Immuno Combos Gain Steam in Blood Cancers

Anas Younes, MD

Nivolumab (Opdivo) may be the only checkpoint inhibitor that the FDA has approved thus far for a hematologic malignancy, but research is moving forward rapidly across the spectrum of blood cancers with ongoing clinical trials for immunotherapy agents alone and in combination with other novel therapies.

Lymphoma

Key researchers in the field provided updates on the evolving landscape for several cancer types during the 34th Annual CFS™ Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow® that Physicians’ Education Resource (PER®) hosted November 9-11, 2016, in New York City.In May, the FDA approved nivolumab as a treatment for patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation and posttransplantation brentuximab vedotin (Adcetris).

The approval was based on an objective response rate of 65% (95% CI, 55-75; n = 62) in a combined analysis of 95 patients with relapsed or refractory cHL who received nivolumab either in the phase II CheckMate-205 trial or the phase I CheckMate-039 trial.¹

Evidence continues to build for single-agent PD-1 inhibitors nivolumab and pembrolizumab (Keytruda) in relapse HL settings, said Anas Younes, MD, chief of the Lymphoma Service at Memorial Sloan Kettering (MSK) Cancer Center, during his presentation (Table). Younes was the key investigator on the pivotal nivolumab trial. Now, studies testing immune checkpoint inhibitors in combination with other drugs for the treatment of both Hodgkin and non-Hodgkin lymphoma are beginning to garner attention among researchers, noted Younes.

“We now have multiple agents for Hodgkin lymphoma [HL], and some of them are highly active as single agents; for example, brentuximab vedotin yields a roughly 75% response rate and a 34% complete response rate, and nivolumab has an approximately 70% response rate,” Younes said.

“There’s a lot of excitement about combining them, because they can be easily combined without overlapping toxicity,” he added. Agents currently being explored in combination with checkpoint inhibitors include brentuximab vedotin, HDAC inhibitors, ibrutinib, and traditional chemotherapy. Preliminary results from a phase I/II study of brentuximab vedotin and nivolumab in the pretransplant setting in patients with relapsed or refractory HL are among those to be shared at the upcoming annual meeting of the American Society of Hematology (ASH) to be held December 3-6, 2016, in San Diego, said Younes, an investigator on the trial.

The combination is currently demonstrating a complete response rate of 50%, but Younes stressed that because these findings are from an ongoing trial, “we’ll have to wait until it finishes.” As a benchmark, he compared this response rate with single-agent brentuximab vedotin, which has a complete response rate of about 30%.

Another potential combination involves HDAC inhibitors. Younes explained that the rationale for investigating these agents with checkpoint inhibition is that they can upregulate tumor-associated antigens and downregulate PD-1.

An earlier study of the oral pan-DAC inhibitor panobinostat, currently approved for the treatment of multiple myeloma, showed an overall response rate of 24% as a single agent, Younes said. Although that was though not sufficient for FDA approval at the time, those findings demonstrate downregulation of PD-1 on the T cells of patients with relapsed HL.

Against that backdrop, a phase I/II trial of the HDAC inhibitor entinostat in combination with pembrolizumab (Keytruda) is currently in development at MSK, Younes said, “and we’ll see if this strategy improves the efficacy.”

Ibrutinib (Imbruvica), a BTK inhibitor approved in mantle cell lymphoma and chronic lymphocytic leukemia, also is being explored in combination with checkpoint inhibition. Antitumor responses and synergy between BTK and PD-1 antibodies have been observed in B-cell lymphoma samples in preclinical research, and Younes said multiple companies are now moving forward with studies of this combination.

One recently completed international trial, PCI32765-LYM-1002, combined nivolumab and ibrutinib in patients with relapsed chronic lymphocytic leukemia, follicular lymphoma, and diffuse large B-cell lymphoma (DLBCL). Analysis of the results will take another few months, but Younes hopes they will be ready in time for the 2017 ASCO Annual Meeting in June.

Finally, there is understandable interest in combining checkpoint inhibitors with chemotherapy, and these agents are being combined with frontline CHOP in DLBCL, with bendamustine-based regimens for follicular lymphoma, and with ABVD in HL. Younes said that these trials are either starting to enroll patients or about to begin enrollment.

With many studies underway exploring the potential of immune checkpoint-based combinations in lymphoma, a number of questions will need to be addressed, Younes noted. The optimal duration of immune checkpoint inhibitors, for example, remains unknown. “For now, we say that it is good to give it until progression,” said Younes, while also monitoring patients for complete responses.

