From the Journals

Molecular profiling a must in advanced NSCLC



All patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) should undergo molecular testing for targetable mutations and for tumor expression of the programmed death–ligand 1 (PD-L1) protein, authors of a review of systemic therapies for NSCLC recommend.

Their opinion is based on evidence showing that 5-year overall survival rate for patients whose tumors have high levels of PD-L1 expression now exceeds 25%, and that patients with ALK-positive tumors have 5-year overall survival rates over 40%. In contrast, 5-year survival rates for patients with metastatic NSCLC prior to the 21st century were less than 5%, according to Kathryn C. Arbour, MD, and Gregory J. Riely, MD, PhD, from Memorial Sloan Kettering Cancer Center in New York.

“Improved understanding of the biology and molecular subtypes of non–small cell lung cancer have led to more biomarker-directed therapies for patients with metastatic disease. These biomarker-directed therapies and newer empirical treatment regimens have improved overall survival for patients with metastatic non–small cell lung cancer,” they wrote in JAMA.

The authors reviewed published studies of clinical trials of medical therapies for NSCLC, including articles on randomized trials, nonrandomized trials leading to practice changes or regulatory approval of new therapies for patients with locally advanced or metastatic NSCLC, and clinical practice guidelines.

Their review showed that approximately 30% of patients with NSCLC have molecular alterations predictive of response to treatment, such as mutations in EGFR, the gene encoding for epidermal growth factor receptor; rearrangements in the ALK (anaplastic lymphoma kinase) and ROS1 genes; and mutations in BRAF V600E.

Patients with somatic activating mutations in EGFR, which occur in approximately 20% of those with advanced NSCLC, have better progression-free survival when treated with an EGFR-target tyrosine kinase inhibitor such as gefitinib (Iressa), erlotinib (Tarceva), or afatinib (Gilotrif), compared with cytotoxic chemotherapy.

Similarly, they noted, patients with ALK rearrangements leading to overexpression of the ALK protein had better overall response rates and progression-free survival when treated with the ALK inhibitor crizotinib (Xalkori), compared with patients with ALK rearrangements treated with pemetrexed and a platinum agent.

For some patients without targetable mutations, immune checkpoint inhibitors either alone or in combination with chemotherapy have resulted in improvements in overall survival.

“These advances are substantial, but long-term durable responses remain uncommon for most patients. These insights into treating metastatic disease have informed the design of trials for new treatment strategies among patients with early-stage disease. The goal of NSCLC research is to understand and address mechanisms of resistant and refractory disease in patients with advanced disease and, ultimately, to increase cure rates,” the reviewers wrote.

The review was supported in part by a grant from the National Cancer Institute to Memorial Sloan Kettering. Dr. Arbour reported serving as a consultant to AstraZeneca and nonfinancial research support from Novartis and Takeda. Dr. Riely reported grants and nonfinancial support from Pfizer, Roche/Genentech/Chugai, Novartis, Merck, and Takeda; a patent pending for an alternate dosing of erlotinib for which he has no right to royalties; and payments from the National Comprehensive Cancer Network to participate in a committee overseeing solicitation and selection of grants to be awarded by AstraZeneca.

SOURCE: Arbour KC and Riely GJ. JAMA. 2019;322(8):764-74.

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