1885 - Combination of the S49076 with gefitinib in NSCLC patients progressing on EGFR-TKI and harboring MET/AXL dysregulation

Background

EGFR T790M mutation is the most common acquired mechanism of resistance in NSCLC patients treated with EGFR-TKI. Alternative mechanisms include activation of the receptor tyrosine kinases MET or AXL. S49076 is a multi-target inhibitor and a potent ATP-competitive TKI that targets MET, AXL and FGFR1/2/3. Here we report phase 1 molecular and safety data of resistant patients without the EGFR T790M mutation that were treated with S49076 combined with gefitinib.

Methods

A dose-escalation of S49076 in combination with gefitinib 250 mg once daily was conducted using a modified Bayesian Continual Reassessment Method. Toxicity was evaluated according to Common Terminology Criteria for Adverse Events (AEs), v4.0. Resistant patients were selected according to a tumor molecular profile including presence of the activating EGFR mutation, absence of T790M and with at least one of the following: MET amplification, or MET or AXL overexpression.

Results

The molecular profile screening has been performed in 46 EGFR/T790M-negative tumour samples. In total, 23/46 met the molecular eligibility criteria: 21 with MET dysregulation (11 MET amplification, 20 MET overexpression and 4 both MET / AXL dysregulations), and 2 with AXL overexpression only. Fourteen patients were treated: 4 received the 500 mg dose and 10 received the 600 mg dose, which was considered as the recommended dose. Related AEs included diarrhoea, paronychia, asthenia, nausea, vomiting, ALAT and ASAT increase, anaemia, peripheral oedema and yellow skin, mostly grade 1-2. One patient experienced a DLT at 600 mg (grade 3 stomatitis); 2 patients experienced 3 serious related AEs (asthenia, atrial fibrillation and diarrhoea). No grade 4-5 AEs were reported. Concomitant intake of gefitinib did not appear to modify the S49076 PK profile as compared to previous data. Limited anti-tumour activity was observed in the 12 evaluable patients: 1 partial response and 9 stable diseases.

Conclusions

S49076 combined with gefitinib is well tolerated and data are consistent with the overall safety profile of each drug. The observed frequency of MET dysregulation was comparable to those reported in the literature whereas AXL overexpression was lower than expected.

Clinical trial identification

EudraCT: 2015-00264631.

Legal entity responsible for the study

Servier group.

Funding

Servier group.

Editorial Acknowledgement

Disclosure

S. Viteri: BMS: Speaker bureau/ Consultant: Roche G.-C. Chang: Honoraria: Hoffman-La-Roche, Merck Sharp & Dohme, BMS, BI, Pfizer, AstraZeneca, Eli Lilly, Compagny Oncology. G. Curigliano: Speaker: Roche, Pfizer, Novartis. T. Hida: Research funding: Novartis, Pfizer, AstraZeneca. D.H. Lee: Honoraria: AstraZeneca, BMS, Ono Pharm, Merck, Lilly, BI, Pfizer, Novartis, CT Cube, Takeda, Roche, Samyang Biopharma, BMS, Janses, MSD, Mundipharma, CJ Healthcare. H. Murakami: Honoraria, Speaker, Grants and Research: AstraZeneca, BMS, Ono Pharm, Merck, Lilly, Chugai Pharm, BI, Pfizer, Taiho, Novartis. M. Nishio: Speaker fees as Honoraria, Consultant, Research funding: Ono Pharmaceutical, Bristol Myers Squibb, Pfizer, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, AstraZeneca, Boehringer ingelheim, MSD, Novartis, Daiichi Sankyo Healthcare, Merck Serono, Astellas. L. Paz-Ares: Honoraria: Roche, Lilly, MSD, BMS, Novartis, Pfizer, Boehringer Ingelheim, AstraZeneca, Merck Serono, Amgem, Clovis Oncology. R.A. Soo: Honoraria, Advisory board, Research: AstraZeneca, BMS, Merck, Lilly, Roche, BI, Pfizer, Taiho, Novartis. V. Cattan, E. Gandossi, H. Heck: Employee: Servier. K. Park: Advisor/consultant: Astellas, AstraZeneca, BI, BMS, Clovis, Daiichi Sankyo, EliLilly, GSK, Hanmi, KHK, MSD, Novartis, Roche Research fund; AstraZeneca. All other authors have declared no conflicts of interest.