PF-114
Another agent in development is PF-114, a third-generation BCR-ABL inhibitor. It is a structural analogue of ponatinib that is modified to avoid inhibiting the VEGFR receptor in an effort to prevent “arterial occlusive and particularly hypertension, adverse events that we see with ponatinib,” he said.
In a phase 1 study of 51 patients with CML who failed at least two prior TKIs or had T315I mutation, the MCyr rate was 50% and the MMR rate was 36%. The drug was very well tolerated: The dose-limiting toxicity was skin toxicity involving psoriasiform lesions, which were manageable, he noted.
“Importantly ... there was no cardiovascular toxicity,” he added.
Those findings were presented at ASH 2018. The drug is now moving to a phase 2 study.
HQP1351 (GZD824)
The orally active, small-molecule BCR-ABL inhibitor HQP1351 is a third-generation TKI with activity against a broad spectrum of BCR-ABL mutations.
A phase 1 study of patients who were resistant to prior TKIs is complete, and results presented at ASH 2019 showed that most patients (67%) had only one or two prior therapies and 63% had T315I mutation. Response rates were better in the patients with T315I mutations (MCyr, 78% vs. 34%; MMR, 52% vs. 15% in 101 chronic phase patients).
The treatment was well tolerated, with grade 3 toxicity involving only hypertriglyceridemia, pyrexia, and proteinuria. No arterial occlusive events were reported.
K0706
K0706 is a selective inhibitor of BCR-ABL1 designed to inhibit enzymatic activity of BCR-ABL. The agent was efficacious and well tolerated with limited off-target activity in preclinical models. It can inhibit wild-type and mutant forms of BCR-ABL, but does not have activity against T315I.
Results of a phase 1 study presented at ASH in 2019 by Dr. Cortes showed that all the patients who received a dose of 174 mg or greater achieved or maintained a cytogenetic response at 6 months, and 50% achieved or maintained an MMR.
“This is a very good response rate in this heavily pretreated population,” he said.
Patients who received prior ponatinib had a somewhat lower response, but still, nearly 45% achieved an MCyr.
“So very good response rates, no arterial occlusive events, and phase 2 studies will be starting at the dose of 174 mg,” he said.
Additional combinations
As for combining TKIs with other agents, efforts are underway around the world to find ways to eradicate minimal residual disease. Examples include TKIs and imatinib, TKIs and azacitidine, and asciminib plus another TKI, to name a few.
One study from Germany showed that adding interferon leads to earlier achievement of MMR, but ultimately the responses were similar, Dr. Cortes said.
Adding venetoclax has shown some activity in the preclinical setting, and studies of that combination will be starting soon in the clinic, he noted.
Implications
The current survival probability in CML patients is 92% when considering CML-related deaths (68% when considering all-cause mortality), compared with 8% in the 1980s and 35%-43% in the early 1990s.
But the current benefits don’t extend to all patients, Dr. Cortes said.
“There are patients who actually end up having worse prognosis than we would expect,” he said, explaining that some CML-related deaths are attributable to lack of access to therapy and good care, but some are related to true poor prognosis, often caused by resistance or inability to tolerate treatments.
In fact, data from studies of various treatments show that almost 40% of patients on dasatinib or nilotinib change therapy by 5 years, and by 10 years, half of those randomized to nilotinib have changed therapy.
“So it is not uncommon that patients have to change therapy for one reason or another,” he said, adding that, as resistance persists through additional treatment options, the prognosis worsens significantly.
“It is important that we have new therapeutic options to be able to help these patients who are going to be in need of additional therapies,” he said.
Dr. Cortes has received grant or research support from Novartis, Pfizer, Takeda, and Sun Pharma, and he is a paid consultant for Pfizer, Novartis, and Takeda.