Despite the fact that lung cancer is both the highest-frequency cancer in terms of incidence and the deadliest cancer in terms of estimated annual mortality rates, few biotech options have successfully tapped into this massive market.

But new data regarding the use of biomarkers, studies of combination treatment regimens, and progress with new targeted agents may be priming the space for a paradigm shift, experts say.

The standard of care for non-small cell lung cancer (NSCLC), which accounts for nearly 90% of lung cancer cases, still involves a lot of chemotherapy. In the front-line setting, about half of NSCLC patients also are eligible for treatment with Avastin from Genentech (South San Francisco, California), and Leerink Swann & Co. (Boston) estimates that about 60% of eligible patients receive the VEGF-inhibitor.

In the second-line setting, Leerink's research shows that about 30% of patients try EGFR-inhibitor Tarceva from Genentech and OSI Pharmaceuticals (Melville, New York), while about twice as many opt for Alimta from Eli Lilly and Co. (Indianapolis), a relatively well-tolerated chemotherapy approved for front-line and second-line use in nonsquamous patients.

The existing options offer survival benefits of only a few months, prompting many to question their high price tags. Yet Renato Martins, a physician and professor affiliated with the University of Washington, the Seattle Cancer Alliance and the Fred Hutchinson Cancer Research Center (all Seattle), said, "The problem is that we've had very inspecific therapies."

Some people have terrific responses to chemotherapy, while others may derive a huge benefit from Avastin or Tarceva, Martins said. He added that "better tailoring of therapy to the individual patient" will be critical in improving cancer care.

Tailoring may also be critical to improving clinical trial success rates for lung cancer drugs. Thus far, it has proven difficult for new targeted agents to outperform chemotherapy in NSCLC trials. Avastin and Tarceva have both stumbled in various trials, as did the multi-kinase inhibitor Nexavar from Onyx Pharmaceuticals (Emeryville, California) and Bayer AG (Leverkusen, Germany).

Perhaps the most noteworthy failure was AstraZeneca's (London) EGFR-inhibitor Iressa, which received accelerated approval for lung cancer only to be yanked off the market when it failed to show survival benefit in a confirmatory trial.

But data on Iressa presented last fall at the annual meeting of the European Society of Medical Oncology (Viganello-Lugano, Switzerland) have gotten physicians "very excited," according to Leerink analyst Howard Liang.

A Phase III study of the drug in an enriched population of 1,217 Asian patients expected to be responsive to EGFR inhibitors demonstrated that Iressa monotherapy significantly improved progression-free survival (PFS) compared to chemotherapy in front-line NSCLC patients with EGFR-activating mutations. In patients without the EGFR mutation, the chemotherapy group had significantly better PFS.

Liang pointed out that Iressa is a drug that couldn't beat placebo in past studies, but in the right patients, was able to beat standard-of-care chemotherapy. He predicted the IPASS data will be "paradigm-changing" – eventually leading to all NSCLC patients with activating EGFR mutations receiving an EGFR inhibitor rather than chemotherapy as first-line treatment. In the future, NSCLC will be a genotypic disease like breast cancer, he said – and that future may be near at hand: Leerink's research shows that about half of doctors have adequate in-house pathology capabilities to test for EGFR.

Martins also noted data published in the New England Journal of Medicine by Massachusetts General Hospital (Boston) researchers regarding the identification and monitoring of EGRF mutations in circulating tumor cells obtained through blood samples. He called the data "one of the most important papers in oncology" in terms of individualizing both diagnosis and treatment.

Other new data in the NSCLC field have indicated how the combination of targeted therapies may find a role.

Like combining targeted drugs with chemotherapy, combining targeted drugs with each other has proven hit or miss. In the Phase III Beta-Lung study, combining Avastin with Tarceva in second-line NSCLC failed to outperform Tarceva alone in the primary endpoint of OS, although there was evidence of activity on PFS.

Outside of lung cancer, trials combining Avastin with EGFR-inhibitors Vectibix from Amgen (Thousand Oaks, California) in colorectal cancer and Erbitux from Eli Lilly in pancreatic cancer and colorectal cancer have also stumbled.

But earlier this month, the Phase III ATLAS trial combining Avastin with Tarceva as a maintenance regimen following response to front-line Avastin and chemotherapy was stopped early when a preplanned interim analysis demonstrated a significant improvement in PFS versus Avastin alone.

Analyst Han Li, of Stanford Group Co. (Houston), noted that maintenance therapy is a "new concept" in NSCLC, where doctors usually use first-line treatment and then wait for progression before starting second-line treatment. Although the previous Phase III SATURN trial had shown Tarceva's efficacy in NSCLC maintenance versus placebo, the new data combining the drug with Avastin, which is already widely used in front-line treatment, could increase Tarceva's use, Li said.

Yet Martins explained that, from a physician's standpoint, maintenance therapy means treating patients who might otherwise be enjoying a drug holiday. He said the ATLAS study would have been more exciting if the Beta-Lung trial had established true synergy.

Li predicted that more trials combining targeted NSCLC drugs will be conducted as more new targeted options advance through the pipeline.

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