Ziftomenib Displays Early-Phase Efficacy in Relapsed or Refractory AML

Harry P. Erba, MD, PhD

Despite an uptick in available therapies for patients with acute myeloid leukemia (AML), novel interventions are needed to address the approximately 40% of patients who relapse and are refractory to first-line treatment.

Venetoclax (Venclexta), FLT3 inhibitors, and IDH inhibitors have demonstrative improvements in patients, but those with relapsed or refractory disease historically have a poor prognosis, with a median overall survival (OS) of approximately 4 months.^1,2

Investigators of the phase 1/2 KOMET-001 trial (NCT04067336) are seeking to address this unmet need with the investigational menin inhibitor ziftomenib.³

Ziftomenib is an oral, potent, and selective small molecule inhibitor that targets the interaction between menin and the KMT2A gene. The agent’s inhibition of the menin-KMT2A complex has shown the potential to combat the survival, growth, and proliferation of leukemia cells.^4,5

“Menin is an important transcriptional cofactor in regulating gene expression in the myeloid compartment,” Harry P. Erba, MD, PhD, professor of medicine in the Division of Hematologic Malignancies and Cellular Therapy at Duke Cancer Institute in Durham, North Carolina, said in an interview with OncologyLive. “Through menin, you can get upregulation of genes [such as] HOXA9 [and] NICE1, and those genes lead to a leukemogenic profile and proliferation, block and differentiation and leukemogenic signature. Drugs that inhibit menin will lead to downregulation of both HOXA9 and NICE1 and can allow them differentiation of leukemic blasts.”

Ziftomenib received an orphan drug designation from the FDA in July 2019.⁵

KOMET-001 is the first-in-human study of ziftomenib, and includes dose-escalation and dose-validation/expansion phases. Phase 1 is enrolling adult patients with relapsed/refractory AML, defined as at least 5% of blasts in the bone marrow, who have failed or are ineligible for standard-of-care treatments such as hematopoietic stem cell transplant (HSCT).

Phase 2 will evaluate the agent specifically in adult patients with relapsed/ refractory AML harboring an NPM1 mutation. Observed in approximately 25% to 30% of patients with AML, an NPM1 mutation has been linked with an improved prognosis among patients treated with intensive chemotherapy. However, it has yet to be determined whether its presence is a favorable prognostic factor for patients who are not fit for intensive chemotherapy and receive treatment with hypomethylating agents. Moreover, NPM1-mutant disease depends on the interaction between menin and wild-type KMT2A to drive leukemogenic gene expression.^4,6

Inclusion criteria for the phase 2 portion include an ECOG performance status of 2 or less, a life expectancy of at least 2 months, and peripheral white blood cell counts not exceeding 30,000/μL. Treatment with hydroxyurea to control and maintain white blood cell count before entering the trial is permitted. Patients who have undergone HSCT without adequate hematologic recovery, have clinically active central nervous system leukemia, or have had major surgery within 4 weeks of the first dose of study treatment will be
excluded from all phases of KOMET-001.³

“Tolerable second-line therapies [are] important, especially for older patients who [may not be able] to proceed to a curative stem cell transplant in first or subsequent remissions,” Erba said. “For younger
patients, we treat them with curative intent with intensive chemotherapy, but the outcomes are still suboptimal. In patients with NPM1-mutated AML, who do not have a FLT3 mutation, that’s considered more favorable-risk [disease], and those patients [can] be potentially cured with just standard intensive chemotherapy. However, the relapse rates are still high and so second-line therapies, [such as] inhibitors of menin for [patients with] NPM1-mutated [disease], I think will be important to improving the outcome of those patients.”

