ECHELON-1 Trial of Brentuximab Vedotin Improves OS in Classical Hodgkin Lymphoma

David J. Straus, MD

The combination of brentuximab vedotin (Adcetris), doxorubicin, vinblastine, and dacarbazine improves overall survival and should be used as a first-line treatment for patients with stage 3 or 4 classical Hodgkin lymphoma, according to findings from the phase 3 ECHELON-1 trial (NCT01712490).

In the study, a total of 1334 patients were enrolled and randomized 1:1 to receive either brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine or brentuximab vedotin plus bleomycin, doxorubicin, vinblastine, and dacarbazine group.

The primary end point of the study was modified progression-free survival (PFS) with key secondary end points of alpha-controlled event-driven analysis of overall survival (OS).

Findings revealed that for patients who were given brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine, the 5-year PFS was 84.9% (95% CI, 81.7%-87.6%) vs 78.9% (95% CI, 75.2%-82.1%) in the brentuximab vedotin plus bleomycin, doxorubicin, vinblastine, and dacarbazine group (HR, 0.66; 95% CI, 0.50-0.88; P = .0035). At 6 years, the estimated PFS rates were 82.3% (95% CI, 79.1%-85.0%) vs 74.5% (95% CI, 70.8%-77.7%) for each arm (HR, 0.68; 95% CI, 0.53-0.86; log-rank P = .002). The median follow-up was 73 months.

OS rates were also improved and at 6 years, they were 93.9% (95% CI, 91.6%-95.5%) in the brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine group compared with 89.4% (95% CI, 86.6%-91.7%) in the brentuximab vedotin plus bleomycin, doxorubicin, vinblastine, and dacarbazine group (HR, 0.59; 95% CI, 0.40-0.88; log-rank P = .009). At 73 months of follow-up, the median OS was not reached.

Overall, these data show that the combination of brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine, should be used in the first-line for patients with stage 3 or 4 classical Hodgkin lymphoma.

In an interview with Targeted Oncology^TM, David J. Straus, MD, medical oncologist and attending physician Memorial Sloan Kettering Cancer Center in New York, New York, discussed the newest data of the ECHELON-1 trial which he presented at the National Comprehensive Cancer Network 2022 Annual Congress: Hematologic Malignancies.

Targeted Oncology: What were the methods and design of the ECHELON-1 trial?

Straus: The ECHELON-1 trial had a very simple design which has been used many times. It was a prospective, randomized, comparison of a standard of care vs a modification of the standard of care, which was the experimental arm. It was a very large trial of over 1300 patients and 1 of the largest ever conducted in patients with newly diagnosed Hodgkin lymphoma. This was for newly diagnosed patients with advanced stage disease, stages III and IV. It was global, so it was a very large trial with over 650 patients in each arm of the study.

What were the primary and secondary end points of the trial?

The primary end point was modified progression-free survival at 2 years of follow up. Patients were randomized to 6 cycles of ABVD, the standard of care at least in North America, and BV brentuximab vedotin plus AVD, omitting bleomycin, 6 cycles roughly every 24 weeks of treatment in both arms. The modified PFS is an unusual end point. It is like event-free survival except that it is counted from the completion of treatment rather than the beginning of treatment. Event free survival accounts for progressions and deaths, but also events leading to discontinuation or switches in treatment due to toxicity or because the treating physician does not feel that they're satisfied with the response.

In the modified PFS, this is from the end of treatment so that if somebody switched therapy or added radiation therapy during treatment, it wasn't counted as an event. It's a peculiar end point but analyses by more classical criteria, like progression-free survival, really were the same. The second important end point was overall survival, which was event driven. It required 113 deaths before analysis would be done. At 6 years median follow-up time, most of the recurrences had occurred early in the follow-up and very few at the later time points in the follow-up. At 103 deaths, the FDA permitted analysis of survival. Then there were other end points of toxicity, pregnancies, peripheral neuropathy, and others that were followed.

What were some of the findings of the trial?

The modified progression-free survival at 2 years was significantly in favor BV plus AVD as compared with ABVD, which led to FDA approval of that regimen for newly-diagnosed Hodgkin lymphoma stages III and IV in the United States. We did several further follow-up studies and found that this was not just an early advantage with 3, 5, and 6 years. This difference in progression-free survival, which is progressions or deaths, was maintained. It was a little bigger at 6 and 7 years.

What was quite remarkable is the survival analysis which showed a small difference in survival overall, which you're talking about: arms of the trial are over 650 patients, at 4.5%. But that meant 39 deaths in the BV plus AVD arm vs 64 deaths in the ABVD arm, a reduction in the risk of death, using BV plus AVD of 41%. That is quite a remarkable finding and it's never been found in any similar trial. As I said, the design of this trial was simple and has been used many times a number of trials. They have shown a progression-free survival advantage for an experimental treatment vs standard treatment, but in Hodgkin lymphoma, you can salvage patients and even cure some with second-line or more treatments. So, it never showed a survival advantage but even though overall 89% vs 93% survival at six years, a 4.5% difference, these are lives, not just relapses. I think that strengthens the case for using this and considering it as a new standard of care.

What do you think these findings mean for the future of this space?

In the United States where we can get insurance to cover this without too much trouble, I think it's preferred in most patients. It benefited most subgroups of patients, but not all. There may be subgroups where you might consider other treatments. I think, in general, this would be a preferred treatment, the toxicities were somewhat different, but no more for the new treatment.

Overall, the cost is an issue and there are plenty of drugs in use here and in other countries, even some that have centralized healthcare, are used with just a PFS benefit. In this case, we're talking about lives. I think that real world studies of the death rates from ABVD standard of care and BV plus AVD will be helpful in deciding whether this benefit and survival seen in the clinical trial is translated into real world clinical practice.

What unmet needs still exist in the space?

Nothing's 100% and there is a small number of patients who don't do well.I think that there are new therapies and new approaches that hopefully will further improve things. Also, there's toxicity to BV plus AVD, particularly peripheral neuropathy. While it doesn't kill you, if you are left with the inability to write or to button your shirt, that's a real toxicity. We [have to] find treatments that improve on or at least show the same excellent results we've achieved [before]. I think there is a room for improvement and we [also] have a clinical trial looking at a new regimen which omits vinblastine.