Triplets and Targeted Therapies May Strengthen the R/R AML Armamentarium

Triplet therapies with novel acute myeloid leukemia (AML) agents, such as IDH inhibitors and FLT3 inhibitors, plus standard azacitidine (Vidaza)/venetoclax (Venclexta), could provide increased clinical activity in patients with relapsed/refractory AML who are unfit for intensive chemotherapy, according to Eunice Wang, MD.

“We are increasingly viewing older patients with AML as candidates for short-term prolongation of survival and potentially for multiple lines of therapies as we move forward in this space with both triplets and novel targeted agents,” Wang said in an interview with OncLive^® ahead of the 27th Annual International Congress on Hematologic Malignancies^®: Focus on Leukemias, Lymphomas, and Myeloma.

In the interview, Wang discussed the current standards for classifying and treating unfit patients with AML, treatment considerations for patients unfit for hypomethylating agents, and the potential role of investigational menin inhibitors and immunotherapies in this population.

In the phase 3 VIALE-A trial (NCT02993523), at a median follow-up of 43.2 months, unfit patients with untreated AML who received azacitidine/venetoclax achieved a median overall survival (OS) of 14.7 months (95% CI, 12.1-18.7) vs 9.6 months (95% CI, 7.4-12.7) in those who received placebo plus azacitidine.1 Wang emphasized how these data support azacitidine/venetoclax as the standard of care (SOC) in this population and contextualized the long-term follow-up data from this trial within the larger AML treatment and research landscape. She also highlighted findings from the phase 1/2 AUGMENT-101 trial (NCT04065399), in which the menin inhibitor revumenib (SNDX-5613) demonstrated an overall response rate (ORR) of 53% in patients with KMT2A-rearranged or NPM1-mutant AML.²

Wang is chief of the Leukemia Service at Roswell Park Comprehensive Cancer Center in Buffalo, New York.

OncLive^®: Could you summarize some recent or ongoing developments in the treatment of unfit patients with AML?

Wang: The long-term results from the VIALE-A trial established venetoclax/azacitidine as the SOC for this older patient population. This regimen, although [it was] effective and led to a median OS of 14.7 months, is not curative in most patients. Although a few patients are still alive 2, 3, and 4 years later, most of them have unfortunately passed on.

Layering on targeted therapies to this venetoclax/azacitidine backbone [is an investigational approach], and triplet regimens [are prevalent]. Regimens are incorporating, for example, IDH inhibitors on top of venetoclax/azacitidine, gilteritinib [Xospata] or other FLT-3 inhibitors on top of venetoclax/azacitidine, or other targeted therapies, such as immunotherapies like magrolimab and antibody-drug conjugates [ADCs] like PVEK [pivekimab sunirine]. Novel therapies for this patient group [include] bispecific antibody therapy, adoptive T-cell therapy, checkpoint inhibitors like magrolimab, as well as a new class of targeted agents, menin inhibitors, which are gaining traction for the treatment of patients with relapsed/refractory NPM1-mutant and KMT2A-rearranged leukemia. [We have] a multitude of options.

How do you distinguish between medically unfit and frail patients, and how does this classification affect patients’ subsequent therapy?

We typically use comorbidity factors. Comorbidity indices try to quantify the contribution of different comorbidities on our patients. With all our patients, we have an informed decision process where we ask them what their treatment goals will be. We also look at functionality, organ dysfunction, [ECOG] performance status, and gait. [Overall, we consider] a combination of prognostic markers, laboratory values, organ dysfunction linked in and overlaid with the patients’ personal treatment choices.

What long-term data have been shown in the VIALE-A trial, and how have these findings laid the foundation for the emerging landscape of AML treatment layering and triplet therapies?

The long-term data in patients treated in VIALE-A were presented at the 2022 ASH Annual Meeting. With 43.2 months of follow-up, the overall end points of that study were validated. [The study showed] an OS benefit of 14.7 months [in patients treated with azacitidine/venetoclax] vs 9.6 months in the patients treated with azacitidine alone and confirmed the continued high ORR and tolerability of the regimen over time. There were no new signals or safety concerns with prolonged therapy. However, there was no significant prolongation in some of those survival end points, suggesting that almost all the patients in the azacitidine arm had passed on over that timed interval. However, a small number of patients were still alive at 43.2 months, which is an accomplishment.

Overall, [these findings] validate that this regimen is both effective and has limitations. These data are key because this has now become the new backbone therapy for adding on targeted agents. Those targeted agents include FLT3 inhibitors, IDH inhibitors, and novel therapeutics, which have shown some degree of efficacy, 20% or 30%, as single agents. We’re trying to bring that [efficacy] up and build upon the 67% ORR with venetoclax/azacitidine to get that closer to 100% with some of those triplet combinatorial approaches.

How do you approach treatment for patients who are not candidates for hypomethylating agents?

This is a small percentage of patients. Anywhere from 5% or 10% to almost a third of patients in that older age category are not candidates for hypomethylating therapy. That may be for several reasons. It could be simple logistic reasons, [such as they] are not able to physically get to your center 7 days a month, or even 5 days a month, to get the treatments. Or, they may have organ toxicity that precludes them from getting that therapy.

We also need to consider, and this has been an increasing recognition, that although many older patients can get 2 or 3 cycles of therapy, the longevity and continuous nature of administering agents provides the most significant obstacles to long-term care. Almost every patient treated with venetoclax/azacitidine will need to come back on a regular basis and have continual dose reductions and truncation of the regimens or lengthening of the interval between treatments to maintain some level of therapy.

