AZD4547, an oral tyrosine kinase inhibitor (TKI) that is selective for FGFR1, 2, and 3, showed only modest activity in patients with advanced cancer characterized by FGFR1, 2 or 3 alterations enrolled in the arm of the National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH). These findings were published in the Journal of Clinical Oncology.

The NCI-MATCH study (ClinicalTrials.gov: NCT02465060) is an ongoing, multinational, phase 2, tissue agnostic clinical trial in which patients with solid tumors, lymphoma, or multiple myeloma that has progressed on at least 1 prior line of standard therapy, or for which no standard therapy exists, are assigned to 1 of multiple single arms (ie, subprotocols) evaluating different targeted therapy approaches on the basis of the presence of potential tumor molecular drivers as determined by next-generation sequencing and other tests.

With a primary study endpoint of overall response rate (ORR), and secondary study endpoints including progression-free survival (PFS) and safety, the main aim of this study is to find efficacy signals that, if present, would be further evaluated in more definitive studies.

Of the 70 patients enrolled in this subprotocol of the NCI-MATCH study, 50 patients received treatment, and 48 were available for analysis. In the latter cohort, the median age was 61 years, 46% patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 48% had received more than 3 prior lines of therapy, and disease was characterized by an FGFR amplification, a single-nucleotide variant in FGFR, or FGFR fusion in 20, 19, and 9 patients, respectively, with FGFR1 amplifications present in 17 patients.


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Of the 41 patients evaluable for efficacy at data cutoff at a median follow-up of 9.2 months, partial response (PR), stable disease, and progressive disease was observed in 4, 18, and 19 patients, respectively, corresponding to 8%, 37.5%, and 39.6%, with 14.6% of patients not evaluable when determined for 48 patients.  Hence, an ORR of at least 16%, a prespecified criterion for promising efficacy, was not reached. 

Those patients with a PR had a median duration of response of 7.9 months, a 6-month PFS rate of 15%, and disease characterized by a point mutation in FGFR2 Y376C or FGFR3 A394E, or an FGFR3-TACC3 fusion. Of note, when only the 20 patients with disease characterized by FGFR fusions were considered, the ORR and 6-month PFS rate were 22% and 56%, respectively.

Co-occurring mutations in PIK3CA were observed in approximately one-third of the tumors in this patient cohort. The presence of the latter was significantly associated with progressive disease as best response (P =.03), leading the study authors to suggest the possibility that oncogenic signaling in the PI3K/AKT/mTOR pathway have circumvented FGFR inhibition in these patients.

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Of the 49 patients treated with AZD4547 evaluable for safety, 39% and 2% experienced grade 3 adverse events (AEs), of which oral mucositis (14%), palmar-plantar erythrodysesthesia (6%), and anemia (4%) were most frequently reported. Grade 4 AEs included diarrhea and sepsis, each observed in 1 patient. In addition, grade 3 laboratory abnormalities occurred in 26.5% of patients, the most common of which were elevations in serum levels of alanine aminotransferase and aspartate aminotransferase. Dose reductions were required for 16.3% of patients during cycle 1 and, after a median of 3.5 cycles, treatment was discontinued by approximately one-quarter of patients due to an AE.

Noting that “it is becoming increasingly recognized that the oncogenic driver role of FGFR aberrations is complex,” the study authors concluded that “careful patient selection with well-defined FGFR aberrations underpins the most successful results with FGFR inhibitors.”

Reference

Chae YK, Hong F, Vaklavas C, et al. Phase II study of AZD4547 in patients with tumors harboring aberrations in the FGFR pathway: Results from the NCI-MATCH Trial (EAY131) subprotocol W. J Clin Oncol [published online May 28, 2020]. doi: 10.1200/JCO.19.02630