Novel Targeted Therapies Shift the Treatment Paradigm in Hodgkin Lymphoma

Single-cell analysis has shed new light on the unique biology of classic HL, expanding the current understanding of its tumor microenvironment (TME) and immune cell interactions. HL subtypes are characterized by a unique TME and cytokine composition.

Over the past two decades, the HL treatment paradigm has shifted toward novel targeted therapies, which have now been incorporated into both the frontline and relapsed or refractory settings, and numerous novel agents are currently under investigation. These novel therapies include immune checkpoint inhibitors; antibody-drug conjugates (ADCs), such as brentuximab vedotin (BV); bispecific antibodies; and chimeric antigen receptor (CAR) T-cell therapies.

Emerging Checkpoint Inhibitor Therapies

While several PD-1 inhibitors have been investigated in HL, the most robust data currently exist for nivolumab and pembrolizumab. Anti-PD-1 antibodies have demonstrated exceptional efficacy in the relapsed or refractory setting and, recently, in the frontline setting. Furthermore, combination regimens of anti-PD-1 antibodies with other targeted agents, such as BV, and combination chemotherapies have demonstrated encouraging outcomes.

The field of immunotherapy in classic HL is now incorporating the use of newer PD-1 inhibitors, which include sintilimab, tislelizumab, penpulimab, zimberelimab, and camrelizumab. These agents have demonstrated promising efficacy, with immune-related adverse events being the predominant safety concern.

ADCs: BV, Camidanlumab Tesirine

Studies have investigated the utility of BV in all aspects of HL treatment within many combination regimens. In the frontline setting, the addition of BV in combination with AVD (BV-AVD) has demonstrated improvement over the traditional ABVD regimen. BV has exhibited a favorable safety profile, but toxicities associated with the treatment include peripheral neuropathy, pneumonitis, and neutropenia.

Initial phase I investigations for another ADC, camidanlumab tesirine, assessed the drug in both HL and non-Hodgkin lymphoma (NHL) in the relapsed or refractory setting. Among 77 patients with classic HL, including 74% with prior BV and checkpoint inhibitor therapy, an overall response rate (ORR) of 71% was reported.

Bispecific Antibodies

A handful of bispecifics are under investigation in classic HL.

AFM13, a CD30xCD16A bispecific, targets CD30 on HRS cells and CD16A on macrophages and NK cells. Modest response rates have been associated with AFM13 monotherapy. Furthermore, the combination regimen of AFM13 and pembrolizumab demonstrated an improved ORR (83%) in a phase lb study, but the contribution of AFM13 in this regimen was unclear. A phase I/II study is currently underway utilizing modified allogeneic umbilical cord blood-derived NK cells combined with AFM13 (AFM13-NK). The results of 30 patients (28 HL, 2 NHL) with double refractory CD30-positive lymphoma were recently presented at the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition, and an excellent ORR of 97% with a complete response (CR) of 63% was observed among patients treated.

Additional bispecifics currently under investigation for the treatment of HL include MGD024, a CD123xCD3 bispecific, and AZD7789, a monovalent bispecific. Overall, the bispecific antibody field is readily evolving.

CAR T-Cell Therapies

There is limited literature assessing CAR-T for the treatment of HL. The results of two trials assessing novel CAR-T constructs, HSP-CAR30 and CAR30.CAR-EBVST, were presented at ASH 2022.

An alternative CAR target may be CD123. In preclinical studies, anti-CD123 CAR-T therapy has demonstrated the ability to eradicate HL in mouse xenograft models. Checkpoint inhibitors may additionally offer an important combination regimen with CAR-T therapies in HL to help make the TME more favorable and result in an improved antitumor response. Although further investigation is needed, CAR T-cell therapy has the potential to serve an important role in the treatment of relapsed or refractory disease, especially post-BV and PD-1 inhibitor failure.

Pathway-Directed Therapies

Multiple agents have emerged that seek to address altered pathways in HRS cells and the TME. In patients with relapsed or refractory HL, ruxolitinib has demonstrated a modest efficacy profile with the more recent phase II, open-label, multicenter trial, JeRiCHO, showing an ORR of 17% and a median progression-free survival (PFS) of 3.6 months in 12 patients.

PI3K and mTOR inhibitors are additional targeted therapies that have been investigated. ldelalisib, a PI3K inhibitor that demonstrated promising preclinical activity, was assessed in 25 patients with relapsed or refractory HL in a phase II trial. This single-agent regimen resulted in an ORR of 20% with a median PFS of 2.3 months. Given the initial promising preclinical data on the mTOR inhibitor everolimus, a phase II trial was conducted in patients with relapsed or refractory HL. Efficacy outcomes with everolimus monotherapy 10 mg/d were adequate, with a phase II study demonstrating an ORR of 46% with a 9% CR rate in 57 enrolled patients.

Many of these single-agent therapies targeting altered pathways demonstrated only modest efficacy outcomes. In an effort to target multiple dysregulated pathways, the phase I/II EVITA study is investigating everolimus plus itacitinib. Results presented at ASH 2020 demonstrated that among 15 patients with relapsed or refractory HL, all having received previous BV or PD-1 inhibitor therapy, the phase I/II ORR was 79% with a CR rate of 14% and a median PFS of 3.8 months, representing improved efficacy over the monotherapy regimens.

Novel Agents Demonstrate Encouraging Activity

Novel agents have demonstrated encouraging activity in classic HL, confirming that the use of agents that target tumor cells or the TME are promising strategies to improve patient outcomes. Investigation into understanding which drugs should be used in combination and the sequence of therapy administration will be exceedingly important to continue improving outcomes for patients. Additionally, promising ongoing studies that assess chemotherapy-free approaches for frontline and salvage treatment may lead to improved patient outcomes, especially if treatment is more tolerable and results in a deeper sustained response.