Originally published Jan. 16.
In a pharmacogenetic investigation conducted by researchers in the Netherlands, Bayer's Nexavar was not able to improve survival in patients with KRAS-mutated non-small cell lung cancer.
In the Phase II multicenter trial, researchers led by Wouter Mellema of VU University Medical Center in Amsterdam assigned 57 patients with NSCLC and a KRAS mutation to 400 mg of Nexavar (sorafenib) twice daily.
At six weeks, Mellema and colleagues reported a 52.6 percent rate of no progression among study participants treated with Nexavar. Fifteen patients had halted drug treatment before the six weeks, and 10 of these patients stopped taking the drug because their disease continued to progress despite Nexavar therapy. Median progression-free survival in the trial was 2.3 months, and median overall survival was 5.3 months. The researchers reported that 14 patients are still alive.
Mellema and colleagues presented the data this week at the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer: Biology, Therapy and Personalized Medicine. In statement, the study authors characterized the findings as "unsatisfactory."
Nexavar is an inhibitor of VEGFR, PDGFR, and the RAF kinases. The drug is approved in the US as a treatment for advanced renal cell carcinoma and a type of liver cancer, called hepatocellular carcinoma, if it cannot be treated with surgery.
“There is a great need for targeted treatment options for patients with non-small cell lung cancer with a KRAS mutation,” Mellema said in a statement. Lung cancer patients with KRAS-mutated tumors generally have poor prognosis and don't respond well to EGFR-inhibiting drugs such as Genentech/Astellas' Tarceva and AstraZeneca's Iressa.
Ahead of this Phase II trial, Mellema and his research team had conducted a pilot study involving 10 KRAS-mutated NSCLC patients, which yielded "promising results," according to the study authors. "We expected that progression-free survival and overall survival would be better [in the phase 2 study],” Mellema said in a statement.
Researchers had hypothesized that Nexavar may be an effective treatment for the KRAS-mutation positive NSCLC population, since the drug inhibits the growth-stimulating signal of the RAS protein. It appears now that the KRAS mutation is causing growth of cancer cells through an alternative pathway. “Future studies currently in preparation in our group should focus on simultaneous inhibition of these pathways,” Mellema said.
Identifying markers of response for anti-angiogenic drugs such as Nexavar and Avastin, which work by cutting off the blood supply to tumors, has proven to be a complex endeavor. Studies suggest that multiple markers in several pathways may need to be interrogated to influence treatment response. Additionally, markers associated with patient response to a given anti-angiogenic drug may vary according to the tumor type and stage of cancer (PGx Reporter 9/28/2011).