Wang Expands on the Continued Investigation of Targeted Therapies in Relapsed/Refractory AML

Eunice S. Wang, MD

Despite the use of targeted treatments like IDH1/2 and FLT3 inhibitors and the adoption of venetoclax (Venclexta) plus azacitidine (Vidaza) for patients who are ineligible for intensive chemotherapy, most patients with acute myeloid leukemia (AML) will experience relapse, a population that still faces poor outcomes with currently available therapeutic options, according to Eunice S. Wang, MD.

Combination therapies, including targeted therapies and immunotherapies, remain an essential area of active investigation. Moreover, menin inhibitors continue to show promise for AML subgroups, such as those with KMT2A/MLL rearrangements and NPM1 mutations, emphasizing the promise of targeted therapies.

“What we need for these patients is effective combination therapies where we’re able to combine modalities to achieve greater long-term disease-free response,” Wang said.

In an interview with OncLive^®, Wang discussed current unmet needs for the treatment of patients with relapsed/refractory AML, highlighted the need for effective combination regimens, and expanded on the use of menin inhibitors, with a focus on moving these treatments into earlier lines of therapy. Wang is chief of the leukemia/benign hematology service in the Department of Medicine, medical director of the Chemotherapy/Infusion Center, leader of the leukemia clinical disease team, a professor of oncology, and assistant member of the Tumor Immunology Program in the Department of Immunology at Roswell Park Comprehensive Cancer Center in Buffalo, New York.

OncLive: What would you define as being the greatest needs in relapsed/refractory AML?

Wang: For patients with relapsed/refractory AML—although we have many targeted therapies and there [have] been many approvals since 2017—the overall outcomes of these patients remain extremely poor. Even the FDA-approved FLT3 inhibitors, IDH inhibitors, and other agents only have an overall response rate of 20% to 30%, with an overall survival [OS] that [ranges] anywhere from 5, 7, to 8 or 9 months.

Although we’re able to get disease control with less toxic, less intensive therapies than we [used] in the past, overall, most of our patients will only live less than a year—or maybe a little longer [if we are lucky]—in the absence of undergoing allogeneic stem cell transplantation [ASCT].

Given the fact that many of our patients are in [their] 60s, 70s, and 80s, that’s not really an option for some of them. We are, unfortunately, then faced with a terminal diagnosis for most of them.

What data need to be seen to push the needle forward in a recognizable way?

[We’d like to see data] combining targeted therapies with some of the agents that we already know and love, like venetoclax and azacitidine, or even developing new modalities of treatment.

As we know, in solid tumors and lymphoid malignancies, immunotherapy has revolutionized outcomes and is generally considered less toxic than the same type of intensive chemotherapy that we’re still giving our patients with AML. What we need is a blockbuster immunotherapeutic agent. We need targeted therapies for these [hard-to-treat] subsets of disease, like p53. We may need to be targeting, sequencing, or doing combination regimens—maybe even up front—to get the higher response rates and longer disease control than we’re currently getting with our standardized therapies.

In terms of immunotherapy development, do blood cancers face the same challenges that solid tumors do, or is there a new host of challenges?

There is a whole new host of challenges. We know, for example, that immunotherapy works for some blood cancers very well. We now have approximately 6 CAR [chimeric antigen receptor] T-cell therapies approved for the treatment of patients with lymphomas and lymphoid cancers, as well as acute lymphocytic leukemia [ALL]. We have several bispecific antibodies that have moved into standard of care for multiple myeloma; however, AML has not seen the same advances in immunotherapy as the other blood cancers.

We do not have an effective bispecific antibody like blinatumomab [Blincyto] for ALL. We do not have CAR T-cell therapy as we do for relapsed/refractory patients with ALL. We also don’t have bispecifics like we have for multiple myeloma. Part of the reason is because myeloid leukemias are a very heterogeneous group. They don’t all express the same surface antigen, meaning they don’t have a consistent, universally expressed protein on their surface that can be targeted by some of these uniform immunotherapeutic approaches.

We’ve been struggling to find the best immunotherapy target that’s expressed on [most] of the AML cells that consistently lead to response. We’ve tried anti-CTLA approaches [in addition to] PD-1 and PD-L1 approaches in AML [and] myelodysplastic syndromes. We see response rates that are 20% to 30% and evidence that these patients have immune exhaustion as opposed to patients with solid tumors, so that they’re not able to have the same benefit from immune checkpoint inhibitors.

We’ve struggled to say maybe there are no newer targets. We are very disappointed with the results of the magrolimab antibody therapy, which was really the big hope that maybe by targeting a macrophage checkpoint, we could get some responses. We are still in the infancy [stage] as compared with some of the other fields in terms of identifying effective immunotherapies.

Looking at the different therapeutics available to patients with AML, based on the mode of disease, what do you see as being the most relevant pathways for therapeutic development?

We are all very encouraged by the early success and activity of menin inhibitors in patients with relapsed/refractory acute leukemias characterized by KMT2A or MLL mixed lineage leukemia rearrangements, as well as AML, characterized by NPM1 mutations. These 2 subtypes of AML, in the relapsed/refractory setting, can be very difficult to treat, and we’ve had no targeted therapies [that] are unique for the biology of those diseases.

