A phase Ib study of a novel c-MET, AXL and VEGFR-2 inhibitor ningetinib and gefitinib combination therapy in Chinese EGFR-TKI resistant NSCLC with T790M negative

9583 Background: Ningetinib is a novel tyrosine kinase inhibitor, targeted at c-Met, Axl, VEGFR-2, Mer and Flt3. This phase Ib trial (NCT03758287) evaluated the safety, determined the recommended phase II dose (RP2D), and further explored the pharmacokinetic and efficacy of Ningetinib + Gefitinib in EGFR-TKIs acquired resistant NSCLC patients (pts) with T790M negative. Methods: Chinese Pts with advanced or metastatic NSCLC, acquired resistant to at least one EGFR-TKI, T790M negative were enrolled. Pts received Ningetinib 30, 40, 60 mg + Gefitinib 250mg orally once daily in dose-escalation (n = 12) by a Fibonacci 3+3 design. Expansion phase (n = 74, enrollment is ongoing) started at tolerated dosage. Safety, RP2D were primary endpoints; PK, antitumor activity were secondary endpoints. Non-mandatory tumor samples at baseline were collected for exploratory objectives. Results: Totally, 86 eligible pts were enrolled between Nov 2016 and Dec 2019, and received treatment (Ningetinib 30 mg, n = 36; 40 mg, n = 46; 60 mg, n = 4), with median age 56.7 years, 36% with baseline brain metastasis, 66%/33%/1% prior 1/2/3 lines EGFR-TKI treatment, respectively. Treatment-related adverse events (TRAEs) occurred in 82 (95%) pts, grade 3/4 in 32 pts (37%). Most common TRAEs (≥30%) were myocardial enzyme elevation (all grade 74.4%; grade 3-4 0%), transaminase elevation (73.3%; 2.3%), skin rash (60.5%; 3.5%), albuminuria (44.2%; 0%), coagulation abnormalities (mostly asymptomatic Fbp decrease; 37.2%; 15.1%), diarrhea (33.7%; 2.3%) and hypertension (32.6%; 11.6%). Two Dose limited toxicities were observed at 60 mg dosage (both were grade 3 Fbg decrease), RP2D was decided at 40 mg. Of 84 efficacy evaluable pts, ORR was 19.1% (16 PR), DCR was 91.7% (61 SD, 7 PD). Totally, 65 (75.6%) progression events occurred at data cut-off (9 Jan 2020), the median PFS for all pts was 4.4 months (95%CI 3.7-4.6). No PFS differences were found between pts grouped by 3rd TKIs history or brain metastasis. C-Met gene amplification by FISH was conducted in 72 pts (83.7%). Pts with higher gene copy number (GCN) responded better in treatment, ORR in the GCN ≥6 (n = 11), GCN ≥5 (n = 16) and GCN ≥3 (n = 37) subgroups was 36.4%, 25.0% and 21.6% respectively. Conclusions: Ningetinib was well tolerated at 30 mg and 40 mg dosage with Gefitinib 250 mg, the RP2D for Ningetinb was 40 mg. This combination therapy showed promising anti-tumor activity in prior EGFR-TKIs acquired resistant NSCLC pts with T790M negative. C-Met GCN was the potential efficacy biomarker. Clinical trial information: NCT03758287 .