Sotomayor Elucidates Updates Including ADC and Bispecific Antibody Combinations in Hematology

Eduardo M. Sotomayor, MD

Intriguing research on agents in the diffuse large B-cell lymphoma (DLBCL) and LBCL treatment paradigms encompasses combining antibody-drug conjugates (ADCs) and bispecific antibodies, according to Eduardo M. Sotomayor, MD, who added that clinical trials on the combinations will need to be further developed.

“Overall, the combination of a bispecific antibody with an ADC is quite promising. These combinations are also showing great results in solid tumors,” he said.

Data from the overall population of a phase 1/2 study (NCT03671018) revealed that patients with relapsed or refractory aggressive LBCL (n = 117) treated with the ADC polatuzumab vedotin-piiq (Polivy) and the bispecific antibody mosunetuzumab-axgb (Lunsumio) achieved an overall response rate of 62.4% (95% CI, 53.0%-71.2%), with a best complete response rate of 50.4%; the median duration of response was 20.8 months (95% CI, 14.8-not estimable). Additionally, the median overall survival was 27.7 months (95% CI, 15.2-not estimable).¹

Sotomayor, president and executive director of the Tampa General Hospital Cancer Institute, Cancer Center of South Florida, discussed updates in the treatment of hematologic malignancies in an interview with OncLive^® following an OncLive State of the Science Summit™, which he chaired.

He also emphasized the importance of financial toxicities associated with clinical trials and highlighted upcoming and ongoing research on vaccines. Additionally, Sotomayor provided further insights into the changing treatment landscape of hematologic malignancies in another interview.

OncLive: What are some of the most intriguing novel agents that have emerged in DLBCL according to the presentation given by D. Alan Kerr, MD, PhD, at the event?

Sotomayor: Dr Kerr went into data on bispecific antibodies [encompassing] all the new data presented at the 2023 ASH Annual Meeting, including data on chimeric antigen receptor [CAR] T-cell therapy and combination therapies. In particular, the combination of a bispecific antibody with other forms of immunotherapies such as ADCs [is interesting]. What got my attention [was the data from the phase 1/2 study evaluating] the combination of polatuzumab vedotin with mosunetuzumab. There were fantastic and positive [outcomes] for patients with aggressive [LBCL].

There are reports about this combination in patients with aggressive mantle cell lymphoma, [as well]. [The combination] is relatively easy to give in the outpatient setting—and to me, that is the future. We have agents that have good efficacy [alone], and now when you put them together the outcomes are even better. However, we need to watch combinations because, with some of them, we’re also going to be adding new toxicities and financial toxicities for patients.

[Although] there are different targets and I don’t [treat] solid tumors, I was happily surprised with how solid tumor treatments are also using bispecific antibodies with ADCs. We are going to see more of those combinations in DLBCL.In 2012 or 2013, the only thing we had was R-CHOP [rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine, and prednisone] for frontline therapy, and we tried to build on R-CHOP with other combinations. Although they failed, we now have several options. Perhaps in the near future we will have combinations that are going to replace conventional chemotherapy in the field of DLBCL. We are not there yet, but we are on our way.

How would you like to see the treatment of hematologic malignancies, such as lymphomas, evolve over time through clinical trials and research?

We need to figure out how to better use these different immunotherapeutic agents. I was invited to give a talk in Spain on how we are going to combine all these drugs. Is there a science in combining [these agents]? Yes, and I like some of the clinical trials that are [looking at] frontline therapy with a combination for a couple cycles. We are going to be learning from those correlative studies that then move into conventional treatment.

There was a recent paper published in Nature that says we need to understand how the immune system responds to these different agents to better sequence them. Currently, we combine [certain agents] with ADCs, which makes sense clinically, but we need to better understand what is happening with the immune system when we use these 2 agents together. Sometimes you follow the scientific rationale saying that, based on what we know, we need to combine [specific agents] and it doesn’t work at all. Then there is a situation where you combine agents without a scientific rationale, and it works. We need to start doing better than that because that’s going to guide the future.

Additionally, these clinical trials are extremely expensive. At the end of the day, there will be big investments of millions of dollars in clinical trials. That was okay when there were only 3 chemotherapy drugs, but now there are 20-plus drugs that have been FDA approved for B-cell lymphoma in the past 10 years. You cannot [continue with trial and error]; that is impossible. The number of permutations and combinations is just impossible. There is no person [or group] who can pay for those clinical trials.

Is there any ongoing or future research planned in hematologic malignancies that you’re involved in?

In the beginning of my career, I began by studying innate immune systems and macrophage myeloid cells in the microenvironment. I am going back to studying macrophages in the lymph node microenvironment. I was involved in the early days of cancer vaccines for lymphoid malignancies and solid tumors, and we failed miserably.

We failed because we didn’t know how the immune system worked. However, we now have better knowledge and can monitor how the immune system responds to therapies and vaccines. Now, we have a very good platform—RNA vaccines. The same platform we use for COVID-19 is now being used to stimulate the immune system of patients with cancer with neopeptides that are the product of mutations. We’re using those mutations as targets where we have drugs, as seen with EGFR mutations in lung cancer, as well as with other mutations in solid tumors.

When the cancer cell makes those mutations, they are also going to create new proteins or new peptides, but you need to put a vaccine together to stimulate the immune system. If you take that RNA vaccine platform where we can put tumor antigens up to 10 peptides, [we can try to create] a vaccine. The data are promising in advanced melanoma and pancreatic cancer, creating a new frontier. We have a better understanding of the immune system and now know that [immunotherapy], like CAR T-cell therapy, can cure cancer.

The reason why CAR T-cell therapy and bispecific antibodies are not curing more patients is because [of] macrophage myeloid cells. They are the last barrier, and removing that barrier is not easy. However, it is important to do so, especially for CAR T-cells in solid tumors—that’s where we are going and that’s the research we are developing at my institute. My colleague and I are going to unify our laboratories working with this. We are working on [a] macrophage cancer vaccine, and he is working on new cell therapies, too. That is our joint research that we are doing for the next 5 to 10 years.