Novel Targeted Immunotherapies Strengthen Frontline Treatment Strategies in Hodgkin Lymphoma

Joshua Brody, MD

Although the current treatment landscape in Hodgkin lymphoma consists of several effective chemotherapy regimens, the development of novel targeted immunotherapies in this space has helped expand treatment options and improve outcomes for patient populations that may not respond to standard frontline treatments, according to Joshua Brody, MD.

“Even [though] Hodgkin lymphoma is a less common disease, we’re still able to make [treatment] advances more rapidly than other tumor types, because we have good targets and understanding of [tumor] biology,” Brody said, following his presentation on updates in HL, which was delivered at the 40th Annual CFS^®. “Overall, we can improve immune responses [by using targeted therapies to] help treat and hopefully cure patients with Hodgkin lymphoma.”

In an interview with OncLive^®, Brody expanded on his presentation by highlighting unmet needs in patient subgroups within Hodgkin lymphoma, recent advancements in the use of antibody-drug conjugates (ADCs) such as brentuximab vedotin (Adcetris) and anti–PD-1 therapies in earlier lines of therapy, and future avenues for expanding the use of immunotherapy in this tumor type.

Brody is a faculty member at Icahn Genomics Institute and director of the Lymphoma Immunotherapy Program at The Tisch Cancer Institute at Mount Sinai in New York, NY.

OncLive^®: What unmet needs still exist for patients with Hodgkin lymphoma?

Brody: [Many clinicians] think of this [disease] as the “good cancer” to have, because Hodgkin lymphoma already [has] a lot of good therapies [available]. Most of our young patients can be not only treated effectively, but cured, and will hopefully go on to live long, full, happy, and healthy lives. Yet, there is still great room for improvement.

About one-quarter of our patients are not getting effective therapies or do not respond to frontline therapy. [Additionally,] our later lines of therapy, [including] stem cell transplants, are still fairly aggressive and toxic for the majority of patients. Although most patients are younger, there’s [also] a whole second subset of patients who peak at 60 and 70 years. All our regimens for those folks are suboptimal in efficacy and tolerability, so there are still a few significant unmet needs in Hodgkin lymphoma.

What updates or key trials have helped improve the treatment paradigm for this disease?

[One of the most] impactful recent updates is a follow-up from the phase 3 ECHELON-1 trial [NCT01712490], the largest randomized trial ever done in Hodgkin lymphoma. It’s amazing that we’re able to [conduct] these large trials for a [less] common disease, and [still] show big impacts. That study [evaluated] the addition of brentuximab vedotin to frontline chemotherapy. For several years now, we’ve seen a significant progression-free survival [PFS] benefit with A+AVD [brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine] compared with ABVD [doxorubicin, bleomycin, vinblastine, and dacarbazine], but the recent update is even more gratifying. It shows a significant benefit in overall survival [(OS) with the addition of] frontline brentuximab vedotin. This is now considered a category 1 National Comprehensive Cancer Network recommendation. [These results] don’t mean that it’s the right therapy for every patient, but this [could] be a new standard of care for most patients based on that OS benefit.

What developments in immunotherapy are on the horizon for this tumor type?

The most obvious advances [are in] PD-1 checkpoint [inhibitors]. There are now lots of data on pembrolizumab [Keytruda] and nivolumab [Opdivo] as monotherapies. The [phase 3] KEYNOTE-204 trial [NCT02684292] showed better outcomes and a significant PFS benefit from anti–PD-1 therapy [vs] brentuximab vedotin in the third-line setting.

These anti–PD-1 therapies are not only highly effective in Hodgkin lymphoma, but in many tumors [such as] melanoma and lung cancer. [However, these agents do show] higher response rates in Hodgkin lymphoma than in other tumor types. Anti–PD-1 agents are now working their way into second-line studies in combination with chemotherapy, such as pembrolizumab plus GVD [gemcitabine, vinorelbine, and liposomal doxorubicin], and we’ve seen unprecedented response rates and complete remission [CR] rates [with such approaches]. We still need more data and follow-up, but you can’t ignore that [exciting] result.

The chemotherapy-free doublet of anti–PD-1 therapy in combination with brentuximab vedotin [has already been] studied in the third line, [and the combination is producing] great data in the second line. A good majority of patients [have achieved] CR with this pretty gentle therapy, and most of [these patients progress] to [autologous] stem cell transplant. [We have] mature data [showing] many durable responses with that second-line therapy plus stem cell transplant.

Anti–PD-1 therapy is working its way up from the third line to the second line. Now we’ve completed accrual in the large, randomized phase 3 SWOG-1826 trial [NCT03907488], where we are trying to beat the new standard A+AVD with anti–PD-1 therapy plus chemotherapy. We hope to get some results from that trial in the next year or 2.

What main message would you like to impart to your colleagues regarding the role of immunotherapy in Hodgkin lymphoma? ​​

The take-home [message] here is the benefits of immunotherapy. Brentuximab vedotin is immunotherapy-based, [and is often administered with] an anti–PD-1 therapy.Now, [the agent is being administered] with both autologous CD30-directed CAR T cells and even some allogeneic CD30-directed CAR T cells—both of which show good response rates. Autologous CAR T-cell therapies now [have] a decent amount of follow-up, with most subsets of patients [achieving] CRs. For example, adding the HDAC inhibitor, entinostat [SNDX-275], to anti–PD-1 therapy [in the phase 2 ENGAGE-501 trial (NCT00866333)] showed that even PD-1–refractory patients can have great partial and complete [responses]. Hopefully these [responses] will be durable and [support] a more nuanced way to improve anti-lymphoma immunotherapy.

Editor’s Note: This interview was conducted prior to the 2022 ASH Annual Meeting.