Nexavar is currently FDA approved for renal cell carcinoma and hepatocellular carcinoma Sorafenib (Nexavar) is designed to interfere with growth of new blood vessels and the growth of new cancer cells.Inhibition of KIT signaling provides a direct anti-tumor effect in most GIST tumors and inhibition of VEGF receptors and PDGFR-β provide antiangiogenesis effects (similar to Sutent). Since RAF is downstream of KIT, inhibition of RAF might also contribute an anti-tumor effect. While inhibition of PDGRF-β has been reported, inhibition of PDGFRα, an alternative target in about 5% of GISTs has NOT BEEN reported.
Clinical data is scant. Phase 2 Study: Combination of Sorafenib with Docetaxel and Cisplatin in the Treatment of Metastatic or Advanced Unresectable Gastric and Gastroesophageal Junction (GEJ) Adenocarcinoma (ECOG 5203) was presented in 2008 Asco. Findings from this single-arm Phase 2 study suggest that Nexavar is active and well tolerated in patients with Gleevec or Gleevec and Sutent resistant GIST. 21 pts (6 IM-RES, 15 IM/SU-RES) enrolled from January 2006 to August 2007. Pt characteristics: male 52%; median age 57 (range 42 to 85); Caucasian 67%; PS 0/1/2: 38/52/10%. 68 cycles of SOR have been given (median 2, range 1-14). 16 pts are evaluable for toxicity (5 too early) and 14 for response (7 too early). Two pts (14%) (1 IM-RES, 1 IM/SU-RES) have ongoing PR; 9 pts (64%) (3 IM-RES, 6 IM/SU-RES) have stable disease (SD). Disease control rate (PR + SD): 78%. Median progression-free survival: 13.3 mo (95% CI: 1.7, 8). Median survival has not been reached. Grade 3/4 toxicities (% pts): rash/desquamation 31%, hand-foot syndrome 25%, diarrhea 19%, fatigue 13%, bleeding 6%, thrombosis 6%. There were no grade 3-4 hematologic toxicities. Conclusions: These preliminary data suggest that SOR is active in pts with IM-and SU-resistant GIST. Enrollment is continuing. During her oral presentation, Dr. Nimieri updated the published abstract with the following data. Among the 6 imatinib-resistant patients, 1 achieved partial response and 3 achieved stable disease. Among the 18 imatinib+sunitinib-resistant patients, 11% achieved partial response and 61% achieved stable disease. This represents 72% clinical benefit (disease control) for the larger group.
This is preliminary data and Naxavar remains promising but investigational at this time. BCBS TEC Assessment concluded: “Lacking evidence from studies that met selection criteria, no conclusions were possible on outcomes of sorafenib to treat NSCLC or GIST, or as adjuvant therapy for resected RCC.”
NCCN does nto list Nexavar in the section on GIST( see p. 21). However, it is listed in regard to GIST in the sof-tissue sarcoma section (p.36)and referenced to the Borden article.
Borden EC, Baker LH, Bell RS, Bramwell V, Demetri GD, Eisenberg BL, Fletcher CD, Fletcher JA, Ladanyi M, Meltzer P, O’Sullivan B, Parkinson DR, Pisters PW, Saxman S, Singer S, Sundaram M, van Oosterom AT, Verweij J, Waalen J, Weiss SW, Brennan MF
Soft tissue sarcomas of adults: state of the translational science.Clin Cancer Res. 2003 Jun;9(6):1941-56.
nccn.org, Sarcoma, GIST