Naval G. Daver, MD, discusses the rationale for investigating uproleselan combinations in patients with acute myeloid leukemia, the current role of quizartinib in patients with FLT3-ITD–mutated disease, and potential future directions with both these agents in the AML field.
An ongoing phase 1 trial (NCT04964505) of uproleselan (GMI-1271) plus azacitidine (Vidaza) and venetoclax (Venclexta) in patients with treatment-naïve acute myeloid leukemia (AML) will contribute to the growing body of research supporting the use of the E-selectin inhibitor in patients with AML, according to Naval G. Daver, MD, who emphasized the importance of considering these study findings within the larger context of the frontline AML treatment paradigm.
This single-arm trial is investigating the uproleselan triplet in patients aged 75 years or older or patients aged 18 to 74 years with comorbidities such as an ECOG performance status of 2 or 3, cardiac history of congestive heart failure, 65% or less forced expiratory volume in 1 second on carbon monoxide diffusing capability test, and any other condition that may render the patient ineligible for intensive chemotherapy. The primary end points of this trial are the incidence of adverse effects and the determination of the recommended phase 2 dose (RP2D).1
Previously, in 2022, a phase 1/2 trial showed that salvage treatment with MEC (mitoxantrone, etoposide, and cytarabine) plus uproleselan at the RP2D of 10 mg/kg twice daily elicited a complete response (CR)/CR with incomplete count recovery (CRi) rate of 41% and a median overall survival (OS) of 8.8 months in patients with relapsed/refractory AML.2 Additionally, in a separate cohort of newly diagnosed patients who received uproleselan plus 7+3 (cytarabine plus daunorubicin) chemotherapy, the CR/CRi rate was 72% and the median OS was 12.6 months.
"Maybe there will be more than 1 potential area where uproleselan could be used," Daver said in an interview with OncLive® during the 2023 SOHO Annual Meeting.
In the interview, Daver discussed the rationale for investigating uproleselan combinations in patients with AML, the current role of quizartinib (Vanflyta) in patients with FLT3-ITD–mutated disease, and potential future directions with both these agents in the AML field.
Daver is an associate professor in the Department of Leukemia in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.
Daver: E-selectin is an important mucosal ligand. It's associated with increased homing of leukemia cells into the bone marrow niche, where they are protected and cannot be targeted by chemotherapy. By targeting E-selectin, we're trying to mobilize the leukemia cells outside the bone marrow niche, where they're sheltered, into the central bone marrow area, or circulation, where they will be much more exposed and susceptible to killing by chemotherapeutic agents. This is the main rationale for [using] uproleselan.
Interestingly, it appears that targeting E-selectin can also enhance mucosal integrity and avoid mucositis and toxicities that are common with intensive chemotherapy. This rationale has led to studies where we're combining drugs with uproleselan, whether it's intensive chemotherapy combination [investigations] that are ongoing, or low-intensity combinations, such as hypomethylating agents [HMAs] and venetoclax. The data that are published so far are with the intensive chemotherapy combinations, where uproleselan was evaluated in the salvage setting in combination with 2 commonly used intensive chemotherapy regimens, MEC and FLAG-Ida [fludarabine, high-dose cytarabine, idarubicin, and granulocyte-colony stimulating factor].
What was published by Daniel DeAngelo, MD, PhD, from Dana-Farber Cancer Institute [in Boston, Massachusetts] is that the combination of intensive chemotherapy/uproleselan in the salvage AML setting was associated with a promising CR/CRi rate of 41%. Historically, in a salvage population, especially in patients with therapy-related AML or high-risk features, which this population had, we expect approximately 20% to 25% CR/CRi rates. It was also interesting that in the evaluable minimal residual disease [MRD] population, they saw an encouraging MRD-negative signal.
That has led to a randomized study where we're investigating uproleselan with intensive chemotherapy vs placebo plus intensive chemotherapy in the relapsed/refractory AML population. That study completed accrual 2 years ago, and we're hoping that maybe [in 2024, we will] see the topline results from that study. If [that study] is positive, [uproleselan] would be the first drug to be approved in relapsed AML that is not mutation specific. We have FLT3 and IDH inhibitors approved, and hopefully menin inhibitors in the near future, but these are all target-specific therapies. No general, non–target specific therapy has been approved for decades in relapsed/refractory AML. This would be exciting and would also open the potential for other combinations.
