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Identifying Correct Molecular Target Essential for Treating Non–Small-Cell Lung Cancer

June 2017, Vol 7, No 6

Orlando, FL—Non–small-cell lung cancer (NSCLC) comprises several different subtypes, necessitating broad molecular panel testing to understand the correct diagnosis and the appropriate treatment, said Wallace Akerley, MD, Senior Director, Community Oncology Research, Huntsman Cancer Institute, University of Utah, Salt Lake City, at the 2017 National Comprehensive Cancer Network (NCCN) annual conference.

Single-driver mutations are found in 64% of NSCLC tumors tested, approximately 25% of which are actionable. EGFR, ALK, and ROS1 mutations are clear drivers that can be treated with NCCN guideline–approved therapies, but other actionable mutations are also in the mix.

Emerging pathways for which no NCCN guidance exists include ERBB2, MET, BRAF, and RET mutations. Because each of these mutations is present in <1% to 3% of patients with NSCLC, randomized clinical trials are practically impossible, so “we’re going to have to work on a different kind of science for those,” said Dr Akerley.

EGFR Mutations and Targeted Therapy

All EGFR mutations are not created equal, he said. Mutations can be associated with drug sensitivity or drug resistance. The most common EGFR resistance mutation is T790M, which is present in up to 60% of patients with an EGFR mutation.

The third-generation EGFR tyrosine kinase inhibitor (TKI) osimertinib (Tagrisso) produces a response as second-line therapy in more than 60% of patients with the EGFR resistance mutation T790M. “A big striking factor is that the intracranial response is 64%,” he said.

In a recent randomized phase 3 study of patients with T790M mutations, progression-free survival (PFS) improved from 4.4 months in patients who received a platinum therapy plus pemetrexed in the second-line setting to 10.1 months in those who received osimertinib (Mok TS, et al. N Engl J Med. 2017;376:629-640). PFS was also significantly superior with osimertinib compared with platinum therapy plus pemetrexed in the subset of patients with brain metastases.

Transformation to small-cell lung cancer occurs in 9% to 14% of patients with resistance to EGFR TKIs. “We are now biopsying to find the second resistance mutation in EGFR, and I think it’s reasonable to look for the small-cell cancer as well,” said Dr Akerley.

An acquired EGFR C797S mutation mediates resistance to osimertinib in NSCLC that harbors the EGFR T790M mutation. Third-line EGFR TKIs that target this mutation are possible in the future, he said.

ALK Mutations and Targeted Therapy

The EML4-ALK translocation mutation is common in NSCLC; the 3 approved TKIs for this translocation include crizotinib (Xalkori), ceritinib (Zykadia), and alectinib (Alecensa), as well as other promising agents.

Ceritinib was recently shown to be superior to chemotherapy in the second-line setting in terms of PFS in patients with advanced ALK-rearranged NSCLC, with and without brain metastases (Soria JC, et al. Lancet. 2017;389:917-929). The over­all survival data from this study are not mature, “but there is a hint that we may see an improvement in survival [with ceritinib] as time goes by,” Dr Akerley said.

With ALK gene rearrangement, “the choice of second line is not so much molecularly directed at this point; it’s a toxicity sort of direction,” Dr Akerley said. “The second-line drugs, ceritinib and alectinib, are defined as being superior largely by their binding affinity, but I think in the near future we’ll be looking at the molecular markers,” he added.

In the J-ALEX study, alectinib was shown to significantly improve PFS and was better tolerated than crizotinib as first-line treatment in Japanese patients with ALK mutation–positive NSCLC. The J-ALEX study investigators are comparing the same 2 drugs in all ethnicities and are expected to report results in the next 6 months, when the best first-line treatment for ALK mutation–positive NSCLC may surface, added Dr Akerley.

Emerging Targeted Agents for NSCLC

Emerging targeted agents for NSCLC are listed in the NCCN guidelines (version 5.2017) with the level of evidence admittedly low for each. Nevertheless, NCCN lists vemurafenib (Zelboraf), dabrafenib (Tafinlar), and the combination of dabrafenib and trametinib (Mekinist) as treatment options for patients with the BRAF V600E mutation; crizotinib for those with high-level MET amplification or MET exon 14 skipping mutation; cabozantinib (Cabometyx) and vandetanib (Caprelsa) for patients with RET rearrangements; and trastuzumab (Herceptin) and afatinib (Gilotrif) for patients with HER2 mutations.

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