Phase II randomized study of the IGF-1R pathway modulator AXL1717 compared to docetaxel in patients with previously treated, locally advanced or metastatic non-small cell lung cancer

Abstract

Harmenberg (2017) Phase II randomized study of the IGF-1R pathway modulator AXL1717 compared to docetaxel in patients with previously treated, locally advanced or metastatic non-small cell lung cancer, Acta Oncologica, 56:3, 441-447, DOI: 10.1080 Background:The primary objective of this study was to compare the progression-free survival (PFS) at 12 weeks between patients treated with IGF-1R pathway modulator AXL1717 (AXL) and patients treated with docetaxel (DCT). Material and methods: The study was conducted at 19 study centers in five countries. A total of 99 patients with previously treated, locally advanced or metastatic non-small cell lung cancer (NSCLC) of the squamous cell carcinoma (SCC) or adenocarcinoma (AC) subtypes in need of additional treatment were randomized and treated with either 300 or 400 mg of AXL as daily BID treatment (58 patients) or DCT given as 75 mg/m 2 in three-week cycles (41 patients) as monotherapy in a 3:2 ratio for each NSCLC subtype. Patients were treated in the primary study treatment period for a maximum of four treatment cycles. Results: The 12-week PFS rate, median PFS and overall survival (OS), as well Kaplan-Meier hazard ratio for PFS and OS, did not show any statistically significant differences between the treatment groups. For the primary endpoint, the AXL group had a lower percentage of patients (25.9%) who were progression-free at Week 12 as compared to the DCT group (39.0%), although the difference was not statistically significant. The most notable difference in the incidence of treatment emergent adverse effects (TEAEs) was the lower incidence of treatment-related grade 3/4 neutropenia in patients treated with AXL. Conclusion: These results suggest neither of the treatments to be superior of the other when treating locally advanced or metastatic NSCLC. Considering the lower incidence of grade 3/4 neutropenia in the AXL group this treatment warrants further research.

EMT-Mediated Acquired EGFR-TKI Resistance in NSCLC: Mechanisms and Strategies

“…The safety profile in this study concluded that there was a lower frequency of adverse events (AEs), especially neutropenia in the cohort of AXL1717 treatment. Unexpectedly, treatment-related fatal events were noted more commonly in this cohort (12 vs. 5) (72). On the whole, largely undesirable effects encountered in clinical settings emphasize the issue that identification of predictive markers indicative of responses to therapeutic strategies is timely and paramount to improving current therapy in carcinomas.…”

Acquisition of EGFR TKI resistance and EMT phenotype is linked with activation of IGF1R/NF-κB pathway in EGFR-mutant NSCLC

“…Therefore, IGF1R seems to be a promising target in treating advanced NSCLC patients. Unfortunately, clinical trials failed to show benefit from targeting IGF1R in treating advanced NSCLC patients, partially due to the lack of biomarkers to select patient populations [ 59 – 62 ].…”

ALK and IGF-1R as independent targets in crizotinib resistant lung cancer

“…The practical feasibility of combination ALK/IGF-1R inhibition as a clinical strategy has been given a boost by recent research into the IGF-1R inhibitor AXL1717 in advanced non-small cell lung cancer. Early results have indicated that as a monotherapy AX1717 is as effective as existing chemotherapy and with less toxicity 22 – 24 . Moreover, the role of IGF-1R activation in non-small lung cancer prognosis has been very recently confirmed in a study of 326 NSCLC patients 25 .…”