Meeting Highlights

2013 European Cancer Congress Walter Alexander

The 2013 European Cancer Congress combined the 17th congress of the European CanCer Organisation (ECCO), the 38th congress of the European Society for Medical Oncology (ESMO), and the 32nd congress of European Society for Therapeutic Radiology and Oncology (ESTRO). The meeting in Amsterdam was attended from September 27 to October 1 by 18,000 researchers and practitioners from 126 countries. This article reviews key sessions on breast cancer, melanoma, lung cancer, and neuroendocrine tumors.

Trastuzumab Emtansine Antibody–Drug Conjugate (Kadcyla) for HER-2–Positive Breast Cancer: TH3RESA, Phase 3 • Hans Wildiers, MD, PhD, University Hospitals, Leuven, Belgium For patients with progressive disease after two or more HER-2–directed regimens for metastatic breast cancer, there is no clear standard of care. Trastuzumab–DM1 (T-DM1) is a conjugated monoclonal antibody that combines trastuzumab (Herceptin, Genentech) and emtansine (DM1). T–DM1 has benefited patients with HER-2–positive metastatic breast cancer who were previously treated with trastuzumab and taxane-based chemotherapy. T-DM1 is the original name of ado-trastuzumab emtansine (Kadcyla, Genentech), which was approved by the FDA in February 2013. In the EMILIA clinical trial of advanced HER-2–positive breast cancer that was resistant to trastuzumab alone, T-DM1 improved survival by 5.8 months compared with a combination of lapatinib (Tykerb, GlaxoSmithKline) and capecitabine (Xeloda, Roche). In the phase 3 TH3RESA trial, investigators enrolled 400 women to receive intravenous (IV) T-DM1 (3.6 mg/kg every 3 weeks) and 200 women to receive a treatment of the physician’s choice (TPC). The women had unresectable tumors or tumor recurrences or metastases after several treatments that included trastuzumab and lapatinib. Participants had undergone a median of four previous treatments, and most of the women (75%) had visceral disease. About 80% had received a trastuzumab-containing regimen. Among patients with measurable disease, response rates were 8.6% for TPC and 31.3% for T-DM1 (P < 0.0001). The rates of study discontinuation were 36.9% for TPC and 21.0% for T-DM1, with death as the cause in 22.1% and 15.1% of patients, respectively. Rates of patient withdrawal were 13.1% with TPC and 4.7% with T-DM1. The difference in median progression-free survival of 2.9 months (from 3.3 months for TPC and 6.2 months for T-DM1) The author is a freelance medical writer living in New York City.

was highly significant, for a stratified hazard ratio (HR) of 0.528 and a 95% confidence interval (CI) of 0.422 to 0.661 (P < 0.0001). A first interim overall survival analysis revealed a similar pattern favoring T-DM1, with overall survival not reached for T-DM1 and 14.9 months for TPC (P = not significant). In general, adverse-event rates were lower with T-DM1 treatment. Rates for adverse events leading to therapy discontinuation were 10.9% for TPC and 6.7% for DM1. Dose reductions were needed in twice as many TPC patients (19.6%) as T-DM1 patients (9.4%). Grade 3 or higher adverse events generally occurred more frequently with TPC (43.5%), compared with T-DM1 (32.3%), specifically for diarrhea (4.3% vs. 0.7%), neutropenia (15.8% vs. 2.5%), and febrile neutropenia (3.8% vs. 0.2%). Grade 3 or higher thrombocytopenia was somewhat more common in the T-DM1 group than in the TPC group (1.6% vs. 4.7%, respectively). Dr. Wildiers concluded, “TH3RESA data demonstrate a consistent benefit for T-DM1 in patients with previously treated HER-2–positive advanced breast cancer.” He commented further, “Few drugs have been able to achieve both improved progression-free survival and a better toxicity profile. These results indicate that this drug has important clinical benefit for patients.”

