BMS Withdraws Romidepsin Relapsed/Refractory PTCL Indication in the United States

Noah Berkowitz, MD, PhD

Bristol Myers Squibb (BMS) has made the decision to withdraw in the indication for romidepsin (Istodax) as a monotherapy for the treatment of adult patients with peripheral T-cell lymphoma (PTCL) who have previously received at least 1 therapy.¹

In June 2011, the FDA granted an accelerated approval to the HDAC inhibitor based on data from 2 phase 2 clinical trials that evaluated the effect of romidepsin on the surrogate end point of overall response rate (ORR) in patients in whom at least 1 prior systemic therapy has failed, as well as findings from a single-arm trial of the agent in patients with PTCL in whom prior therapy has failed.²

The decision to withdraw the indication follows findings from the confirmatory phase 3 Ro-CHOP trial (NCT01796002) evaluating the addition of romidepsin to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) vs CHOP alone in the frontline treatment of patients with PTCL. Results indicated that the addition of the agent to CHOP did not improve progression-frees survival (PFS) in this population, missing the primary end point of the study.³

“While the outcome of the confirmatory study in PTCL is disappointing, BMS will continue to provide [romidepsin] for patients with cutaneous T-cell lymphoma [CTCL], where it remains an approved and important treatment option,” Noah Berkowitz, MD, PhD, senior vice president of Hematology Development at BMS, stated 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 randomized, multicenter phase 3 trial enrolled adult patients with previously untreated PTCL who had nodal or extranodal entities including primary cutaneous non-epidermotropic T-cell lymphoma, with the exclusion of those with ALK-positive anaplastic large cell lymphomas and Epstein-Barr virus–positive extranodal natural killer/T-cell lymphomas.

After diagnostic biopsies underwent central review, patients were randomized based on their International Prognostic Index (IPI) score at baseline (<2 vs ≥2), age (≤60 vs >60), and histology (nodal vs extranodal) to receive either romidepsin plus CHOP or CHOP alone.

All participants were administered CHOP in 3-week cycles for the duration of 6 cycles, with dose reductions to 10 mg/m2 and 8 mg/m2 depending on toxicity. The primary end point of the trial was PFS per Response Adjudication Committee assessment, in accordance with International Working Group 1999 criteria. Important secondary end points comprised OS, ORR, complete response (CR) + unconfirmed CR (CRu), and safety.

At a data cutoff date of December 13, 2019, a total of 421 patients were enrolled to the intent-to-treat population; of these patients, 211 received romidepsin plus CHOP and 210 received CHOP alone.

The median age of study participants was 65 years (range, 25-81), 18% had an ECOG performance status of 2 to 3, 63% had Ann Arbor stage IV disease, and 81% had an IPI score of 2 or higher.

At a median follow-up of 27.5 months, the median PFS with romidepsin plus CHOP was 12.0 months (95% CI, 9.0-25.8) vs 10.2 months (95% CI, 7.4-13.2) with CHOP alone (HR, 0.81; 95% CI, 0.63-1.04; P = .096), which was not statistically significant.

Moreover, the median OS in the investigative and control arms was 51.8 months (95% CI, 35.7-72.6) and 42.9 months (95% CI, 29.9–not evaluable). Romidepsin/CHOP elicited an ORR of 63% vs 60% with CHOP alone, and the CR + CRu rates were 41% and 37%, respectively.

Investigators examined safety in 210 patients who received romidepsin plus CHOP and 208 patients who were given CHOP alone. Any-grade treatment-emergent adverse effects (TEAEs) that were reported in 40% or more of patients in the investigative and control arms comprised anemia (67% vs 38%, respectively), nausea (55% vs 31%), thrombocytopenia (52% vs 17%), neutropenia (51% vs 37%), and vomiting (40% vs 10%).

Grade 3 TEAEs experienced by 30% or more of patients in the investigative and control arms included thrombocytopenia (50% vs 10%), respectively), neutropenia (49% vs 33%), anemia (47% vs 17%), and leukopenia (32% vs 20%). Only 1 grade 5 TEAE was observed in the romidepsin/CHOP arm, and this was Escherichia coli sepsis; 2 grade 5 TEAEs, colitis and acute cholecystitis, were reported on the CHOP-alone arm.

TEAEs that resulted in dose interruptions were reported in 36% of those on the investigative arm vs 20% of those on the control arm. The rates of TEAEs that resulted in dose reductions in the investigative and control arms were 26% and 15%, respectively. In the investigative arm, the rates of TEAEs that resulted in the interruption, reduction, or discontinuation of romidepsin were 63%, 37%, and 8%, respectively.

BMS is in the process of notifying healthcare professionals about the withdrawal. The agent continues to be on the market for use in patient with CTCL who have previously received at least 1 systemic therapy.

References

1. Bristol Myers Squibb statement on Istodax (romidepsin) relapsed/refractory peripheral T-cell lymphoma US indication. News release. Bristol Myers Squibb. August 2, 2021. Accessed August 3, 2021. https://bit.ly/3rPVBCl
2. FDA grants accelerated approval of ISTODAX as treatment for patients with peripheral T-cell lymphoma who have received at least one prior therapy. News release. Celgene Corporation. June 16, 2011. Accessed August 3, 2021. https://bit.ly/37gQ7H8
3. Bachy E, Camus V, Thieblemont C, et al. Final analysis of the Ro-CHOP phase III study (conducted by LYSA): romidepsin plus CHOP in patients with peripheral T-cell lymphoma. Blood. 2020;136(suppl 1):32-33. doi:10.1182/blood-2020-134440