For frail patients who are too weak or have too much organ dysfunction, we are performing mutational analyses to see whether they can receive, for example, single-agent IDH1 and/or IDH2 inhibitor therapy. To select patients, we are also offering treatment with other regimens such as single-agent gemtuzumab ozogamicin [Mylotarg], a CD33-targeted ADC, or supportive care. We’ve maintained elderly patients with hydroxyurea, transfusion support, and prophylactic anti-infectives. We try to tailor this to our patient population. I had 1 patient with TP53-mutant disease who was a paraplegic and was supported with growth factors and transfusions for several months before he declined. He never received any therapy, hypomethylating agents or otherwise, for his underlying AML.

What investigational AML agents could shift practice in the future?

The most promising novel approaches for AML in the elderly or frail population [may be] the further development of targeted therapies. We have add-on therapies for the triplets, and we have menin inhibitors, which are showing [complete] response rates of 20% to 30% in patients with relapsed/refractory AML characterized by NPM1 and/or KMT2A rearrangements. In phase 1 first-in-human studies, both revumenib, the Syndax compound, and ziftomenib (KO-539), the Kura compound, have shown clear evidence of activity in these disease populations, [which include patients] who have progressed on [several] prior lines of therapy [and many patients who have progressed on] prior stem cell transplantation.

Revumenib, in 68 patients with relapsed/refractory disease, showed a median OS of 7 months, with several patients who achieved a response going on to stem cell transplantation. Ziftomenib showed an ORR of 42% in patients with NPM1-mutant disease in the same setting

These agents are rapidly moving forward. It is key to perform mutational analyses in these elderly and frail patients before making a [treatment] decision [to determine] that these patients are not eligible for any therapies or clinical trials. It’s also important to remember that although our patients are older and potentially not as robust as younger, more fit patients, they’re still candidates for therapy. The VIALE-A trial would never have been done if we didn’t recognize that patients above the age of 75 years deserved and needed new therapies purely because they were in an elderly age bracket.

Immunotherapeutics offers the potential for myeloid malignancies to join other solid tumor and lymphoid malignancies as an area where immunotherapies, particularly immune checkpoint [inhibitors], have activity. We have tried multiple T-cell checkpoint inhibitors over the past few years, with underwhelming results. The data emerging now with SIRPα- and CD47-targeted therapies suggest that macrophage checkpoint inhibition might be the way forward for myeloid cancers, including AML.

Data with magrolimab, particularly in TP53-mutant disease, look promising. It’s well tolerated in combination with hypomethylating agents, and it does not [cause much myelosuppression], albeit it, like venetoclax/azacitidine, [is associated with] hemolytic anemic adverse effects. [The potential for this regimen to be] equally efficacious and/or preferred for TP53-mutant disease or be better tolerated is appealing.

We are also awaiting data with sabatolimab [MBG453], a TIM-3 inhibitor, [that will report the] ORR and tolerability with the lack of myelosuppression with that regimen. Additionally, moving menin inhibitors forward in the treatment paradigm to potentially treat patients earlier in the disease course is an appealing approach similar to what we’ve seen with the FLT-3 inhibitors, [such as] moving gilteritinib up from the relapsed/refractory space to a potential frontline triplet approach for newly diagnosed patients.

One caveat is the doses and regimens need to be worked out. As seen with some of the triplet data presented by [investigators at] The University of Texas MD Anderson Cancer Center [in Houston], for example, when we combine gilteritinib, venetoclax, and azacitidine, most patients can only receive 2 weeks of therapy. There’s the thought process that we don’t need to give 28 days of all 3 agents. Although we can do that, we don’t want to because of toxicity. Dosing will be important. The recommended dosing by those MD Anderson investigators was to use gilteritinib at 80 mg, not 120 mg.

Lastly, we are moving forward with, similarly in our patients [receiving 7+3], performing maybe a day-14 bone marrow biopsy in patients treated with venetoclax/azacitidine. That may be enough to limit or minimize the toxicities with these multiple triplets moving forward.

What ongoing and planned AML research at Roswell Park Comprehensive Cancer Center would you like to highlight?

We are 1 of the first-in-human sites for the ziftomenib menin inhibitor study. We are enthusiastic about menin inhibitors, including other agents that are being developed by other sponsors.

We are developing an active CAR T-cell program at our site. Renier Brentjens, MD, PhD, and his team from Memorial Sloan Kettering Cancer Center [in New York, New York] joined us, and we are eagerly awaiting the opening of investigator-initiated [trials evaluating] CD33 [inhibitors] or potentially other CAR T-cell therapies for AML. Those immunotherapeutic approaches might be well tolerated as another means of adoptive cell therapy by older individuals who cannot undergo, for example, allogeneic stem cell transplantation.

I have a trial about PARP inhibitors in combination with some targeted therapies. These might offer a different mechanism of action to enhance or supplement the other known conventional agents which are effective in older or unfit patients with AML. We have some unique [approaches] here, and we look forward to seeing additional progress for the treatment of this difficult and challenging patient population.

References

1. Pratz KW, Jonas BA, Pullarkat VA, et al. Long-term follow-up of the phase 3 Viale-a clinical trial of venetoclax plus azacitidine for patients with untreated acute myeloid leukemia ineligible for intensive chemotherapy. Blood. 2022;140(supplement 1):529-531. doi:10.1182/blood-2022-158518
2. Issa GC, Aldoss I, DiPersio JF, et al. The menin inhibitor SNDX-5613 (revumenib) leads to durable responses in patients (pts) with KMT2A-rearranged or NPM1 mutant AML: updated results of a phase (ph) 1 study. Blood. 2022;140(supplement 1):150-152. doi:10.1182/blood-2022-164849