ASH 2020 | Brentuximab vedotin in treatment naïve cHL patients: a 5-year update of the ECHELON-1 trial

I will be reporting on the five-year follow-up results on the ECHELON-1 study, which was a randomized trial of brentuximab vedotin, plus doxorubicin, vinblastine and dacarbazine, or AVD, as compared with standard of care with ABVD, doxorubicin, bleomycin, vinblastine and dacarbazine, for previously untreated patients with stage III and IV classical Hodgkin lymphoma. This was a large international randomized trial of over 1,300 patients, randomized one-to-one to each arm of the study.

The patients receive six cycles of each regimen. The primary endpoint was the modified progression-free survival at two years of follow-up, which was defined as relapses, deaths or incomplete responses leading to initiation of new treatment. So this is very similar to event-free survival, but the difference is event-free survival was from the initiation of treatment, and modified progression-free survival is from the end of treatment. This was one of the primary endpoints, and at two years, there was a 5% advantage in modified PFS favoring BV plus AVD, 82.1% versus ABVD standard of care, 77.2%. This was statistically significant and led to the approval of BV plus AVD as a frontline treatment choice for patients with previously untreated stage III and IV Hodgkin lymphoma in the U.S.

A second primary endpoint is overall survival based on the number of death events, and these have not been reached as yet, so the secondary, this other primary endpoint survival has not been met at patients continue in follow up. So we did analysis after three and four year follow up using progression-free survival per investigator. The mPFS was per central review. The central review committee was disbanded after that. So the later analysis are three, four, and now five years per investigator progression-free survival and what we found in the intent-to-treat population. And so we report now the five-year results, which are really kind of a very important endpoint because in an advanced stage Hodgkin lymphoma treated with this type of chemotherapy, 95% of relapses and events re-occur within the first five years and only 5% after five years. And so we now also report a certain toxicity and safety data. So at five years, we found as we did a three and four years, that this difference in progression-free survival favoring BV plus AVD was maintained. There was a 7% difference in PFS, 82.2% for BV plus AVD versus a 75.3% for ABVD.

We also found in a forest plot, which is in the poster, the advantage was seen in really, basically all prognostic subgroups, including age, IPI score, stage, presence or absence of B-symptoms, nodal extranodal sites and performance status. So we looked at certain long-term toxicity things among them, peripheral neuropathy, which was a major problem and higher in patients with BV plus AVD as compared with those with treated with standard ABVD.

However, at the two-year point of the primary end point of a modified PFS, 67% of the BV plus AVD patients had improvement in peripheral neuropathy, 75% of the ABVD arm. And at five years, this was increased to 84% for the BV plus AVD patients and 85% for the ABVD patients. All but less than 3% or less of remaining toxicity was grade one and two. But the improvement was seen in 84% of the BV plus AVD arm showing that this problem resolves in most patients with time. New data that we really needed the longer follow-up included second malignancies. And importantly, there did not seem to be an excess of second malignancies in patients treated with BV plus AVD as compared to those treated with ABVD. There were 20, there were 19 second malignancies in the BV plus AVD arm and 29 in the ABVD arm.

Another important thing that we’re reporting is pregnancies and we found that there was no increased infertility in patients in pregnancies and no difference in pregnancies, importantly, difference in pregnancies between the two arms of the study. So we had 150 on-site pregnancies in participants or their partners, and all of these were ongoing or resulted in live births. We feel that these five-year results are very important because most of the relapses in events occur within the first five years and only 5% or so after that time.

We find a sustained benefit and progression-free survival with a BV plus AVD. We have not had enough events as yet to report on survival. And we did not find an excess of infertility in patients on the BV plus AVD arm. And we did not find a excessive number of second malignancies. We do not anticipate that we will see a lot of late second malignancies, which are associated with radiation therapy, which was not used in this trial. So we feel that BV plus AVD can be considered a very attractive option for all patients regardless of prognostic factors and stage for previously untreated stage III and IV classical Hodgkin lymphoma.