Novel Combinations Excite the R/R Hodgkin Lymphoma Treatment Landscape

Alex F. Herrera, MD

While the treatment of relapsed or refractory (R/R) Hodgkin lymphoma (HL) has seen novel approaches in recent years improving outcomes for many patients, high-risk patients develop progressive disease and have limited treatment options.¹

Two studies presented during the 62nd American Society of Hematology Annual Meeting and Exposition explored new therapeutic strategies for this patient population. First, results from a phase 2 study (NCT04052997) suggest that camidanlumab tesirine (ADCT-301) can achieve anti-tumor activity in patients with R/R classical HL (cHL). Camidanlumab tesirine an antibody-drug conjugate composed of human IgG1 anti-CD25 monoclonal antibody stochastically conjugated to a potent pyrrolobenzodiazepine dimer warhead. The agent triggers cell death via the formation of highly cytotoxic interstranded cross-links.¹

The study enrolled 117 participants. The primary end point of the study was objective response rate (ORR). Secondary outcomes included duration of response (DOR), complete response (CR), relapse-free survival (RFS), progression free survival (PFS) and overall survival (OS).¹

During the study, patients received camidanlumab tesirine as a 30-minute intravenous infusion on day 1 of each 3-week cycles. It was also administered as a dose of 45 μg/kg every 3 weeks for 2 cycles then 30 μg/kg for subsequent cycles.¹

Furthermore, in a phase 2 study, the combination of nivolumab (Opdivo) plus brentuximab vedotin (Adcetris) was evaluated in patients with high-risk Hodgkin lymphoma. Most patients with R/R HL are treated with salvage therapy followed by stem-cell therapy. However, most patients will relapse. The combination of these 2 agents aims to determine if the combination will improve PFS.²

In an interview with Targeted Oncology, Alex F. Herrera, MD, an oncologist at the City of Hope Cancer Center discussed the study of single- agent camidanlumab tesirine as treatment of patients with R/R cHL and the combination of nivolumab and brentuximab vedotin as post-transplant consolidation therapy for patients with R/R HL.

TARGETED ONCOLOGY: What research set the stage for this phase 2 trial?

HERRERA: Patients with relapsed/refractory Hodgkin lymphoma have many treatment options that have become available in recent years, including brentuximab vedotin, an antibody-drug conjugate that's targeted to CD30 on the tumor cells and Hodgkin lymphoma. Or drugs like nivolumab or pembrolizumab, which are immunotherapies that activate a patient's immune system to fight the lymphoma. But patients who have received these drugs and are resistant, have quite limited options. Unfortunately, many patients are not cured by these drugs. So, we're still in need of new therapies for patients who are resistant to these drugs. And one such drug is camidanlumab tesirine. It's an antibody-drug conjugate directed against CD25, which can be expressed on tumor cells. It's an antibody that binds CD25 and delivers a potent chemotherapy, in this case, PVD to the cancer cell and can result in NETosis in the cancer cell.

TARGETED ONCOLOGY: What was the design of the trial and what were the key endpoints that were measured?

HERRERA: It's a single-arm, phase 2 trial. The primary objective of the trial was to look at the response rate to camidanlumab tesirine. And patients received two cycles of 45 micrograms per kilogram of the camidanlumab tesirine. And then the drug was given every 3weeks. And then the dose was reduced to 30 micrograms per kilogram, again, every 3 weeks. And patients could receive treatment every 3 weeks for up to 1 year. Patients had their disease evaluated after a couple of cycles. And in addition to the overall response rate, we did evaluate the CR, rate of DOR, and PFS. Although admittedly, the results of this presentation, we have not reported the DOR, or PFS, just because those data aren't mature at this time.

TARGETED ONCOLOGY: What were the findings of this study?

HERRERA: In the phase 1 study, that preceded this study, we did see an excellent response rate and CR rate in patients who had relapsed/refractory Hodgkin lymphoma, who were resistant to rituximab vedotin and PD-1 blockade. In this phase 2trial, we've seen similar results. So, the OR rate was 83%, the CR rate was 32%. There's only one patient I believe, who had primary progressive disease as their best response. Almost 11% of patients were able to proceed to a stem cell transplant after receiving this therapy. And so, the efficacy is aligned with what we've seen before and is certainly promising. The efficacy that we've seen there were some toxicities that have been noted with this kind of a drug in the past. And so that the classic PBD toxicities are skin toxicity, edema, swelling, or effusions, fluid accumulation in different parts of the body. And then another toxicity that has been seen with this drug before is Guillain–Barré syndrome, or demyelinating polyneuropathy. Those were observed in this trial as well. Skin toxicity was observed in 70% of patients all in all. Eighteen percent of patients are so had grade 3 or higher skin toxicity. Edema and effusion weren’t seen at such a high rate in this study, 18% and 6% of patients had Guillain–Barré syndrome, which is identical to what was seen in the phase 1 study. So, these are notable toxicities that are certainly nothing to shrug at. But they were manageable by either holding the drug and just using supportive therapy, steroids for immune related kind of components of these toxicities. And for the most part, these toxicities resolved but holding therapy and using support measures.

