. However, TKI-resistant clones continue to progress, leading to relatively brief duration of benefit," said Dr. Kang.

The investigators enrolled patients with metastatic and/or unresectable GIST who had previously had either disease control with first-line imatinib for longer than 6 months, or who experienced disease progression on both first-line imatinib and second-line sunitinib. The patients had Eastern Cooperative Oncology Group (ECOG) performance status scores from 0 to 3.

A total of 41 patients were randomized in a double-blinded fashion to imatinib until disease progression, at which point they could stop or continue on imatinib, and 40 were randomized to placebo until disease progression, after which they could be crossed over to receive imatinib. In each group, 16 patients had previously received treatment with three or more TKIs, including nilotinib (Tasigna), sorafenib (Nexavar), regorafenib (Stivarga), or dovitinib.

Of the 40 patients in the placebo arm, 37 crossed over to imatinib after disease progression. Median PFS after crossover in these patients approached that of patients initially assigned to imatinib at 1.7 months.

Grade 3 or 4 fatigue occurred in four patients on imatinib vs. none on placebo, and grade 3 or 4 hyperbilirubinemia occurred in three patients and one patient, respectively. Grade 3 or 4 anemias were detected in 12 patients on imatinib vs. 3 on placebo.

The trial demonstrates the wisdom of the adage "if at first you don’t succeed, try, try again," said invited discussant Dr. Shreyaskumar Patel, professor of sarcoma oncology at the University of Texas MD Anderson Cancer Center in Houston.

If patients have "run out of all sorts of options, randomizing them to imatinib instead of placebo certainly slows down the rate of progression, even in the absence of a response, and certainly can [have an] impact on their overall quality of life and their natural history," he said.

The results also support the use of a kinase inhibitor rather than placebo in the control arm of future trials for novel anti-GIST agents, he added.

Dr. Kang and Dr. Patel disclosed ties to Novartis. Dr. Kang disclosed ties with Novartis and Bayer Schering Pharma. The RIGHT trial was sponsored in part by Novartis.