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October 01, 2010 (Vol. 30, No. 17)

Treatment Paradigm Shifting for NSCLC

Non-Small-Cell Lung Cancer Standards of Care Challenged by a Cornucopia of New Drugs

  • Non-small-cell lung cancer (NSCLC), which afflicts about 195,000 patients per year, is the top cancer killer in the U.S. Throughout the 1990s and early part of 2000s, standards of care for inoperable forms of the disease involved platinum-doublet cytotoxic therapies in front-line settings followed by single-agent use of docetaxel (Taxotere, Sanofi Aventis) in second-line settings.

    Numerous randomized trials evaluating the addition of other cytotoxic compounds on top of these standards of care have had no meaningful impact on the 10-month overall survival rates typically seen with this disease.

    Treating all NSCLC with the same brute-force approach may be part of the reason why progress beyond platinum-doublet chemotherapy has often failed. Comprehensive subgroup analysis of completed trials and subsequent execution of prospectively designed confirmatory trials has revealed that not all NSCLC is the same. Demographic considerations such as tumor histology, patient ethnicity, patient gender, smoking history, and, perhaps most importantly, tumor genotype largely predict treatment response.

    While histological analysis of tumor biopsies is the standard to guide treatment regimens, a move to tumor genotype analysis is gaining favor—particularly for nonsquamous cell-core biopsies. The days of formulaic and indiscriminate administration of cytotoxic therapy for progressive and inoperable disease are coming to an end.

  • Moving the Needle

    The first inkling that NSCLC standards of care could be in for major change came in 2002 when single-arm trial data supporting FDA approval of gefitinib (Iressa, AstraZeneca) was released. The data showed a 10% tumor response rate in treatment-experienced patients.

    In 2004, treatment with erlotinib (Tarceva, Roche/Astellas), a similar molecule, was shown in the BR.21 trial to provide an overall survival benefit. Like previous precedent-setting Her2+ breast cancer treatment with trastuzumab (Herceptin, Roche) and metastatic colorectal cancer treatment with cetuximab (Erbitux, BMS/Lilly), this data firmly supported the potential of targeted therapies for NSCLC treatment.

    Another major advancement in 2004 was approval of the cytotoxic agent pemetrexed (Alimta, Lilly). Sanction was based on results from a randomized trial comparing pemetrexed head-to-head with docetaxel in a second-line setting. Equivalent survival benefits were noted, but pemetrexed proved to be much better tolerated, thus providing second-line patients, particularly those with nonsquamous disease, with a more favorable treatment alternative.

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