TARGETED ONCOLOGY: Acknowledging that we don't have head-to-head data, how does this agent seem to compare with the PD-1 inhibitors?

HERRERA: So far, we've primarily studied the struggling patients who have resistance. It would be difficult to see what we might expect when you compare them head-to-head. The toxicity profiles are different. I think with some of these toxicities like the high proportion of skin toxicity, it’s more than what we would expect with PD-1 blockade. Guillain–Barré is possible, but very rare with the PD-1 blockade but, it's seen a little bit more frequently here. From an efficacy perspective, seeing a 40% response rate in patients who are resistant to PD-1 blockade is notable because the CR rates to a single-agent PD-1 blockade typically wouldn't be that high.It is maybe a third of patients who have a CR to PD-1blockade. I think they each have their toxicity profiles and their merits.

TARGETED ONCOLOGY: Were there any unique findings or signals in this study?

HERRERA: It was surprising that it's pretty much in line almost identically with what was seen in the phase 1 trial. The efficacy and safety were almost identical. The reason we performed this analysis was because it was a pre-specified safety analysis. Once a couple of patients had Guillain–Barré syndrome, an independent safety review committee reviewed the results. It was kind of unbalanced, given that the rate of toxicity that was seen, like Guillain–Barré syndrome, for example, was similar to what we've seen previously. But given the efficacy of the drug, the trial has been allowed to continue, and it's actually nearing completion. So, hopefully, we'll have forthcoming results in the future. And we'll also have more results on the duration of these responses. I think that's a really critical piece of information that we haven't been able to report yet as part of this study.

TARGETED ONCOLOGY: What were your main take home points from this research? What are the next steps with this research?

HERRERA: I think the main takeaways from this particular study are these known toxicities of this drug that are manageable. They are in line what we have come to understand when using this drug. I do think that patients who have R/R who are resistant to rituximab vedotin and PD-1 blockade, really do have limited options. So, this drug is effective in patients with disease resistance to rituximab vedotin and PD-1 blockade, and we may find that it has an important role in those patients. I think that this study is a pivotal phase 2 study, depending on the final results from an advocacy standpoint, and from a safety standpoint. I think if they're promising enough, the plan is to submit them for regulatory approval. We're eager to complete enrollment of the study and observe the final results and report those.

TARGETED ONCOLOGY: Data from a trial of consolidation of nivolumab (Opdivo) and brentuximab vedotin were also R/R HL?

HERRERA: Patients with high risk of R/R HL who undergo autologous stem cell transplant are going to have their disease recur a little over half the time. That's what we saw on the randomized AFFAIR trial (NCT01712490). In patients who received placebo on that trial, the five-year PFS was I believe 42%, or maybe 41. In those patients, the AFFAIR trial demonstrated that if you used rituximab vedotin consolidation for 16 psychiatric transplants, you could improve PFS and at five years, 59% of patients were alive and in remission. That was certainly an improvement from what we were doing previously. But I think we can all understand that there's room to improve there. Another area where there was room to improve in these patients is 16 cycles of therapies is a long time after patients undergo second-line therapy and a stem cell transplant. The rate of discontinuation of a brentuximab vedotin consolidation is relatively high due to toxicities like peripheral neuropathy. We saw an opportunity to both potentially intensify therapy, to try to improve the efficacy and improve the outcomes, but also potentially shorten the duration of therapy to hopefully observe fewer toxicities. So, we conducted a phase 2 study combining brentuximab vedotin with nivolumab as consolidation after autologous stem cell transplant (ASCT) for patients with high-risk R/R HL.

We chose to shorten the duration of therapy to 8 cycles as opposed to 16 which we thought would hopefully result in similar efficacy given that we were intensifying therapy or even improved efficacy, but hopefully also improve patients’ ability to stick with therapy and reduce toxicities. We enrolled 59 patients from 5transplant centers around the country including the City of Hope Cancer Center, where I practice Fred Hutchinson Cancer Research Center in Seattle, MD Anderson Cancer Center, Mayo Clinic Cancer Center, Rochester Cancer Center, Minnesota Cancer Center, and Hackensack University Cancer Center in New Jersey. We enrolled 59 patients with high-risk HL who had undergone ASCT and treated them with rituximab and nivolumab. The therapy started between day 30 and 60 typically, after autologous stem cell transplant. There are some patients started as late as day plus 75, if they had some kind of unresolved toxicity from SCT.

