ARQ 197 + VEGF inhibitors / TKI - works for solid tumors

[Fictional]

FYI, From the ASCO meetings it looks as if ARQ197 + Sorafenib works for a lot of solid tumors... 2/3 to be exact. In ASPS, it looks as if Sutent may be better than Sorafenib. The obvious next line of thought is that Sutent + ARQ197 might be a good combination. 2/3 had stable or partial response.

ARQ197 might be approved soon because it looks beneficial in non small cell lung cancer. That would be cool because Sutent is already approved and available from the pharmacy. It makes sense - VEGF inhibitor to attack the blood supply, but ARQ to inhibit new metastases.


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A phase I dose-escalation trial evaluating ARQ 197 administered in combination with sorafenib in adult patients (pts) with advanced solid tumors.
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Sub-category:
Tyrosine Kinase Inhibitors
Category:
Developmental Therapeutics - Experimental Therapeutics
Meeting:
2010 ASCO Annual Meeting
Session Type and Session Title:
Poster Discussion Session, Developmental Therapeutics - Experimental Therapeutics
Abstract No:
3024
Citation:
J Clin Oncol 28:7s, 2010 (suppl; abstr 3024)
Author(s):
A. A. Adjei, J. A. Sosman, G. K. Dy, W. Ma, G. J. Fetterly, D. Skupien, J. A. Means, R. Savage, F. Chai, I. Puzanov; Roswell Park Cancer Institute, Buffalo, NY; Vanderbilt University Medical Center, Nashville, TN; ArQule, Woburn, MA
Abstract:

Background: ARQ 197 (A) is a selective non-ATP competitive inhibitor of c-MET, a RTK implicated in tumor cell proliferation, invasion and angiogenesis. Maximum tolerated dose (MTD) and recommend phase II dose (RP2D) of A in monotherapy and in combination with erlotinib were reported previously. Based on preclinical synergy of A in combination with sorafenib (S) in a number of cell lines, a phase I study was undertaken to define safety and RP2D of A+S combination. Secondary objectives include evaluation of pharmacokinetics (PK) and biomarkers (HGF, VEGF, soluble c-MET). Methods: A traditional 3+3 dose escalation schema was employed. An initial cohort was treated at dose level (DL) 1 (A 360 mg PO BID + S 200 mg PO BID). With no DLT observed at this DL, dosing was escalated to DL2 (A 360 mg BID + S 400 mg BID), which represents full single-agent doses of both drugs. Results: To date, 14 pts (2 F/12 M; mean age: 58.7 yrs) have been treated at the 2 DLs, 5 in DL1 w/o DLT and 9 in DL2 with 1 experiencing 2 DLTs [grade (G) 3 fatigue and G3 dyspnea]. Accordingly, DL2 is the RP2D. No A-related serious adverse events (AEs) or G4 AEs were reported. G3 A-related AEs have been reported in 4/14 pts (29%) (fatigue, dyspnoea, dry skin, musculoskeletal chest pain, hyperbilirubinaemia 1 each); G1/2 in 7 pts (50%) (2 fatigue, thrombocytopenia, lymphopenia, diarrhea, nausea, vomiting, abdominal tenderness, AST increased, anorexia, nipple pain, and rash 1 each). PK analysis of A showed that on day 1 mean Cmax(n=8) was 1766 ± 1452 ng/mL and mean AUC(0-12) was 14053 ± 13736 hr*ng/mL. On day 29 mean Cmax (n=6) was 1986 ± 1487 ng/mL and mean AUC(0-12) was 15,003 ± 13428 hr*ng/mL. Nine of 14 pts are evaluable for efficacy with 6/9 (67%) demonstrating a best RECIST response of stable disease (8+ to 29+ wks) including 1 renal cell carcinoma pt with 22% tumor regression. Conclusions: The combination of A + S is safe and well tolerated, with 360 mg PO BID A + 400 mg PO BID S recommended for subsequent phase II evaluation. PK parameters indicated that S had no effect on the disposition of A. Preliminary evidence of anticancer activity has been observed, indicating that the combined inhibition of c-MET and angiogenic signaling has therapeutic potential.