ATLANTA – Forty years after the establishment of ABVD – adriamycin, bleomycin, vinblastine and dacarbazine – as standard-of-care front-line therapy in patients with previously untreated advanced classical Hodgkin lymphoma (cHL), Seattle Genetics Inc. (Seagen) revealed details supporting its contention that replacing bleomycin with Adcetris (brentuximab vedotin) could improve efficacy and reduce toxicity in those patients, improving their chance of a cure with the first round of treatment.

Findings from the phase III ECHELON-1 trial that evaluated Adcetris plus AVD (A+AVD) were presented by Joseph Connors, clinical director at the Center for Lymphoid Cancer at BC Cancer in Vancouver, British Columbia, at the 59th American Society of Hematology (ASH) annual meeting and simultaneously published online in The New England Journal of Medicine (NEJM).

Previous efforts to alter the ABVD regimen either failed to improve outcomes or caused severe side effects.

Adcetris, an antibody-drug conjugate (ADC) directed to CD30, is approved to treat subpopulations of HL. A nod as front-line therapy could represent a notable increase in the drug's market potential.

"The most important indication for Adcetris that we've always looked for is front-line Hodgkin lymphoma," said Clay Siegall, president and CEO of Seagen, based in Bothell, Wash., recounting the five-year story of ECHELON-1, which enrolled 1,334 patients with histologically confirmed stage III or IV cHL who were not previously treated with systemic chemotherapy or radiotherapy.

"In Hodgkin lymphoma, unlike some other cancers, you can aspire to cure patients," Siegall told BioWorld Asia during a meeting at ASH. "You can cure patients with chemotherapy, but we wanted to cure more, and we also wanted to get rid of bleomycin, which causes a lot of pulmonary toxicity."

Top-line data, reported in June, showed that ECHELON-1 met its primary endpoint, showing statistically significant improvement in modified progression-free survival (modified PFS) per independent review facility (IRF) compared to the ABVD control arm (HR 0.77; p=0.035), corresponding to a 23 percent reduction in the risk of progression, death or need for additional cancer therapy.

At median follow-up of 24.9 months, per IRF assessment, the modified PFS rate for patients in the A+AVD arm was 82.1 percent compared to 77.2 percent in the control arm. Details presented at ASH showed that, per the assessment of physician investigators, the two-year modified PFS rate for patients in the A+AVD arm was 81 percent compared to 74.4 percent in the control arm (HR 0.73; p=0.007), corresponding to a 27 percent reduction in the risk of progression, death or need for additional cancer therapy.

Secondary endpoints also trended in favor of the A+AVD arm, though most showed only modest improvement. Complete response (CR) rate at the end of the randomized regimen was 73 percent in the A+AVD arm compared to 70 percent in the control arm (p=0.22), and objective response rate (ORR) was 86 percent in the A+AVD arm compared to 83 percent in the control arm (p=0.12).

In the A+AVD arm, however, 33 percent fewer patients received subsequent salvage chemotherapy or high-dose chemotherapy and transplant.

The safety profile of A+AVD in ECHELON-1 was generally consistent with that known for single-agent components of the regimen. The most common clinically relevant adverse events (AEs) of any grade that occurred in at least 15 percent of patients in the A+AVD and ABVD arms, respectively, were neutropenia (58 vs. 45 percent), constipation (42 vs. 37 percent), vomiting (33 vs. 28 percent), fatigue (both 32 percent), peripheral sensory neuropathy (29 vs. 17 percent), diarrhea (27 vs. 18 percent), pyrexia (27 vs. 22 percent), peripheral neuropathy (26 vs. 13 percent), abdominal pain (21 vs. 10 percent) and stomatitis (21 vs. 16 percent).

In both arms of the trial, the most common grade 3 or 4 events were neutropenia, febrile neutropenia and neutrophil count decrease. As Connors reported, however, febrile neutropenia was reduced through the use of prophylactic growth factors (G-CSF) in a subset of patients, and use of G-CSF as primary prophylaxis with A+AVD showed a decreased incidence of febrile neutropenia, neutropenia and serious AEs, leading to its recommendation for that use in all A+AVD-treated patients.

Pulmonary toxicity – a major concern when using ABVD to treat patients with advanced cHL – was reported in 2 percent of patients in the A+AVD arm vs. 7 percent in the ABVD arm. Grade ≥3 events were reported in fewer than 1 percent vs. 3 percent, respectively, in the Adcetris and control arms.

Nine study deaths occurred in the A+AVD arm, with seven attributed to neutropenia or associated complications – all in patients who did not receive primary prophylaxis with G-CSF excepting a patient with pre-existing neutropenia. The two remaining deaths were due to myocardial infarction. Thirteen study deaths occurred in the control arm, including 11 due to or associated with pulmonary-related toxicity, one due to cardiopulmonary failure and one of unknown cause.

'Logical to move forward' with targeted therapies

On Nov. 1, Seattle Genetics submitted a supplemental biologics license application to the FDA in the breakthrough therapy-designated front-line advanced cHL indication, requesting accelerated approval. Partner Takeda Pharmaceutical Co. Ltd., of Osaka, Japan, which holds rights to Adcetris outside the U.S. and Canada, also started to submit data from ECHELON-1 to regulatory agencies in its territories, beginning at the end of November with the EMA.

Siegall pointed to the significance of ECHELON-1 by noting that the NEJM paper was just the second in the company's history.

