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

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

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.