There is an [investigation of an] upfront combination already ongoing, where intensive chemotherapy is combined with uproleselan vs intensive chemotherapy alone in patients with secondary therapy–related AML. The study is led by Geoffrey L. Uy, MD, from Washington University School of Medicine [in St. Louis, Missouri]. There's also a single-arm study of azacitidine plus venetoclax plus uproleselan that Brian Jonas, MD, PhD, of the University of California, Davis has been leading. Both these [trials] have shown encouraging signals, so we're waiting for the final data readouts from them. Clinically, what we saw that's interesting is that in the salvage population in the publication by DeAngelo and colleagues, there was reduced mucositis and toxicity with uproleselan added to intensive chemotherapy compared with what has historically been seen. Therefore, there may be an efficacy improvement [with the addition of uproleselan to this regimen] as well as better tolerability or a safety benefit, which would be cool. We're looking forward to seeing those results.
The azacitidine/venetoclax combination is now the most frequently used combination for patients above 75 years of age [as well as those] in the 60 years to 75 years population. In newly diagnosed, frontline AML, close to 60% or 70% of patients are getting azacitidine/venetoclax based treatment, and ideally so, because it is associated with a good response rate, good tolerability, and, if we want to move a patient to allogeneic stem cell transplant [ASCT], that is still feasible with the azacitidine/venetoclax backbone approach.
The next steps are, although azacitidine/venetoclax is good, with an updated median OS [of 14.7 months], is there a way to move beyond this to make [the outcomes] better? That is where we have started adding additional drugs, targeted therapies such as FLT3, IDH, or CD123 inhibitors, to the backbone. We've presented and published many of those data from MD Anderson Cancer Center and other groups.
Dr Jonas and his team have taken the approach of adding the E-selectin inhibitor uproleselan. The rationale [for that trial] is based on preclinical data that have been published showing synergy with venetoclax and uproleselan. Also, when we add a third drug to azacitidine/venetoclax, we want an agent with a good safety profile that will not add significant cumulative myelosuppression, neutropenia, [or other] toxicities. Uproleselan seems to meet that bill, so it makes sense to look at it in a 3-drug combination. We're waiting to see data from that study.
The relapsed/refractory setting will be an easier approach [to adopt] because there's a randomized phase 3 study. If that study is positive, it will lead to approval. The drug may be used quite a bit in the salvage setting, especially in patients without targetable mutations, such as FLT3, IDH1, IDH2, MLL, and NPM1. Approximately 60% of the AML population does not have a targetable mutation. That is where I see the first use for it.
In the frontline setting, we need to see the data of the intensive chemotherapy plus uproleselan study that are expected soon. The interim analysis, if it's positive, will lead to a full phase 3 expansion study. If that's positive, there will be consideration [for uproleselan in the frontline]. The frontline setting is a bit more crowded. FLT3 inhibitors are working well and are frequently used. Venetoclax is added to intensive chemotherapy, such as FLAG-Ida/venetoclax and CLIA [cladribine, idarubicin, and cytarabine]/venetoclax, and those data are good. We will need to look at the comparative data and then decide [on the best frontline treatment].
We're excited about the approval of quizartinib in the frontline. Approximately 12 years ago, MD Anderson Cancer Center was the first center to, with Jorge Cortes, MD, [currently of Augusta University in Georgia], start the initial phase 1 studies of quizartinib and salvage therapy. It was clear to us from the beginning that this is a potent, effective, and well-tolerated drug. We didn't see gastrointestinal [GI] toxicities, nausea, diarrhea, or liver function test issues. It unfortunately took a long time to get approved, but the good news is that it got there eventually.
Quizartinib is a potent, selective FLT3 inhibitor. Of all the FLT3 inhibitors, quizartinib was the most potent in the preclinical setting. One important note to realize is that it only targets ITD, it does not target TKD. Approximately 80% of FLT3 mutations are FLT3-ITD mutations, so that's fine. [In patients with] a FLT3-TKD mutation, either alone or along with an FLT3-ITD mutation, I would not use quizartinib and would consider using midostaurin [Rydapt] or gilteritinib [Xospata], which cover both ITD and TKD mutations. However, if there's just a FLT3-ITD mutation, then the [phase 3] QuANTUM-First trial [NCT02668653] data clearly show an improvement in OS, good tolerability, and a good ability to move patients to ASCT [with quizartinib].
A couple of considerations that are important to focus on, especially for community audiences or fellows, is that many people debate between the [phase 3] RATIFY study [NCT00651261] with midostaurin and QuANTUM-First. The first note to highlight is that these [trials] had different populations. One of the big differences is that in the quizartinib study, approximately 40% of the patients were older than 60 years of age, whereas RATIFY only allowed patients aged 18 to 60 years. A much older population [was enrolled in] QuANTUM-First, which is usually associated with the more difficulties, [such as] more toxicity, comorbidities, and early mortality.
