IDH1 Inhibitors, CAR T-Cell Therapy, and Third-Generation TKIs Refresh Relapsed/Refractory Leukemia Landscape

The novel agents olutasidenib, brexucabtagene autoleucel (Tecartus), and ponatinib (Iclusig) demonstrated encouraging data at the 2021 ASCO Annual Meeting in leukemias, according to Jamile M. Shammo, MD, renewing hope in the ability to salvage patients with relapsed/refractory disease.

Acute Myeloid Leukemia

Historical complete response (CR)/CR with incomplete hematologic recovery rates with approved IDH inhibitors, enasidenib (Idhifa) and ivosidenib (Tibsovo), hover around 30% and have a median overall survival (OS) of approximately 9 months in the relapsed/refractory setting, said Shammo, a professor of medicine and pathology at Rush University Medical Center, in a virtual presentation during the 2021 ASCO Direct HighlightsTM webcast in Chicago, a program developed by Physicians’ Education Resource® LLC.

Olutasidenib, a highly potent, orally active, selective IDH1 inhibitor, was developed to improve outcomes in the 7% to 14% of patients with AML who harbor IDH1 mutations.

In the phase 1/2 2102-HEM-101 trial (NCT02719574), 150 mg of oral olutasidenib was evaluated as a single agent and in combination with azacitidine across 8 cohorts of patients with acute myeloid leukemia (AML) and myelodysplastic syndromes. Findings from the planned interim analysis, which were presented during the 2021 ASCO Annual Meeting, focused on cohort 1, which enrolled 153 patients with relapsed/refractory, IDH1-mutant AML.¹

In the efficacy-evaluable population (n = 123), 37% of patients had secondary AML, 73% of patients had intermediate cytogenetic risk, 44% of patients were refractory to their last line of therapy, and 11% had failed allogeneic stem cell transplant, reflecting a difficult population to treat, said Shammo.

The primary end point, CR/CR with partial hematologic recovery (CRh), was 33% (95% CI, 25.1%-42.4%), and most CR/CRh responders had a CR (30%; 95% CI, 22.1%-39.0%).

“Transfusion independence was achieved in all response groups, particularly those achieving a CR,” said Shammo.

The agent also demonstrated durable CR/CRh benefit, with a median duration of CR/CRh that was not reached and a median duration of response (DOR) of 11.7 months. In a sensitivity analysis with transplant considered as the end of a response, the median duration of CR/CRh response was 13.8 months.

“Those who responded well had a much longer DOR, and a fraction of those patients managed to go onto stem cell transplant, which is what you would like to do in relapsed/refractory AML,” said Shammo.

Better response was strongly associated with longer survival as well. At a median follow-up of 9.7 months, the median OS was not reached in patients who had achieved a CR/CRh, with an estimated 18-month OS rate of 87%. In the safety population (n = 153), the median OS was 10.5 months (95% CI, 7.7-15.5). Among non–CR/CRh responders and non-responders, the median OS was 15.0 months (95% CI, 5.0–not evaluable) and 4.1 months (95% CI, 3.2-5.8), respectively.

“Clinical benefit, as evidenced by DOR and OS, extended to patients who responded but did not achieve CR/CRh,” said Shammo.

The primary treatment-emergent adverse effects (AEs) included leukocytosis (all-grade, 25%; grade 3/4, 9%) and febrile neutropenia (all-grade, 22%; grade 3/4, 20%), said Shammo. AEs of special interest reflected reports of differentiation syndrome (all-grade, 14%; grade 3/4, 7%), QTc prolongation (all-grade, 8%; grade 3/4, <1%), and liver abnormalities (all-grade, 21%; grade 3/4, 10%).

“Olutasidenib was well tolerated with a safety profile largely consistent with that of other IDH inhibitors, but patients should be monitored for differentiation syndrome and liver abnormalities,” said Shammo.

“These results are very promising and very impressive, and, hopefully, we will see more results not only with the single agent but also with the combination with azacitidine in other myeloid malignancies,” added Shammo.

