The accelerated approval status for romidepsin for the treatment of patients with relapsed/refractory peripheral T-cell lymphoma has been withdrawn following the results of the confirmatory phase 3 Ro-CHOP trial.
Bristol Myers Squibb announced the withdrawal of accelerated approval status for romidepsin (Istodax) as therapy for of patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) from the United States market due to a lack of benefit identified in the confirmatory phase 3 Ro-CHOP trial (NCT01796002), according to a press release from the company.1
The trial—which assessed the efficacy of combination romidepsin plus cyclophosphamide, doxorubicin, vincristine, and prednisone (Ro-CHOP) in the first-line setting—did not meet its primary end point of statistically significantly improved median progression-free survival (PFS) vs CHOP alone after a median follow-up of 27.5 months. Patients who received the experimental regimen experienced a median PFS of 12.0 months (95% CI, 9.0-25.8) vs 10.2 months (95% CI, 7.4-13.2) in the control arm (HR, 0.81; 95% CI, 0.63-1.04; P = .096). Additionally, the objective response rate (ORR) of Ro-CHOP was 63% vs 60% in the CHOP arm. Patients achieved complete response (CR) and unconfirmed CR (CRu) rates of 41% and 37% in both arms, respectively.2
“While the outcome of the confirmatory study in peripheral T-cell lymphoma is disappointing, Bristol Myers Squibb will continue to provide Istodax for patients with cutaneous T-cell lymphoma, where it remains an approved and important treatment option,” Noah Berkowitz, MD, PhD, senior vice president, Hematology Development at Bristol Myers Squibb, said in a press release. “As always, our efforts across blood cancer research and development remain centered on delivering better outcomes for patients in need.”
The randomize, multicenter trial enrolled adult patients with previously untreated disease. Patients who were enrolled were randomized based on baseline International Prognostic Index, age, and histology to receive either Ro-CHOP or CHOP.
All patients were treated with CHOP in 6 cycles of 3 weeks. Those in the experimental arm also received a 12 mg/m2 intravenous dose of romidepsin on days 1 and 8 of each cycle for 6 cycles.
In terms of safety, the most common any-grade treatment-emergent adverse effects (TEAEs) in both the experimental and control arms included anemia (67% vs 38%), nausea (55% vs 31%), thrombocytopenia (52% vs 17%), neutropenia (51% vs 37%), and vomiting (40% vs 10%). The most common grade 3/4 TEAEs that occurred in both respective arms were thrombocytopenia (50% vs 10%), neutropenia (49% vs 33%), anemia (47% vs 17%), and leukopenia (32% vs 20%). A single case of grade 5 E. coli sepsis was reported in the Ro-CHOP arm vs 2 reports of grade 5 TEAEs in the CHOP arm, including colitis and acute cholecystitis.
TEAEs leading to dose interruption occurred in 36% and 20% of patients in the Ro-CHOP and CHOP arms, respectively, with 26% and 15% of patients requiring dose reduction. Additionally, 3% of patients in both respective arms discontinued treatment entirely due to TEAEs.
The accelerated approval of romidepsin, which was granted in 2011 by the FDA, was based on the results of 2 clinical studies that assessed the histone deacetylase inhibitor’s impact on the surrogate end point of ORR. These studies included a single-arm clinical trial examining the agent in patient with PTCL who had progressed following a prior therapy, as well as a multicenter, international, open-label, single-arm trial that examined romidepsin in patients with PTCL who had progressed on at least 1 prior therapy.
In the latter study, patients achieved an ORR of 25% (33/130), including a CR/CRu of 15%.3 Additionally, patients had a median duration of response of 17 months, with the longest response lasting for longer than 34 months. Among those experienced a CR/CRu, 89% did not experience disease progression after a median follow-up of 13.4 months.
Notably, romidepsin will remain on the market for the treatment of cutaneous T-cell lymphoma in those who have received at least 1 prior systemic therapy. It is also worth noting that since the approval of romidepsin nearly a decade ago, numerous other treatment options have become available for patients across a wide range of hematologic malignancies that may be considered instead.