Metastatic renal cell carcinoma agent nearly doubles survival

Orlando, FL-A personalized immunotherapy (AGS-003) nearly doubled expected progression-free survival and overall survival when added to standard sunitinib (Sutent) in patients with unfavorable-risk metastatic renal cell carcinoma, according to results from a single-arm phase II study.

The results support an ongoing phase III study of the approach in which patients with metastatic clear-cell RCC are being randomized to personalized immunotherapy plus sunitinib or sunitinib alone, with overall survival as the primary endpoint, said first author Asim Amin, MD, PhD.

At the Genitourinary Cancers Symposium in Orlando, FL, Dr. Amin described long-term survival in 21 patients with intermediate- or poor-risk metastatic RCC who were treated with autologous dendritic cell immunotherapy in combination with sunitinib.

AGS-003 is produced using mRNA from the patient’s own tumor harvested at the time of nephrectomy.

“To the best of our knowledge, this is the first such platform,” Dr. Amin said. “At the time of nephrectomy, we get a little piece of the tumor and isolate the messenger RNA from the patient’s own tumor. That is electroporated into the patient’s own dendritic cells. The hope is that those dendritic cells will then express the patient’s own tumor antigens to the T cells.”

AGS-003 provides signals to induce an adaptive immune response. It is designed to expand the population of CD8+CD28+ central/effector memory T cells. In this way, it complements sunitinib-induced suppression of regulatory T cells and myeloid-derived suppressor cells.

In the phase II study, 21 patients with unfavorable-risk metastatic RCC were treated. Treatment consisted of standard 6-week cycles of sunitinib plus AGS-003, five doses given 3 weeks apart, and then every 12 weeks as maintenance.

“Using sunitinib made sense because it’s an accepted first-line standard of care and it actually may make the environment more appropriate for an immunotherapeutic to act,” said Dr. Amin, co-director of immunotherapy at Levine Cancer Institute, Charlotte, NC.

No grade 3-4 adverse events reported

More than 150 doses of AGS-003 were administered; no grade 3 or 4 adverse events related to immunotherapy were reported. Observed adverse events were consistent with expected sunitinib toxicities in advanced RCC, with the exception of grade-1 injection site reactions in about half of the patients.

Laboratory assessments for markers of autoimmune responses found no evidence of emergent autoimmune disease.

For the overall study population, median progression-free survival was 11.2 months and the final median overall survival was 30.2 months. Fifty-two percent had overall survival greater than 30 months. Seven of the 21 (33%) are still alive nearly 4 years from registration.

When analyzed by baseline Heng risk status, the median progression-free survival was 19.4 months for intermediate-risk patients and 5.8 months for subjects with poor-risk features at baseline. The estimated median overall survival is 39.5 months for intermediate- and 9.1 months for poor-risk subjects.

By comparison, in a pivotal trial, treatment with sunitinib yielded a median overall survival of 20.7 months for intermediate-risk and 5.3 months for poor-risk subjects. Only about 13% of sunitinib-treated, unfavorable-risk metastatic RCC patients survive longer than 30 months.

The ongoing phase III ADAPT (The Autologous Dendritic Cell Immunotherapy Plus Standard Treatment of Advanced Renal Cell Carcinoma) study is using this approach to personalized immunotherapy, with the goal of randomizing 450 patients. Eighty to 90 sites in North America and 30 to 40 additional sites in Europe and Israel are expected to participate.

Dr. Amin is a consultant/adviser for Argos Therapeutics. Several of his co-authors are consultant/advisers, have employment/leadership positions with; and/or own stock in Argos Therapeutics. One co-author is a consultant/adviser for Axcelo MSL Solutions.UT