By Turna Ray
Pfizer will use Qiagen's KRAS test to identify best responders to its investigational non-small cell lung cancer drug dacomitinib in Phase III trials, which may enable the company to differentiate the new drug from top-selling NSCLC drug Tarceva.
Dacomitinib (PF-00299804) is an oral irreversible inhibitor of HER1, HER2, and HER4 tyrosine kinases that has been internally developed at Pfizer. In addition to providing a KRAS test for use in clinical trials of dacomitinib, Qiagen will also develop a commercial companion diagnostic that will be launched alongside the drug following regulatory approval in US and international markets.
A Pfizer spokesperson told PGx Reporter that dacomitinib will be investigated with the aid of the KRAS companion test in a Phase III study, called ARCHER 1009. The double-blind, multi-center trial is comparing dacomitinib to Genentech's Tarceva in the second- and third-line setting. Patients with advanced or metastatic NSCLC who are not responsive or couldn't tolerate prior chemotherapy will be enrolled in the trial.
Pfizer plans to evaluate dacomitinib's safety and efficacy compared to Tarceva in the overall study population, as well as in patients with KRAS wild-type tumors. This trial is open for enrollment in the US, and will begin enrolling in other countries soon.
Previous studies suggest that NSCLC patients with EGFR-mutated tumors respond well to EGFR inhibitors such as Tarceva or AstraZeneca's Iressa. However, patients with EGFR T790M mutations and mutations in the KRAS gene downstream of the EGFR pathway are more likely to develop resistance to EGFR inhibitors. Testing for these mutation types in NSCLC could help oncologists decide whether to treat patients with an EGFR-inhibiting agent or an irreversible pan-HER inhibitor, such as dacomitinib.
If Pfizer can show that dacomitinib is not only more effective than currently marketed EGFR inhibitors in advanced lung cancer patients, but is specifically superior to such drugs in a molecularly defined subset of refractory NSCLC patients, then that would be a way to carve out a specific market for the newer drug and distinguish dacomitinib from more established treatments in terms of price.
Qiagen estimates that there are more than 1.5 million NSCLC cases reported each year globally. Published data suggests that between 10 percent and 20 percent of NSCLC patients have KRAS mutations.
Meanwhile, sponsors of EGFR inhibitors are also investing in personalizing their drugs with companion tests. Although Iressa is not marketed in the US, AstraZeneca has launched the drug in international markets for use in NSCLC patients with EGFR mutations. Genentech, meanwhile, has applied to the European Medicines Agency and plans to apply to the US Food and Drug Administration to extend the label for Tarceva as a first-line treatment for advanced NSCLC patients with EGFR-activating tumors (PGx Reporter 06/08/2011).
Tarceva is already approved as a maintenance therapy and second- and third-line treatment for advanced lung cancer patients. The drug brought in over $1 billion in revenues last year. By adding the first-line NSCLC indication in EGFR-mutated patients, Genentech stands to further bolster its revenues for a blockbuster drug.
In personalizing treatment with Tarceva, Genentech is working with parent company Roche to develop a companion EGFR test that runs on the Cobas 4800 PCR platform. AstraZeneca, meanwhile, is working with Qiagen and other laboratories to provide EGFR testing for patients receiving Iressa in markets outside the US.
The KRAS test that Pfizer is using for dacomitinib is also based on Qiagen's PCR-based therascreen KRAS RGQ kit. This is the same platform upon which the company has built KRAS companion tests for two colorectal drugs, Amgen's Vectibix and Bristol-Myers Squibb's Erbitux.
"The Pfizer drug companion diagnostic test is being specifically developed for use in lung cancer tissue," Qiagen said in a statement. "It uses the same core assay component as the Therascreen KRAS RGQ kit for colorectal cancers but varies in the workflow to allow for lung tissue-specific sample technology in a fully automated workflow."
This is the second drug/diagnostic codevelopment deal between Pfizer and Qiagen. In February last year, the companies announced they would investigate the safety and efficacy of PF-04948568, an investigational drug for glioblastoma multiforme, in patients with tumors expressing EGFRvIII mutations. Under that deal, Qiagen is developing a PCR-based companion test that will pick out the 40 percent of GBM patients who express this mutated form of EGFR (PGx Reporter 2/2/2010).
Pfizer is also exploring dacomitinib in other types of cancer, including head and neck cancer patients with EGFRvIII mutations.
Pfizer launched the ARCHER 1009 trial after garnering positive leads from earlier-phase studies.
At the American Society of Clinical Oncology's annual meeting in 2010, researchers from Pfizer, the National Cancer Institute, and several academic centers reported efficacy and safety data from a Phase II study in 62 advanced NSCLC patients with KRAS wild-type tumors treated with dacomitinib. Patients enrolled in the study had refractory NSCLC that was unresponsive to prior treatment with EGFR inhibitors and chemotherapies.
In this study, led by Pfizer's Alicyn Campbell, three patients experienced a partial response to dacomitinib, and 35 had stable disease at six weeks. Common toxicities experienced by patients were diarrhea, fatigue, rash, and stomach inflammation. Most of the lower grade adverse reactions seen in patients were manageable.
"Patients with adeno or nonadeno refractory NSCLC receiving [dacomitinib] in this study experience clinical benefit despite prior [treatment] with [Genentech's Tarceva]," Campbell et al. concluded. "Patients report relief of NSCLC symptoms, including clinically meaningful improvements in key symptoms of cough, dyspnea, and pain. Treatment-related adverse events were manageable."
In Phase II trials, Pfizer has also compared the safety and efficacy of dacomitinib with Tarceva in molecularly defined NSCLC patient subgroups. In a Phase II trial published in the Journal of Clinical Oncology, researchers from Pfizer and elsewhere compared how advanced NSCLC patients fared when treated with dacomitinib or Tarceva. Among 188 patients, 16 percent had KRAS mutations and 16 percent had EGFR mutations.
In the overall population, dacomitinib stopped patients' disease from progressing 4.1 weeks longer than Tarceva did — 12.4 weeks as opposed to 8.3 weeks. Among patients with EGFR mutations, dacomitinib-treated patients experienced a median progression-free survival of 28.4 weeks compared to 24 weeks with Tarceva. KRAS wild-type and EGFR wild-type patients, meanwhile, had median progression-free survival of 11.1 weeks on dacomitinib versus 8 weeks in the Tarceva arm.
"[Dacomitinib] showed significantly longer progression-free survival versus [Tarceva] in the overall population (p=0.017), with benefit consistent across several subgroups including EGFR wild-type," wrote lead study author Michael Boyer of the Sydney Cancer Center in the JCO paper.
To further evaluate dacomitinib's efficacy in refractory NSCLC patients with KRAS wild-type tumors, the National Cancer Institute of Canada Clinical Trials Group is currently conducting a large, blinded, Phase III trial. The trial, BR.26, is investigating the efficacy and safety of dacomitinib in patients with stage IIIb/IV NSCLC whose disease has progressed despite treatment with standard chemotherapies and EGFR-inhibiting drugs, such as Tarceva.
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