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Treating ALK-positive lung cancer—early successes and future challenges

Nature Reviews Clinical Oncology volume 9, pages 268–277 (2012)Cite this article

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Abstract

Rearrangements of the anaplastic lymphoma kinase (ALK) gene occur infrequently in non-small-cell lung cancer (NSCLC), but provide an important paradigm for oncogene-directed therapy in this disease. Crizotinib, an orally bioavailable inhibitor of ALK, provides significant benefit for patients with ALK-positive (ALK+) NSCLC in association with characteristic, mostly mild, toxic effects, and this drug has been approved by the FDA for clinical use in this molecularly defined subgroup of lung cancer. Many new ALK inhibitors are being developed and understanding the challenges of determining and addressing the adverse effects that are likely to be ALK specific, while maximizing the time of benefit on targeted agents, and understanding the mechanisms that underlie drug resistance will be critical in the future for informing the optimal therapy of ALK+ NSCLC.

Key Points

  • Crizotinib shows significant benefit in terms of both radiographic response and progression-free survival in ALK-positive (ALK+) non-small-cell lung cancer (NSCLC)

  • Crizotinib is generally well tolerated and associated with common mild adverse effects such as gastrointestinal disturbance, visual changes, and low testosterone, as well as rare serious adverse effects such as transaminitis

  • Crizotinib resistance occurs through multiple different mechanisms including mutations and copy number gain that preserve ALK dominance, and the emergence of other oncogenic drivers that may weaken ALK dominance

  • In addition to a change in the biology of the cancer, cases of isolated central nervous system (CNS) progression on crizotinib could reflect inadequate CNS drug penetration

  • Newer ALK inhibitors, HSP90 inhibitors and pemetrexed have shown preclinical or clinical activity in ALK+ NSCLC and are being investigated further in patients with crizotinib resistant and crizotinib-naive ALK+ disease

  • The potential of these new agents to show activity in patients with CNS disease or crizotinib resistance will be critical to determine their roles in the management of ALK+ NSCLC

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Figure 1: ALK activation mechanisms.
Figure 2: Resistance mutation spectra in EGFR-mutant, ALK-positive and BCR–ABL-positive cancers.
Figure 3: Mechanisms of resistance to crizotinib in ALK-positive NSCLC.

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  1. Division of Medical Oncology, University of Colorado Cancer Center, Anschutz Medical Campus, Anschutz Cancer Pavillion, Mailstop F704, 1665 North Aurora Court, Aurora, 80045, CO, USA

    D. Ross Camidge & Robert C. Doebele

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Both authors researched the data for this article, made a substantial contribution to the discussion of content, wrote, edited, and revised the manuscript prior to submission.

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D. R. Camidge acts as a consultant for Ariad, Chugai, Eli Lilly, Novartis and Pfizer. R. C. Doebele receives honoraria from Abbott Laboratories, receives research support from Eli Lilly, and receives honoraria and research support from Pfizer.

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Camidge, D., Doebele, R. Treating ALK-positive lung cancer—early successes and future challenges. Nat Rev Clin Oncol 9, 268–277 (2012). https://doi.org/10.1038/nrclinonc.2012.43

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