Brentuximab Vedotin Demonstrates Durable Long-Term PFS Benefit in Hodgkin Lymphoma

Nancy Bartlett, MD

The addition of brentuximab vedotin (Adcetris) to standard 3-drug chemotherapy for patients with newly diagnosed, advanced-stage classical Hodgkin lymphoma (cHL) continued to outperform a 4-drug chemotherapy standard, according to 4-year follow-up data from the phase III ECHELON-1 trial presented at the 2019 ASH Annual Meeting.¹

In the multicenter, open-label trial, patients who received the the antibody-drug conjugate (ADC) brentuximab vedotin in addition to chemotherapy (A+AVD) had a statistically significant 31% reduction in the risk of disease progression or death after a median follow-up of 48.4 months. Progression-free survival (PFS) at 4 years was 81.7% (95% CI, 78.3-84.6) with the brentuximab vedotin combination versus 75.1% (95% CI, 71.4-78.4) with chemotherapy alone (ABVD).

The results mirrored those from the previously reported primary analysis at 2 years and an exploratory analysis of 3-year PFS, said Nancy Bartlett, MD, a medical oncologist at Siteman Cancer Center, and the and Koman Chair in Medical Oncology at the Washington University School of Medicine, in a poster presentation at the meeting.

“This PFS analysis at 4 years provides further support of a robust and durable benefit with A+AVD versus ABVD in the frontline treatment of patients with stage III/IV cHL,” added Bartlett. “Peripheral neuropathy continues to resolve and improve over time, with most patients experiencing complete resolution.

Although most patients with newly diagnosed advanced-stage cHL respond to up-front treatment with standard chemotherapy, about 30% will become refractory to or will subsequently relapse after frontline treatment. In the ECHELON-1 trial, 1,334 patients with newly diagnosed stage III or IV cHL were randomized to receive A+AVD (n = 664) or ABVD (n = 670) intravenously on days 1 and 15 of each 28-day cycle for up to 6 cycles.

The primary end point of the trial was modified PFS by independent radiologic review at 2 years. Results from the primary analysis showed a PFS of 82.1% (95% CI, 78.8-85.0) with A+AVD and 77.2% (95% CI, 73.7-80.4) with ABVD. The difference translated to a 23% reduction in the risk of progression or death (hazard ratio [HR], 0.77; 95% CI, 0.60-0.98; P = .03).² PFS by investigator assessment was 84.2% with A+AVD and 78.0% with ABVD (HR, 0.70; 95% CI, 0.54-0.91; P = .006).³ An exploratory analysis of 3-year investigator-assessed PFS continued to demonstrate superiority for A+AVD (83.1% [95% CI, 79.9-85.9] vs 76.0% [95% CI, 72.4-79.2]; HR, 0.70; 95% CI, 0.55-0.90; P =.005).⁴

At the 2019 ASH Annual Meeting, Bennett and colleagues reported findings from a posthoc analysis of 4-year PFS by investigator assessment. They also evaluated PFS by imaging status, age, and other key subgroups.

The updated analysis confirmed the superiority of A+AVD over ABVD, as well as the durability of treatment effect with A+AVD. The reduction in the HR remained statistically significant (HR, 0.691; 95% CI, 0.542-0.881; P = .003).

Furthermore, an extensive subgroup analysis showed a consistently lower risk of progression or death in patients treated with A+AVD. HRs ranged from 0.493 in North-American patients (95% CI, 0.319-0.764) to 0.827 in patients 60 years of age or older (95% CI, 0.496-1.379). Only Asian patients did not appear to benefit from the regimen (HR, 1.212; 95% CI, 0.616-2.387).

“The PFS for important subgroups, such as both stage III and stage IV disease, age, extranodal sites, and International Prognostic scores were generally consistent with the intention-to-treat population and numerically in favor of A+AVD, with overlapping confidence intervals,” the investigators noted.

The trial protocol included assessment by PET imaging after the second cycle of therapy (PET2). Imaging results showed that 89% of patients in the A+AVD arm and 86% of those in the ABVD arm had negative PET2 results; 7% and 9% of the patients had positive scans and PET2 status was unknown in the remaining patients. A PFS benefit favoring A+AVD was observed in all patients, independent of PET2 status.

Peripheral neuropathy was an adverse event of special interest in the trial. At the primary analysis, 67% of patients in the A+AVD arm and 43% of those in the ABVD arm had peripheral neuropathy.⁵ The 4-year follow-up analysis showed that peripheral neuropathy had resolved or improved in 83% (n = 365) of the A+AVD group and 84% (n = 240) of those in the ABVD group. Ongoing peripheral neuropathy at 4 years was grade 1/2 in most cases.

The median time to complete resolution of peripheral neuropathy was 30 weeks (range, 0-262 weeks) in the A+AVD arm and 15 weeks (range, 0-234 weeks) in the ABVD arm. The median time to improvement without complete resolution was 41 weeks (range, 8-205 weeks) with A+AVD and 12 weeks (range, 2-70 weeks) with ABVD.

“The PFS benefit for A+AVD is independent of PET2 status, disease stage, age, and IPS,” the investigators concluded. In [patients with] stage III and stage IV, A+AVD compares favorably to PET-adapted strategies without requiring a change of therapy based on PET2 status; [the regimen also] completely eliminates exposure to bleomycin.”

References

1. Bartlett NL, Straus DJ, Dlugosz-Danecka M, et al. Brentuximab vedotin with chemotherapy for stage 3/4 classical Hodgkin lymphoma (cHL): 4-year update of the Echeleon-1 study. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 4026. bit.ly/34ru1Og.
2. Connors JM, Jurczak W, Straus DJ, et al. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma. N Engl J Med. 2018;378(4):331-344. doi: 10.1056/NEJMOa1708984.
3. Connors JM, Younes A, Gallamini A, et al. Brentuximab vedotin plus chemotherapy in patients with advanced-stage classical Hodgkin lymphoma (cHL): evaluation of modified progression-free survival (mPFS) and traditional PFS in the phase 3 ECHELON-1 study. Blood. 2018;132(suppl 1):2904. doi: 10.1182/blood-2018-99-118828.
4. Chen RW, Ansell SM, Gallamini A, et al. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin lymphoma (HL): impact of cycle 2 PET result on modified progression-free survival (mPFS). J Clin Oncol. 2018;36(suppl 15; abstr 7539). doi: 10.1200/JCO.2018.36.15_suppl.7539.
5. Tomassetti S and Herrera AF. Update on the role of brentuximab vedotin in classical Hodgkin lymphoma. Ther Adv Hematol. 2018;9(9):261-272. doi: 10.1177/2040620718786833.