The phase III ADAPT trial investigating rocapuldencel-T in patients with metastatic renal cell carcinoma has been stopped by Argos Therapeutics after findings of an interim analysis revealed the immunotherapy was unlikely to meet any of the primary endpoints.
The phase III ADAPT trial investigating rocapuldencel-T in patients with metastatic renal cell carcinoma (mRCC) has been stopped by Argos Therapeutics after findings of an interim analysis revealed the immunotherapy was unlikely to meet any of the primary endpoints.
One of the 4 coprimary endpoints, median overall survival (OS) in the intent-to-treat population, was 28.2 months (95% CI, 23.4-35.2) for the combination of rocapuldencel-T with standard therapy versus 31.2 months (95% CI, 23.0-44.5) with standard therapy alone (HR, 1.10; 95% CI, 0.85-1.42).
Two other primary endpoints missed at the most recent analysis were OS for patients who were alive at the previous interim analysis in February 2017, and OS among all patients with at least 12 months of follow-up data. There was insufficient data to assess the fourth comprimary endpoint of 5-year survival. Argos had recently submitted a protocol amendment for the trial to the FDA detailing these 4 coprimary endpoints.
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.
Data from a previous analysis were presented at the 2017 ESMO Congress. In that analysis, the 2 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.
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. 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 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 rocapuldencel-T (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.