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AACR annual meeting 2012
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AACR annual meeting 2012 Steve Gschmeissner/Science Photo Library
TH-302 in pancreatic cancer
Published Online April 13, 2012 DOI:10.1016/S14702045(12)70160-2 The American Association for Cancer Research annual meeting was held on March 31–April 4, 2012, in Chicago, IL, USA
A phase 2b trial of the hypoxiaactivated cytotoxic prodrug TH-302 showed that patients with advanced, first-line pancreatic cancer lived longer without disease progression when the drug was combined with gemcitabine compared with gemcitabine alone. Mitesh Borad (Scottsdale, AZ, USA) and colleagues randomly assigned 214 patients, including 77% with distant metastases, to receive either gemcitabine, TH-302 240 mg/m2 plus gemcitabine, or TH-302 340 mg/m2 plus gemcitabine intravenously. Progression-free survival (PFS) in the combination groups was 5·6 months versus 3·6 months with gemcitabine (hazard ratio 0·61 [95% CI 0·43–0·87], p=0·005). Median PFS in the higher dose TH-302 group was 6·0 months (hazard ratio 0·58 [95% CI 0·39–0·87], p=0·008). Response rate also showed the same positive trend: 12% for gemcitabine, 17% in the low-dose TH-302 group and 27% in the high-dose TH-302 group. Rash and stomatitis, mostly grades 1 and 2, were significantly greater in the combination groups. Myelosuppression was a dose-limiting toxic effect in the combination groups but did not result in an increase in treatment discontinuation.
Selumetinib The MEK-1/2 inhibitor selumetinib showed activity in recurrent, lowgrade serous ovarian or peritoneal cancer in a phase 2 study. John Farley (Phoenix, AZ, USA) and colleagues tested a twice-daily 50 mg oral dose of selumetinib in 52 patients, 58% of whom had received at least three previous chemotherapy regimens. Eight patients (15%) had complete (one) or partial (seven) responses, while another 34 (65%) had stable disease, for a disease control rate of 81%. The 15% response rate was about three times higher than that seen for cytotoxic chemotherapy 454
in this setting. Median PFS of 11 months was also higher than that seen with chemotherapy. The most common grade 3 toxic effects were nausea, vomiting, and rash, and only three patients had grade 4 toxic effects. In a molecular analysis of 34 tumour specimens, the activity of the drug did not seem to depend on whether patients had mutated RAS or RAF, possibly due to the low number of specimens analysed, while those who overexpressed phospho-ERK had a 100% disease control rate. Investigators have proposed a phase 3 trial comparing a MEK inhibitor with chemotherapy in recurrent low-grade serous carcinoma.
Ibrutinib in DLBCL The first-in-class Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib showed early efficacy, including complete responses, in a poor prognosis form of diffuse large B-cell lymphoma (DLBCL). Louis Staudt (Bethesda, MD, USA) and colleagues did a phase 1 pilot study of ten relapsed or refractory patients with the activated B-cell-like subtype of DLBCL. A 560 mg daily dose of oral ibrutinib induced two complete responses, including one still ongoing after 16 months, one partial response in a patient with primary refractory disease, and one stable disease. Responses were not dependent on whether patients had mutations in the B-cell receptor. Grade 1 or 2 toxic effects included diarrhoea, nausea, and fatigue. Preliminary results from an ongoing phase 2 study also showed some responses in nonactivated B-cell DLBCL, suggesting a broader role for the drug in the disease.
BCG strains in bladder cancer A phase 3 study comparing the two most commonly used strains in Europe and the USA of bacillus
Calmette-Guérin (BCG) immunotherapy is the first to show significantly greater efficacy of one in preventing recurrences in patients with non-muscle-invasive bladder cancer at high risk of recurrence. In the trial done by George Thalmann (Bern, Switzerland) and colleagues, 149 patients underwent surgical resection and were then randomised to receive six weekly injections of either the Tice or Connaught strains of BCG and followed up for recurrence. Patients treated with BCG Connaught had significantly fewer recurrences than those treated with BCG Tice (p<0·002). 5-year recurrence-free survival was 75% (95% CI 65–87) in patients given the Connaught strain versus 46% (34–62) in those given the Tice strain. Overall survival did not reach a significant difference in the two groups. Investigators said that the result should be confirmed in other populations.
Pazopanib Final results from a phase 2 trial of the antiangiogenic drug pazopanib showed it to be the first targeted therapy to meet its primary endpoint in metastatic urothelial cancer. In the study done by Andrea Necchi (Milan, Italy) and colleagues, about half of the 41 patients were treated in the third-line or beyond and 46% of patients had chemorefractory disease. Patients were treated with 800 mg once-daily pazopanib. At follow-up, seven patients (17%) had a partial response to therapy and 24 (59%) patients had stable disease for an overall clinical benefit rate of 76%. Median PFS and overall survival were 2·6 months (95% CI 1·7–3·7) and 4·7 months (4·2–7·3), respectively. Early rising levels of interleukin-8 (after 4 weeks of treatment) were associated with tumour progression and shorter overall survival.