Ipilimumab (Yervoy) in Advanced, Unresectable Melanoma: Phases 2 and 3

• Stephen Hodi, MD, Assistant Professor of Medicine, Dana Farber Cancer Institute, Boston, Massachusetts • Alexander M. M. Eggermont, Professor of Surgical Oncology, Erasmus University of Rotterdam, and Head, Department of Surgical Oncology, University Hospital of Rotterdam, Daniel den Hoed Cancer Center, The Netherlands Ipilimumab (Yervoy, Bristol-Myers Squibb) is a human monoclonal antibody that targets cytotoxic T-lymphocyte antigen-4 (CTLA-4). In melanoma, CTLA-4 is inhibited from recognizing and destroying tumor cells. Ipilimumab switches off the inhibitory mechanism. It has been known that some patients receiving ipilimumab survive over long periods, Dr. Hodi said at an ECCO press briefing. One phase 3 trial reported a 5-year overall survival rate of 18%. To estimate the long-term benefit of ipilimumab more precisely, Dr. Hodi and colleagues from Germany, France, and the U.S. pooled data for a primary analysis of overall survival. They evaluated data from 1,861 patients who were treated with ipilimumab in 12 studies (two phase 3 studies, eight phase 2 studies, and two observational studies) across different doses and treatment regimens. All patients had metastatic or locally advanced unresectable melanoma. In some patients, the followup period extended to 10 years. Median overall survival was 11.4% (95% CI, 10.7–12.1), and 3-year overall survival was 22% (95% CI, 20–24). Dr. Hodi pointed

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Meeting Highlights: 2013 European Cancer Congress out that a survival plateau was evident regardless of the dose used (3 or 10 mg), previous treatment, or maintenance treatment. Therapy was started at 3 years and continued through 10 years. When patients were stratified according to whether or not they had received prior treatment, median overall survival in treatment-naive patients was 13.5% (95% CI, 11.9–15.4), and 3-year overall survival was 26% (95% CI, 21–30). Among previously treated patients, median overall survival was 10.7% (95% CI, 9.6–11.4), and 3-year overall survival was 20% (95% CI, 18–23). An additional analysis included data from 2,985 patients who had received ipilimumab but had not been included in any trial. With the addition of these patients, median overall survival was 9.5% (95% CI, 9.0–10.0). The slightly lower 3-year overall survival rate in the extended population (21% vs. 26% for treatment-naive patients), Dr. Hodi explained, was accounted for by the tendency of patients in the extended-access program to be more ill with more advanced disease. Commenting on the analysis at the press conference, Professor Eggermont (past president of ECCO) said, “This pooled analysis clearly demonstrates that ipilimumab can lead to long-lasting tumor control in metastatic melanoma patients.”

PV-10 (Rose Bengal) in Metastatic Melanoma: Phase 2 Update

• Sanjiv S. Agarwala, MD, Chief, Medical Oncology and Hematology, St. Luke’s University Health Network, Bethlehem, Pennsylvania, and Professor of Medicine, Temple University, Philadelphia, Pennsylvania In an updated analysis of a phase 2 study of intralesional PV-10 (10% Rose Bengal disodium, Provectus), response rates were high, and a significant correlation was observed between blistering of lesions and responses in patients with advanced melanoma. Dr. Agarwala said in an interview: The principle is that this agent has a local chemoablative effect, one where we believe it enters into lysosomes, causing local necrosis and sometimes blistering of the lesion—indicative of an observed systemic effect in ‘bystander’ lesions that we think is immunologically mediated.

In the study, 80 patients with stage IIIB-IV melanoma that was refractory to a median of six earlier interventions, up to 10 cutaneous or subcutaneous target lesions were injected with intralesional PV-10. The lesions were re-injected, if necessary, at weeks 8, 12, and 16. Up to two additional cutaneous or subcutaneous lesions were left untreated to assess bystander response. The primary endpoint was best overall response rate in up to 10 target lesions. In all subjects, the best overall response rates were 51%, consisting of 26% complete responses (CRs) and 25% partial responses (PRs). The amount of tumor burden accessible to PV-10 injection was prognostic for the outcome, Dr. Agarwala said; both magnitude and duration of response were inversely related to untreated tumor burden. For patients in whom all

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lesions (except for up to two untreated bystander lesions) could be treated, the best overall response rate was 63%. For subjects in whom all disease was treated, the CR rate (50%) plus the PR rate (21%) were further increased to 71%. Also in this subgroup, the clinical response rate (CR plus PR plus stable disease [locoregional disease control]) was 82%. In patients experiencing blistering of target lesions, the CR plus PR plus stable disease rate was 91%, compared with 54% in patients whose lesions were without blistering (P = 0.001). Dr. Agarwala commented: Patients get very concerned when blistering develops, because they feel it may be indicating an infection. But now I can tell them that it’s actually a good thing, maybe correlating with a benefit, and, secondly, signaling that their immune system is activating—because that’s how you get the lymphocytes and the fluids in there.