In an accompanying editorial, NEJM deputy editor Dan Longo of Brigham and Women's Hospital and Vincent DeVita of the Yale Cancer Center noted that little progress was made in advancing the ABVD cocktail prior to the application of Adcetris and the PD-1 inhibitor Opdivo (nivolumab, Bristol-Myers Squibb Co.) to the treatment of the estimated 25 percent to 35 percent of patients with cHL who were not cured with initial treatment.

"The incorporation of these new active agents into front-line therapy has been eagerly anticipated, and the wait is over for brentuximab vedotin," Longo and DeVita wrote.

Replacing bleomycin with Adcetris offers the opportunity for more patients with front-line advanced cHL – many of them young adults – to respond to the cancer treatment without relapse and with less fear of potentially fatal breathing problems and lung scarring, according to Siegall. Connors also pointed to irreversible side effects, such as sterility, associated with ABVD and said the four-drug protocol isn't indicated for patients over age 50.

"We're breaking new ground with a regimen that hasn't been redefined in 40 years," Siegall said.

Although initial approval for Adcetris came six years ago, the agent remains the focus of more than 70 ongoing trials. Other phase III studies include the ongoing ECHELON-2 trial in front-line mature T-cell lymphomas (MTCL) and the ongoing CHECKMATE 812 trial in combination with Opdivo in relapsed/refractory HL. At ASH, Seagen presented five-year data from the phase I trial of Adcetris in front-line MTCL showing an estimated PFS rate of 52 percent and overall survival (OS) rate of 80 percent, with no disease progression events since three-year follow-up.

Also at ASH, Seagen presented data from the phase III ALCANZA trial in CD30-expressing cutaneous T-cell lymphoma (CTCL) that showed longer-term durability data with Adcetris as a single agent to treat patients with primary cutaneous anaplastic large-cell lymphoma or CD30-expressing mycosis fungoides.

During the ECHELON-1 briefing, Laurie Sehn, clinical assistant professor and clinical investigator at the BC Cancer Agency's Center for Lymphoid Cancer, who treats patients with HL, said toxicities associated with ABVD are a major concern and many patients are flat out refusing to use the 40-year-old treatment.

"If you look at all the progress made in cancer across the board, it's quite astounding that for this quite common hematological indication we're still using a platform that was developed at the start of chemotherapy," Sehn said. "It seems logical to move forward with platforms that are much more targeted and would be more effective but also minimize the side effects seen long term with chemotherapy."

Analyst reaction was mixed. In his ASH note, RBC analyst Kennen MacKay wrote that "full ECHELON-1 results favor Adcetris' utility in stage 3/4 1L HL and support our peak $1.45B U.S. sales estimate despite continuing debate on pharmacoeconomic value." The updated ALCANZA results further support the CTCL market opportunity, MacKay added, with the five-year phase I MTCL data offering positive read-through for ECHELON-2 outcomes compared with standard of care.

While continuing to expect broad use in stage 3 and 4 patients regardless of disease burden and risk stratification, MacKay nevertheless acknowledged that "we see the breadth of Adcetris utility in the [first-line] setting as a source of continued debate" following the NEJM publication and ASH presentation.

In his ASH weekend takeaway, Leerink Partners LLC analyst Michael Schmidt characterized the ECHELON-1 update as "incremental," writing that new data revealed in the plenary session related mainly to the OS hazard ratio, which trended strongly positive (HR=0.72, data not yet mature) and a variety of subgroup analyses, which trended in favor of A+AVD. In his view, Connors' presentation also provided a valid explanation for using modified PFS as the primary endpoint – "a topic of investor controversy," Schmidt wrote – with a goal of more accurately detecting failure of front-line therapy.

But Suntrust Robinson Humphrey analyst Yatin Suneja was "incrementally more cautious on the uptake for Adcetris" in front-line cHL, despite characterizing the two-year modified PFS numbers as in-line with top-line data. He focused, instead, on the lack of difference in CR and ORR between the study arms and pointed out that "the majority of the Adcetris+AVD's benefit is occurring in stage IV patients (HR 0.71, CI 0.53–0.96), which represents [approximately] 64 percent of the patient population enrolled in the trial. The A+AVD combo showed minimal effect in stage III (HR=0.92; CI 0.60–1.4) patients." He noted that stage 3 and 4, combined, represent approximately 40 percent of HL patients, "and based on the trial population, stage 4 would represent [approximately] 26 percent of the overall HL pool."

Like other analysts, Suneja predicted approval of A+AVD in advanced cHL but forecast the market potential for Adcetris in the indication "might be <$500MM."

In her comments, Sehn characterized as "significant" the finding that one-fourth of patients who otherwise would have failed ABVD seemed to achieve CR with the A+AVD regimen. And Siegall, while conceding the ECHELON-1 data are not yet mature enough to confirm "higher cure rates" than ABVD in cHL, suggested they portend that potential.

"When you look at the Kaplan–Meier plots in this disease, once you're out two or three years, they're pretty much a flat line," he said.

Seagen is counting on Adcetris to show continued staying power as it seeks to advance its early stage pipeline – upstream of the Nectin-4 inhibitor enfortumab vedotin (ASG-22ME), partnered with Astellas Pharma Inc., and tissue factor inhibitor tisotumab vedotin, partnered with Genmab A/S – on its own.

"We're morphing into a multiproduct, global oncology company," Siegall maintained. "We still have work to do to get there, but that's our goal." 

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