Malini Guha www.thelancet.com/oncology Vol 13 May 2012
AACR annual meeting 2012 Steve Gschmeissner/Science Photo Library
TH-302 in pancreatic cancer
Published Online April 13, 2012 DOI:10.1016/S14702045(12)70160-2 The American Association for Cancer Research annual meeting was held on March 31–April 4, 2012, in Chicago, IL, USA
A phase 2b trial of the hypoxiaactivated cytotoxic prodrug TH-302 showed that patients with advanced, first-line pancreatic cancer lived longer without disease progression when the drug was combined with gemcitabine compared with gemcitabine alone. Mitesh Borad (Scottsdale, AZ, USA) and colleagues randomly assigned 214 patients, including 77% with distant metastases, to receive either gemcitabine, TH-302 240 mg/m2 plus gemcitabine, or TH-302 340 mg/m2 plus gemcitabine intravenously. Progression-free survival (PFS) in the combination groups was 5·6 months versus 3·6 months with gemcitabine (hazard ratio 0·61 [95% CI 0·43–0·87], p=0·005). Median PFS in the higher dose TH-302 group was 6·0 months (hazard ratio 0·58 [95% CI 0·39–0·87], p=0·008). Response rate also showed the same positive trend: 12% for gemcitabine, 17% in the low-dose TH-302 group and 27% in the high-dose TH-302 group. Rash and stomatitis, mostly grades 1 and 2, were significantly greater in the combination groups. Myelosuppression was a dose-limiting toxic effect in the combination groups but did not result in an increase in treatment discontinuation.
Selumetinib The MEK-1/2 inhibitor selumetinib showed activity in recurrent, lowgrade serous ovarian or peritoneal cancer in a phase 2 study. John Farley (Phoenix, AZ, USA) and colleagues tested a twice-daily 50 mg oral dose of selumetinib in 52 patients, 58% of whom had received at least three previous chemotherapy regimens. Eight patients (15%) had complete (one) or partial (seven) responses, while another 34 (65%) had stable disease, for a disease control rate of 81%. The 15% response rate was about three times higher than that seen for cytotoxic chemotherapy 454
in this setting. Median PFS of 11 months was also higher than that seen with chemotherapy. The most common grade 3 toxic effects were nausea, vomiting, and rash, and only three patients had grade 4 toxic effects. In a molecular analysis of 34 tumour specimens, the activity of the drug did not seem to depend on whether patients had mutated RAS or RAF, possibly due to the low number of specimens analysed, while those who overexpressed phospho-ERK had a 100% disease control rate. Investigators have proposed a phase 3 trial comparing a MEK inhibitor with chemotherapy in recurrent low-grade serous carcinoma.
Ibrutinib in DLBCL The first-in-class Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib showed early efficacy, including complete responses, in a poor prognosis form of diffuse large B-cell lymphoma (DLBCL). Louis Staudt (Bethesda, MD, USA) and colleagues did a phase 1 pilot study of ten relapsed or refractory patients with the activated B-cell-like subtype of DLBCL. A 560 mg daily dose of oral ibrutinib induced two complete responses, including one still ongoing after 16 months, one partial response in a patient with primary refractory disease, and one stable disease. Responses were not dependent on whether patients had mutations in the B-cell receptor. Grade 1 or 2 toxic effects included diarrhoea, nausea, and fatigue. Preliminary results from an ongoing phase 2 study also showed some responses in nonactivated B-cell DLBCL, suggesting a broader role for the drug in the disease.
BCG strains in bladder cancer A phase 3 study comparing the two most commonly used strains in Europe and the USA of bacillus
Calmette-Guérin (BCG) immunotherapy is the first to show significantly greater efficacy of one in preventing recurrences in patients with non-muscle-invasive bladder cancer at high risk of recurrence. In the trial done by George Thalmann (Bern, Switzerland) and colleagues, 149 patients underwent surgical resection and were then randomised to receive six weekly injections of either the Tice or Connaught strains of BCG and followed up for recurrence. Patients treated with BCG Connaught had significantly fewer recurrences than those treated with BCG Tice (p<0·002). 5-year recurrence-free survival was 75% (95% CI 65–87) in patients given the Connaught strain versus 46% (34–62) in those given the Tice strain. Overall survival did not reach a significant difference in the two groups. Investigators said that the result should be confirmed in other populations.
Pazopanib Final results from a phase 2 trial of the antiangiogenic drug pazopanib showed it to be the first targeted therapy to meet its primary endpoint in metastatic urothelial cancer. In the study done by Andrea Necchi (Milan, Italy) and colleagues, about half of the 41 patients were treated in the third-line or beyond and 46% of patients had chemorefractory disease. Patients were treated with 800 mg once-daily pazopanib. At follow-up, seven patients (17%) had a partial response to therapy and 24 (59%) patients had stable disease for an overall clinical benefit rate of 76%. Median PFS and overall survival were 2·6 months (95% CI 1·7–3·7) and 4·7 months (4·2–7·3), respectively. Early rising levels of interleukin-8 (after 4 weeks of treatment) were associated with tumour progression and shorter overall survival.
Malini Guha www.thelancet.com/oncology Vol 13 May 2012