Investigating Ziftomenib

In the dose-escalation phase 1a, oral ziftomenib is given orally daily in 28-day cycles. The phase 1b dose-validation/expansion portion consists of 2 cohorts of patients with KMT2Arearranged/NPM1-mutant relapsed/refractory AML, and patients in each group will be given once daily oral ziftomenib at a dose previously studied in phase 1a. Finally, in phase 2, patients with relapsed/refractory NPM1-mutant
AML will receive once-daily oral ziftomenib at the recommended phase 2 dose (RP2D) determined in phase 1.³

In December 2022, the manufacturer of ziftomenib presented updated data from phase 1 of KOMET-001 during the 64th American Society of Hematology Annual Meeting and Exposition. During the dose-escalation phase, all-comer patients received the agent at a dose of 50 mg (n = 1), 100 mg (n = 1), 200 mg (n = 6), 400 mg (n = 5), 600 mg (n = 5), 800 mg (n = 11), or 1000 mg (n = 1). Then in phase 1b, patients were treated with ziftomenib at a dose of 200 mg (n = 17) or 600 mg (n = 36). The RP2D was determined to be 600 mg.⁷

Participants’ median age was 65.5 years (range, 22-85) in phase 1a. Most patients were men (56.7%), had an ECOG performance status of 1 (63.3%), had received venetoclax (73.3%), and had non–KMT2A-rearranged or non–NPM1-mutant disease (53.3%). The median number of prior lines of therapy was 3.5 (range, 1-9).7 In phase 1b, the median age of patients was 49.0 years (range, 30-79) and 54.5 years (range, 18-86) in the 200-mg and 600-mg cohorts, respectively. Most patients in both cohorts were women (58.8% vs 58.3%), had received venetoclax (64.7% vs 61.1%), and had not received a prior stem cell transplant (70.6% vs 77.8%). Notably, most patients in the 200-mg cohort had a KMT2A rearrangement (76.5%) and a majority of patients in the 600-mg cohort displayed an NPM1 mutation (55.6%).⁷

At the October 24, 2022, data cutoff, patients with NPM1-mutant AML who received ziftomenib at a dose of 600 mg during phase 1a and phase 1b (n = 20) achieved an overall response rate (ORR) of 40.0%, including a complete response (CR) rate of 30.0% and a composite CR (CRc) rate of 35.0%. At the 200-mg dose (n = 6), the ORR and CR and CRc rates were 33.3%, 16.7%, and 16.7%, respectively.⁷

For patients with KMT2A-rearranged disease, the ORR was 16.7% with a CRc rate of 11.1% among those who received the 600-mg dose of ziftomenib. Patients with this rearrangement treated at the 200-mg dose (n = 14) did not display a response.⁷

Regarding safety, in the phase 2 dose-escalation portion of the trial, dose-limiting toxicities were reported. Treatment-emergent AEs (TEAEs) of grade 3 or higher severity mostly occurred in the 200-mg to 800-mg dose range and included pneumonia, neutropenia, febrile neutropenia, and decreased appetite, all of which were reported at a
rate of 33.3% or less.

In phase 1b, patients with NPM1-mutant disease did not experience any grade 3 or higher TEAEs. Patients with KMT2A-rearranged disease experienced grade 3 or greater differentiation syndrome at a rate of 30.8% and 25.0% at the 200-mg and 600-mg dose levels, respectively. Additionally, 2 cases of febrile neutropenia were observed at the 600-mg level.⁷

Further examination of the rate of differentiation syndrome showed that in the phase 1a/1b population, the toxicity was not present among patients with NPM1-mutant disease treated at the 200-mg dose level (n = 4). Among patients with KMT2A-rearranged disease (n = 13), the rate of all-grade and grade 3 or higher differentiation syndrome was 38.5% and 30.8%, respectively.

For those with NPM1-mutant AML (n = 20) who received the 600-mg dose, the rate of any-grade and grade 3 or higher differentiation syndrome was 20.0% and 5.0%, respectively. For those with disease harboring a KMT2A rearrangement, these rates were 37.5% and 25.0%, respectively.⁷

“The major [toxicity] profile as far as AEs [are concerned] has been mostly related to on-target effect, and that’s differentiation syndrome,” Ghayas C. Issa, MD, an assistant professor in the Department of Leukemia, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, said in an interview with OncologyLive. “The other AEs are mostly things
that we see in acute leukemias in general, some infections or febrile neutropenia, but not clearly attributed to the drug.”

