Expanding landscape for relapsed Hodgkin lymphoma

In this issue of Blood, Advani et al¹  provide a 3-year follow-up analysis of the safety and efficacy using the combination of brentuximab vedotin (brentuximab) and the checkpoint inhibitor nivolumab as initial salvage therapy in patients with relapsed or refractory classic Hodgkin lymphoma (R/R cHL).

For nearly 30 years before the advent of brentuximab,²  the standard of care for R/R cHL was cytotoxic chemotherapy, followed by an autologous stem cell transplantation (SCT) for chemotherapy-sensitive patients, with a cure rate of ∼50% and a low survival rate for patients who relapsed after SCT or did not achieve adequate disease control to proceed to SCT. With the emergence of brentuximab and checkpoint inhibitor therapy, the therapeutic landscape of the R/R cHL has seen a dramatic expansion of novel treatment options. There has been significant interest in using these agents to increase cure and enhance disease control, while decreasing therapy-related toxicity.

We are poised at an exciting juncture where a variety of novel therapies for R/R cHL have demonstrated impressive response rates in small, single-arm studies for second-line or later treatment. Studies of checkpoint inhibitors combined with chemotherapy have produced impressive complete remission (CR) rates.^3-5  Another chemotherapy-free regimen combining pembrolizumab with AFM13, a bispecific antibody targeting CD30 on Hodgkin Reed-Sternberg cells and CD16 on natural killer cells, has shown high antitumor activity with manageable toxicity in a phase 1b study.⁶  The triplet combination of brentuximab, nivolumab, and ipilimumab produced a CR rate of 73% in the phase 1 setting,⁷  and the combination of brentuximab and bendamustine has shown a similarly high CR rate.⁸ 

The 3-year follow-up analysis for the combination of brentuximab and nivolumab described by Advani et al confirms the earlier data demonstrating that the regimen is well-tolerated and active in the first salvage setting, with an overall response rate of 85% and a CR rate of 67%. These results are consistent with the response rates recently reported for the brentuximab-nivolumab doublet in the ECOG-ACRIN E4412 study.⁷  With a median follow-up of 34.3 months in Advani et al, the estimated progression-free survival (PFS) was 77% and was higher in patients who proceeded directly to autologous SCT than in those who required further salvage therapy.

It is not clear whether the durable post-SCT PFS reported in this study was a function of the high CR rate compared with standard chemotherapy regimens or the result of the combination of immune and targeted therapy. It has been suggested that a checkpoint inhibitor may either sensitize patients to subsequent chemotherapy⁹  or synergize with chemotherapy.³  Arguing for high CR rate as the driving force in improved PFS is the evidence that novel chemotherapy regimens with high CR rates, such as brentuximab and bendamustine, also demonstrate impressive PFS data when compared with historical controls.^8,10  The 3-year PFS rate in the present study was significantly higher in patients who achieved CR (90%) compared with those who did not (42%), suggesting that sensitivity to therapy before SCT remains an important indicator of post-SCT durable response.

As brentuximab becomes more integrated into upfront therapy, the impact on its use as salvage therapy is unclear. The present study excluded patients with prior brentuximab exposure in parts 1 and 2. In the E4412 study, which did not have the same exclusion criterion, responses to the brentuximab-nivolumab combination were equivalent for brentuximab-pretreated patients and -naive patients.⁷ 

A weakness of this study is that the heterogeneity of consolidation treatments makes drawing any broad conclusions regarding the durability or pure benefit of the brentuximab-nivolumab regimen difficult. In addition, there are no data to answer the question of whether a subset of these patients could have had durable remissions without the consolidation SCT, as all patients were treated for first-line salvage and nearly all (92%) proceeded to SCT.

Future studies in relapsed HL should focus on addressing the questions of what the most effective pretransplant salvage regimens are and whether there are therapies that can obviate the need for SCT in select subsets of patients. Advani et al provide a compelling rationale to study the brentuximab-nivolumab regimen further in a randomized fashion with other regimens to answer the former question, but the latter question will be more challenging to address. Larger randomized studies with more homogeneous follow-up are needed to evaluate brentuximab and nivolumab regimens as a first choice for pre-SCT salvage, or as an alternative to SCT.

In Advani et al, the biomarker experiments did not clearly delineate which patients were most likely to benefit or have treatment failure. Identifying predictive biomarkers of brentuximab-nivolumab and other novel targeted and immunotherapy combinations is vital for tailoring therapeutic intensity to risk and should be an integral component of any large study going forward.

In summary, Advani et al demonstrate tolerability and a high response rate of the brentuximab-nivolumab combination as salvage therapy before autologous SCT without compromising stem cell mobilization or engraftment. This regimen has the potential to provide an alternative to cytotoxic chemotherapy regimens such as ifosfamide, carboplatin and etoposide as a first salvage therapy, if the findings are confirmed in a randomized study. Optimal sequencing of the brentuximab-nivolumab regimen with standard salvage chemotherapy and other immunotherapies and the evolving role for SCT as a function of highly active second-line salvage regimens remain important questions for future studies.