AGS-003 Vaccine Achieves Survival Benefits in mRCC

Robert Figlin, MD

Professor, Medicine and Biomedical Sciences, Director, Division of Hematology/Oncology, Deputy Director, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center,

Los Angeles, CA

AGS-003, a personalized dendritic cell immunotherapy, demonstrated prolonged survival benefits in patients with metastatic renal cell carcinoma (mRCC), with one-third of those who took the drug during a phase II trial still alive after nearly four years, according to updated results reported at the 2013 Genitourinary Cancers Symposium.¹

In the open-label study, 21 patients with unfavorable- risk mRCC received the targeted therapy sunitinib plus AGS-003, which is custom-made for each patient using RNA isolated from a tumor specimen and dendritic cells harvested through leukapheresis.

The final median overall survival (OS) was 30.2 months. When responses were analyzed by baseline Heng risk status, patients in the intermediaterisk group (n = 11) had not yet reached median OS and are estimated to achieve an OS of at least 39.5 months. For poor-risk patients (n =10), the median OS was 9.1 months. Seven patients (33%) remained alive at the time of the presentation.

These results represent a dramatic improvement over the survival rates expected for patients with mRCC, investigators indicated. Median OS levels are 22.5 months for intermediate-risk patients and 7.8 months for poor-risk patients, according to the Heng risk model for patients treated with therapies such as sunitinib that target vascular endothelial growth factor (VEGF), investigators said in their poster presentation.

The positive findings have laid the groundwork for the pivotal phase III ADAPT trial, which will compare AGS-003 plus sunitinib with sunitinib alone in an estimated 450 patients with newly diagnosed, unfavorable-risk mRCC (www.ClinicalTrials.gov, NCT01582672).

“Those are the kinds of results that one wouldn’t expect from traditional, currently available FDA-approved therapies,” said Robert Figlin, MD, primary investigator for the ADAPT trial, in an interview. “They’re very exciting. We’re looking for opportunities to improve survival in kidney cancer, especially for those patients with a poor prognosis. And, although a small phase II study to start, the results are impressive and are justifying our randomized phase III trial.”

Figlin, who is director of the Division of Hematology/Oncology at Cedars-Sinai Medical Center in Los Angeles, said the side effect profile of patients who participated in the phase II trial was “very favorable.” He said adverse events (AEs) for patients treated with a combination of standard plus immune therapies usually stem from the standard treatment, and not the immune-based therapy.

ADAPT Study Design¹

^a 50 mg daily for 4 weeks, then 2 weeks off

^b Other compatible agents may be substituted for sunitinib.

SD indicates stable disease; PD, progressive disease.

In the phase II trial, the most common AEs that patients experienced were diarrhea (61.9%), fatigue (57.1%), and nausea (52.4%). No grade 3/4 AEs were attributed to AGS-003; a total of five patients experienced grade 3/4 events, including two patients with fatigue, two with weight decrease, and one with diarrhea.

Dosing and Immune Response

The overall clinical benefit rate, including partial responses and stable disease, was 62% (13 of 21 patients) from the first dose of AGS-003 and an estimated 81% (17 of 21 patients) from screening.Patients received sunitinib for one 6-week cycle (4 weeks on followed by 2 weeks off) and then AGS-003 for five doses (3 weeks apart), followed by AGS-003 quarterly and continued sunitinib until progressive disease. Each dose of AGS-003 consisted of three 0.2 mL intradermal injections.

During the course of the trial, that regimen translated into more than 150 doses of AGS-003 for each patient, yet only tumor specimens from the initial nephrectomy or metastectomy and a single leukapheresis were needed to create the vaccine.

“Many patients with kidney cancer have their tumor extracted from their primary site, and these are often very large tumors with much material available for extraction,” Figlin said. “The technology also facilitates the ability to make large amounts of the vaccine with only a single leukapheresis, so although we don’t know the duration of what a person would otherwise benefit from, by being able to generate multiple months’ to years’ worth of vaccine from a single harvest, it gives this therapy the chance to continue to stimulate the immune system.”

Notably, investigators found a statistically significant correlation between OS and participants’ immune response, defined as an increase in the absolute number of memory T-cells measured prospectively by nonparametric bivariate analysis (Kendall’s τ = 0.5; P <0.02).

In the ADAPT trial, investigators will be looking at T-cell response as well as OS. Argos Therapeutics Inc, the Durham, North Carolina-based company developing AGS-003, said patient enrollment began in January and ultimately is expected to include participants at 120 sites, mostly in the United States, and also in Canada, Israel, Italy, Germany, Spain, and the United Kingdom.

Final data from the trial are expected during the second half of 2015, Argos said. If positive, the company would submit a Biologic License Application (BLA) to the FDA.

The 2013 Genitourinary Cancers Symposium was held in Orlando, Florida, February 14-16. The symposium was cosponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Reference

1. Amin A, Dudek A, Logan T, et al. Prolonged survival with personalized immunotherapy (AGS-003) in combination with sunitinib in unfavorable risk metastatic RCC (mRCC). Poster presented at: 2013 Genitourinary Cancers Symposium; February 14-16, 2013; Orlando, FL. Abstract 357.