The second consideration [showing that the QuANTUM-First population was less favorable] is that all patients needed to have FLT3-ITD mutations, whereas in RATIFY, only 77.4% of patients had FLT3-ITD mutations, and patients with FLT3-TKD mutations, which made up 22.6% of the RATIFY population, tended to do better [with midostaurin]. The population of QuANTUM-First was more difficult, [since patients were] older and all had FLT3-ITD mutations. If we get equivalent results with a much more difficult population, that suggests quizartinib is a better drug.
Data have been shown with quizartinib [in patients younger and older than 60 years of age]. [In the population of patients younger than 60 years], compared with RATIFY, we see a 4-year OS [rate] close to 60% compared with 50% with midostaurin in that younger population, and that's still with all the patients in QuANTUM-First having FLT3-ITD mutations vs 70% [of patients in RATIFY]. [We need to consider the] statistical caveats of doing a cross-trial comparison, which is not ideal but is a reality and [necessary] because we need to decide [which agent to recommend]. That fact, given [quizartinib's] selective development as a pure FLT3 inhibitor, whereas midostaurin was a broad kinase inhibitor from solid tumors taken to FLT3, and the good GI tolerability of quizartinib, with no nausea or diarrhea issues, makes us think [quizartinib] is the drug we would use in all frontline patients with FLT3-ITD mutations.
There are toxicities [associated] with quizartinib. The toxicity that one needs to be aware of and be careful to manage, but which can be managed well, is QTc prolongation. In my view, this [concern] as well as the use of much higher doses in the phase 1 study than we eventually found out we needed, are what delayed the full approval of quizartinib. That process led to a delay of approximately 5 or 6 years. We had expanded all the way up to 180 mg and 210 mg of quizartinib and found that 60 mg and 30 mg were giving equivalent results, but with approximately 1/5 or 1/6 of the grade 3 QTc prolongation rates.
In QuANTUM-First, we used lower doses of 30 mg and 60 mg, and we found that the grade 3 QTc prolongation rate was 3% to 5%. This is in line with other kinase inhibitors, [such as] menin inhibitors and IDH inhibitors, and is manageable. However, one needs to be careful to not use too many cumulative drugs that can cause QTc prolongation. If you're going to start quizartinib, try to avoid ondansetron, potent azoles, and other such agents, otherwise [patients] could develop QTc prolongation. Other than that, [there have been] no major toxicity issues, and [quizartinib] will be used a lot in frontline FLT3-ITD–mutated disease.
Quizartinib was evaluated in the salvage setting in the [phase 3] QuANTUM-R study [NCT02039726] vs intensive chemotherapy. This trial showed a statistically significant OS benefit [with quizartinib]. However, because of the design of the study and the concerns over therapeutic equipoise and potential cardiac signals that were not fully explainable, [quizartinib] did not get full approval in the United States [in that setting]. It did get approval in Japan [in 2019] based on the results of that study.
Going back in the relapsed setting and asking whether we can consider this drug, especially in patients who have progressed on frontline therapies and potentially gilteritinib makes sense. There's no other option for them. Quizartinib, now that we know how to manage it, use the right dose, and avoid cumulative QTc-prolonging drugs, should be fine. Hopefully, it will be available in the future in the salvage setting.
The second [future direction for quizartinib] is combinations. MD Anderson Cancer Center has been leading [studies with] combinations of HMAs and venetoclax with FLT3 inhibitors, including quizartinib and gilteritinib. We've shown some of the early data. [In the] salvage setting, the triplet is important, but the durations of remissions and survival are short. However, in the frontline setting, [the triplet is] potent and durability seems to be good. We hope to update those data at the 2023 ASH Annual Meeting and Exposition.
Then, the question is: Can this [research] be taken into a multicenter expansion trial and be a path for a future label of HMAs/venetoclax/FLT3 inhibitors for patients who are older than 65 or 70 years and in whom intensive chemotherapy may still cause toxicity? Other combinations that will be considered are combinations with menin inhibitors and IDH inhibitors, as well as post-transplant maintenance approaches. Many of these are being reviewed and discussed. Quizartinib may be an important and key player in the AML landscape.
Lastly, there are also data with quizartinib in the wild-type setting. It's the only FLT3 inhibitor that has shown persistent, consistent wild-type activity. In a phase 1 study, we found a 32% CR/CRi rate in patients with relapsed/refractory, FLT3 wild-type disease with quizartinib. Additionally, the group from [the University Hospital La Fe in Valencia, Spain], Pau Montesinos, MD, PhD, and colleagues, showed data of 7+3 and quizartinib vs 7+3 in FLT3 wild-type disease, showing a clear OS benefit [with quizartinib], especially in the intermediate-favorable population. There may be a path and role for quizartinib even in wild-type, non-FLT3–mutated AML.