Multiple Myeloma

“Clinical trials with maintenance immune checkpoint inhibitor therapy also should evaluate the effect on minimal residual disease [MRD],” he concluded. He added that by giving these agents in the adjuvant setting after chemotherapy, the approach has the potential to eradicate MRD, and most trials in this setting now include assessment of MRD.In multiple myeloma, the search for durable responses in patients is prompting investigators to look toward immunotherapy. “In combinations we really do see dramatic increases in efficacy, when lenalidomide and dexamethasone are used in the combinations,” said Eric L. Smith, MD, PhD, a medical oncologist at MSK. “The monotherapy results are somewhat less exciting. Combination therapies are really going to be the key here.”

As single agents, many of the immunotherapies have demonstrated lackluster findings for patients with relapsed multiple myeloma. In these studies, the anti—SLAMF7 agent elotuzumab (Empliciti) failed to elicit responses, though the stable disease rate was 26.5%. Monotherapy with the CD38 antibody daratumumab (Darzalex) fared slightly better, Smith noted, with a single-agent response rate of 36%, which included complete remissions (CRs). When looking at these antibodies in combination, the results were far more substantial. In the phase III ELOQUENT-2 study, the combination of elotuzumab, lenalidomide (Revlimid), and dexamethasone elicited an objective response rate (ORR) of 78.5% and a median progression-free survival (PFS) of 19.4 months.² Similarly, in the phase III POLLUX trial exploring daratumumab, lenalidomide, and dexamethasone, the ORR was 92.9%, and the 12-month PFS was 83.2%.³

On November 21, the FDA approved the combination of daratumumab with lenalidomide and dexamethasone or with bortezomib and dexamethasone for patients with relapsed multiple myeloma after at least 1 prior therapy.

Further immunotherapeutic potential has been realized across various types of cancer through the inhibition of various checkpoints, such as PD-1 and CTLA-4. To this end, monotherapy with nivolumab was explored across hematologic malignancies. Unfortunately, only 1 of 27 patients with myeloma responded to the single agent. In a separate experience using pembrolizumab, the combination of the PD-1 inhibitor with lenalidomide and dexamethasone reduced M protein levels in 88% of patients with myeloma.⁴ The ORR in this relapsed/refractory population was 50%, which included 1 CR.

“Even in a lenalidomide-refractory population, we still see really impressive overall response rates, again, going back to the fact that combination therapies are really working to have the T cells overcome the immune suppression of the myeloma cell microenvironment,” said Smith.

In addition to monoclonal antibodies and checkpoint inhibitors, cellular therapies, such as chimeric antigen receptor (CAR)-modified T-cell therapies, are also under exploration. This approach builds upon years of experience with allogeneic stem cell transplantation, said Smith.

To date, the main concerns with this approach have been cytokine release syndrome and neurotoxicity. Treatment algorithms are being put into place to counter these adverse events, primarily through the use of IL-6 antibodies, Smith noted. Additionally, the construct of these therapies are evolving to help ameliorate these events.

“The CAR T-cell therapy field is advancing. We’re now putting in not only 1 or 2 genes but 3 genes into the cell, that include ways to modify the microenvironment or to secrete cytokines or to express other ligands that might give the cells an advantage,” said Smith.

The CAR T-cell therapies have been explored in myeloma with intriguing, yet limited, results. These early studies have utilized CAR T-cell therapies directed against CD19, which is not heavily expressed in myeloma. As a result, a new target was needed, noted Smith. In the past year, B-cell maturation antigen (BCMA) has moved to the forefront of development for its myeloma-specific activity.

AML and MDS

In a small study, a BCMA-targeted CAR T-cell therapy was explored in 12 patients with myeloma following cyclophosphamide and fludarabine preconditioning. Overall, there was 1 stringent CR that lasted for 17 weeks and 1 very good partial response that was still ongoing at 26 weeks.⁵ More results from this approach are expected in the next 12 months.In acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), the focus is on determining whether immune checkpoint inhibitors can be effective in this patient population and a number of studies are currently assessing new combination strategies, according to Naval G. Daver, MD.

“We have a lot of work going on in this area to see what the expression of these checkpoints are and how we can clinically use them,” said Daver, assistant professor, Department of Leukemia, MD Anderson Cancer Center. “The next step, like with most leukemias, is how we can combine them with approved agents for these diseases.”

