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Shepherd Says Molecular Pathology Has Made EGFR+ NSCLC Example for Field Advancements

Lisa Astor
Published: Friday, Jul 27, 2018

Frances A. Shepherd, MD, FRCPC, OOnt, OC
Frances A. Shepherd, MD,
FRCPC, OOnt, OC
Molecular pathologists have helped to advance translational research significantly for lung cancer over the past 10 years; nowhere is that more obvious than in EGFR-mutant non–small cell lung cancer (NSCLC), according to a keynote address by Frances A. Shepherd, MD, FRCPC, OOnt, OC, during the 19th Annual International Lung Cancer Congress.

“Our translational research has really been translated into standard of care,” said Shepherd, the Scott Taylor Chair in Lung Cancer Research at the Princess Margaret Cancer Centre, the professor of medicine at the University of Toronto, and a 2016 Giant of Cancer Care® in Lung Cancer. “We’ve learned so much and our translational molecular pathologists have helped us so much.”

Broader EGFR Testing Could Guide Treatment Decisions

It has become standard of care for patients with NSCLC harboring EGFR mutations to be treated with an EGFR tyrosine kinase inhibitor (TKI) in the first-line setting, as EGFR-targeted therapies have shown superiority over chemotherapy in this patient population.

Recent advancements have also shown that increased information from the pathologist regarding specific EGFR mutations can help oncologists decide which EGFR inhibitor to give each patient.

The second-generation EGFR inhibitor afatinib (Gilotrif) was approved in 2013 for the treatment of patients with metastatic NSCLC with exon 19 deletions or exon 21 L858R substitutions. The approval was expanded in January 2018 to include uncommon EGFR alterations, including L861Q, G719X, and/or S768I based on results from the LUX Lung trials.

Afatinib demonstrated significant benefit over chemotherapy in patients with exon 19 deletions in pooled analyses from the LUX Lung 3 and 6 trials. In the LUX Lung 3 trial, the median overall survival (OS) was 33.3 months with afatinib compared with 21.1 months with pemetrexed/cisplatin chemotherapy (HR, 0.54; 95% CI, 0.36-0.79; P = .0015), and in LUX Lung 6, the median OS was 31.4 months with afatinib versus 18.4 months with gemcitabine/cisplatin (HR, 0.64; 95% CI, 0.44-0.94; P = .023).1

In the LUX Lung 7 trial, however, patients with EGFR-mutant advanced NSCLC demonstrated modest improved survival with afatinib compared with gefitinib (Iressa). Patients with exon 19 deletions, specifically, had a median OS of 30.7 months compared with 26.4 months with gefitinib (HR, 0.83; 05% CI, 0.58-1.17; P = .2841).2 Although the OS benefit was not found to be statistically significant and the toxicity profile of afatinib is more difficult, Shepherd noted that in fit patients with exon 19 deletions, she will prescribe afatinib. For less fit patients, she recommended gefitinib.

In updated results from the ARCHER 1050 trial presented at the 2018 ASCO Annual Meeting, dacomitinib, another EGFR TKI, showed improved OS in comparison with gefitinib in patients with treatment-naïve EGFR exon 19 deletion or exon 21 L858R mutations.3 Dacomitinib, which was granted a priority review by the FDA in April 2018 for this setting, demonstrated a median OS of 34.1 months compared with 26.8 months with gefitinib (HR, 0.760; 95% CI, 0.582-0.993; 2-sided P = .0438). The OS benefit was particularly significant among patients with exon 21 L858R mutations specifically, with a median OS of 32.5 months with dacomitinib versus 23.2 months with gefitinib (HR, 0.707; 95% CI, 0.478-1.045; P = .0805).

Responses to afatinib were also seen in patients who had point mutations or duplications in exons 18 through 21 in the LUX Lung trials. Of 38 patients in this group, 27 patients responded to treatment and demonstrated a median OS of 19.4 months (95% CI, 16.4-26.9), whereas patients with exon 20 insertions (n = 23) had a median OS of 9.2 months (95% CI, 4.1-14.2) and only 2 patients had objective responses.4 Shepherd explained that patients with exon 20 insertions had the worst prognoses compared with other more common EGFR mutations, and most of these insertions were not responsive to EGFR TKIs.

“Initially, we were only testing for [exons] 19 and 21, now we have much broader EGFR panels, and so our pathologists can guide our therapy and help us select the appropriate TKI,” Shepherd said.

Don’t Stop Testing at One Mutation

Shepherd added that it may be important to also know of co-mutations in addition to EGFR. For example, co-mutation of EGFR and TP53 frequently occurs, and may help in predicting which patients will transform to small cell lung cancer (SCLC).


View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Community Practice Connections™: 18th Annual International Lung Cancer Congress®Oct 31, 20181.5
Clinical Interchange™: Translating Research to Inform Changing Paradigms: Assessment of Emerging Immuno-Oncology Strategies and Combinations across Lung, Head and Neck, and Bladder CancersOct 31, 20182.0
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