Ansell Discusses Combination Potential in Hodgkin Lymphoma

Stephen M. Ansell, MD, PhD, professor of medicine at Mayo Clinic

Stephen M. Ansell, MD, PhD

Immune checkpoint inhibitors have scored impressive hits against Hodgkin lymphoma (HL) in recent years, but looking beyond these gains, there is a need for a more complete victory over this disease, Stephen M. Ansell, MD, PhD, told a gathering at the 2018 Pan Pacific Lymphoma Conference in Maui, Hawaii.

“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 the Mayo Clinic in Rochester, Minnesota.

He discussed the efficacy of PD-L1 blockade in HL, patient treatment that has encouraged him to look for deeper solutions, alternative drug combinations that appear 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 were no longer itching. 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 then.

“As an immunologist I was super disappointed,” Ansell said. It was clear that despite efficacy of treatment, the immune cells were not demonstrating sufficient immunological memory. “If you really 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.” The other thing Ansell found disturbing was that 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 months), and median progression free survival of 14.7 months (95% CI, 11.3 – 18.5 months).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 rate (CR) 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 treatment of cHL. However, “What’s disappointing here is it’s not really a plateau. Patients are slowly progressing, telling us we did something right,” but didn’t solve the problem, Ansell 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 partial response in 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 benefitting. 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). Nivolumab works as a PD-L1 blocker and ipilimumab targets the immune system downregulating action of CTLA-4. In CheckMate 039, this resulted in an ORR of 74% (n = 23) and a CR rate of 19% (n = 6).5 “But does that really 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 potential way to improve 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 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 is being attempted. “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 been attempted, with 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: 28 cHL patients in the phase I study achieved partial response (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 represent 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 participating in a phase I, open label, multicenter study to evaluate the safety and tolerability, and to 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 one 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 checkpoint therapy.”

References

1. Ansell SM. Beyond check point inhibitors for Hodgkin lymphoma. In: Proceedings from 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. 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. Ansell S, Gutierrez ME, Shipp MA, et al. A phase I study of nivolumab in combination with ipilimumab for relapsed or refractory hematologic malignancies (CheckMate 039). Blood. 2016;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.