Pharma steps back from Hodgkin lymphoma: now what? Open Access

In this issue of Blood Advances, Herrera et al¹ have published the results of a phase 2 study of camidanlumab tesirine (Cami), a CD25 antibody–drug conjugate with a pyrrolobenzodiazepine payload, in relapsed/refractory classic Hodgkin lymphoma. CD25 (also known as interleukin-2 receptor alpha) is expressed on the surface of most leukocytes, including Hodgkin Reed-Sternberg cells and regulatory T cells within the Hodgkin lymphoma microenvironment and elsewhere. Enrolled patients were required to have prior exposure to both brentuximab vedotin and a programmed cell death protein 1 inhibitor, with at least 3 prior lines of therapy (or at least 2 if ineligible for hematopoietic stem cell transplant). Substantial activity was observed in the 117 patients who were heavily pretreated (median prior lines of therapy, 6), with an overall response rate of 70.1% and a complete response rate of 33.3%. However, nearly 30% of patients discontinued treatment due to adverse events. Notable toxicities included grade ≥3 rash in 22% of patients, and serious neurologic events (including Guillain-Barré syndrome, transverse myelitis, and polyneuropathy) in 8%.

So why isn’t Cami available for patients in light of its activity in relapsed/refractory Hodgkin lymphoma? Until recently, the US Food and Drug Administration’s (FDA’s) accelerated approval pathway allowed drugs with promising efficacy in areas of unmet need to reach the market based on small, single-arm phase 2 studies. Although a phase 3 confirmatory study was eventually required, the timeline for this was often ambiguous. In 2022, the FDA shifted course, paying much closer attention to toxicity profiles, and requiring confirmatory phase 3 trials to be designed and fully accrued before granting accelerated approval.² In the lymphoma world, the phosphatidylinositol 3-kinase inhibitor experience became a cautionary tale: multiple agents approved via phase 2 data were later withdrawn due to significant safety concerns or underwhelming efficacy in phase 3 randomized trials in disease settings that otherwise have favorable prognoses.

Cami was no exception to this new scrutiny. In 2020, the FDA placed a partial clinical hold on the phase 2 trial after several patients developed Guillain-Barré syndrome.³ Although the hold was later lifted, toxicity remained a defining feature of the drug. Toxicity alone might have been tolerated had the drug produced durable responses, but the median duration of response was only 13.7 months.¹ At best, Cami would have been a palliative or bridging option for select patients with relapsed/refractory Hodgkin lymphoma, never likely advancing to earlier lines of therapy unless an approach to abrogate the safety signal was identified.

In November 2022, ADC Therapeutics, the sponsor of the study, issued a press release summarizing its discussions with the FDA.⁴ A randomized phase 3 confirmatory trial would be required before accelerated approval could be granted. The company also announced that it would be “pausing any material investments in the (Hodgkin lymphoma) program” and would evaluate further steps with a “disciplined and strategic approach to resource allocation.” Nearly 3 years later, no such study has been or will be designed.

This is not just a story about 1 drug, but a symptom of a larger challenge. From the perspective of the pharmaceutical industry, it may no longer be “strategic” or “disciplined” to invest in Hodgkin lymphoma. This is largely because frontline therapy is working exceptionally well. Recent clinical trials have achieved remarkable outcomes, particularly with checkpoint inhibitor–based regimens. Based on the S1826 study,⁵ almost 90% of patients with advanced-stage disease are likely cured with nivolumab plus chemotherapy. In early-stage disease, phase 2 data suggest that most patients can be cured (sometimes without radiation) using brentuximab vedotin or checkpoint inhibitor–based combinations now reflected in National Comprehensive Cancer Network guidelines.^6,7 These same agents remain highly effective among the few patients who do relapse. As a result, the number of patients truly refractory to all standard therapies and who might benefit from a new agent is becoming vanishingly small. The return on investment in this shrinking relapsed/refractory population is unlikely to justify the cost of drug development unless the agent can eventually be used in the frontline setting.

However, the reality is that another large phase 3 superiority study for untreated Hodgkin lymphoma would require a huge investment for potentially small gains in cure rates. For this reason, the field needs to shift focus to precision strategies that reduce both short- and long-term toxicity and treatment burden for the curable majority while identifying patients at high risk who may benefit the most from more intensive strategies. Emerging circulating tumor DNA data suggest that most patients have undetectable measurable residual disease very early in their treatment course, and perhaps are cured well before finishing treatment.^8,9 The eventual goal should be chemotherapy-free treatment for most patients with Hodgkin lymphoma.^10,11 There is still room for a new drug to help break the ubiquitous anthracycline-based chemotherapy backbones universally employed today.

Despite its high response rate, Cami failed to advance not just because of its toxicity, but because the goalposts moved during the study for what is required for FDA-accelerated approval in refractory Hodgkin lymphoma. Allogeneic transplant, still often used in this setting, has much higher rates of short- and long-term toxicities, graft-versus-host disease, and nonrelapse mortality than what was seen with Cami.¹² So if Cami was available, this may be a preferred on-label option in select patients. Instead, in the absence of FDA-approved agents in programmed cell death protein 1–refractory Hodgkin lymphoma, we must select from off-label options in the National Comprehensive Cancer Network guidelines including allogeneic transplant as well as other drugs only tested in small phase 2 studies, like vorinostat¹³ and decitabine.¹⁴ 

There is still room for improvement in Hodgkin lymphoma. Though most of the gains will likely be made by maintaining efficacy while reducing toxicity in the frontline setting, there is still a need for better options for the small group of patients where standard therapies fail.

Conflict-of-interest disclosure: A.K.G. reports research funding from Merck, I-Mab Biopharma, IGM Biosciences, Takeda, Gilead, AstraZeneca, Agios, Janssen, Bristol Myers Squibb, SeaGen, Teva, Genmab, BeiGene, Pfizer, and Umoja; consultancy/honoraria for Incyte, Kite, Morphosys/Incyte, ADC Therapeutics, Acrotech, Merck, Karyopharm, Servier, BeiGene, Cellectar, Janssen, Compliment, SeaGen, Epizyme, I-Mab Biopharma, Gilead, Genentech, Lilly, Caribou, Fresenius-Kabi, SciTech, Sana, Compliment, Incyte, Kite, ADC Therapeutics, Acrotech, Servier, BeiGene, Compliment, Genentech, Lilly, Caribou, Fresenius-Kabi, Scitek, and Sana; and owns stock options for Compliment Corporation and SciTech. R.C.L. reports research funding from TG Therapeutics, Incyte, Bayer, Cyteir, Genentech, Pfizer, Rapt, Merck, Janssen, and Allogene; and consultancy/honoraria from SeaGen, AbbVie, Janssen, Merck, ADC Therapeutics, Foresight Diagnostics, and Genentech.