A Phase Ib Open-Label Multicenter Study of AZD4547 in Patients with Advanced Squamous Cell Lung Cancers

Abstract

Purpose Squamous cell lung cancers (SQCLC) account for 25% of all NSCLCs, yet the prognosis of these patients is poor and treatment options are limited. Amplified FGFR1 is one of the most common oncogenic events in SQCLCs, occurring in ~20% of cases. AZD4547 is a potent and selective FGFR1-3 inhibitor with anti-tumor activity in FGFR1 amplified SQCLC cell lines and patient-derived xenografts. Design Based on these data, we performed a phase 1 study of AZD4547 in patients with previously treated stage IV FGFR1 amplified SQCLCs (NCT00979134). FGFR1 amplification (FGFR1:CEP8 ≥ 2) was determined by FISH. The primary endpoint was safety/tolerability. Secondary endpoints included anti-tumor activity, pharmacokinetics, pharmacodynamics, and molecular analyses. Results 15 FGFR1 amplified patients were treated. The most common related AEs were gastrointestinal and dermatologic. Grade ≥ 3 related AEs occurred in 3 patients (23%). Thirteen patients were evaluable for radiographic response assessment. The overall response rate was 8% (1 PR). 2/15 (13.3%) patients were progression free at 12 weeks and the median overall survival was 4.9 months. Molecular tests including next-generation sequencing, gene expression analysis, and FGFR1 immunohistochemistry showed poor correlation between gene amplification and expression; potential genomic modifiers of efficacy; and heterogeneity in the 8p11 amplicon. Conclusion AZD4547 was tolerable at the 80mg po bid dose with modest anti-tumor activity. Detailed molecular studies show that these tumors are heterogeneous, with a range of mutational co-variates and stark differences in gene expression of the 8p11 amplicon that likely explain the modest efficacy of FGFR inhibition in this disease.

Preselection of Lung Cancer Cases Using FGFR1 mRNA and Gene Copy Number for Treatment With Ponatinib

“…As demonstrated in our study and in other pre-clinical and clinical studies, FGFR1 ISH and SISH only partially overlap, suggesting that FGFR1 gene amplification does not always lead to downstream transcription and also that elevated transcription can occur in the absence of gene amplification. 20,22 All of this evidence strongly suggests that FGFR1 gene amplification is insufficient as a predictive biomarker when used in isolation. This study is an early effort to explore the feasibility of using novel biomarkers instead of or in addition to FGFR1 gene amplification to predict response to FGFR1 inhibitors such as ponatinib.…”

Relevance of genetic alterations in squamous and small cell lung cancer

“…Wynes and colleagues suggested that this might be the case in their analysis of cell lines harboring varying degrees of FGFR1 copy number, mRNA, and protein expression, demonstrating that a correlation between DNA polysomy and expression was not uniform, rendering FGFR1 copy number as the least robust predictive biomarker of response to the drug ponatinib (13). Comprehensive molecular analysis of SQCLC patients treated with the FGFR inhibitor AZD4547 by Paik and colleagues supports this to be the case in patient samples, where receptor amplification was found to variably lead to increased mRNA and protein expression (14). In addition, expression analysis of the 8p11 amplicon showed striking differences between the expression patterns found in positive control FGFR1 amplified cell lung cancer cell lines that are known to be sensitive to AZD4547 and those from patient biopsies.…”

“…The overall response rate in each of these biomarker-selected trials was modest and disappointing, ranging from 8-15% (8)(9)(10)(11).…”

Alterations in genes other than <i>EGFR/ALK/ROS1</i> in non-small cell lung cancer: trials and treatment options

“…As FGFR was increasingly recognized as an important therapeutic target in multiple malignancies including lung cancer, next generation agents were developed for their selective FGFR inhibitory activity. Hyperphosphatemia is a mechanism-based toxicity caused by potent FGFR kinase inhibitors due to inhibition of the FGF23/Klotho signaling axis, thereby causing a decrease in renal phosphate excretion 47 . FGF ligand trap agents however that spare "hormonal" FGF23, such as FP-1039, may potentially avoid this particular toxicity.…”