At the data cutoff, no patients in phase 1b remained on treatment at the 200-mg dose level compared with 10 patients at the 600-mg level. Discontinuation of ziftomenib at the 200-mg and 600-mg doses was attributed to AEs (11.8% vs 11.1%), death (23.5% vs 8.3%), and disease progression (29.4% vs 30.6%). Most patients at
both dose levels were off study at data cutoff (94.1% vs 52.8%).⁷

Investigators concluded that the activity of ziftomenib was optimal at the 600-mg dose, and a more demonstrative favorable risk/benefit
was seen among patients with NPM1-mutant disease. Additionally, the promising monotherapy data support the examination of combination approaches that include ziftomenib, they wrote.⁷

On February 9, 2023, the manufacturer of ziftomenib announced that the first patients had received doses in the phase 2 portion of KOMET-001. Approximately 85 patients in the United States and Europe are expected to be enrolled.⁸

In terms of identifying and enrolling patients to studies such as KOMET-001 when other treatment options are available, Erba noted that taking time to analyze and review the sequencing and best options based on patient characteristics is the most important component. “The community at large is getting better at collecting myeloid gene panels for patients, and we still have a little bit of education to do around waiting for some of those data to come back, especially NPM1, which may be in a myeloid gene panel and not visible for approximately 2 weeks,” Erba said on waiting for full testing results to truly determine all treatment options. “Some of the challenges we face in the clinic [include] trying to explain all of the options that these patients now have that are based on pretty sophisticated science. You can imagine that these are difficult discussions to have.

“For our patients who are older with comorbidities [and] who are not enamored with spending a lot of time in our clinics getting intravenous or subcutaneous therapies, the single agent that gives them remission that can be durable—even 4 months—is a step forward,” Erba added, noting that the favorable toxicity profile and durability of single agents should be encouraging for FDA approval. “I would encourage clinicians who are taking care of these patients to look for NPM1 [mutations and] KMT2a rearrangements and look for clinical trials, because we have so much more to learn about the efficacy of these drugs in different combinations.”

References

1. Kantarjian H, Kadia T, DiNardo C, et al. Acute myeloid leukemia: current progress and future directions. Blood Cancer J 2021;11(2):41. doi:10.1038/s41408-021-00425-3
2. Russell-Smith TA, Gurskyte L, Muresan B, et al. Efficacy of non-intensive therapies approved for relapsed/refractory acute myeloid leukemia: a systematic literature review. Future Oncol. 2022;18(16):2029-2039. doi:10.2217/fon-2021-1355
3. First in human study of ziftomenib in relapsed or refractory acute myeloid leukemia. ClinicalTrials.gov. Updated May 15, 2023. Accessed May 25, 2023. https://clinicaltrials.gov/ct2/show/NCT04067336
4. KOMET-001. Kura Oncology. Accessed May 25, 2023. bit.ly/3WKf8nk
5. Kura Oncology’s menin-MLL inhibitor KO-539 receives orphan drug designation from FDA for treatment of acute myeloid leukemia. News release. Kura Oncology. July 24, 2019. Accessed May 25, 2023. bit.ly/3MIFO2V
6. Prata PH, Bally C, Prebet T, et al. NPM1 mutation is not associated with prolonged complete remission in acute myeloid leukemia patients treated with hypomethylating agents. Haematologica. 2018;103(10):e4
   55-e457. doi:10.3324/haematol.2018.189886
7. Erba HP, Fathi AT, Issa GC, et al. Update on a phase 1/2 first-in-human study of the menin-KMT2A (MLL) inhibitor ziftomenib (KO-539) in patients with relapsed or refractory acute myeloid leukemia. Blood. 2022;140(suppl 1):153-156. doi:10.1182/blood-2022-167412
8. Kura Oncology announces first patients dosed in phase 2
   registration-directed trial of ziftomenib in NPM1-mutant acute myeloid leukemia. News release. Kura Oncology. February 9, 2023. Accessed May 25, 2023. bit.ly/3N1oR5m