Non-Small-Cell Lung Cancer: Targeting Pathways and Patients

Dec 01, 2010

Although the most common cancer worldwide, lung cancer remains poorly treated, with the highest mortality rate. Non-small-cell lung (NSCL) cancers account for 85 percent of all lung cancers, and despite the fact that they are relatively slow growing, they remain highly lethal because they are often undetected until in an advanced stage and therefore inoperable. Average survival even after treatment is about a year.

NSCL is a diverse group of cancers fueled by a wide range of genes and pathways, resulting in a big target for many pipeline products. Many, but by no means all, NSCL cancers are set in motion by one of two oncogenes: EGFR or KRAS. The response rate to treatment of EGFR-fueled tumors is an impressive 60 percent; KRAS-caused cancers are largely immune to targeted EGFR therapies.

Hundreds of targeted therapies are being tested against NSCL cancers—the need is great, the targets are many, and the bar is low. Three late-stage candidates illustrate the great expectations and growing pressures of the oncology R&D scene.

Pfizer's crizotinib is yet another of the late-stage pipeline's targeted therapies that have taken researchers and physicians by storm this year. The kinase inhibitor blocks the expression of the ALK (anaplastic lymphoma) gene, which, when awry, is the single cause of one type of NSCL cancer. On the model of Herceptin and Gleevec, crizotinib shows extraordinary efficacy at shrinking or at least stabilizing these tumors—72 percent in a Phase II study of 82 people. Some have gone more than 15 months without disease progression.

Unfortunately, only about 2 percent to 7 percent of all NSCL tumors are driven by the ALK mutation—some 10,000 patients in the US, generally younger nonsmokers. Fast-tracked by the FDA, crizotinib's NDA will be filed in 2011 along with a gene diagnostic test that Pfizer is developing with Abbott. Personalized medicine takes another baby step forward.

Boehringer Ingelheim's Tovok (afatinib) may offer the first, albeit short, lifeline to patients with EGFR-fueled tumors resistant to standard treatments. Researchers theorize that the mutation of a second gene, T790M, is what clinches drug failure. New data from a Phase IIb/III trial of 585 patients with advanced NSCL cancers and both mutations show that those taking afatinib had longer progression-free survival than those on placebo, 3.3 months versus 1.1 months. Yet somewhat perversely, afatinib lost out to placebo in terms of overall survival, 10.8 months versus 12 months. These conflicting results beg the question that regulatory agencies and public and private payers are increasingly asking: Does this cancer drug offer sufficient clinical value to merit the inevitable five-digit price tag?

"If I was a health minister, I could see why it might be difficult to justify spending money on this," said Dr. David Kerr, president of the European Society of Medical Oncology, where the data were presented. "We need to increase the sharpness of end points or we need to explain to patients and governments about overall survival." Boehringer Ingelheim is running two Phase III trials of Tovok as a first-line treatment in the EGFR subgroup of patients

Necitumumab, ImClone's follow-on of its megablockbuster Erbitux, is in Phase III trials for advanced NSCL cancer. "It's more selective and more active on the EGRF pathway than Erbitux, and that may well translate into greater efficacy," says Wolters Kluwer's Ben Weintraub. A fully human monoclonal antibody where Erbitux is part man, part mouse, necitumumab may well also offer a better safety profile. After squabbling over the rights to the son of Erbitux, Lilly and BMS are sharing the risk of the development program, starting in NSCL cancer and expanding into other tumors. Analysts have observed that by 2015, when necitumumab will face the FDA music, comparative effectiveness pressures will likely force the son of Erbitux to go head to head against its father.

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