Longer Follow-Up Shows Survival Increase With Rocapuldencel-T in mRCC

Robert A. Figlin, MD, FACP

Patients with metastatic renal cell carcinoma (RCC) appeared to derive a substantial survival benefit with rocapuldencel-T, an immunotherapy made from dendritic cells, according to updated results from the phase III randomized ADAPT trial presented at the 2017 ESMO Congress.

The patients with the longest follow-up—approximately one-third of the total study population—had a median overall survival (OS) of 30.1 months with the combination of rocapuldencel-T plus standard therapy versus 22.2 months for patients who received standard therapy alone. Interim results for all treated patients had shown almost a 5-month survival advantage in favor of the control arm.

The preliminary findings from extended follow-up support the concept of a potential delayed treatment effect with immunotherapeutic agents, the so-called tail of the survival curve, Robert Figlin, MD, said during the meeting.

“Rocapuldencel-T induces long-term memory immune responses,” said Figlin, chair of Hematology-Oncology at Cedars-Sinai Medical Center. “More than 50% of subjects were censored in both treatment groups at the interim analysis, and 98% of censored subjects remained alive. Interim analyses may not fully capture the potential benefit of an active immunotherapy due to insufficient long-term follow-up. In this trial, there was limited survival follow-up at the time of the interim analysis, at a median of 20 months.”

The next analysis of data from the trial will occur during the first half of 2018, he added.

Rocapuldencel-T consists of autologous dendritic cells programmed by exposure to amplified RNA from a patient’s primary tumor. The agent is designed to overcome immunosuppression and induce broadly reactive, long-lasting antitumor memory T cells, said Figlin.

The phase III ADAPT trial involved 462 patients with newly diagnosed metastatic RCC with clear cell histology. Three-fourths of patients had intermediate-risk characteristics, and the remaining patients had poor-risk features. All patients received 6 weeks of treatment with sunitinib (Sutent) and then were randomized 2:1 to standard therapy alone or in combination with rocapuldencel-T.

Patients assigned to rocapuldencel-T received treatment at weeks 6, 9, 12, 15, 18, and 24, and then quarterly thereafter. The primary endpoint was OS. Key secondary endpoints included progression-free survival (PFS), response rate, and disease control rate (DCR). Investigators at 107 sites in North America, Europe, and Israel participated in the trial.

The two treatment groups did not differ significantly with respect to baseline characteristics. At the interim data analysis, follow-up of individual patients ranged from 0.4 to 47.7 months. Patients in the rocapuldencel-T arm had received a median of 8 doses of the agent over 48 weeks.

The interim analysis showed a median OS of 27.7 months with rocapuldencel-T and 32.4 months with standard therapy alone. The difference translated into an unadjusted hazard ratio of 1.10 and an adjusted hazard of 1.06. Median PFS was 6.0 months with combination therapy and 7.8 months with standard therapy alone, representing a hazard ratio of 1.15. None of the differences achieved statistical significance.

Figlin said the median survival in the control group is the longest reported to date from any study of intermediate-/poor-risk patients with metastatic RCC.

At the interim analysis, the combination arm had an objective response rate of 42.7% (including 9 complete responses) versus 39.4% in the control group (3 complete responses). Median duration of response was 8.4 months with the combination and 6.3 months with standard therapy alone. DCR was 82.4% with rocapuldencel-T and 76.1% with standard therapy alone.

During randomized therapy, 58.2% of patients in the combination arm had all-grade adverse events (AEs) attributable to rocapuldencel-T, and 95% of patients in both groups had AEs linked to standard therapy. The incidence of grade ≥3 AEs attributable to rocapuldencel-T was 2.0%, and about half of patients in each group had grade ≥3 AEs- related to standard therapy.

The rationale for continued follow-up in the trial came from previous studies of immunotherapy suggesting a tail-of-curve treatment effect. A phase II trial of rocapuldencel-T showed a survival curve inflection point at about 18 months of follow-up, similar to the median follow-up in ADAPT at the time of the interim analysis, Figlin noted. The phase II trial showed a median OS of 30.2 months with the immunotherapeutic agent, and 7 of 21 evaluable patients survived 4.5 years, including 2 who remained alive at 8 years.

ADAPT investigators performed a survival analysis by time of randomization. The analysis showed that the first 33% of patients randomized had a 30.1-month median OS in the rocapuldencel-T arm and 22.2 months in the control group. Analysis of the first two-thirds of patients randomized showed median survival values of 30.4 months in the combination arm and 32.4 months with standard therapy. Analysis of all randomized patients produced the values reported at the interim analysis.

“The benefit in median overall survival for the combination arm versus the control arm is seen in subjects with the longest survival follow-up,” said Figlin. “This suggests that the interim analysis of median overall survival may be premature.”

The analysis also showed a significant association between the increase in antigen-specific memory T cells after seven doses of rocapuldencel-T and improved survival (P < .0021).

Figlin R, Nicolette C, Tannir N, et al. Interim analysis of the phase 3 ADAPT trial evaluating rocapuldencelT (AGS-003), an individualized immunotherapy for the treatment of newly-diagnosed patients with metastatic renal cell carcinoma (mRCC). In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract 11370.