Nearly 16,000 people from 16 countries attended this year’s European Multidisciplinary Cancer Congress, held recently in Stockholm. The ASCO Post has featured several key reports from the meeting and will offer further coverage in upcoming issues. Additional noteworthy studies presented at the meeting are summarized below.
Vorinostat Falls Short in Mesothelioma
As a second-line treatment for advanced mesothelioma, the oral histone deacetylase inhibitor vorinostat (Zolinza) failed to extend survival in the VANTAGE014 phase III trial.1 The study was the largest of its kind in advanced mesothelioma, enrolling 660 patients with disease progression on first-line pemetrexed (Alimta) plus cisplatin or carboplatin.
Lee Krug, MD, of Memorial Sloan-Kettering Cancer Center, New York, reported that median overall survival was 30.7 weeks with vorinostat and 27.1 weeks with placebo. There was a statistically significant advantage for progression-free survival with vorinostat, but at a median of 6.3 vs 6.1 weeks, respectively (P < .001), this was not clinically meaningful, Dr. Krug said.
Rolf Stahel, MD, PhD, of the University Hospital Zurich, applauded the conduct of such a large study, “but despite this effort, the result is clearly negative,” he noted.
OCEANS Subanalysis Shows Benefit in Main Subgroups
The addition of bevacizumab (Avastin) to carboplatin/gemcitabine given at first recurrence of platinum-sensitive epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer achieved a 52% reduction in disease progression in the OCEANS trial (reported previously). A subgroup analysis reported in Stockholm showed that the treatment effect of bevacizumab was consistent across the majority of clinically relevant subgroups, including patients with partially platinum-sensitive disease, and those with bulky and less bulky disease.2
In the experimental arm of OCEANS, bevacizumab at 15 mg/kg was given concurrently with chemotherapy, followed by bevacizumab maintenance until disease progression or unacceptable toxicity; the control arm received chemotherapy plus placebo and placebo maintenance. The study included 484 women who experienced first recurrence of disease and had received no prior bevacizumab. Consistent with other trials, adverse events associated with bevacizumab, including hypertension, were more common in the experimental arm. Overall survival data are not yet mature.
“Bevacizumab plus chemotherapy followed by bevacizumab until disease progression should be considered an option for recurrent ovarian cancer,” said Carol Aghajanian, MD, Memorial Sloan-Kettering Cancer Center, New York.
Regarding these results, as well as those of ICON-7 and GOG-218, formal discussant Stanley Kaye, MD, Royal Marsden Hospital and Institute for Cancer Research, London, said, “These results taken together certainly indicate that bevacizumab should play a role in the treatment of ovarian cancer. In choosing who to treat, one approach is to select those who have the most to gain, including suboptimally debulked first-line patients as well as patients with recurrent disease. A key message is that in recurrent disease, bevacizumab should be given with chemotherapy and continued until disease progression.”
Quality of Life with Front-line Bevacizumab Not Compromised
Two related abstracts analyzing quality of life in the ICON-7 and GOG-218 trials, respectively, showed that incorporating bevacizumab into front-line therapy of ovarian cancer neither worsened nor improved quality of life.3,4
The trials had different definitions of endpoints and used different doses of bevacizumab. Nevertheless, both studies provide “an unprecedented database on quality of life in ovarian cancer that will be valuable for future studies. More mature quality-of-life data are needed. We would have smarter trial designs if we could select patients who benefit from bevacizumab,” stated formal discussant of these trials, Ate Van der Zee, MD, University Medical Center, Groningen, The Netherlands.
BIBF 1120 Does Not Beat Bevacizumab in Colorectal Cancer
A phase I/II trial failed to show a superior benefit for the novel triple angiokinase inhibitor BIBF 1120 plus modified (m)FOLFOX6 (leucovorin, fluorouracil [5-FU], oxaliplatin) compared with bevacizumab plus mFOLFOX6 in patients with metastatic colorectal cancer, reported Eric Van Cutsem, MD, of University Hospital Leuven in Belgium.5 Interim analysis of the 126 patients showed 9-month progression-free survival to be 63% with BIBF 1120 and 69% with bevacizumab. Median progression-free survival was 10.6 months in each arm.
“In comparison to bevacizumab, there was similar magnitude of efficacy, safety, tolerability, exposure, and dose intensity of mFOLFOX6, but a lower incidence of serious adverse events,” Dr. Van Cutsem reported. Serious adverse events occurred in 34.1% in the BIBF 1120 arm compared to 53.7% in the bevacizumab arm, primarily due to less gastrointestinal toxicity (11.8% vs 29.3%). The study is ongoing, and overall survival and quality-of-life factors are being evaluated.
Panitumumab Shows Limited Effect in Wild-type KRAS Colorectal Cancer
In chemoresistant patients with colorectal cancer selected for the wild-type KRAS gene, panitumumab (Vectibix), given with irinotecan as second-line therapy, produced an insignificant impact on overall survival and a modest improvement in progression-free survival, despite marked improvement in response rates.6 These were the results of PICCOLO, a large randomized trial with prospective molecular stratification, which included 696 patients randomized to irinotecan with or without panitumumab, of whom 460 had wild-type KRAS tumors and had received no prior anti-EGFRtherapy.