Menin inhibitors were designed primarily to treat those rarer KMT2A- or MLL-rearranged leukemias, both AML [and] ALL. They work by turning off a pathway between the menin protein and the KMT2A epigenomic complex, and it is important for the underlying leukemogenic mechanism of both [patients with NPM1 mutations and] KMT2A-rearranged leukemia.

Those oral menin inhibitors in patients heavily pretreated with up to 6 or 7 prior therapies, including prior ASCT, prior intensive therapy, and prior venetoclax/azacitidine, have consistently demonstrated a response rate of 20% to 30%. Again, the OS is limited at 7, 8, 9 months in the absence of any ASCT, but the responses these patients get are real complete responses and morphologically-free states. We know these agents are biologically active because we see evidence of clinical differentiation syndrome, which is a mode of activity that we’ve seen with other AML therapies.

In bridging some of my patients to ASCT, I have been able to salvage some of them. We are excited by those agents. We also are exploring agents targeting other pathways. We’ve looked at…other immune modulatory pathways, such as the TIM-3 pathway. Some work is being done regarding targeting the bone marrow microenvironment that the AML cells are sitting in to see whether we could target the leukemia cells within their own microenvironment and try to disrupt some of those survival pathways to see whether that could be a mutation-independent way to target AML cells.

For the menin inhibitors and the early work with the TIM-3 inhibitors, what do you see as being the path ahead for regulatory approval?

For the menin inhibitors, this mode of activity—and the activity we’ve seen across many different menin inhibitors made by many different companies—validates what we saw in the early days of the FLT3 inhibitors, where it wasn’t the specific agent but the targeting of the pathway, regardless of the agent, that was leading to the responses.

Now that we’ve seen evidence of clinical activity with revumenib [SNDX-5613], ziftomenib [KO-539], and others, we’re likely going to see approval of a menin inhibitor as the next targeted therapy for those AML subtypes. That’s very important because NPM1-mutant disease represents up to a third of newly diagnosed AML and KMT2A, about 5% or 10%. This will offer about a third or more of our patients in the relapsed setting a potential for a targeted therapy.

Moving forward, combinatorial therapies and moving [these agents] up front are the way to go. Even with the menin inhibitors, response rates are 20% to 30% and OS is 7 [to] 8 months. There [are] early data suggesting that up to 39% of patients treated with 1 menin inhibitor, revumenib, can quickly develop the emergence of menin resistance mutations. That’s giving us pause that these agents, as monotherapies, are quickly going to be ineffective. Combining them with intensive therapy [is] what is currently being explored by many companies in ongoing clinical trials, which are rapidly accruing both at my site and [others].

We look forward to the approval of the single agents in the relapsed/refractory setting. Similarly, for example, gilteritinib [Xospata], which was initially approved in the relapsed/refractory setting, is now standard of care in the up-front setting. We’d like to see the same sort of transition and incorporation of those agents earlier, because…the best way to treat relapsed disease is to prevent it from happening in the first place.

With the emergence of more targeted agents and personalized chemotherapeutic regimens, how has the discussion about survivorship changed?

In the past, we had very few survivors, [so] our survivorship group was unfortunately something we weren’t spending a lot of time on. I now have patients who, with targeted therapies and oral medications, are living many years. We routinely see even older patients because we now have newer therapies specifically for patients [older than] 75 [years], which is remarkable, and I have some of those patients living 2 to 4 years. Particularly, as we move into longer survival and oral medications for older individuals, much more of the focus, discussion, and shared decision-making then is about quality of life. What are our patients aiming for? Are they looking for something that’s going to keep them going? Do they want to be inpatient vs outpatient? Do they want to go for ASCT with the advances in transplantation, or do they want a reduced intensity transplant?

We have a lot of things to discuss, and survivorship is something we are new to in the oncology field but is gaining a lot of attention as the effectiveness of our therapies improves. For example, many years ago, [when we would] report the results of AML clinical trials, we would only really be talking about 2-year OS or 5-year OS for rare patients [who] we thought might be cured. We’re routinely now seeing studies being published saying, ‘[These are] the 5-year survival outcomes of patients treated on a clinical trial.’ That is a huge advancement.

What would you like your community colleagues who may not treat many patients with AML to be able to apply to their practices based on this discussion?

It’s important for our colleagues in the community to realize that we now have up-front chemotherapy for patients who are 75 years and [older]. In the past, those patients [who] we might have said were too sick, [old], or frail to get therapy or get treatment options, that’s no longer true. I would encourage my community colleagues to not use age alone as the only measure of whether somebody is suitable for therapy for AML.

Secondly, I would highly encourage them to perform diagnostic testing, including detailed mutational testing, or refer patients for detailed mutational testing or other transplant options in all patients diagnosed with AML. We now have targeted therapies for [several] different diseases; not only [older] individuals can get venetoclax-based therapies. We have IDH inhibitors in the up-front setting, we have FLT3 inhibitors, and we soon will have menin inhibitors.

Being able to offer the widest range and the most personalized care for our patients with AML is going to require a detailed analysis and, for me, next-generation sequencing cytogenetic blood cytometric analysis. I would encourage them to perform that on patients and refer [them] for consideration of potential clinical trials or novel therapies, some of which could be fairly nontoxic and oral given in the outpatient setting.

We can start our patients on those, and we’re happy to send those patients back to the community for long-term management and follow-up.