Improving Upon Checkpoint Blockade Responses With Combinations in Hodgkin Lymphoma

Stephen M. Ansell, MD, PhD

Despite progress seen with immune checkpoint inhibitors in Hodgkin lymphoma (HL), there remains an unmet need for greater responses, which could be filled by potential combination approaches, according to Stephen M. Ansell, MD, PhD.

“We’re learning lessons from the biology of Hodgkin lymphoma. That gives us opportunities to do things—to create combinations that will benefit patients,” said Ansell, chair of the Lymphoma Group at Mayo Clinic in Rochester, Minnesota, during a discussion at the 2018 Pan Pacific Lymphoma Conference.

He discussed the efficacy of PD-L1 blockade in HL, patient treatments that have encouraged him to look for deeper solutions, alternative drug combinations that seem to be making headway, and potential avenues of discovery for the future.¹

Ansell cited the case of a patient with HL who called him one night to announce that his treatment with nivolumab (Opdivo) was working. The patient had, among other symptoms, lymphadenopathy, and he explained that his armpits no longer itched. Sure enough, it turned out that his HL was on the retreat, but after a 2-year course of treatment, the disease was not completely gone. After an interim, he went back on the drug, and his progress has seesawed since.

“As an immunologist, I was super disappointed,” Ansell said. It was clear that despite the efficacy of the treatment, the immune cells were not demonstrating sufficient immunological memory. “If you have an immune system that saw something it didn’t like, it would create memory cells, and every time it saw that antigen, it would go nuts and focus in and kill it right away.” Another thing Ansell found disturbing: It appeared that patients would have to be treated throughout their lifetimes.

In a review of the evidence for nivolumab as checkpoint therapy, Ansell cited the single-arm phase II CheckMate 205 trial for relapsed/refractory (R/R) classic (cHL), which after a median follow-up of 18 months demonstrated an overall response rate (ORR) of 69% (95% CI, 63%-75%), a median duration of response of 16.6 months (95% CI, 13.2-20.3), and median progression-free survival of 14.7 months (95% CI, 11.3-18.5).²

He also discussed the KEYNOTE-087 single-arm phase II study of pembrolizumab (Keytruda) for R/R cHL, in which the agent achieved an ORR of 69.0% (95% CI, 62.3%-75.2%) and a complete response (CR) rate of 22.4% (95% CI, 16.9%-28.6%). Thirty-one patients experienced a response ≥6 months.³

Results of both trials contributed to the notion that a new paradigm had been achieved in the treatment of cHL. “What’s disappointing here is [that] it’s not really a plateau,” Ansell said. “Patients are slowly progressing, telling us we did something right.” However, the problem isn’t solved, he said.

The phase I JAVELIN study tested avelumab (Bavencio) as a selective binder to PD-L1 in R/R HL. The ORR for all 31 patients was 41.9%, and the partial response (PR) rate was 25.8%, Ansell noted. The median time to response was 1.5 months (range, 1.4-6.2).⁴“Overall, you can tell that the majority of patients are benefiting. I’m not sure whether you’re seeing a different outcome whether you block on the ligand side or the receptor side,” he said.

Reed-Sternberg cells tend to be surrounded by macrophages that overexpress PD-L1 and interfere with effector cells that mount an immune response. “[However,] a number of patients have a copy number gain or an amplification of the locus, resulting in overexpression of PD-L1 and PD-L2, but that actually is associated with responses. It does tell us that these very high PD-L1—expressing patients are the ones who have the greatest degree of benefit,” Ansell said.

“PD-L1 is actually shed and secreted into the bloodstream, and so you can have an effect at a distant site from this high PD-L1 expression. It might be important not only to block PD-L1 at the tumor site but in the macro environment, too,” he added.

This has been attempted by combining the immune checkpoint inhibitors nivolumab and ipilimumab (Yervoy). In CheckMate 039, this resulted in an ORR of 74% (n = 23) and a CR rate of 19% (n = 6).⁵“But does that look different than nivolumab [action] alone? It’ll take a randomized trial to show that. There may be some modest increment in benefit,” Ansell said.