Further analysis showed that the benefit of panitumumab was confined to patients whose tumors were also wild-type for BRAF, NRAS, PIK3CA, and KRAS codon 146. Matt Seymour, MD, University of Leeds, UK, said, “We found mutations in one of these other genes in 29% of patients with wild-type KRAS tumors, and for these patients panitumumab produced borderline significantly worse survival. Conversely, patients with no mutations had increased benefit in terms of response rate, though disappointingly overall survival was not significantly improved.”
“These results suggest that around 30% of patients currently being selected for EGFR therapies based on standard KRAS tests may be gaining no benefit or even being harmed,” Dr. Seymour told listeners.
“The value of this study is that the authors went further and looked beyond KRAS mutations,” said Dr. Van Cutsem. “This is pushing us to do more in-depth analysis in our trials. The data are not fully conclusive.”
Chemotherapy Infusion for Liver Metastases in Uveal Melanoma
Patients with liver metastases from uveal melanoma experienced a survival benefit after treatment with percutaneous hepatic perfusion, in which chemotherapy is directly infused into the liver.7
“This is the first treatment to show a clinical benefit within a randomized trial in patients with liver metastases from ocular melanoma,” said James F. Pingpank, MD, of the University of Pittsburgh School of Medicine, Pennsylvania.
The phase III trial randomly assigned 93 patients to percutaneous hepatic perfusion or best alternative care. Percutaneous hepatic perfusion saturates the liver with high doses of melphalan delivered via hepatic artery infusion every 4 to 5 weeks.
Patients receiving percutaneous hepatic perfusion had a median progression-free survival of 6.1 months, compared with 1.6 months with best alternative care, a 64% reduction in risk (P < .001). For patients with disease predominantly confined to the liver, median hepatic-only progression-free survival reached 8.0 months vs 1.6 months with best alternative care (P < .0001). “These were highly significant results in the experimental arm,” Dr. Pingpank noted.
Overall survival at 1 year, however, was not significantly improved: 29% with percutaneous hepatic perfusion and 26% with best alternative care, with median overall survival being 11.4 and 9.9 months, respectively. This was most likely due to high (> 50%) crossover, he said.
Alexander Eggermont, MD, of the Institut de Cancérologie Gustave Roussy in Paris, commented, “One of the interesting points is that those patients who crossed over from the best alternative care arm of the study had progression-free survival after ‘late’ treatment with percutaneous hepatic perfusion that is about the same as when percutaneous hepatic perfusion was given upfront [6.5 months overall and 9.2 months with disease confined to the liver].”
Percutaneous hepatic perfusion was associated with more grade 3/4 hematologic toxicity, but this was transient. The investigators said this approach might also be used in patients with liver metastases from other cancers. ■
BI Dr. Krug received research funding from Merck. Dr. Seymour reported that the PICCOLO study received some financial support from Amgen. Dr. Kaye is a member of a Roche advisory board for which he has received honoraria. Dr. Eggermont has served on advisory boards for Bristol-Myers Squibb, Delcath, GlaxoSmithKline, Merck, and Roche.
References
1. Krug LM, Kindler H, Calvert H, et al: Vorinostat in patients with advanced malignant pleural mesothelioma who have failed prior pemetrexed and either cisplatin or carboplatin therapy: A phase III, randomized, double-blind, placebo-controlled trial. 2011 European Multidisciplinary Cancer Congress. Abstract 3BA. Presented September 26, 2011.
2. Aghajanian C, Blank SV, Goff B, et al: Efficacy in patient subgroups in OCEANS, a randomized, placebo-controlled phase 3 trial of chemotherapy ± bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. 2011 European Multidisciplinary Cancer Congress. Abstract 5LBA. Presented September 25, 2011.
3. Stark D, Nankivell M, Hipert F, et al: Quality of life in the ICON7 GIG phase III randomized clinical trial. 2011 European Multidisciplinary Cancer Congress. Abstract 22LBA. Presented September 26, 2011.
4. Monk BJ, Huang H, Burger RA, et al: Quality of life outcomes of a randomized, placebo-controlled trial of bevacizumab in the front-line treatment of ovarian cancer: A Gynecology Oncology Group study. 2011 European Multidisciplinary Cancer Congress. Abstract 23LBA. Presented September 26, 2011.
5. Van Cutsem E, Prenen H, Guillén-Ponce C, et al: A phase I/II open-label, randomized study of BIBF 1120 plus mFOLFOX6 compared to bevacizumab plus mFOLFOX6 in patients with metastatic colorectal cancer. 2011 European Multidisciplinary Cancer Congress. Abstract 14LBA. Presented September 27, 2011.
6. Seymour MT, Brown SR, Richman S, et al: Panitumumab in combination with irinotecan for chemoresistant advanced colorectal cancer: Results of PICCOLO, a large, randomized trial with prospective molecular marker stratification. 2011 European Multidisciplinary Cancer Congress. Abstract 6007. Presented September 24, 2011.
7. Pingpank JF, Hughes M, Alexander HR, et al: Percutaneous hepatic perfusion versus best alternative care for patients with melanoma liver metastases—efficacy update of the phase III trial. 2011 European Multidisciplinary Cancer Congress. Abstract 9304. Presented September 24, 2011.
