Page 79 - Haematologica May 2022

Analysis of older cHL patients in ECHELON-1
Introduction
Older patients (aged ≥60 years) account for approxi- mately 20-25% of cases of classical Hodgkin lymphoma (cHL) in population-based studies.1-3 While outcomes for younger patients with cHL have improved significantly in recent decades, similar progress has not been seen for older patients,4 in particular for those with advanced- stage disease.2,3,5 This has been attributable to biological disease differences and co-morbidities associated with advanced age resulting in poor tolerance of chemothera- py and increased incidence of severe toxicities, including treatment-related deaths.4,6 Intensive regimens, such as bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) are too toxic for older patients and may result in increased treatment-related mortality.7 In addition, bleomycin, a component of the doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) regimen is associated with a sig- nificantly elevated risk of pulmonary toxicity in older patients,5,8-10 particularly in those aged ≥70 years.11-13
Brentuximab vedotin has been evaluated as an alterna- tive treatment approach in older, less fit patients with previously untreated cHL, both as monotherapy14,15 and in combination regimens.16-18 Results from these early- phase trials demonstrated tolerability and encouraging efficacy, with objective response rates of 98–100% and complete response rates of 44–87%.16-18 Sequential thera- py in a phase II multicenter study with two cycles of brentuximab vedotin followed by six cycles of doxoru- bicin, vinblastine, and dacarbazine (AVD) yielded encour- aging results.19
There has been a relative paucity of randomized phase III clinical trials in the frontline cHL setting that have included older patients in the contemporary era. In the primary analysis of the phase III ECHELON-1 study per- formed after a median follow-up of 24.6 months, front- line administration of brentuximab vedotin in combina- tion with AVD (A+AVD) significantly improved the pri- mary endpoint, modified progression-free survival (PFS) per independent review facility (IRF), compared with ABVD (hazard ratio [HR]=0.77 [95% confidence interval (CI): 0.60–0.98], P=0.035).20 Exploratory 3- and 5-year analyses reported continued provision of per-investigator PFS benefits for A+AVD compared with ABVD.21,22 Here we report the results of pre-specified analyses and post hoc analyses with extended follow-up of the efficacy and safety of A+AVD versus ABVD in 186 older cHL patients (aged ≥60 years).
Methods
Study design and assessments
The study design and population of patients for the open- label, global, randomized, phase III ECHELON-1 study have been described previously.20 Briefly, patients aged ≥18 years (no upper age limit) with histologically confirmed, advanced (Ann Arbor stage III/IV) cHL who had received no prior systemic chemotherapy or radiotherapy were randomized 1:1 to receive A+AVD (brentuximab vedotin 1.2 mg/kg, doxorubicin 25 mg/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2) or ABVD (doxorubicin 25 mg/m2, bleomycin 10 units/m2, vinblas- tine 6 mg/m2, and dacarbazine 375 mg/m2) intravenously on days 1 and 15 of each 28-day cycle for up to six cycles. Dose
reductions and modifications for brentuximab vedotin, includ- ing for the management of peripheral neuropathy, have been described previously.20
Patients were assessed for response to study treatment per IRF in accordance with the 2007 Revised Response Criteria for Malignant Lymphoma.23 Computed tomography scans were performed at screening, at the end of cycle 2, after administra- tion of the last dose of frontline therapy, and during follow-up (every 3 months in the first year, and every 6 months thereafter). Positron emission tomography (PET) scans were performed at screening, the end of cycle 2, and the end of treatment. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.
ECHELON-1 was conducted in accordance with regulatory requirements; the protocol was approved by the institutional review boards and ethics committees at each registered site. Written informed consent, in accordance with local ethics com- mittee instructions, was mandatory before enrollment. This study was conducted according to the guideline of the International Conference on Harmonization Good Clinical Practice.
Endpoints and analyses
The primary endpoint for ECHELON-1 was modified PFS per IRF, defined as the time to progression, death, or evidence of non-complete response per IRF (Deauville score ≥3) after com- pletion of frontline therapy, followed by subsequent anticancer therapy (chemotherapy and/or radiotherapy). Overall survival (OS) was defined as the time from randomization to death from any cause and was the key secondary endpoint.
Here we report a pre-specified subgroup analysis of modified PFS per IRF in older patients (defined as ≥60 years of age), as well as exploratory analyses, including PFS per investigator assess- ment (the time from randomization to relapse/progression or death) and safety. Subgroups of patients for efficacy and safety analyses were derived from the intention-to-treat (all random- ized patients enrolled in ECHELON-1) and safety (all patients who received at least one dose of trial drug) populations, respec- tively. Following the primary analysis, the protocol did not require investigators to submit further information to the IRF, thus extended follow-up for analysis of modified PFS or PFS by IRF was not conducted. Modified PFS and PFS were summarized using the Kaplan-Meier methodology. ECHELON-1 was not powered for age-based subgroup analyses, so reported P-values are descriptive and without multiplicity adjustment.
Results
Patients
As reported previously, 1,334 patients were included in the intention-to-treat population;20 of whom 186/1,334 (14%; A+AVD: n=84, ABVD: n=102) were aged ≥60 years (A+AVD arm: median age 68 years [range, 60–82], ABVD arm: median age 66 years [range, 60–83]) and were included in these sub-analyses. Patients’ demographics and disease characteristics were well balanced across the treatment arms in both older and younger patients. Within both arms, older patients tended to have a poorer Eastern Cooperative Oncology performance status than younger patients (Table 1).
Efficacy in older patients
At the time of the primary analysis the median follow- up for older patients was 25 months (range, 24.2–25.8).
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