The majority of GIST patients have KIT or PDGFRA mutations; and, whereas the advent of tyrosine kinase inhibitors (TKIs) has improved their prognosis, tumours with the rare SDH-deficient subtype tend not to respond to these drugs.
Surgery may be successful in the short-term, but relapse is common — with a 5-year event-free survival rate of just 24%. There is no current standard of care treatment for patients with relapsed or advanced SDH-deficient GIST.
A potential treatment, olverembatinib, is being developed by Ascentage Pharma and Innovent Biologics.
Already approved in China to treat TKI-resistant chronic-phase chronic myeloid leukaemia with the T315I mutation and being looked at in other blood cancers, it is now being investigated in GIST.
Olverembatinib is a third-generation BCR-ABL inhibitor that has potential in TKI-resistant succinate dehydrogenase-deficient GIST and can interact with various BCR-ABL mutations.
Results of an open label Phase Ib/II study in GIST have been released.1 In all, 20 patients with SDH-deficient GIST were given 20, 40 or 50 mg doses every other day in 28 day cycles.
The median duration of treatment was 7.8 months, with the longest period being 42 months; five patients achieved a partial response. All the patients had at least one treatment-emergent adverse event; most of these were grade 1 or 2, but two patients had a grade 3 event.
One suffered from neutropenia and 11 developed anaemia. It was well tolerated up to the 50 mg dose level and, in the 16 patients treated for at least 16 weeks, there was a clinical benefit rate of about 94%.
Trials also continue in a variety of blood cancers, including Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukaemia (ALL). Treatment for these patients was revolutionised by TKIs, but resistance and mutation occur with both first- and second-generation TKIs.
Olverembatinib was therefore investigated in a group of four Ph+ ALL patients as a first-line treatment.2 Subjects were given 40 mg oral doses every other day for 28 days, along with 1 mg/kg/day of prednisone for 14 days, tapering off during the next 14 days, and 4 mg doses of vindesine on days 1, 8 and 15.
This was then followed by cytarabine and methotrexate with oral olverembatinib ahead of stem cell transplantation. All patients achieved complete remission after the induction therapy.
Further studies are required. In a trial in paediatric patients with relapsed Ph+ ALL, a population with particularly poor outcomes, children who had previously either received dasatinib, or were intolerant to it, were given doses of olverembatinib, with a median duration of treatment of 70 days.3
Four out of five evaluable patients achieved complete remission, two of whom were given the new drug as a single agent. The safety profile was good, with pain, myopathy and fever being the most severe adverse events. It appears to be both safe and effective in this patient population.
References
- H. Qiu, et al., J. Clin. Oncol. 41(Suppl. 16), Abstr. 11540 (2023).
- X. Tan, et al., Anticancer Drugs 34, 599 (2023).
- X. Li, et al., Clin. Lymphoma Myeloma Leuk. 23, 660 (2023).