Acute Lymphoblastic Leukemia

Turning to acute lymphoblastic leukemia (AML), Shammo discussed the results of the phase 1/2 ZUMA-3 trial (NCT02614066), which evaluated the CD19-directed chimeric antigen receptor (CAR) T-cell therapy brexucabtagene autoleucel in patients with relapsed/refractory ALL.²

Approximately 40% to 50% of adults with B-ALL experience relapse after initial treatment, with a 1-year OS rate of 26% after first salvage therapy, said Shammo in explaining the rationale for the study.

In the phase 1 portion of the study, brexucabtagene autoleucel demonstrated a CR/CRi rate of 83% and manageable safety profile. In the phase 2 portion, 71 patients were enrolled, and 55 patients received brexucabtagene autoleucel.

Patients could have received prior treatment with blinatumomab (Blincyto) and underwent conditioning chemotherapy with fludarabine and cyclophosphamide prior to treatment with the recommended phase 2 dose of brexucabtagene autoleucel: 1 x 106 CAR T cells/kg.

Brexucabtagene autoleucel was successfully manufactured in 92% of patients, and the median time from leukapheresis to manufacturing release was 13 days for patients in the United States, which Shammo called “remarkable.”

Regarding baseline demographics, 27% of patients had Philadelphia chromosome–positive disease, 100% of which had central nervous system disease at baseline, and 47% of patients had received at least 3 lines of prior therapy.

Additionally, 45% of patients received prior blinatumomab, 42% underwent prior allogeneic transplant, and the median blast count was 65.0 and 59.0 at screening and preconditioning after bridging chemotherapy, respectively.

At a median follow-up of 16.4 months, the primary end point of CR/CRi rate by central assessment, was 70.9% (CR, 56.4%; CRi, 14.5%); 31% of responders were in ongoing remission at the data cutoff.

“[We saw] a high and durable response rate in heavily pretreated adults with relapsed/refractory B-ALL, most of whom had high disease burden,” said Shammo.

The median time to initial CR/CRi was 1.1 months. The minimal residual disease (MRD)–negativity rate was 97% in responders, and 10 patients, including 9 with CR/CRi and 1 with blast-free hypoplastic or aplastic bone marrow underwent allogeneic transplant a median of 98 days (range, 60-207) following CAR T-cell infusion.

“This is exactly what you would like to do: induce patients into remission to take them to allogeneic transplant,” said Shammo. “What’s remarkable is that MRD negativity in patients who had this treatment approximated 100%.”

Among patients with CR/CRi (n = 39), the median OS was not reached (95% CI, 16.2-NE) and the median relapse-free survival (RFS) was 14.2 months (95% CI, 11.6-NE). All-treated patients (n = 39) had a median OS and RFS of 18.2 months (95% CI, 15.9-NE) and 11.6 months (95% CI, 2.7-15.5) respectively. Non-CR/CRi responders (n = 16) had a median OS and RFS of 2.4 months (95% CI, 0.7-NE) and 0.0 months (95% CI, NE-NE), respectively.

Regarding safety, any-grade cytokine release syndrome (CRS) occurred in 89% of patients, and grade 3 or higher CRS occurred in 24% of patients, with a median onset of 5 days and manifestation of pyrexia and hypotension.

“That’s relatively favorable compared with what you might expect with [CAR T-cell therapy],” said Shammo.

No cases of grade 5 CRS were reported, although 1 patient had grade brain herniation related to study treatment.

Any-grade neurologic events were reported in 60% of patients, and grade 3 or greater events occurred in 25% of patients, with a median onset of 9 days and manifestation of tremor and confused state.

Tocilizumab (Actemra), steroids, and vasopressors were given to 80%, 75%, and 40% of patients, respectively.

“The safety profile was manageable, and AEs were largely reversible,” said Shammo. “The efficacy, rapid manufacturing, and manageable safety support the promising potential of brexucabtagene autoleucel to provide long-term clinical benefit in adults with relapsed/refractory B-ALL.”

On April 2, 2021, a supplemental biologics license application was submitted to the FDA for brexucabtagene autoleucel as a treatment for adult patients with relapsed/refractory B-cell precursor ALL.³

If approved, brexucabtagene autoleucel would become the first and only CAR T-cell therapy approved for adults aged at least 18 years old with relapsed/refractory ALL.

