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Case: Molecular Pathways in Non–Small Cell Lung Cancer

Recent guidelines call for molecular testing for 2 specific actionable alterations in any patient with non–small cell lung cancer (NSCLC) with an adenocarcinoma component: EGFR mutation and ALK fusion. Testing should be performed at the time of diagnosis.

A case demonstrating standard of care for the management of a patient with lung adenocarcinoma was presented by Mark A. Socinski, MD, at PMO Live 2015.

Genotyping of stage IV lung adenocarcinoma reveals targetable mutations in 64%, including a large number of sensitizing EGFR mutations and ALK rearrangement.

“We are now in an era of doing subsequent biopsies with repeat molecular testing as a standard of care in this population,” said Socinski, Director, Lung Cancer Section, Division of Hematology/Oncology, and Co-Director, UPMC Center for Excellence in Lung Cancer, Pittsburgh, PA.


A 58-year-old never-smoker male presented with right-sided chest pain and a cough. Chest x-ray revealed a 2.2-cm right upper lobe (RUL) nodule, and a chest CT scan confirmed a 3.1-cm RUL mass with bilateral pulmonary nodules too numerous to count. Initial biopsy showed adenocarcinoma. Molecular profiling of the tumor showed exon 21 L858R EGFR mutation. Erlotinib was initiated in January 2012.

The patient’s symptoms resolved quickly.


EGFR mutations occur essentially in the kinase domain. “These are hyperresponsive to ligand and are very significantly inhibited by tyrosine kinase inhibitors [TKIs],” said Socinski.

The vast majority—about 90%—of these mutations occur in exons 19 and 21. “We refer to these as the sensitizing mutations in this setting,” he said.

The IPASS study “was a transformational trial in lung cancer,” he said. In IPASS (N Engl J Med. 2009;361:947-957), gefitinib at 250 mg/day was compared with carboplatin/paclitaxel 3 times weekly in an Asian population of 1217 nonsmokers or former light smokers (79% female) with NSCLC with adenocarcinoma histology. The rate of EGFR mutation was 60%. “If you didn’t have the genotype, the TKI was a very poor treatment,” he said. In contrast, gefitinib extended progression-free survival (PFS) in EGFR mutation–positive patients (hazard ratio, 0.48; P <.0001).

Subsequently, 8 trials of first-line treatment with EGFR TKIs demonstrated superiority on the end point of objective response rate versus chemotherapy in patients with EGFR mutations, and a combined analysis of the LUX-Lung 3 and LUX-Lung 6 trials established a survival advantage for EGFR TKIs over chemotherapy, and it has now become the standard of care. The survival advantage for EGFR TKIs in this setting is driven by the exon 19 mutation, noted Socinski. With the mutation in exon 21, no difference between treatments on the end point of overall survival was observed.

Case Continued

A chest CT scan showed progression of the RUL nodule, so a rebiopsy was performed in January 2014. Pathology was the same (adenocarcinoma), as was the sensitizing mutation (exon 21 L858R EGFR mutation), but he developed the primary resistance mutation (exon 20 T790M EGFR mutation).

The T790M mutation occurs in about half of patients on rebiopsy, said Socinski. “The reason that rebiopsy is important is that we have a couple of drugs close to FDA approval that are highly active in patients with T790M-positive disease after first- or second-generation TKIs,” he said. These are rociletinib and AZD9291.

This case exemplifies the standard of care in the management of EGFR mutation–positive patients. Test all nonsquamous and squamous cancers (if a positive smoking history). The standard-of-care treatment is an EGFR TKI (erlotinib, afatinib, or gefitinib in the United States, gefitinib elsewhere), with rebiopsy at the time of progression. “All of us tolerate slowly progressive asymptomatic disease, and you don’t necessarily have to change therapy,” he said. “Optimal therapy for progressive disease is guided by repeat molecular testing.”

Less Common Alterations

The other actionable genotype is ALK rearrangement, first described in lung cancer in 2007. In this population, crizotinib is the standard treatment, with a high degree of activity. “We do have evidence, as with EGFR-mutant disease, that patients do better with targeted therapy vs standard chemotherapy.” Second-generation agents have activity even in patients previously exposed to crizotinib.

ROS1 is another biomarker we go hunting for, although you won’t see it very commonly,” he said. ROS1 is a driver mutation in 1% to 2% of lung adenocarcinomas. The clinical response to crizotinib in patients with ROS1 mutations is also dramatic, with an overall response rate of 72% and an impressive PFS of 19.2 months (N Engl J Med. 2014;371:1963-1971).

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