Herrera Spotlights Key Research Across Hematologic Malignancies From the 2023 ASCO Annual Meeting

Alex Herrera, MD

Positive findings from the phase 3 SWOG S1826 trial (NCT03907488) have set the stage for ongoing efforts to align the treatment of adult and pediatric patients with newly diagnosed stage III/IV Hodgkin lymphoma (HL), and support the undertaking of more collaborative efforts in this space, according to Alex Herrera, MD.

Primary results from SWOG S1826 were presented at the 2023 ASCO Annual Meeting, and demonstrated that the addition of nivolumab (Opdivo) to standard-of-care doxorubicin, vinblastine, and dacarbazine (AVD) improved progression-free survival (PFS) vs brentuximab vedotin (Adcetris) plus AVD in this population (HR, 0.48; 99% CI, 0.27-0.87; 1-sided log-rank P = .0005), meeting the primary end point of the trial. The experimental regimen was also was well tolerated, with a discontinuation rate of 11% with nivolumab vs 22% with brentuximab vedotin.¹

“We went from using radiation in more than half of the youngest patients to barely using it at all,” said Herrera about the trial in an interview with OncLive® News Network: On Location during the 2023 ASCO Annual Meeting. “Hopefully, [use of this regimen is] going to improve outcomes, reduce toxicity, and potentially [reduce] the late [adverse effects] AEs that we see from these therapies.”

In the interview, Herrera presented key data from the SWOG S1826 trial and expanded on the trial’s clinical significance in HL. Herrera also touched on primary overall survival (OS) data from the phase 3 ZUMA-7 trial (NCT03391466), a pooled analysis of cohorts 2a and 2b of the phase 1/2 EPCORE NHL-2 trial (NCT04663347), and other key research in hematologic malignancies presented at the 2023 ASCO Annual Meeting.

Herrera is a hematologist/oncologist, an associate professor, and chief of the Division of Lymphoma in the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope in Duarte, California.

OncLive: SWOG S1826 compared nivolumab plus AVD vs standard brentuximab vedotin plus AVD. What was the rationale for replacing such an effective agent with nivolumab in this trial?

Herrera: There were a number of reasons for doing the trial. The standard for many years in [classical] HL has been to use combination chemotherapy, but we use different regimens globally. We used to use ABVD [doxorubicin, bleomycin, vinblastine, and dacarbazine] on this side of the pond and BEACOPP [bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone] in Europe. Even within North America, pediatric doctors and adult doctors use different regimens. In fact, the majority of pediatric patients receive consolidative radiation after their chemotherapy. These are the patients most vulnerable to toxic effects from the chemotherapy and radiation that we use, and a majority were receiving radiation. There was certainly room to improve and harmonize the treatment of [patients with] advanced stage HL.

Brentuximab vedotin is a potent agent for HL. When we combined it with AVD chemotherapy, it improved modified PFS, PFS, and OS compared with AVD [alone]. It's become a standard, if not the standard treatment in advanced HL. PD-1 blockade is very effective for the treatment of treatment-resistant HL. In fact, it's a highly targeted therapy for HL, as there are genetic changes in HL tumor cells that lead to expression of PD-1 ligands on the cell surface. Over the years, we've been using it earlier and earlier in the course of therapy. Early data showed that if you incorporate nivolumab into frontline therapy, combined with AVD chemotherapy, the results were quite good. That was where we were in 2018.

When we had to design the trial, rituximab [Rituxan] was becoming a standard of care. Nivolumab was very effective and moving into earlier lines of therapy. The study question kind of asked itself, [and we thought to] use the same chemotherapy backbone. I led the trial as part of the SWOG Cancer Network. We collaborated with other cooperative groups of the National Cancer Institute and National Clinical Trials Network, including the Children’s Oncology Group. This is the first time in the history of HL research that all the adult and pediatric collaborative groups [worked together] on a study. We [evaluated] all adults and pediatric patients who [were] going to receive AVD chemotherapy and randomly assigned patients to receive either nivolumab or brentuximab vedotin.

Could you expand on the efficacy and safety results from this trial?

The results are remarkable. Brentuximab vedotin combined with AVD is effective [in HL], but many patients still relapse across the age spectrum. In fact, using brentuximab vedotin combined with AVD added toxicity in adults compared vs ABVD. At only a second interim analysis, the primary end point of PFS crossed the protocol-specified statistical boundary and demonstrated that nivolumab plus AVD improved PFS compared with brentuximab vedotin plus AVD. The hazard ratio was 0.48, so there was a 52% reduction in the risk of disease progression or death. This was a dramatic improvement in outcomes.

Nivolumab and AVD were well tolerated, and there was less neuropathy and liver function test abnormalities [compared with brentuximab vedotin plus AVD]. Unexpectedly, the rates of immune-related toxicities were similar between the arms. We didn't see a huge increase in immune-related toxicity [with nivolumab]. There was more neutropenia in the nivolumab and AVD arm because we didn't require that patients in this arm receive G-CSF. Patients in the brentuximab arm were required to receive G-CSF, so there was more neutropenia in the nivolumab arm, but there was no increase in infectious toxicity, which is [something] that we would be worried about. We improved PFS [with] nivolumab and AVD, [and this regimen] was better tolerated. Only 6 out of nearly 1000 patients enrolled across [both] arms received radiotherapy.

Do these results affect treatment expectations for both adult and pediatric patients with HL? Could they change the way clinical trials are conducted in this space?

