The clinical trial that we are discussing is Echelon-1. This is a study specifically for patients with advanced-stage Hodgkin’s lymphoma stages 3 and 4, and it’s a study really evaluating the addition of new novel targets to frontline therapy. Brentuximab vedotin is an antibody-drug conjugate that has been very successful in patients with Hodgkin’s lymphoma in the relapse setting.
And now is being tested in the frontline in comparison to ABVD chemotherapy. So, the echelon one trial compared brentuximab vedotin and ABVD chemotherapy. To a standard of care which is ABVD chemotherapy. And the key findings have been reported over time. The initial first key finding was there was an improvement in the modified progression-free survival in favor of brentuximab vedotin plus ABVD chemotherapy; subsequently, presentation showed that progression-free survival.
Was improved, but the big finding and the report from the ASCO meeting was that overall survival is improved with brentuximab and ABVD chemotherapy over ABVD chemotherapy. And I think this is highly relevant because it’s actually the first study that has shown a survival advantage for a new regimen over ABVD chemotherapy to date.
I think there are a few things that are asked about the study, the first being, how is it that an overall survival advantage is determined? Particularly when the dogma in the past has been that you can always salvage patients with Hodgkin’s Lymphoma if they were to relapse. So, one of the sort of rationales in the past has been you could do less therapy in the beginning because there may be less toxicity and should patients have disease come back.
You can always go to salvage treatment and a stem cell transplant rather than intensifying treatment right away. I would say that the data from this trial challenged that because as we looked at the subsequent therapies in both arms patients who had not received brentuximab vedotin in the frontline as per the trial, who relapsed, could then get it. Subsequently, many patients on both arms went on to receive an auto-autologous transplant.
And other patients also received other novel agents, including PD, one blockade, and. There is still an overall survival advantage for patients receiving brentuximab vedotin, and ABVD as frontline therapy. So, I think this really reminds us that your most optimal opportunity for a durable remission is the first thing you do.
therefore, I think it clearly has made brentuximab vedotin and ABVD chemotherapy, the preferred frontline therapy. A second thing. That’s really interesting is what additional findings could account for this difference in survival outcome. And I think there are two main messages there. The first being that fewer patients progressed and subsequently died from Hodgkin’s Lymphoma.
Again, showing that the addition of brentuximab vedotin and 2 standard chemotherapy improves the likelihood of the disease being cured. The second thing that was quite a surprise, but it was also notable was the fact that there are more patients with second malignancies in the ABVD chemotherapy arm, rather than in the brentuximab vedotin ABVD chemotherapy arm.
And interestingly, when one looks at solid tumors, which are more commonly, the second malignancy, they were identical in both arms when one looked at myelodysplastic syndrome or second leukemia. They also were not different in the two arms, but what was different was the fact that a second lymphoid malignancy in the way of a T-cell or B-cell lymphoma was actually greater in the ABVD chemotherapy arm, suggesting that brentuximab vedotin may actually target a precursor cell, which may actually then suppress the likelihood of there being a second lymphoma that may develop in these patients.
And that obviously impacted survival.
I think this definitely impacts clinicians today. Brentuximab vedotin and ABVD chemotherapy has actually been approved as frontline therapy for patients with advanced-stage classical Hodgkin’s Lymphoma. But I think this really provides the impetus for this to be the preferred standard of care treatment.
Because clearly, if we actually can cure more patients as this study shows, that really should be the way in which we manage patients. There is more in the way of hematological toxicity. In other words, you need to use a growth factor with the brentuximab vedotin ABVD chemotherapy treatment. So I think that’s notable.
I also think it’s important that clearly, even though this is a more expensive regimen. These are young patients whom we are potentially curing and restoring to useful participation in society. So I really do believe that this use of brentuximab vedotin and ABVD chemotherapy is really the preferred way to treat patients.
As I mentioned, brentuximab vedotin and ABVD chemotherapy has really pushed the bar forward. And I think we’ve set a new, higher standard and a preferred therapy for patients with advanced stage classical Hodgkin’s Lymphoma. I think the key next question is. Can we push the bar yet higher by utilizing other targeted therapies?
