SIDEBAR: Molecular Heterogeneity Complicates Management of Resistance

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The molecular heterogeneity of lung cancers will make it a challenge to manage resistance in this era of targeted therapy, according to D. Ross Camidge, MD, PhD, of the University of Colorado, Denver. A case in point: the anaplastic lymphoma kinase (ALK) story.

Recently updated data for crizotinib (Xalkori), an ALK inhibitor, show that it is active in ALK-positive NSCLC, with an overall response rate of 61% and a median progression-free survival of 10 months.1 The 6- and 12-month rates of overall survival were 90% and 81%. “This is still really impressive data when you are giving the right drug to a very molecularly defined group of people,” he commented. Yet some patients clearly develop resistance.

Use of Hsp90 Inhibitors

Meanwhile, research has suggested that heat shock protein 90 (Hsp90) inhibitors may be most active in NSCLC with an ALK gene rearrangement. In a trial testing the Hsp90 inhibitor ganetespib in advanced NSCLC after failure of prior treatments, the patients having the greatest response indeed had ALK-positive tumors.2 But in a first-ever observation, two patients with disease progression on the drug had ALK-positive tumors and had experienced treatment failure with crizotinib.

“The initial assumption was [that] Hsp90 inhibitors may be the next best thing for ALK-positive patients after failure of crizotinib,” Dr. Camidge commented. “Yet both of these people are not responding to the Hsp90 inhibitor.”

This observation attests to tumors’ molecular heterogeneity and underscores its importance in therapy. When you use a very specific inhibitor, and then after many months, “the cancer squirms out [by] finding acquired resistance, then it’s back to the beginning again. Heterogeneity will reemerge in terms of mechanisms of resistance,” he explained. “Therefore, the assumption that you should be able to go straight from one drug to the next without recharacterizing the tumor almost certainly will not be true.” ■


1. Camidge DR, Bang Y, Kwak EL, et al: Progression-free survival (PFS) from a phase I study of crizotinib (PF-02341066) in patients with ALK-positive non-small cell lung cancer (NSCLC). ASCO Meeting 2011. Abstract 2501. Presented June 3, 2011.

2. Wong K, Koczywas M, Goldman JW, et al: An open-label phase II study of the Hsp90 inhibitor ganetespib (STA-9090) as monotherapy in patients with advanced non-small cell lung cancer (NSCLC). ASCO Meeting 2011. Abstract 7500. Presented June 4, 2011.

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