Dr. Agarwala envisioned three scenarios of PV-10 use if it is ultimately approved by the FDA; a phase 3 trial is in the planning stages. The first, he said, would be in patients with disease that is refractory to all other therapies and who have injectable lesions. The second scenario would be in patients with injectable lesions but who are not eligible for systemic therapy, such as the elderly or those with comorbidities. The third scenario would involve a combination of PV-10 with other medications such as ipilimumab, nivolumab (Bristol-Myers Squibb), or both. “Of course, all of these need to be tested in clinical trials,” he said. Discussing the interest in the use of PV-10 by his surgical colleagues, Dr. Agarwala added other potential benefits of presurgical intralesional injection—turning unresectable lesions into resectable ones and stimulating the immune system to lower the odds of recurrence.

Crizotinib (Xalkori) in ALK-Positive Advanced Non–Small-Cell Lung Cancer • Maurice Pérol, MD, Département de Cancérologie Médicale, Centre Léon Bérard, Lyon, France

Crizotinib (Xalkori, Pfizer), a selective inhibitor of MET, ALK, and ROS1 tyrosine kinases, was approved by the FDA in 2011 and by the European Medicines Agency in 2012 for the treatment of advanced anaplastic lymphoma kinase (ALK). The drug had been available earlier through a French Temporary Authorization, which allowed assessment of “real-life” practice treatment of patients with ALK mutation–positive non–small-cell lung cancer (NSCLC). Dr. Péroly evaluated the 3.7% of patients who had ALKpositive adenocarcinoma among the 9,911 patients with advanced non-squamous cell carcinomas in the French National Cancer Institute Biomarker Program. Enrolled patients (median age, 58 years) had advanced NSCLC and evidence of ALK fusion gene rearrangement, as demonstrated by fluorescence in situ hybridization (FISH), immunohistochemistry, or both. Patients had been pretreated with chemotherapy. Investigators were especially interested in evaluating patients with brain

Meeting Highlights: 2013 European Cancer Congress metastases, scores of 3 or higher on the Eastern Cooperative Oncology Group (ECOG) Performance Status scale, patients with three or more prior treatments, and elderly patients. The most commonly used previous treatment had included a platinum agent plus pemetrexed injection (Alimta, Eli Lilly) with or without bevacizumab (Avastin, Genentech/Roche) in 58.2% of patients. About 28% of patients had received three or more treatments. Most patients had ECOG Performance Status scores of 0 to 1. Median duration of follow-up in 249 patients was 5.2 months (range, 0.03–27.8 months). The median duration of treatment was 3.8 months (range, 0.03–21.8 months). Dr. Pérol reported the best response analysis revealing complete responses (CRs) in 5.2% of all patients, in 5% of patients with brain metastases, and 7% of patients who had three or more previous lines of therapy. Partial responses (PRs) were noted in 51% of all patients, in 40% of those with a performance status of 3 or higher, in 61% of those with brain metastases, and in 48% of those who had received three or more lines of therapy. Transaminase elevations (in 6 of 310 patients), neutropenia (in 8 of 310 patients), and hepatocellular injury (in 12 of 310 patients) were the most commonly reported serious treatmentrelated adverse events. In routine clinical practice, Dr. Pérol concluded, overall response rates with crizotinib are similar to those reported in clinical trials (e.g., PROFILE 1005), with a good safety profile in unselected ALK-positive patients with NSCLC.

