Considerations for Frontline Treatment of Advanced Hodgkin Lymphoma

Craig Moskowitz, MD

Professor

Physician-in-Chief, Oncology Service Line

Don Soffer Clinical Research Center

University of Miami Sylvester Comprehensive Cancer Center

Miami, FL

Targeted Oncology^TM: What studies led to the use of brentuximab vedotin (Adecetris) for patients with advanced Hodgkin lymphoma?

CRAIG MOSKOWITZ, MD: The ECHELON-1 [NCT01712490] study which compared ABVD [doxorubicin, bleomycin, vinblastine, and dacarbazine] with BV-AVD [brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine] was published a number of years ago in the New England Journal of Medicine.¹ It has a [complicated] history to it. Whether it was the best study to do is unclear, but it was a large, randomized industry-sponsored study for patients with stage III and IV disease, which is important, because a lot of the random assignment trials that are cooperative group-based, or from the German group, included patients with stage IIB disease as well.

In fact, there's a study called the RATHL study [NCT00678327], where you give ABVD for 2 cycles, and if the PET scan is negative, then you de-escalate, drop bleomycin, and give AVD [doxorubicin, vinblastine, and dacarbazine] for 4 months. [Over] 40% of patients in that study had stage II disease [including stage IIA with adverse features].² That's not a study of patients with advanced-stage Hodgkin lymphoma.

One of the things I like about the ECHELON-1 trial is that it is truly for patients with advanced stage disease. It has been published multiple times now in various formats, and shockingly, the last time the data was reassessed, there was an overall survival [OS] advantage to the BV-AVD arm.³ It's [nearly] unheard of in the management of aggressive lymphoma. There is almost no aggressive lymphoma study out there, [whether] in large cell lymphoma, Hodgkin lymphoma, Burkitt lymphoma, mantle cell lymphoma, [or other types], where 1 arm shows an OS advantage.

They almost always show a progression-free survival advantage, or what the German [researchers] call freedom from treatment failure, and you can decide what treatment failure is. When I was at Memorial Sloan Kettering Cancer Center, we used to use event-free survival [EFS].

In lymphoma management in general, it's almost shocking for there to be an OS advantage. So, when this study came out, nobody ever thought that this particular treatment program, BV-AVD, would have a survival advantage over ABVD. The results are what they are. I started studying brentuximab vedotin in 2009. We participated in the phase 2 single-agent [frontline] brentuximab vedotin study [NCT01716806], and then I wrote the AETHERA study [NCT01100502] [for patients with high-risk Hodgkin lymphoma following autologous stem cell transplant] and published that in 2015. That is how brentuximab got approved in those settings.

Then we started studying nivolumab [Opdivo] and pembrolizumab [Keytruda], and those drugs got approved. Eventually, these drugs have both moved earlier [in the treatment paradigm, as has] brentuximab. Brentuximab is approved, the other 2 have not been approved [in the first line].⁴ Pembrolizumab has been shown to be superior to BV in the palliative setting.⁵ That is what we know.

How are patients with stage III or IV Hodgkin lymphoma evaluated after receiving frontline BV-AVD or ABVD therapy for Hodgkin lymphoma?

Hodgkin lymphoma is an aggressive lymphoma. It’s not as aggressive as diffuse large B-cell lymphoma, but patients die from it. In reality, what you want to do is [separate] patients with primary refractory disease. It’s divided into 2 different groups. Years ago, we defined in large cell lymphoma, as well as later in Hodgkin lymphoma, that not all patients with primary refractory disease are the same. There are 2 possibilities. The first possibility is that the patient gets a complete course of treatment. At the end of the treatment, the imaging is abnormal, you do a biopsy, and the patient has disease. That means they have received a complete course of therapy, but it didn't work. That, by definition, is primary refractory disease.

The other possibility is [the physician] gave the patient 3 different treatments, and now they have a new node in their neck. And then [the physician] biopsies the patient, and they have lymphoma. That's also primary refractory disease. Some physicians would argue that those things are different. Some would argue that the second group of patients have [what is] maybe called primary progressive lymphoma. That means a patient had an incomplete course of primary treatment, and progressed on that.

But the world has combined those 2 things together. In reality, we've published and shown that the first group of patients do exactly the same as relapsed patients. And the primary progressive patients almost never catch up.

What I think has happened is that the patients who have primary progression have not been helped by either one of these treatments. The patients who have had primary refractory disease but had an incomplete response to full-course therapy probably don't exist [if they receive frontline] BV-AVD. BV-AVD is curing those patients, and that's why the [Kaplan-Meier] curves [in the ECHELON-1 trial] start splaying after they have completed their treatment.¹

Because if the first thing was true, the [Kaplan-Meier] curves would splay early. Remember, if there were no one progressing on treatment, then the BV-AVD arm would be flat at the top. But that's not the case. It drops. So I think that there is still a small group of patient with Hodgkin lymphoma…5% to 8% of patients who progress on primary treatment. Those patients are not being helped by BV. It's the other group of patients who are.

So if you were giving somebody BV-AVD and they were on cycle 3, and you did a PET scan, you would have 2 possibilities. No. 1, the disease was shrinking down [but] there was still mild activity. And possibility No. 2 was that the disease was shrinking down, but they had a new lesion in the spleen. Those patients need to have therapy changed. They will not go into remission [with BV-AVD].

The first group of patients where everything is shrinking down and there's still slight abnormality, they probably will go into remission. I've been doing this for a long time, so I've seen these things, but to me, that's the most important take-home point from these things.

_REFERENCES

_{1. Connors JM, Jurczak W, Straus DJ, et al. Brentuximab vedotin with chemotherapy for stage III or IV hodgkin's lymphoma. N Engl J Med. 2018;378(4):331-344. doi:10.1056/NEJMoa1708984}

_{2. Johnson P, Federico M, Kirkwood A, et al. Adapted treatment guided by interim PET-CT Scan in advanced Hodgkin's lymphoma. N Engl J Med. 2016;374(25):2419-2429. doi:10.1056/NEJMoa1510093}

_{3. Ansell SM, Radford J, Connors JM, et al. Overall survival with brentuximab vedotin in stage III or IV Hodgkin's lymphoma. N Engl J Med. 2022;387(4):310-320. doi:10.1056/NEJMoa2206125}

_{4. FDA expands approval of Adcetris for first-line treatment of stage III or IV classical Hodgkin lymphoma in combination with chemotherapy. News release. FDA. March 20, 2018. Accessed March 29, 2023. https://bit.ly/42MBFT0}

_{5. Kuruvilla J, Ramchandren R, Santoro A, et al. Pembrolizumab versus brentuximab vedotin in relapsed or refractory classical Hodgkin lymphoma (KEYNOTE-204): an interim analysis of a multicentre, randomised, open-label, phase 3 study. Lancet Oncol. 2021;22(4):512-524. doi:10.1016/S1470-2045(21)00005-X}