Update Details Brentuximab Vedotin Survival Benefit in CD30+ PTCL

Steven Horwitz, MD

Steven Horwitz, MD

The addition of brentuximab vedotin (Adcetris) to chemotherapy led to a clinically meaningful improvement in progression-free and overall survival (OS) in patients with CD30-expressing peripheral T-cell lymphoma (PTCL), according to phase III results of the ECHELON-2 trial presented at the 2018 ASH Annual Meeting and published online at Lancet Oncology.^1,2

Brentuximab vedotin plus CHP (cyclophosphamide, doxorubicin, and prednisone; A+CHP) led to a 29% reduction in the risk of disease progression (HR, 0.71; 95% CI, 0.54-0.93; P = .011), a 34% reduction in the risk of death (HR, 0.66; 0.46-0.95; P = .0244), and a 3-year progression-free survival (PFS) rate of 57.1% versus 44% with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), announced lead study author Steven M. Horwitz, MD, in a presentation during the meeting.

“ECHELON-2 is the first prospective trial in peripheral T-cell lymphoma to show an overall benefit over CHOP,” said Horwitz, a medical oncologist at Memorial Sloan Kettering Cancer Center. “A+CHP provided clinically meaningful improvement in PFS and overall survival versus CHOP, with a 29% reduction in the risk of a progression event, and a 34% reduction in the risk of death.”

The FDA approved brentuximab vedotin for use in combination with chemotherapy for the frontline treatment of patients with CD30-expressing PTCL based on the ECHELON-2 findings in November 2018.

Frontline standard of care for patients with PTCL has been CHOP or CHOP-like regimen with curative intent, Horwitz explained. ALK-positive systemic ALCL (sALCL), however, has more favorable outcomes depending on age and International Prognostic Index (IPI) score. Overall, there is an unmet need for new therapies for these patients as there is a high risk for relapse or disease progression. Approximately 50% of patients with PTCL express CD30, and it is universally expressed in patients with sALCL.

Prior phase I results of brentuximab vedotin plus CHP in the frontline setting showed that at 5 years, 50% of patients remain in remission and the median overall survival (OS) is not reached. Those results also showed that the combination has a manageable safety profile.³

ECHELON-2 (NCT01777152) is an international, double-blind, double-dummy, placebo-controlled, active comparator, randomized, phase III trial of 452 patients conducted at 132 sites in 17 countries. Patients were randomized 1:1 to receive brentuximab vedotin at 1.8 mg/kg, cyclophosphamide at 750 mg/m², doxorubicin at 50 mg/m², and prednisone at 100 mg on days 1 to 5, every 3 weeks for 6 to 8 cycles or CHP plus vincristine at 1.4 mg/m². G-CSF was given as primary prophylaxis or radiation therapy (RT) and stem cell transplantation (SCT) consolidation per investigator discretion. All patients then underwent EOT/PET scan imaging.

The primary endpoint was PFS per blinded independent central review (BICR), with SCT or RT consolidation therapy not counting as events. Secondary endpoints included OS, PFS per BICR in patients with sALCL, complete response rate, objective response rate, and safety. Endpoints were type I error controlled.

To be eligible for enrollment, patients with PTCL were ≥18 years of age, had ≥10% CD30 expression on cells, and received no prior treatment. Patients were stratified by IPI score (0-1 vs 2-3 vs 4-5) and histologic subtype: sALCL (70%), PTCL-not otherwise specified (NOS; 16%), angioimmunoblastic T-cell lymphoma (AITL; 12%), adult T-cell leukemia lymphoma (ATLL; 1.5%) enteropathy-associated T-cell lymphoma (EATL; 0.5%), and hepatosplenic T-cell lymphoma (HTCL; 0%).

Baseline characteristics were similar between both arms; the median age was 58 years old. The percentage of patients receiving A+CHP with an IPI score of 0 or 1, 2 to 3, and 4 to 5 were 23%, 62%, and 15% compared with those who received CHP at 21%, 64%, and 15%, respectively. Approximately 80.5% of patients had stage III/IV disease.

As of the data cutoff on August 15, 2018, treatment was completed in 85% of A+CHP treated patients and 79% of those who received CHOP. Patients who discontinued treatment due to disease progression, adverse events (AEs), and other was 3%, 7%, and 4% in the A+CHP arm and 12%, 7%, and 3% in the CHOP arm, respectively. Twenty-seven percent of patients receiving A+CHP received consolidative therapy versus 19% of those who received CHOP.

Subsequent therapy for residual or progression disease was administered in 26% and 42% of patients on the A+CHP and CHOP arms, respectively. Palliative radiation was given in 4% of patients in each group.

