BMS withdraws romidepsin’s PTCL indication from the U.S. market following failure of confirmatory phase III study

A decade after the histone deacetylase inhibitor romidepsin received accelerated approval by the U.S. Food and Drug Administration (FDA) as monotherapy for the treatment of relapsed/refractory peripheral T-cell lymphoma (PTCL), Bristol Myers Squibb has withdrawn the indication. The initial accelerated approval was based on results from two clinical studies that evaluated the overall response rate of romidepsin.^1,2

The FDA requires evaluation of all accelerated approvals that have not demonstrated sufficient clinical benefit, and a confirmatory phase III study evaluating romidepsin in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) as first-line treatment for PTCL failed to meet its primary endpoint of progression-free survival (PFS). The results of this study have no bearing on romidepsin’s cutaneous T-cell lymphoma indication.^1,3

Ro-CHOP phase III study design

The Ro-CHOP phase III study (NCT01796002) was a randomized, multicenter study comparing romidepsin + CHOP (Ro-CHOP) with CHOP in adult patients with previously untreated PTCL (excluding ALK-positive anaplastic large cell lymphomas and EBV-positive extranodal NK/T-cell lymphomas).³

There were 421 patients in the intent-to-treat population who were randomized to Ro-CHOP or CHOP based on:

• International Prognostic Index score at baseline (<2 vs ≥2);
• age (≤60 years vs >60 years); and
• histology type (nodal vs extranodal).

Patients in both arms received six cycles of CHOP given in 3-week cycles; those in the Ro-CHOP arm also received 12 mg/m² romidepsin administered intravenously on Day 1 and Day 8 of each 3-week cycle for six cycles. The primary endpoint was PFS, and secondary endpoints included overall survival, overall response rate, complete response and complete response unconfirmed, and safety.

Results

Median follow-up was 27.5 months, at which time Ro-CHOP did not meet its primary endpoint. Efficacy results are shown in Table 1.

Table 1. Ro-CHOP vs CHOP efficacy results*

CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; CI, confidence interval; CR, complete response; CRu, CR unconfirmed; NE, not evaluable; ORR, overall response rate; OS, overall survival; PFS, progress-free survival; Ro-CHOP, romidepsin + CHOP. *Data from Bachy, et al.3
Endpoints	Ro-CHOP (n = 211)	CHOP (n = 210)
Median PFS, months (95% CI)	12.0 (9.0–25.8)	10.2 (7.4–13.2)
Median OS, months (95% CI)	51.8 (35.7–72.6)	42.9 (29.9–NE)
ORR, %	63	60
CR + Cru, %	41	37

There was no statistically significant improvement in PFS with Ro-CHOP vs CHOP alone, and improvements at the secondary endpoints were also not significant. Treatment-emergent adverse events (TEAEs) led to CHOP dose interruption in 36% of patients in the Ro-CHOP arm vs 20% of patients in the CHOP arm; dose reduction in 26% of patients in the Ro-CHOP arm vs 15% of patients in the CHOP arm; and discontinuation in 3% of patients in each arm. In the Ro-CHOP arm, TEAEs led to romidepsin interruption in 63% of patients, reduction in 37% of patients, and discontinuation in 8% of patients.

Based on these results, the investigators concluded that Ro-CHOP has not demonstrated a sufficient clinical benefit, particularly as other therapeutic options for PTCL have been approved in the intervening decade.  

Bristol Myers Squibb is notifying healthcare providers about the withdrawal of this indication, and, as romidepsin will remain on the market for the treatment of cutaneous T-cell lymphoma, it will still be available for patients with PTCL who decide to remain on treatment after consulting with their physician.¹