Lanreotide (Somatuline Autogel) For Gastroenteropancreatic Neuroendocrine Tumors: CLARINET, Late-Breaking Results

• Phillippe Ruszniewski, MD, Professor of Gastroenterology, and Chief, Division of Gastroenterology and Pancreatology, Beaujon Hospital, Clichy, France, and Paris Diderot University, Paris, France • Kjell Öberg, MD, PhD, Discussant, Uppsala University Hospital, Uppsala, Sweden Results of the CLARINET trial (Controlled study of Lanreotide Antiproliferative Response in patients with gastroentero- pancreatic NeuroEndocrine Tumors) led ECCO session discussant Dr. Öberg to suggest that guidelines be revised to include wider indications for somatostatin analogues and to include nonfunctioning neuroendocrine tumors (NETs). Dr. Öberg commented “the previous restriction on the use of somatostatin analogues to only functioning tumors is no longer justified.” Only one prospective trial prior to CLARINET had shown efficacy for somatostatin analogues in gastroenteropancreatic NETs (GEP–NETs). As a result, the antiproliferative role of these agents remains limited, Dr. Ruszniewski stated in his oral presentation. CLARINET is the first large-scale, multinational phase 3 trial to prospectively evaluate the antiproliferative effects of lanreotide (Somatuline Autogel, Ipsen) 120 mg, a long-acting somatostatin analogue, in a population of patients with GEP– NETs (including midgut, hindgut, and pancreatic NETs). Patients enrolled in CLARINET (n = 204) had well-differentiated or moderately differentiated (Ki67 less than 10%),

nonfunctioning GEP–NETs, with no hormone-related symptoms. (Antigen Ki67 is a nuclear protein associated with cellular proliferation.) The patients had not received somatostatin analogues, interferon, chemoembolization, or chemotherapy in the previous 6 months. They were randomly assigned to receive lanreotide 120 mg (n = 101) or placebo (n = 103) every 4 weeks for 96 weeks or until progressive disease or death. The primary endpoint was progression-free survival. Most patients (96%) had stable disease and were treatmentnaive (81%). Disease was World Health Organization grade 2 (Ki67 3%–10%) in 22% of patients, and 33% had a hepatic tumor load exceeding 25%. At enrollment, the primary tumor sites were the pancreas (45%), the midgut (36%), the hindgut (7%), and unknown (13%). After 2 years of treatment, median progression-free survival was not reached in the lanreotide group (32 events) and was 18.0 months for the placebo patients (60 events) (95% CI, 12.1–24.0). Of the patients receiving placebo, 22% remained alive at 2 years, compared with 62% in the lanreotide group (HR = 0.47; 95% CI, 0.30–0.73; P = 0.0002). When the investigators conducted a subgroup analysis based on tumor location, they found a significantly favorable HR for treatment with lanreotide in patients with midgut tumors (HR = 0.35; 95% CI, 0.16–0.80; P = 0.0091) and a favorable trend in patients with pancreatic tumors (HR = 0.58; 95% CI, 0.32–1.04; P = 0.0637). According to tumor grade, the analysis revealed greater benefits for patients with a lower hepatic tumor burden (25% or less; HR = 0.34; 95% CI, 0.18–0.62; P = 0.0002) than for patients with a higher hepatic burden (above 25%; HR = 0.45; 95% CI, 0.23–0.88; P = 0.0170). A larger benefit for lanreotide, compared with placebo, was noted in patients with both grade 1 and grade 2 tumors. With 19 deaths in the lanreotide arm and 17 deaths in the placebo arm, overall survival rates were similar between the groups (P = 0.8791). Dr. Ruszniewski reported that adverse events were consistent with the known profile of lanreotide (diarrhea, 26%; abdominal pain, 14%; and cholelithiasis, 10%). There were few with- drawals resulting from treatment-emergent adverse events (3% in both groups). Dr. Ruszniewski concluded, “Progression-free survival was substantially prolonged with lanreotide 120 mg for metastatic well-to-moderately differentiated enteropancreatic neuroendocrine tumors.” He added, “This antiproliferative effect of lanreotide may support its place in treatment algorithms for enteropancreatic neuroendocrine tumors.” n

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2013 European cancer congress.

Therapies for breast cancer, melanoma, lung cancer, and neuroendocrine tumors...
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