At a median follow-up of 36.2 months, results showed that the median PFS was doubled in patients treated with A+CHP was 48.2 months (95% CI, 35.2-not evaluable) compared with 20.8 months (12.7-47.6) in those on the CHOP arm. The 3-year PFS rates were 57% and 44% with A+CHP and CHOP, respectively. Data from the prespecified subset analysis demonstrated that the PFS benefit was generally observed across all patient subgroups, most notably in patients with ALK-positive sALCL (HR, 0.29; 95% CI, 0.11-0.79). The benefit was less in those with AITL (HR, 1.40; 95% CI, 0.64-3.07) or an IPI score of 4 to 5 (HR, 1.03; 95% CI, 0.55-1.92).

Horwitz noted that the study was not powered to compare efficacy between individual histologic subtypes, and all confidence intervals overlapped.

There was still a PFS benefit censored at time of consolidative therapy with ASCT or RT (HR, 0.71; 95% CI, 0.53-0.94; P = .017).

The median OS was not reached at a 75^th percentile with A+CHP and was 17.5 months with CHOP at a median follow-up of 42.1 months. Findings from the subset analysis showed the highest benefit in patients with ALK-positive sALCL (HR, 0.38; 95% CI, 0.12-1.22) and an IPI score of 0 or 1 (HR, 0.48; 95% CI, 0.16-1.33).

Additionally, in the intent-to-treat population, the ORR was 83% with A+CHP versus 72% with CHOP (P = .0032); CR rates were 68% versus 56%, respectively (P = .0066). In the subset analysis of patients with sALCL, 34% of those on the A+CHP arm had a PFS event compared with 48% on the CHP arm (HR, 0.59; 95% CI, 0.42-0.84; P = .0031).

The safety profiles of A+CHP and CHOP were similar with 99% and 98% of patients in each arm, respectively, experiencing AEs, including those that were grade ≥3 (66% vs 65%), and serious AEs (39% versus 38%). There were 7 (3%) deaths on the brentuximab vedotin arm and 9 (4%) on the CHOP arm.

“The incidence and severity of common AEs were generally comparably between the 2 arms,” explained Horwitz. “There was more diarrhea in the A+CHP [arm] although the majority of diarrhea was grade 1.”

The most common treatment-related AEs that occurred overall in more than 20% of patients with A+CHP and CHOP, respectively, were nausea (46% and 38%), peripheral sensory neuropathy (45% vs 41%), neutropenia (38% in each), diarrhea (38% and 20%), constipation (29% and 30%), alopecia (26% vs 25%), pyrexia (26% and 19%), vomiting (26% vs 17%), fatigue (24% and 20%), and anemia (21% and 16%). Grade ≥3 neutropenia and febrile neutropenia occurred in 49% and 20% with A+CHP versus 46% and 16% with CHP, respectively.

The most common grade ≥3 AEs occurring in the A+CHP and CHOP arms were neutropenia (35% vs 34%, respectively) and anemia (13% vs 10%, respectively). Neutropenia was similar between arms, but lower in the subset of patients who received primary prophylaxis with G-CSF. Febrile neutropenia was reported in 18% of patients receiving A+CHP and 15% of those on the CHOP arm.

New or worsening treatment-emergent peripheral neuropathy occurred in 52% of A+CHP patients and 55% in the CHOP arm; the majority were a maximum severity of grade 1. At the most recent follow-up, peripheral neuropathy returned to baseline or was lower in 50% of the patients in the A+CHP versus 64% in the CHOP arm; the median time to resolution was 17 weeks and 11.4 weeks, respectively.

“A+CHP has a comparable safety profile to CHOP and this data led to a fairly rapid FDA approval for brentuximab vedotin in combination with CHP for adults with previously untreated systemic sALCL and other CD30-expressing peripheral T-cell lymphomas, including AITL and PTCL-NOS,” Horwitz concluded.

References

1. Horwitz S, O’Connor OA, Pro B, et al. The phase 3 ECHELON-2 trial: results of a randomized, double-blind, active-controlled study of brentuximab vedotin and CHP (A + CHP) versus CHOP in previously untreated subjects with CD30-expressing peripheral T-cell lymphoma (PTCL). In: Proceedings from the 2018 ASH Annual Meeting and Exposition; December 1-4, 2018; San Diego, California. Abstract 997.
2. Horwitz S, O’Connor OA, Pro B, et al. Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial [published online ahead of print December 3, 2018]. Lancet Oncol. doi: 10.1016/S0140-6736(18)32984-2.
3. Fanale MA, Horwitz SM, Forero-Torres A, Bartlett NL, et al. Five-year outcomes for frontline brentuximab vedotin with CHP for CD30-expressing peripheral T-cell lymphomas. Blood. 2018;131(19):2120-2124. doi: 10.1182/blood-2017-12-821009.