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

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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.

Frances A. Shepherd, MD,


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.

Broader EGFR Testing Could Guide Treatment Decisions

“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.”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.

Don’t Stop Testing at One Mutation

“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.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).

A prospective analysis of 65 patients with EGFR-mutant lung adenocarcinoma that had transformed into SCLCs that were resistant to EGFR TKIs revealed that patients harboring completely inactivated RB1 and TP53 had a 43-fold greater risk of transforming to SCLC (relative risk, 42.8; 95% CI, 5.88-311).5 Shepherd said that by knowing which patients have an increased risk for transformation, these patients can be watched more closely.

The TP53 co-mutation also serves as both a prognostic and predictive biomarker in EGFR-mutant NSCLC as patients with EGFR and TP53 co-mutations have a worse prognosis than TP53 wild-type patients and demonstrate worse progression-free survival (PFS) on EGFR TKIs (HR, 1.74; P = .06). Additionally, patients with TP53 co-mutations had a shorter time to development of central nervous system metastasis (HR, 1.43; P = .25).6

Resistance to EGFR TKIs and Improved Detection

“[Even though] we have no treatment strategy to apply to TP53/EGFR-mutant tumors…we might screen more frequently for brain metastases, we might biopsy earlier for SCLC transformation. We might learn something,” Shepherd noted.Shepherd said that molecular pathologists are even more important in determining mechanisms of resistance to EGFR TKI therapy. “Resistance, this is where molecular pathologists have to be our friends for sure,” she commented.

Although T790M is the most common resistance mutation, appearing in approximately 60% of patients, it is far from the only mechanism of resistance. However, third-generation EGFR TKIs have shown sensitivity to T790M, and osimertinib (Tagrisso) was granted FDA approval in 2017 for the treatment of patients with EGFR T790M—mutant NSCLC who progressed on an EGFR TKI, based on results from the phase III AURA3 trial.

In addition to demonstrating a PFS benefit for osimertinib over chemotherapy in EGFR T790M—mutant patients, the AURA3 trial also demonstrated that early clearance of plasma EGFR mutations could be used as a predictor of response to osimertinib. In an analysis from the AURA3 trial led by Shepherd, patients who demonstrated shedding of EGFR mutation in the peripheral blood had worse PFS compared with nonshedders (8.3 vs 14.0 months) and worse objective response rates (68% vs 75%).7

Additional genomic aberrations could also be found in the peripheral blood, and Shepherd noted that there was no improvement in PFS with the detection of TP53 mutations in plasma (HR, 1.17; 86% CI, 0.78-1.76).

“Technology has advanced so much that we can even do next-generation sequencing on little peripheral blood sample,” Shepherd commented.


  1. Yang JC, Wu YL, Schuler M, et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015;16(2):141-151. doi: 10.1016/S1470-2045(14)71173-8.
  2. Paz-Ares L, Tan EH, O’Byrne K, et al. Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial. Ann Oncol. 2017;28(2):270-277. doi: 10.1093/annonc/mdw611.
  3. Mok T, Cheng Y, Zhou X, et al. Dacomitinib (daco) versus gefitinib (gef) for first-line treatment of advanced NSCLC (ARCHER 1050): Final overall survival (OS) analysis. J Clin Oncol. 2018;36(suppl; abstr 9004).
  4. Yang JCH, Sequist LV, Geater SL, et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015;16(7):830-838. doi: 10.1016/S1470-2045(15)00026-1.
  5. Lee JK, Lee J, Kim S, et al. Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas. J Clin Oncol. 2017;35(26):3065-3074. doi: 10.1200/JCO.2016.71.9096.
  6. Labbé C, Cabanero M, Korpanty GJ, et al. Prognostic and predictive effects of TP53 co-mutation in patients with EGFR-mutated non-small cell lung cancer (NSCLC). Lung Cancer. 2017;111:23-29. doi: 10.1016/j.lungcan.2017.06.014.
  7. Shepherd FA, Papadimitrakopoulou V, Mok T, et al. Early clearance of plasma EGFR mutations as a predictor of response to osimertinib in the AURA3 trial. J Clin Oncol. 2018;36(suppl; abstr 9027).

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