Activity in R/R PTCL Seen With Duvelisib plus Romidepsin

Duvelisib (Copiktra) plus romidepsin (Istodax; DR) had high activity levels in patients with relapsed/peripheral T-cell lymphoma (PTCL), according to final results from the dose expansion stage of a phase 1 trial (NCT02783625) presented at the 2021 ASH Annual Meeting and Exposition.

Efficacy-evaluable patients with relapsed/refractory PTCL treated with the maximum tolerated dose (MTD) of DR (n = 48) achieved an overall response rate (ORR) of 56%, including 21 (44%) patients with a complete response (CR). The combination also proved to be active in patients with relapsed/refractory cutaneous T-cell lymphoma (CTCL); among 9 efficacy-evaluable patients the ORR was 44%. The median progression-free survival (PFS) was 6.8 months (95% CI, 4.0-not reached [NR]) and 5.3 months (95% CI, 2.8-NR) in the PTCL and CTCL cohorts, respectively.1

“Adding romidepsin to duvelisib is feasible and resulted in lower rates of grade 3/4 transaminitis compared with the phase 1 study of duvelisib at the same dose,” said Steven Horwitz, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York. “The high rates of CR and frequent bridging to allotransplant support the value of DR for patients with relapsed/refractory PTCL.”

The trial employed a parallel 3 plus 3 design with patients in arm A (n = 59) receiving DR and patients in arm B receiving duvelisib plus bortezomib (Velcade) in the dose-escalation stage. Ten patients received a lead-in cycle with single agent duvelisib before the dose expansion phase at the MTD. The MTD of DR was previously determined to be intravenous romidepsin 10 mg/m2 plus 75 mg oral duvelisib twice daily.

The primary end point of the trial was to define the MTD and to characterize the safety and toxicity of DR and duvelisib plus bortezomib. Secondary objectives included ORR at the MTD, CR rate, partial response rate, time to response, duration of response, and event-free survival. The exploratory end points were correlation of response with prior therapy and tissue collection for further correlative predictors of response or resistance to therapy.

The objective of the PTCL expansion cohort was to show that DR is more effective than single agent romidepsin. In a phase 2 study (NCT00426764), treatment with romidepsin resulted in an ORR of 25% (CI 17.6%-32.4%) among 130 patients with relapsed/refractory PTCL.2 The targeted ORR for DR in the phase 1 trial was 50% to within plus/minus 15% with confidence intervals of 35%-65%.

Patients treated with the combination at the MTD (n = 59) had a median age of 64 (range, 20-81) and were predominately male (66%) and White (80%). The median number of prior lines of therapy was 3 (range, 1-16). Nineteen percent had prior transplants, including 15% previously receiving autologous stem cell transplantation and 3% previously receiving allogenic stem cell transplantation.

Common PTCL subtypes included PTCL not otherwise specified (PTCL NOS; n =17), angioimmunoblastic T-Cell lymphoma (AITL; n = 18), and anaplastic large cell lymphoma (ALCL; n = 3). Five patients with CTCL had mycosis fungoides and 4 patients had Sezary syndrome.

Patients with PTCL NOS treated with the combination had an ORR of 47%, including 5 (29%) CRs. Patients with AITL achieved an ORR of 71% and a CR rate of 65%. Notably, the ALCL subgroup had an ORR of 100% with a 67% CR rate. Patients with mycosis fungoides had an ORR of 40% and those with Sezary syndrome had an ORR of 50%.

Among the 14 previously transplanted patients, the median PFS was NR (95% CI, 12.7-NR). These patients had a median age of 57 (range, 20-69), a median of 2 prior lines of therapy (range, 1-5), and were mostly male (71%).

In terms of safety, the rate of grade 3/4 transaminitis for all patients treated at the MTD was 14%, 40% in patients initiated with a single agent lead-in cycle (n = 10), and 8% in patients initiated with DR at MTD (n = 49). Other common grade 3/4 adverse events for patients initiated with the combination at the MTD included decreased neutrophil count (39%), diarrhea and infections (both 12%), decreased platelet count (10%), and rash (8%).

A biomarker analysis revealed that TET2, LOF, RHOA, and VAV1 mutations were associated with response among patients with PTCL treated with DR, while TP53­ mutations were associated with non-response. Patients with TET2 (n = 16), RHOA (n = 3), and VAV1 (n = 2) mutations achieved ORRs of 88%, 100%, and 100%, respectively. No patients with a TP53­ mutation experienced a response when treated with the combination. Investigators also noted that transcriptional signatures for PI3K signaling decreased from baseline to end of treatment in responders but not in non-responders, suggesting that PI3K signaling was still deactivated at progression on treatment.

“TET2 mutations appear to predict for response while TP53­ mutations were exclusively seen in non-responders in PTCL but not CTCL,” said Horwitz. “Preliminary findings [also] show response associated with T follicular helper cell biology.”

_References

_{Horwitz S, Nikitina A, Kotlov N, et al. The combination of duvelisib and romidepsin (DR) is highly active against relapsed/refractory peripheral t-cell lymphoma with low rates of transaminitis: final results and biomarker analysis. Paper presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 619.}

_{Foss F, Horwitz S, Pro B, et al. Romidepsin for the treatment of relapsed/refractory peripheral T cell lymphoma: prolonged stable disease provides clinical benefits for patients in the pivotal trial. J Hematol Oncol. 2017;10(1):154. doi: 10.1186/s13045-017-0518-8}