Early research into the viability of checkpoint inhibitors in hematologic malignancies focused heavily on identifying which checkpoints might have the greatest activity. In these studies, DNA methyltransferase (DNMT) was found to upregulate PD-L1 and PD-1, which was linked to resistance to therapy and worse outcomes.

Clinical activity, specifically for patients with AML, was first demonstrated in a phase I/Ib study assessing the CTLA-4 inhibitor ipilimumab (Yervoy) for relapsed hematologic malignancies following allogeneic stem cell transplantation. Among 12 patients with AML treated with ipilimumab at 10 mg/kg, the CR rate was 42%.⁶

Additionally, a separate phase I study assessed the combination of the hypomethylating agent azacitidine with nivolumab for patients with relapsed/refractory AML.⁷ After a median follow-up of 8.3 months across 35 patients, the CR and CR with incomplete hematologic recovery (CRi) rate was 18%. The ORR was 32%.

Although the data were still immature and the patient population was small, there was a strong trend toward improved OS, according to Daver.

The median OS with azacitidine plus nivolumab was 9.3 months, which compared favorably with a historical OS of 4.7 months for this population (P = .02). Overall, 12 patients in the study experienced a grade 2 to 4 adverse event (AE), which included pneumonitis (n = 11), nephritis (n = 5), skin rash (n = 2), and colitis (n = 2). A majority of the AEs occurred within the first 6 weeks of treatment and all toxicities responded rapidly to treatment with steroids.

“The toxicity has been a learning curve for me and for my group, since leukemia doctors have not yet been using these drugs,” said Daver. “The pattern and profile of toxicities seem to be different than what was seen for solid tumors. The majority of toxicities have been pneumonitis, and the others have been colitis and skin related.”

When looking at T-cell subpopulations before and after nivolumab/ azacitidine, the number of CD3-positive cells and the ratio of CD8- positive cells to Tregs predicted response to treatment. In these early observations, PD-L1 expression did not appear to impact results. “There were some hints that baseline immune infiltrate is able to predict for response,” added Daver. A study assessing immunotherapies for MDS demonstrated similar promise. In this trial, patients received single-agent nivolumab (n = 15), azacitidine plus nivolumab (n = 13), or ipilimumab (n = 13). The combination demonstrated an ORR of 68% and responses were still pending for ipilimumab.

Monotherapy with nivolumab did not elicit a response. A second study is looking at the combination of the killer-cell immunoglobulin-like receptors (KIR) inhibitor lirilumab and azacitidine. In early data from 3 patients treated with the combination, the ORR was 100% and there were no unexpected toxicities. This phase I/II study is currently enrolling patients with AML to receive azacitidine plus lirilumab in a dose-finding cohort followed by a phase II portion utilizing the maximum tolerated dose. Further results from the study will be presented at the 2016 ASH Annual Meeting.

References

1. Nivolumab (Opdivo) for Hodgkin lymphoma [news release]. US Food and Drug Administration. https://goo.gl/JoC7Se. Published May 17, 2016. Accessed November 14, 2016.
2. Lonial S, Dimopoulos M, Palumbo A, et al; ELOQUENT-2 Investigators. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015;373(7):621-631. doi:10.1056/NEJMoa1505654.
3. Dimopoulos MA, Oriol A, Nahi H, et al; POLLUX Investigators. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(14):1319-1331. doi:10.1056/NEJMoa1607751.
4. Mateos MV, Orlowski RZ, DiCapua Siegel DS, et al. Pembrolizumab in combination with lenalidomide and low-dose dexamethasone for relapsed/refractory multiple myeloma (RRMM): final efficacy and safety analysis. J Clin Oncol. 2016;34(suppl; abstr 8010).
5. Garfall AL, Maus MV, Hwang WT, et al. Chimeric antigen receptor T cells against CD19 for multiple myeloma. N Engl J Med. 2015;373(11):1040-1047. doi:10.1056/NEJMoa1504542.
6. Davids MS, Kim HT, Costello CL, et al. A multicenter phase I/Ib study of ipilimumab for relapsed hematologic malignancies after allogeneic hematopoietic stem cell transplantation. Blood. 2015;126(23):860. doi:dx.doi.org.
7. Daver N, Cortes J, Ravandi F, et al. Phase Ib/II study of nivolumab in combination with 5-azacytidine (Aza) In patients (Pts) with relapsed acute myeloid leukemia (AML). Poster presented at: 21st Congress of the European Hematology Association; June 9-12, 2016; Copenhagen, Denmark. P189.