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Brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine in patients with advanced‐stage, classical Hodgkin lymphoma: A prespecified subgroup analysis of high‐risk patients from the ECHELON‐1 study

Abstract Approximately one‐third of patients diagnosed with Hodgkin lymphoma presenting with Stage IV disease do not survive past 5 years. We present updated efficacy and safety analyses in high‐risk patient subgroups, defined by Stage IV disease or International Prognostic Score (IPS) of 4–7, enrolled in the ECHELON‐1 study that compared brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A + AVD) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as first‐line therapy after a median follow‐up of 37.1 months. Among patients treated with A + AVD (n = 664) or ABVD (n = 670), 64% had Stage IV disease and 26% had an IPS of 4–7. Patients with Stage IV disease treated with A + AVD showed consistent improvements in PFS at 3 years as assessed by investigator (hazard ratio [HR], 0.723; 95% confidence interval [CI], 0.537–0.973; p = 0.032). Similar improvements were seen in the subgroup of patients with IPS of 4–7 (HR, 0.588; 95% CI, 0.386–0.894; p = 0.012). The most common adverse events (AEs) in A + AVD‐treated versus ABVD‐treated patients with Stage IV disease were peripheral neuropathy (67% vs. 40%) and neutropenia (71% vs. 55%); in patients with IPS of 4–7, the most common AEs were peripheral neuropathy (69% vs. 45%), neutropenia (66% vs. 55%), and febrile neutropenia (23% vs. 9%), respectively. Patients in high‐risk subgroups did not experience greater AE incidence or severity than patients in the total population. This updated analysis of ECHELON‐1 shows a favorable benefit‐risk balance in high‐risk patients.


| INTRODUCTION
Despite advances in recent years, advanced-stage classical Hodgkin lymphoma (cHL) treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) relapses or becomes refractory in 25%-30% of patients. [1][2][3] Bleomycin, etoposide, doxorubicin hydrochloride, cyclophosphamide, vincristine, procarbazine, and prednisone (BEA-COPPesc) results in higher initial disease control in younger, fit patients but at the expense of significantly higher acute and late toxicity, secondary malignancies, and treatment-related mortality. [4][5][6] Patients with Stage IV disease have a relatively poor prognosis, with an overall survival (OS) rate of approximately 76% at 5 years. 7 The development of more-effective yet tolerable treatment options for patients with advanced-stage cHL, especially those with high-risk characteristics, is warranted.
Brentuximab vedotin (BV) is a novel antibody-drug conjugate targeting the CD30 antigen expressed on Hodgkin Reed-Sternberg cells. Across a range of trials, BV has been shown to induce durable remissions in patients with cHL who relapsed after autologous stem cell transplant. In the pivotal trial, BV treatment resulted in a complete response (CR) rate of 34% (95% confidence interval [CI], 25. 2-44.4) and objective response rate of 75% (95% CI, 64.9-82.6) per independent review committee. 8 Notably, a subset of 15 patients from this study achieved complete remission and maintained their response for ≥5 years; of these, six patients received consolidative allogeneic stem cell transplant, and nine patients received no further therapy after completing BV treatment. 9 The use of BV as a consolidation treatment option for adult patients with cHL at high risk of relapse or progression following autologous hematopoietic stem cell transplant resulted in improved progression-free survival (PFS) compared with placebo. 10 In a Phase 1 dose-escalation study of BV in combination with AVD, 24 of 25 patients (96%) with newly diagnosed cHL achieved complete remission. 11 Based on these findings, a global, multicenter, open-label, randomized, phase 3 clinical study, the ECHELON-1 trial, was conducted to assess the efficacy and safety of a therapeutic combination of BV plus AVD (A + AVD) versus ABVD as first-line therapy in advanced stage (III and IV) cHL. 12 At a median follow-up of 24.6 months, primary analyses of ECHELON-1 showed a 23% risk reduction for modified PFS (hazard ratio [HR] for progression, death, or modified progression event, 0.77; 95% CI, 0.60-0.98; p = 0.035) in patients receiving A + AVD, with 2-year modified PFS rates of 82.1% (95% CI, 78.8%-85.0%) in patients receiving A + AVD and 77.2% (95% CI, 73.7%-80.4%) in those receiving ABVD. 12 At the primary analysis, 28 deaths had occurred with A + AVD and 39 with ABVD (HR for interim OS, 0.72; 95% CI, 0.44-1.17; p = 0.19). 12 This post hoc analysis includes the updated 3-year efficacy and safety of A + AVD compared with ABVD (data cutoff, 15 October 2018; median follow-up for PFS was 37.1 months) in a prespecified high-risk patient subgroup presenting at baseline with Stage IV disease or an International Prognostic Score (IPS) of 4-7.

| Patient eligibility and study design
Full details of the ECHELON-1 study (ClinicalTrials.gov identifier NCT01712490; EudraCT 2011-005450-60) have been published. 12,13 Briefly, we recruited patients aged ≥18 years with histologically confirmed cHL (Ann Arbor stage III or IV) who had not been previously treated with systemic chemotherapy or radiotherapy 186and had an Eastern Cooperative Oncology Group performance status of 0-2 ( Figure S1).

| Endpoints
The primary endpoint was modified PFS per an independent review facility (IRF), defined as the time to disease progression, death, or modified progression event (with the latter defined as evidence of non-CR after completion of frontline therapy according to review by an independent committee, followed by subsequent anticancer therapy). 12 Non-CR was defined by an end-of-therapy positron emission tomography (PET) scan with a Deauville five-point scale score of 3-5. The key secondary endpoint was OS (time from date of randomization to date of death). These endpoints were specified in the primary analysis (data cutoff, 20 April 2017).
PFS per investigator for the intent-to-treat (ITT) population was a preplanned supportive analysis. At a median follow-up of 37.1 months, we report extended follow-up of PFS (defined as time to progression or death) per the investigator for patients with Stage IV disease or an IPS of 4-7. Following the primary analysis, the protocol did not require investigators to submit further information to the IRF.

