Emerging Therapies in CML Undergo Investigation in Chronic-Phase Illness

October 7, 2020
Tony Berberabe, MPH

Targeted Therapies in Oncology, October 1, 2020, Volume 9, Issue 13
Pages: 62

Today’s patients diagnosed with chronic myeloid leukemia can look forward to a near-normal life expectancy, provided they have good access to treatment and monitoring and are properly managed, said Jorge Cortes, MD.

With the emergence of 5 tyrosine kinase inhibitors (TKIs) in the chronic myeloid leukemia (CML) landscape, patients affected by the disease have many treatment options. Today’s patients diagnosed with CML can look forward to a near-normal life expectancy, provided they have good access to treatment and monitoring and are properly managed, said Jorge Cortes, MD, director of the Georgia Cancer Center at Augusta University in Georgia.

Despite the plethora of treatments, there are still challenges to optimal care and these include poor clinical response, resistance to therapy, and toxicities. Therefore, the need for newer treatment options remains.

“One of the advantages of having several treatment options is that you can choose the best one for the patient,” Cortes said. For many patients, all TKIs are good choices. But when the patient has numerous comorbidities, it makes the choices less clear. “Based on those comorbidities, I choose the appropriate TKI that may be expected to decrease the risk of that comorbidity having an impact on the patient’s ability to stay on therapy and to remain in good health.” It is also important, however, to properly manage the comorbidities. “Unfortunately, managing comorbidities isn’t always done as well as it should be,” he said.

Resistance to TKIs

Another factor to address is resistance to TKIs that develops over time. Cortes said that fortunately, resistance is not that common, particularly with the second generation TKIs. If resistance emerges, it is important to check for the presence of mutations. “Although it’s an important aspect of managing the patient’s care, it is informative in only a small percentage of cases, but we still do it because it provides us with valuable information in some instances,” he said.

Given the need to optimize care despite the numerous treatments available, Cortes addressed emerging treatments in CML during the eighth annual Society of Hematologic Oncology meeting.

In Development

The most advanced treatment currently in development is asciminib (formerly ABL001), an ABL1 inhibitor that is undergoing clinical development testing in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia.

“This new tyrosine kinase inhibitor is different than the others in that it binds in a completely different area of the BCR-ABL protein,” Cortes said.

In a dose escalation study, 141 patients in chronic-phase CML and 9 in the accelerated phase who had resistance to or unacceptable adverse effects (AEs) from 2 previous TKIs were evaluated after undergoing treatment with asciminib.1

The primary objective was to determine the maximum tolerated dose (MTD) or the recommended dose (or both) of asciminib. “We saw very good responses in these very heavily pretreated patients populations,” said Cortes.

Investigators reported that the MTD had not been reached. In 34 patients who were in the chronic phase of CML, 92% with a hematologic relapse experienced a complete hematologic response (CHR). Fifty-four percent of patients without a complete cytogenetic response (CCyR) at baseline achieved a CCyR with asciminib.

Forty-eight percent of patients who could be evaluated achieved or maintained major molecular responses. Investigators also observed this response in 57% of patients who had developed resistance or unacceptable AEs from ponatinib (Iclusig), a third-generation TKI.

Among patients with a T315I mutation, 28% demonstrated or maintained a major molecular response by 12 months. Common AEs included fatigue, headache, arthralgia, hypertension, and thrombocytopenia. Dose-limiting effects included asymptomatic elevations in the lipase level and clinical pancreatitis, according to investigators.

Cortes also mentioned K0706, a novel third-generation TKI that has significantly less off-target activity compared with existing TKIs. The agent has recently undergone a multicenter, open-label, dose escalation and expansion study to evaluate its safety and antileukemic activity and to determine the maximum therapeutic dose (NCT02629692).2

At data cutoff, 35 patients had undergone treatment with the agent. “The agent has demonstrated potent activity against all mutations except for T315I,” Cortes said.

At a median follow-up of 6.9 months (range, 0.5-26), 68.6% of patients remained on K0706 and 31.5% completed 12 or more months of therapy.

Another agent undergoing investigation is HQP1351, with a phase I clinical study presented at the 2019 American Society of Hematology (ASH) Annual Meeting.3 The open-label, dose escalation, and expansion trial was designed to determine the MTD and to identify dose-limiting toxicities in patients with CML in the chronic phase or accelerated phase who were resistant or intolerant to 2 or more prior TKIs or those with T3151 mutation after 1 or more prior TKIs.3 The FDA granted HQP1351 an orphan drug designation in May 2020.4

“This is an interesting drug because it has activity against T315I,” Cortes said.

HQP1351 showed potent antileukemic activities in patients with CML. Of the 68 evaluable patientv with non-CHR at baseline, 63 (92.6%) achieved CHR, including 52 out of 55 (94.5%) patients in the chronic phase and 11 out of 13 (84.6%) patients in the acute phase, respectively.

Of the 95 evaluable patients with non-CCyR at baseline, 69.1% in the chronic phase achieved major cytogenetic response (MCyR), including 60.5% achieving CCyR; and 42.9% of patients in the acute phase achieved MCyR, with 35.7% achieving CCyR, respectively.

Another interesting agent in development is PF-114, Cortes added. This is an agent that has shown some activity against wild-type and mutated BCR-ABL1 isoforms, including those with a BCR-ABL1 mutation.5

“Among these 4 [agents], asciminib is the most advanced in development. The others will need more research, but they all have good clinical data that suggest that they have potential value,” Cortes concluded.

References:

1. Hughes TP, Mauro MJ, Cortes JE, et al. Asciminib in chronic myeloid leukemia after ABL kinase inhibitor failure. N Engl J Med. 2019;381(24):2315- 2326. doi:10.1056/NEJMoa1902328

2. Cortes JE, Kim DW, Nicolini FE, et al. Phase 1 trial of K0706, a novel oral BCR-ABL1 tyrosine kinase inhibitor (TKI): in patients with chronic myelogenous leukemia (CML) and Phildelphia positive, acute lymphoblastic leukemia (Ph + ALL) failing ≥ 3 prior TKI therapies: initial safety and efficacy. Blood. 2019;134(suppl 1):4158. doi:10.1182/blood-2019-129751

3. Jiang Q, Huang X, Chen Z, et al. An updated safety and efficacy results of phase 1 study of HQP1351, a novel 3rd generation of BCR-ABL tyrosine kinase inhibitor (TKI), in patients with TKI resistant chronic myeloid leukemia. Blood. 2019;134(suppl 1):493. doi:10.1182/blood-2019-124295

4. Ascentage Pharma’s core drug candidate HQP1351 granted orphan drug designation by the US FDA for the treatment of patients with chronic myeloid leukemia. News release. PR Newswire; May 4, 2020. Accessed August 4, 2020. https://prn.to/2Xkrh4F

5. Ivanova ES, Tatarskiy VV, Yastrebova MA, et al. PF‑114, a novel selective inhibitor of BCR‑ABL tyrosine kinase, is a potent inducer of apoptosis in chronic myelogenous leukemia cells. Int J Oncol. 2019;55(1):289-297. doi:10.3892/ijo.2019.4801