Another improvement on checkpoint blockade has been attempted through brentuximab vedotin (Adcetris) with nivolumab as salvage therapy. “You’re hoping for an immunological cell death,which means that as the cell dies, it releases neoantigens that are then mopped up by macrophages and dendritic cells and shown to the immune system. That whole process is inhibited by PD-L1 expression. If you could prevent that, you could get a nice 2-for-1 where you increase death, increase antigens, and increase tumor cell activation and have a better result,” Ansell said. Via this method, Diefenbach et al achieved an ORR of 100% (n = 12) and a CR rate of 66% (n = 8).1 More time is needed to see whether these responses are durable, Ansell said.

Using PD-L1 blockade at the start of treatment also has potential. “There are data that show you can do that successfully. Is getting PD-1 blockade at the same time as chemotherapy the answer? It might be, but I think we’re going to need randomized studies to prove that,” Ansell said.

The use of bispecific antibodies has also brought promising results, he said. In targeting CD30 with AFM13, a bispecific anti-CD30/CD16A antibody construct, Rothe et al achieved what Ansell called modest responses: In the phase I study, 28 cHL patients achieved a PR of 12% and stable disease (SD) of 50%. With higher doses, the PR and SD rates improved to 23% and 54%, respectively.¹

Finally, triggering macrophages to recognize tumor cells and break them apart may be another way to evoke a more complete response. However, this process is inhibited by CD47 binding to signal regulatory protein alpha (SIRPα), a regulatory membrane glycoprotein. In an attempt to wake up macrophages so that they behave toward tumor cells like “bar bouncers, ” Ansel is involved in a phase I, open-label, multicenter study to evaluate the safety and tolerability and identify the maximum tolerated dose of TTI-621, a soluble recombinant fusion protein consisting of the CD47 binding domain of human SIRPα linked to the Fc region of human IgG1, in patients with R/R lymphomas.⁶

“Can we tell you this is an effective therapy in Hodgkin lymphoma? Not yet, but getting the innate immune system to work with the adaptive immune system is 1 of the ways, and there are now trials moving forward,” Ansell said. “Bispecific antibodies and macrophage-directed approaches, I think, are going to be the future in combinations as we go beyond immune check point therapy.”

References:

1. Ansell SM. Beyond checkpoint inhibitors for Hodgkin lymphoma. Presented at: the 2018 Pan Pacific Lymphoma Conference; July 16-20, 2018; Maui, Hawaii.
2. Armand P, Engert A, Younes A, et al. Nivolumab for relapsed/refractory classic Hodgkin lymphoma after failure of autologous hematopoietic cell transplantation: extended follow-up of the multicohort single-arm phase II CheckMate 205 trial.J Clin Oncol.2018;36(14):1428- 1439. doi: 10.1200/JCO.2017.76.0793.
3. Chen R, Zinzani PL, Fanale MA, et al; KEYNOTE-087. Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma.J Clin Oncol.2017;35(19):2125-2132. doi: 0.1200/JCO.2016.72.1316.
4. Chen R, Gibb AL, Collins GP, et al. Blockade of the PD-1 checkpoint with anti-PD-L1 antibody avelumab is sufficient for clinical activity in relapsed/refractory classical Hodgkin lymphoma (cHL).Hematol Oncol.2017;35(suppl S2):67. doi: 10.1002/hon.2437_54.
5. 5. Ansell S, Gutierrez ME, Shipp MA, et al. A phase 1 study of nivolumab in combination with ipilimumab for relapsed or refractory hematologic malignancies (CheckMate 039).Blood.2016;128(22):183. www.bloodjournal.org/content/128/22/183.
6. Ansell S, Chen RW, Flinn IW, et al. A phase 1 study of TTI-621, a novel immune checkpoint inhibitor targeting CD47, in patients with relapsed or refractory hematologic malignancies.Blood.2016;128(22):1812. www.bloodjournal.org/content/128/22/1812.