Background
Phase 3, open-label, international RCT. 304 patients with advanced (inoperable or metastatic) adrenocortical carcinoma (ACC). ACC is a rare malignancy with dismal prognosis; mitotane monotherapy had been the only established systemic treatment prior to this trial. Median age 48 years; ECOG PS 0–2. Stratified by prior treatment and mitotane status.
Interventions and follow up
Arm A: EDP+M — etoposide 100 mg/m² days 2–4, doxorubicin 40 mg/m² day 1, cisplatin 40 mg/m² days 3–4 (q4wk) + mitotane (titrated to target serum levels 14–20 mg/L)
Arm B: Sz+M — streptozotocin 1 g/day × 5 days (cycle 1), then 2 g day 1 (subsequent cycles, q3wk) + mitotane (same serum target)
Primary endpoint: Overall survival
mFollow up: Median 6.7 months (event-driven OS analysis)
Arm B: Sz+M — streptozotocin 1 g/day × 5 days (cycle 1), then 2 g day 1 (subsequent cycles, q3wk) + mitotane (same serum target)
Primary endpoint: Overall survival
mFollow up: Median 6.7 months (event-driven OS analysis)
Results
ORR: 23.2% vs 9.2%, P<.001
mPFS: 5.0 vs 2.1 months, HR 0.55, 95% CI 0.43–0.69, P<.001
mOS: 14.8 vs 12.0 months, HR 0.79, 95% CI 0.61–1.02, P=.07 — primary endpoint not met
2-year OS: 29% vs 23%
mPFS: 5.0 vs 2.1 months, HR 0.55, 95% CI 0.43–0.69, P<.001
mOS: 14.8 vs 12.0 months, HR 0.79, 95% CI 0.61–1.02, P=.07 — primary endpoint not met
2-year OS: 29% vs 23%
Adverse events
Main adverse events: Grade ≥3 AEs higher in EDP+M arm: neutropenia 47% vs 17%; nausea/vomiting grade ≥3 more frequent with EDP+M. Mitotane toxicity present in both arms: fatigue, GI intolerance, neurotoxicity (cerebellar ataxia at serum levels >20 mg/L). Dose reductions for mitotane toxicity common in both groups; toxic serum levels were an important management challenge.
Conclusions
EDP+mitotane significantly improved ORR and PFS over streptozotocin+mitotane in advanced ACC, establishing EDP+M as the reference first-line regimen. The primary OS endpoint did not reach statistical significance (HR 0.79, P=.07), likely due to underpowering and possible crossover. EDP+mitotane is now the de facto standard of care for first-line advanced ACC based on superior PFS and ORR in this, the only Phase 3 RCT ever completed in ACC.
Key Limitations
Key Limitations: The primary OS endpoint was not met (P=.07); survival benefit is directional but not formally proven. High dropout and dose modifications due to mitotane toxicity in both arms confound interpretation. ACC is extremely rare, limiting enrollment rate and statistical power (underpowered for OS). No biomarker-driven patient selection; molecular heterogeneity of ACC is not addressed. Median PFS of 5 months in the superior arm underscores the refractory nature of advanced disease. Mitotane monitoring (serum levels) requires specialized expertise not universally available.
Clinical Context
FIRM-ACT is the only Phase 3 RCT completed in ACC and defines the current standard of care. EDP+mitotane is universally adopted as first-line systemic therapy and endorsed by ESMO, ENSAT, and NCCN guidelines. Mitotane (Lysodren) is the only FDA-approved drug for ACC; adjuvant mitotane after resection of high-risk ACC is also guideline-endorsed. Second-line options are limited; pembrolizumab and cabozantinib have modest activity in refractory ACC. Osilodrostat (steroidogenesis inhibitor) is used for Cushing syndrome control in functional ACC.
References
References: Fassnacht M et al, NEJM 2012 (FIRM-ACT)