What we observed was that when the drugs were used in combination, they actually produced promising efficacy. At 18 months, the PFS that we observed in the 59 patients was 92%. There were 3 patients out of 59 who relapsed in the cohort. This was a high-risk cohort. All in all, we found efficacy results were quite promising.

We did observe perhaps a bit more toxicity with the combination of nivolumab and brentuximab vedotin than we have observed when we use these drugs in combination together prior to stem cell transplant. I think it was 28% of patients requiring steroids for immune related toxicity, as opposed to maybe 15% or so in the pre transplant setting. The combination was tolerable on the whole. There were no treatment-related deaths. These immune-related toxicities can be managed with steroids, but we did see that half of patients have peripheral neuropathy. About 1/3 of patients had neutropenia. And like I mentioned 27% of patients required steroids. Overall, we were pleased with the results, and we feel like it's a promising approach that does merit further study.

TARGETED ONCOLOGY: Do you anticipate then that the combination would be suitable for all comers in this setting? Or would patient selection for those fitter patients be necessary?

HERRERA: I think the study evaluated patients with high-risk disease and so I certainly wouldn't advocate for using it in patients unless they met those criteria, which would be primary refractory HL, or HL that relapsed within 1 year of the completion of initial therap with extra nodal involvement, B-symptoms at the time of relapse. So, these are the different criteria that we use to enroll patients in the study. I would say that's the kind of population that we would think about for using this kind of therapy or certainly for studying this therapy in the future. This is not necessarily for all comers, but all comers with high-risk disease. I think it certainly is an approach that we think should be studied further in that population. Looking at brentuximab vedotin consolidation, you didn't see that there was an increased benefit for patients who had higher-risk disease. We also saw promising results in those groups. So, I wouldespecially in those patients with the highest risk, this would be a group of patients who we think might be worth studying this further in.

TARGETED ONCOLOGY: Are there any planned research efforts in that regard?

HERRERA: Now that we have the results from this study, it'll be important for the field to look at the landscape of treatment for patients with R/R disease, but also for how we're using these drugs in initial therapy. How we incorporate these novel agents in the treatment of HL is getting more and more complicated. We have trials looking at these drugs in the first-line and second-line settings, now we've used them after transplant as consolidation. We've used them in patients who relapsed after a transplant. So, I think that there are a set of ongoing studies right now, which I think can inform our next efforts.

This is an important question for the field to answer. Many of us are planning and thinking about how we can design trials to better answer these questions of when is the optimal time to incorporate these drugs into a patient's care?

TARGETED ONCOLOGY: Is there anything else about this trial that you wanted to emphasize?

HERRERA: One thing to emphasize about this trial, as compared to the AFFAIR trial is that in your third trial patients, the era that study was done in patients who had only received chemotherapy prior to their transplant. And so, none of them had received brentuximab, none had received PD-1 blockade. In this trial, about half of the patients had received brentuximab. I think 42% had received PD-1 blockade prior to entering the trial. We don't know the benefit of consolidation of brentuximab vedotin after transplant is unclear in patients who have had prior novel agents. In this study, about half the patients were exposed to one of the novel agents. There were not enough patients to compare outcomes in patients who had versus those who hadn't had a prior novel agent. But certainly, it didn't seem like there was any impact on the outcomes if a patient had received them as long as they weren't resistant to the novel drugs. From this study, I think we can say our results are applicable to patients who have received prior novel agents and remain sensitive to them prior to transfer.

_REFERENCE:

_{1.Herrera, A., Carlo-Stella, C., Collins, G., et al. Preliminary results of a phase 2 study of camidanlumab tesirine (cami), a novel pyrrolobenzodiazepine-based antibody-drug conjugate, in patients with relapsed or refractory hodgkin lymphomaASH December 6, 2020. Accessed April 6, 2021. https://bit.ly/39TQn0K}

_{2.Herrera, A., Chen, L., Nieto, Y., et al. Consolidation with nivolumab and brentuximab vedotin after autologous hematopoietic cell transplantation in patients with high-risk Hodgkin lymphoma. ASH. December 6, 2020. Accessed April 6, 2021. https://bit.ly/2Q5BLEc}