Therapeutic Options for NSCLC With KRAS Mutations

The reviewers reported that all therapeutic approaches targeting KRAS directly (eg, ARS-853) are in preclinical stages and “are likely years away from being used in the clinic.”


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They also found that 2 of the most extensively used inhibitors of MEK1 and MEK2 (selumetinib and trametinib), which inhibit molecules downstream of RAS, have been evaluated in NSCLC. In a phase 2 study, second-line selumetinib plus docetaxel bestowed significant survival advantage in patients with KRAS-mutant NSCLC (median survival: 9.4 months vs 5.2 months for docetaxel alone; hazard ratio, 0.80; P = .21). Objective partial responses were notable (37% [16/43] vs 0% [0/43] for docetaxel alone). However, in a study evaluating trametinib, response rates were independent of KRAS status. Several in-progress phase 2 and 3 clinical trials in NSCLC are using different strategies:

Drug(s)

Targets

Selumetinib

Docetaxel

MEK1 and MEK2 inhibitors

Bortezomib

Inhibits the proteasome pathway

Retaspimycin

Everolimus

Heat shock protein 90 (Hsp90) inhibitor

Mammalian target of rapamycin (mTOR) inhibitor

Defactinib

Focal-adhesion kinase (FAK) inhibitor

The reviewers noted that preclinical studies are evaluating dual inhibition with targeted agents directed at different molecules, both downstream of KRAS.

They concluded that we may be entering a new era in targeting KRAS NSCLC, noting that while KRAS-mutant NSCLC has not seen the success of EGFR– and ALK-mutated lung cancer, “success in the clinical setting is beginning to be seen, particularly with MEK1 and MEK2 inhibitors.”

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KRAS represents one of the most commonly mutated genes in NSCLC,” the reviewers noted. “It is critical we continue working to understand KRAS mutations and to investigate drugs to inhibit the effects of KRAS mutations.”

Reference

  1. Wood K, Hensing T, Malik R, Salgia R. Prognostic and predictive value in KRAS in non-small-cell lung cancer: a review [published online ahead of print April 21, 2016]. JAMA Oncol. doi: 10.1001/jamaoncol.2016.0405.