Chronic Myeloid Leukemia

The final study Shammo highlighted was the phase 2 OPTIC trial (NCT02467270), which evaluated 3 daily starting doses of ponatinib––45 mg (n = 93), 30 mg (n = 93), and 15 mg (n = 91)––in patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant to a prior second-generation BCR-ABL1 TKI inhibitor or with a T315I mutation.⁴

Patients in the 45-mg and 35-mg arms were dose reduced to 15 mg daily upon achievement of 1% or less BCR-ABL1 and across arms were dose reduced to 10 mg daily in the presence of AEs.

Ponatinib, the only pan-BCR-ABL1 inhibitor, is a third-generation TKI designed to inhibit BCR-ABL1 with or without any single resistance mutation, including T315I.

In the pivotal, phase 2 PACE trial (NCT01207440), ponatinib demonstrated deep and durable responses to 45 mg of ponatinib in patients with resistant and intolerant CP-CML. However, a high incidence of arterial occlusive events (AOEs) was reported in the study, thought to be dose dependent, which ultimately compromised the utility of the drug, said Shammo.

“[OPTIC] asked what dose is needed to be sure that the patient’s disease is under control and that perhaps we had mitigated the AOEs,” said Shammo.

Notably, more than half of patients across dose cohorts had received at least 3 prior TKIs, and approximately a quarter of patients had a T315I mutation, said Shammo.

At a median follow-up of 32 months, the percentage of patients with 1% or less BCR-ABL1 at 12 months was 44.1% (95% CI, 31.7%-57.0%), 29.0% (95% CI, 18.4%-41.6%), and 23.1% (95% CI, 13.4%-35.3%) in the 45-mg, 30-mg, and 15-mg cohorts, respectively.

“In the 30-mg and 15-mg cohorts, patients with less-resistant disease and without a T315I mutation at baseline had greater benefit than those with [a] T315I [mutation],” said Shammo.

The 3-year OS probabilities were “very reasonable,” said Shammo, at 89.29%, 88.58%, and 91.71%, respectively. Notably, robust survival outcomes were reported in patients with and without BCR-ABL1 mutations, said Shammo.

“What was interesting is that if you had the T315I mutation at baseline, you do need the 45-mg dose, because the response rates [with that dose] seem to be so much better than [those] patients who received a lower dose of ponatinib,” said Shammo.

In terms of safety, any-grade treatment-emergent AOEs occurred in 9.6% of patients in the 45-mg arm, 5.3% in the 30-mg arm, and 3.2% in the 15-mg arm; grade 3 or greater rates occurred in 5.3%, 5.3%, and 3.2% of patients, respectively.

“At this primary analysis, novel response-based ponatinib dosing regimens had clinically manageable safety and AOE profiles, with an optimal benefit-risk profile achieved with a 45-mg starting dose reduced to 15 mg upon response,” concluded Shammo.

References

1. De Botton S, Yee KWL, Recher C, et al. Effect of olutasidenib (FT-2102) on complete remissions in patients with relapsed/refractory (R/R) mIDH1 acute myeloid leukemia (AML): Results from a planned interim analysis of a phase 2 clinical trial. J Clin Oncol. 2021;39(suppl 15):7006. doi:10.1200/JCO.2021.39.15_suppl.7006
2. Shah BD, Ghobadi A, Oluwole OO, et al. Phase 2 results of the ZUMA-3 study evaluating KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in adult patients (pts) with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). J Clin Oncol. 2021;39(suppl 15):7002. doi:10.1200/JCO.2021.39.15_suppl.7002
3. Kite submits supplemental biologics license application to U.S. Food And Drug Administration for Tecartus in adult patients with relapsed or refractory acute lymphoblastic leukemia. News release. Kite Pharma. Published April 1, 2021. Accessed August 2, 2021.
4. Cortes JE, Apperley J, Lomaia E, et al. OPTIC primary analysis: a dose-optimization study of 3 starting doses of ponatinib (PON). J Clin Oncol. 2021;39(suppl 15):7000. doi:10.1200/JCO.2021.39.15_suppl.7000