Hodgkin’s lymphoma (HL) represents one of the more successful stories in oncology. The four-regimen combination of adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) is the standard of care for newly diagnosed patients, and prognosis is excellent for patients who respond, demonstrating a five-year overall survival of approximately 80%.1 However, about 20% of patients relapse or are refractory to first-line therapy,2 and prognosis has traditionally been poor for this population, who typically receive salvage chemotherapy followed by autologous stem cell transplantation (auto-SCT), which provides a cure rate of about 50%.3 For patients who relapse after auto-SCT, allogeneic SCT or best supportive care was the only an option. The approval of Adcetris® (brentuximab vendotin, Seattle Genetics/Takeda) in 2011 after second-line relapse or transplant failure changed this grim landscape and provided an important and effective new treatment option for patients. The compelling results from its pivotal Phase II trial, which showed an objective response rate (ORR) of 75% and median progression-free survival (PFS) of 5.6 months,4 helped pave the way to make Adcetris the new standard of care in relapsed/refractory patients. Indeed, about one-third of patients receive Adcetris following SCT failure or as second-line systemic therapy. 5 Given the effectiveness of Adcetris following SCT failure, one salient question arises: Can Adcetris also be used to minimize the risk of relapse post-SCT if given early as part of consolidation therapy following auto-SCT?
The AETHERA trial (SG035-0005; NCT01100502) was initiated to answer that very question, and interim efficacy data were presented at the American Society of Hematology (ASH) Conference held in San Francisco on Dec, 8, 2014.6 This trial enrolled 329 patients who had failed first-line therapy for newly diagnosed HL, treated them with salvage chemotherapy followed by auto-SCT, and then randomized them to consolidation therapy with Adcetris (1.8 mg/kg every three weeks for up to 12 months) plus best supportive care (BSC) versus placebo plus BSC. Patients were stratified into three high-risk groups at the time of enrollment/salvage chemotherapy: those with refractory HL, those who relapsed or progressed within one year from receiving front-line chemotherapy, and those who relapsed at or more than one year after front-line chemotherapy and had extranodal disease. Following completion of salvage chemotherapy, patients were restaged and stratified again based on response to salvage therapy prior to auto-SCT: complete response (CR), partial response (PR), or stable disease (SD); patients who had progressive disease following salvage therapy were excluded from the study.
As determined by independent review, the trial met its primary endpoint, and the results are compelling. The PFS was 43 months in the Adcetris arm and 24 months in the placebo arm (HR 0.57; 95%CI: 0.40-0.81, p=0.001). There was also some suggestion of a durable response by the PFS rate at two years, which was 63% in the Adcetris arm and 51% in the placebo arm. Subgroup analysis showed that the PFS benefit favored Adcetris in all pre-specified patient stratification groups. The OS was not significantly different between the two arms (p=0.62); however, patients who progressed on study were unblinded and allowed to cross over to the Adcetris arm, thus confounding the OS results. Indeed, 85% of patients in the placebo arm went on to receive Adcetris as subsequent therapy. As was seen with the pivotal trial that led to its approval, peripheral neuropathy of any grade was a common adverse event in these patients (any grade: 67% vs. 19% with placebo), as were neutropenia (any grade: 35% vs. 12%; Grade 3: 13% vs. 1%), nausea (any grade: 22% vs. 8%) and fatigue (any grade: 24% vs. 18%).
As with most therapeutics studied in a maintenance setting for patients in remission, an inevitable question is, “Does early maintenance therapy have a meaningful impact on the disease compared to treating the patient upon relapse?” The gold standard used across oncology to answer this question has been overall survival. The lack of survival benefit in AETHERA is concerning since it suggests that patients will do equally well (in the long run) whether they receive Adcetris in remission as maintenance or upon relapse. However, countering this stance is the argument that there is inherent value in delaying progression. In other tumors where this debate has occurred (e.g., non-small cell lung cancer, ovarian cancer), the PFS benefit has been in the range of two to four months. The 19-month improvement in median PFS seen in AETHERA is certainly more robust and supports enthusiasm among the hematologic oncology community. This level of PFS benefit is all the more exciting when we consider that many patients reached a point where they were enjoying a treatment-free remission since consolidation Adcetris was given for up to one year; at this interim analysis, one-half of patients who had discontinued therapy did so because they completed the 12 months of treatment in the absence of disease progression. Seattle Genetics has guided that it will seek approval for Adcetris in the maintenance/consolidation setting in early 2015, and the large level of benefit observed in this study is expected to support an expanded regulatory label.
The encouraging results in the relapsed and now in post-SCT maintenance settings support continued development of Adcetris in earlier lines of therapy for HL. The Phase III ECHELON-1 trial (NCT01712490) is examining whether Adcetris in combination with AVD will yield better efficacy than ABVD alone. For now, it looks as if Adcetris’ “hold” in relapsed/refractory HL is assured. One emerging area of need in HL is in patients who have relapsed or are refractory to Adcetris. While there is evidence that re-treatment with Adcetris following progression is efficacious,7 the potential for cumulative neuropathy may not make this a feasible option. In that vein, the PD-1 inhibitors have made their entry into the hematological malignancies. Keytruda® (pembrolizumab, Merck) and Opdivo® (nivolumab, BMS)8,9 were shown at ASH to be effective in the relapsed setting for HL following Adcetris. The data were from Phase I trials, so any firm conclusions will need to be reserved until later-stage studies are conducted, but these preliminary results are interesting. Additionally, Opdivo was tested in patients post-transplantation, which would put it in direct competition with Adcetris and may set the stage for an “immunotherapeutics showdown” between Opdivo and Adcetris. The high response rates and tolerable safety profile of PD-1 inhibitors may prove to be substantial competition for Adcetris down the road if Opdivo or Keytruda ultimately enter the relapsed/refractory HL market. For the time being, however, Adcetris will continue to be the dominant choice on the market for patients with relapsed HL.
By: Stephanie Hawthorne, Ph.D., Senior Director, Clinical and Scientific Assessment, Kantar Health and Len Kusdra, Analyst, Clinical and Scientific Assessment, Kantar Health
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