Harmonizing the treatment of adults and pediatric patients is a tremendous event. To get everybody in the room to sit down together, design the trial together, and use the same regimen was a huge advance. Going forward, this trial has sparked ongoing collaboration [on] all future trials that affect adolescents and young adults [with lymphoma] between the Children’s Oncology Group and the adult cooperative groups. For many reasons, this was a truly groundbreaking trial. We expect it to be practice changing given the magnitude of the benefit.

It was a tremendous opportunity to be able to lead this study. When you design a study, you're obviously hoping it's a positive study and that you're going to improve the lives of patients with cancer. To be able to improve outcomes, reduce toxicity, hopefully reduce late AEs, be part of nucleating an ongoing collaboration across all the lymphoma cooperative groups was pretty special. That's a once in a lifetime [opportunity].

How might the results from the primary OS analysis of the ZUMA-7 trial of axicabtagene ciloleucel (axi-cel; Yescarta)² influence sequencing strategies in relapsed/refractory large B-cell lymphoma (LBCL)?

[ZUMA-7] is an important trial. We know that ZUMA-7 led to axi-cel becoming the standard of care in the second line for patients with primary refractory diffuse large B-cell lymphoma or early relapsed aggressive B-cell lymphoma. Seeing an OS benefit solidifies its role there. For patients who are truly chemotherapy refractory, these results suggest that we should be switching our approach and using immunotherapy. It [also] seems that starting off with a traditional chemotherapy and transplant approach and then getting CAR T cells later may be insufficient if it's not leading to equivalent survival [benefit]. The results of ZUMA-7 have been practice-changing already, but [these survival results] solidify the importance of using CAR T-cell therapy for patients who are refractory to frontline therapy.

This year's meeting also featured a presentation on responses with epcoritamab-bysp (Epkinly), rituximab (Rituxan), and lenalidomide (Revlimid) in patients with relapsed/refractory follicular lymphoma (FL) regardless of whether they had progressed within 24 months of first-line chemoimmunotherapy (POD24).³ How do you expect these data will inform practice and referral patterns for transplant in the community?

These are important data. We know that patients with POD24 have poor outcomes. Clearly these are biologically worse-acting FLs. The ability for novel therapies to overcome that negative prognostic [feature] of POD24, which is really about chemotherapy resistance, is important. It suggests that bispecific antibodies or immunotherapy combined with immune-modulating therapy can positively change a [more] negative biological situation. In terms of how it [affects] referrals, if patients are not responsive to frontline therapy or [experience progression on] frontline therapy, that's the time when patients should be referred. If there's a standard option that patients can receive in the community, that's appropriate in some cases. However, we need to understand what the best treatment approaches [are] for these patients, and there may be different options in the future. My hope is that these patients can be referred early so we can think about how to sequence therapies, and work together with our community partners to administer them.

What other research from this year’s meeting were you excited to see presented?

There was a lot of exciting data presented at the meeting. [We saw] longer-term follow up [data for] lisocabtagene maraleucel [liso-cel; Breyanzi] in patients with chronic lymphocytic leukemia [CLL]. We've heard a lot about targeted therapies with CLL in the past decade. Now, with longer follow-up, we've seen that some of these responses to CAR T cells in these patients with CLL can be durable. That's exciting because these patients on the study had progressed on the available targeted therapies that we have. There was a moderate amount of toxicity [with liso-cel], and that is something that we have to contend with. [Overall], it was exciting to see the durability of benefit for patients with limited treatment options.

[We now also have] real-world confirmation of the effectiveness of brexucabtagene autoleucel (brexu-cel; Tecartus) in patients with mantle cell lymphoma [through] registry analysis coming from the CIBMTR.4 It's always good to see that we can confirm what happens on clinical trials in the real world. [It] also looks at the effect of prior treatment [on outcomes]. If patients received prior stem-cell transplant, or bendamustine, or a BTK inhibitor, did that affect the response or durability of the benefit with brexu-cel? Thankfully, it didn't seem like any of those prior treatments negatively affected or had any effect on response. That's important because when brexu-cel was approved, the label was quite broad. [These data confirm that] patients who hadn't [previously] received a BTK inhibitor can receive it. That's a nice way to answer a question that wasn't necessarily answered in clinical trials through registry data.

Editor’s note: This interview was conducted prior to the conclusion of the 2023 ASCO Annual Meeting.

References

1. Herrera AF, LeBlanc ML, Castellino SM, et al. SWOG S1826, a randomized study of nivolumab(N)-AVD versus brentuximab vedotin(BV)-AVD in advanced stage (AS) classic Hodgkin lymphoma (HL). J Clin Oncol. 2023;41(suppl 17):LBA4. doi:10.1200/JCO.2023.41.17_suppl.LBA4
2. Westin JR, Oluwole OO, Kersten MJ, et al. Primary overall survival analysis of the phase 3 randomized ZUMA-7 study of axicabtagene ciloleucel versus standard-of-care therapy in relapsed/refractory large B-cell lymphoma. J Clin Oncol. 2023;41(suppl 17):LBA107. doi:10.1200/JCO.2023.41.17_suppl.LBA107
3. Merryman R, Belada D, Sureda A, et al. Epcoritamab + R2 regimen and responses in high-risk follicular lymphoma, regardless of POD24 status. J Clin Oncol. 2023;41(suppl 16):7506. doi:10.1200/JCO.2023.41.16_suppl.7506