June 2011

Immunotherapy Takes Center Stage During ASCO Week

Immunotherapy took center stage, for the second year in a row, at the American Society of Clinical Oncology (ASCO) Annual Meeting, with a particular focus on immunotherapy as a form of treatment for melanoma.

SITC Cancer Immunotherapy Guidelines, Melanoma Task Force

SITC established the Cancer Immunotherapy Guidelines (CIG) Task Force to develop recommendations for the clinical application of cancer immunotherapies. On June 2, under the leadership of SITC member Howard Kaufman, MD, Rush University Medical Center, the CIG melanoma working group convened.

This consensus meeting, made up of over 30 melanoma experts, including physicians, clinical investigators, nurses and patient advocates, was the first major step in developing clinical guidelines for immunotherapy of melanoma. This SITC initiative will result in evidence-based and consensus recommendations on FDA-approved melanoma immunotherapies with special consideration on patient eligibility, toxicity assessment and management, assessment of response and treatment termination, and therapy sequencing and combination strategies. Following the task force meeting, a draft manuscript will be prepared with recommendations and areas of knowledge gaps. This draft will be presented at the SITC 26th Annual Meeting, November 4-6, at which time SITC membership will have an opportunity to provide feedback and suggestions prior the manuscript's publication.

Positive Immunotherapy Trials Reported

During an exciting ASCO Plenary session on June 5, SITC member Jedd Wolchok, MD, PhD, Memorial Sloan-Kettering Cancer Center, reported positive results of a multinational, randomized phase III clinical trial that combined ipilimumab (Yervoy™, Bristol-Myers Squibb; 10mg/kg) with dacarbazine for previously untreated patients with metastatic melanoma. Dr. Wolchok reported that ipilimumab provided a durable response as a first-line treatment of advanced melanoma.

The study, published online June 5, 2011 in the New England Journal of Medicine, revealed a significantly longer median overall survival (11.2 vs. 9.1 months) among patients who received ipilimumab plus dacarbazine, compared to those who received placebo plus dacarbazine. The rate of overall survival (OS) was likewise higher in the ipilimumab-dacarbazine group: 47.3% vs. 36.3 % at year 1; 28.5% vs. 17.9% at year 2; and 20.8% vs. 12.2% at year 3 (hazard ratio for death with ipilimumab-dacarbazine, 0.72; p < 0.001). The improved OS with ipilimumab was observed across patient subgroups, including those defined according to age, sex, performance status, serum lactate dehydrogenase (LDH) level and substage of metastatic disease. Tumors were not routinely assessed for the BRAF V600E mutation. Half of the patients had M1c disease and 35% had elevated LDH levels at baseline associated with poor survival. Nevertheless, the median duration of best overall response was 19.3 months in the ipilimumab-dacarbazine group compared to 8.1 months with placebo plus dacarbazine. The risk of progression with ipilimumab plus dacarbazine was reduced 24% (p = 0.006) compared to placebo plus dacarbazine.

Grade 3 or 4 adverse events (AEs) were reported in 56.3% of patients who received ipilimumab plus dacarbazine and in 27.5% who received placebo plus dacarbazine (p = 0.001). There were no reported cases of gastrointestinal perforation and no drug-related deaths in the ipilimumab-dacarbazine group. Severe immune-mediated AEs were observed in 38.1% of patients in the ipilimumab-dacarbazine group compared to 4.4% in the dacarbazine group. The most frequent grade 3 or 4 immune-mediated AE was immune-mediated hepatitis (31.6% vs 2.4%, respectively). Immune-mediated enterocolitis was observed in 4.9% of patients who received ipilimumab plus dacarbazine and was not reported in the dacarbazine group. There were no patient deaths as a result of immune-mediated hepatitis or enterocolitis. The rate of hepatic toxicities was higher than expected from previous ipilimumab monotherapy trials; the investigators postulated that it may have been a combination effect with dacarbazine. The rate of enterocolitis was lower than expected. The main side effects of ipilimumab were managed using established guidelines.

Another study presented at the ASCO Annual Meeting by SITC member Kevin Heller, MD and colleagues indicated that ipilimumab at 10mg/kg in patients with brain metastasis was associated with prolonged survival (31% OS at 1 year and 26% OS at 2 years), durable responses and a safety profile similar to that observed in patients without brain metastasis.

A retrospective review of pooled ipilimumab safety data (1,498 patients; 14 phase I-III trials) by Ramy A. Ibrahim, MD et al, was also presented at the ASCO Annual Meeting. Results of this review indicated that inflammation-related adverse events (AEs) occurred in 64.2% of patients and resulted in death in <1% of patients. Most AEs occurred during ipilimumab induction (initial 4 does) and were generally mild and were managed using established product-specific treatment guidelines.

Combination Immunotherapies

The June 2, 2011 issue of the New England Journal of Medicine reported positive results of a phase III multicenter trial that combined gp100 peptide vaccine and high-dose interleukin-2 (IL-2) in patients with advanced melanoma. In this randomized trial involving 185 patients, SITC member Douglas J. Schwartzentruber, MD and colleagues demonstrated that the overall response rate was higher in the vaccine-IL-2 combination group than in the patient group that received only IL-2 (16% vs. 6%; p = 0.03). The combination group likewise demonstrated longer progression-free survival and median overall survival. This study shows that a cancer vaccine can enhance cytokine therapy in melanoma patients and emphasizes the potential of a rational immunotherapy combination.

Additional results from a phase II combination immunotherapy trial for advanced melanoma were also reported at ASCO, by SITC member Adam I. Riker, MD and colleagues. In this study, combination of the melanoma vaccine NLG-12036 (NewLinks Genetics) with pegylated interferon demonstrated efficacy with tumor regression and concomitant immune activation, and without significant grade 3 or 4 toxicities. Seventeen (17) of 25 patients in the trial were alive at the time of reporting, with a median survival of 20 months.

SITC member F. Stephen Hodi, MD, Dana-Farber Cancer Institute,also presented a study at ASCO with findings that suggested that ipilimumab synergized with bevacizumab in a phase I trial in patients with unresectable stage III or IV melanoma, with two-thirds of patients experiencing durable clinical benefit.

SITC Young Investigator Awarded at ASCO

SITC Member Davide Bedognetti, MD from the National Institutes of Health received a 2011 Young Investigator Award from the Conquer Cancer Foundation of the American Society of Clinical Oncology for his research on "Genomic, Functional Genomics and Proteomics Signature in Advanced Ovarian Cancer Patients and Their Prognostic and/or Predictive Implications." The research will be performed in collaboration with George Coukos, MD, PhD, University of Pennsylvania Medical Center. Dr. Bedognetti (mentored by Francesco Marincola, MD, National Institutes of Health) was also a 2010 SITC/iSBTc Travel Award Recipient for his research on predictive biomarkers in adoptive therapy in melanoma patients (in collaboration with Steven A Rosenberg, MD, PhD, Surgery Branch of the National Cancer Institute). Dr. Bedognetti is also a PhD Fellow in Clinical and Experimental Oncology and Hematology at the University of Genoa, Italy. He received his MD and Medical Oncology Board Certification from the same University and joined Dr. Marincola's lab in 2009 thanks to a scholarship supported by the Italian Association of Medical Oncology (AIOM) Foundation.

 

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