And in fact, there’s a large intergroup study, which has almost completed an accrual, which is comparing brentuximab vedotin and ABVD chemotherapy to the same ABVD chemotherapy but adding a PD 1 blocking antibody nivolumab. So, this is a head-to-head comparison of 2 targeted therapies to see whether 1 is superior to the other.
We’re waiting on those data. There will probably be another year or so before that’s available, but clearly that is gonna be very impactful. If one improves the outcome over the other.
I think a lot of people are always concerned about is there are more in the way of long term toxicities and side effects that impact patients. And the data presented at ASCO actually addressed 2 of those 1 being, did the treatments impact the likelihood of the patient or their spouse for getting pregnant.
And the answer was that brentuximab vedotin and ABVD chemotherapy-treated patients actually had more pregnancies than the standard suggesting that there really is no adverse events or adverse impact on pregnancies with the use of brentuximab vedotin. The other side effect that people need to pay attention to with brentuximab vedotin is neuropathy.
So now with 6 years of follow up close follow up of the neuropathy has shown that in greater than 85% of patients, this either resolves or becomes profoundly less. In patients over time. So, this again, suggests that while these drugs do bring more in the way of side effects, these side effects are not to the degree where they really impact patients’ quality of life and long term activity of daily living.
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Steven Ansell, MD, Ph.D., Professor of Medicine at Mayo Clinic. In this video, he speaks about the ASCO Abstract – First-line brentuximab vedotin plus chemotherapy to improve overall survival in patients with stage III/IV classical Hodgkin lymphoma: An updated analysis of ECHELON-1.
Origins:
To date, an overall survival (OS) benefit from innovative therapy combinations over conventional treatments in first-line classical Hodgkin lymphoma has seldom been demonstrated (cHL). The development of more active medicines for relapsed/refractory illness has made demonstrating increased OS with first-line therapy difficult. In ECHELON-1 (NCT01712490), 5-year follow-up studies supported the long-term progression-free survival (PFS) benefit of first-line brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) vs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in patients with stage III/IV A+AVD had a reasonable long-term safety profile, with fewer second malignancies and a higher number of pregnancies observed compared to ABVD (Connors et al, NEJM 2018; Straus et al, Lancet Haematol 2021). After approximately 6 years of follow-up, we present a prespecified OS analysis (cut-off, June 1, 2021).
Methodology:
Pts were randomly assigned to one of six cycles of A+AVD (n = 664) or ABVD (n = 670) on day one and 15 every 28 days. The primary secondary endpoint was OS, which was an event-driven, pre-specified, alpha-controlled study in an intention-to-treat sample.
Outcomes:
At a median follow-up of 73 months, 39 and 64 OS incidents occurred in the A+AVD and ABVD arms, respectively: OS favored A+AVD over ABVD (HR 0.590; 95 percent CI 0.396–0.879; p = 0.009). Estimated 6-year OS rates (95 percent CI) for A+AVD vs ABVD were 93.9 percent (91.6–95.5) vs 89.4 percent (86.6–91.7), respectively. Across prespecified subgroups, there was a consistent OS advantage for A+AVD vs ABVD. The 6-year PFS estimate for A+AVD vs ABVD was 82.3 percent (79.1–85.0) vs 74.5 percent (70.8–77.7) (HR 0.678 [95 percent CI 0.532–0.863]). Overall, A+AVD showed a long-term safety profile similar to ABVD. Treatment-emergent peripheral neuropathy improved or resolved in both arms, with 86 percent (379/443) and 87 percent (249/286) of cases in the A+AVD and ABVD arms either entirely resolving (72 percent vs 79 percent) or improving (14 percent vs 8 percent) by the last follow-up. There were fewer second malignancies reported in the A+AVD arm compared to the ABVD arm (23 vs 32). Female patients in the A+AVD arm reported more pregnancy (49 vs 28) or live births (42 vs 19 in females) than in the ABVD arm; no stillbirths were observed. There were no new safety signals discovered.
Observations:
Treatment with A+AVD resulted in a statistically significant 41 percent reduction in the risk of death compared to ABVD, with a manageable safety profile similar with previous studies. These findings support A+AVD as a treatment option for patients with previously untreated stage III/IV cHL. NCT01712490 is the clinical trial number.