| Statistical analysis
Stratified log-rank testing was used to compare modified PFS and OS between the two treatment arms as part of the primary analysis and key secondary analysis in the ITT population. Stratification factors included geographic region and IPS at baseline. HRs, along with 95% CIs, were estimated using a stratified Cox model, with treatment as the explanatory variable.
In the primary analysis, a broad number of prespecified subgroup analyses was performed, including region, extranodal site involvement, IPS, sex, disease stage, and age. 12 The present subgroup analyses for PFS used unstratified Cox models and unstratified log-rank testing and included the following subgroups: stage (III vs. IV) and IPS Extended follow-up of modified PFS per IRF was not feasible following the primary analysis because the protocol did not require investigators to submit further information to the IRF. Additional supportive analyses were performed to evaluate the treatment effects on PFS per the investigator and OS in these two prespecified groups. An unstratified Cox proportional hazards model was used to estimate HRs. All p values from subgroup analyses were based on unstratified log-rank tests and are for descriptive purposes only, without multiplicity adjustment.
Safety was summarized for type, incidence, severity, seriousness, and relatedness of adverse events (AEs), as well as type, incidence, and severity of laboratory abnormalities. AEs were coded using the  Overall, 64% of patients had Stage IV disease (64% in the A + AVD arm; 63% in the ABVD arm); 26% had an IPS of 4-7 (25% in the A + AVD arm; 27% in the ABVD arm). Baseline characteristics were balanced between the two treatment arms and are presented in Table 1 for patients with Stage IV disease (n = 846) and in Table S1 for those with an IPS of 4-7 (n = 347).

| RESULTS
In patients with Stage IV disease at the time of the primary analysis, there was a 28.9% reduction in the risk of a modified PFS per IRF event in the A + AVD arm compared with the ABVD arm (HR, 0.711; 95% CI, 0.529-0.956; p = 0.023). The modified PFS rate per IRF at 2 years was 82.0% (95% CI, 77.8%-85.5%) in the A + AVD arm compared with 75.3% (95% CI, 70.6%-79.3%) in the ABVD arm ( Figure 1A). An interim analysis of OS indicated that patients with Stage IV disease who received A + AVD had an almost 50% reduction

| DISCUSSION
Although cHL has a high 5-year failure-free survival rate of more than 80% in all disease stages, patients with Stage IV disease treated with ABVD have a comparatively lower 5-year failure-free survival rate (76%). 1,7,14,15 Similarly, patients with an IPS of 4-7 at diagnosis often have a poor prognosis. 16 The ECHELON-1 trial showed a statistically significant improvement in modified PFS by the IRF and additional improvement in PFS per the investigator in patients with stage III or IV disease who received A + AVD compared with those who received ABVD. 12 In this analysis, we focused on patients at a high risk of treatment IV disease as well as those with a high IPS. The safety profile of A + AVD observed in the two high-risk subgroups was comparable to that observed in the overall safety population, and no new safety signals were identified. Importantly, patients with high-risk cHL did not experience an increased incidence or severity of AEs, consistent with what was observed in the overall safety population.
Since the primary analysis, this patient population has also been assessed at a median follow-up of approximately 3 years. A previously published analysis of the ITT population at 3 years demonstrated the durable benefit of A + AVD versus ABVD in patients independent of age, disease stage, or risk-factor score without requiring change of therapy or exposure to bleomycin. 13 In this   follow-up, and the rate increased to 14% with 5.9 years of followup. 17 In the RATHL and HD0607 trials, the rate of secondary malignancies was lower, but the follow-up in these two studies was shorter. 16,17 In ECHELON-1, the rate of secondary malignancies on the A + AVD arm was 2.8% (Stage IV, 2.6%; IPS of 4-7, 3.3%) and 3% in the ABVD arm (Stage IV, 3.3%; IPS of 4-7, 5.7%). Although followup is ongoing, these secondary malignancy data from ECHELON-1 suggest that the rate with A + AVD did not exceed that with ABVD; hence, A + AVD could provide an effective alternative to BEA-COPPesc that could potentially spare patients the associated longterm toxicities.
One notable limitation to these analyses is that although these subgroups were prespecified, they were not alpha-controlled; thus, p values cannot be adjusted for inferential purposes. Additionally, there is a potential for a close interaction between subgroups to confound the observed treatment benefit. For example, the presence of Stage IV disease is one of the seven risk factors included in the IPS, resulting in a higher chance that a patient will be in both subgroups. 20 Overlapping of other risk factors, such as extranodal involvement, advanced age, or subtype, may also exist. It is therefore difficult to ascertain the exact attribute or attributes that determine greater benefit with A + AVD.

AUTHOR CONTRIBUTIONS
Martin Hutchings contributed to the study design, patient accrual, data collection, data interpretation, data analysis, manuscript writing, writing. Hina Jolin contributed to protocol writing, data collection, data analysis, and data interpretation. Rachael Liu contributed to data collection, data analysis, and data interpretation. Ashish Gautam contributed to data collection, data analysis, and data interpretation.
Andrea Gallamini contributed to the study design, patient accrual, data collection, data interpretation, data analysis, manuscript writing, critical revision of the manuscript, and final approval of the manuscript.