Shepherd Says Translational Research in EGFR+ Lung Cancer Thanks to Molecular Pathology

Frances A. Shepherd, MD

In a keynote address by Frances A. Shepherd, MD, FRCPC, OOnt, OC, during the19th AnnualInternational Lung Cancer Congress, Shepherd expressed thatEGFR-mutant non—small cell lung cancer (NSCLC) is a model for how far the field of lung cancer has progressed in the past decade, thanks in large part to molecular pathologists.

“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, and the professor of medicine at the University of Toronto. “We’ve learned so much and our translational molecular pathologists have helped us so much.”

BroaderEGFRTesting Could Guide Treatment Decisions

It has become standard of care for patients with NSCLC harboringEGFRmutations 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 specificEGFRmutations 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 uncommonEGFRalterations, 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 withEGFR-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).²Although 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 recently at the 2018 ASCO Annual Meeting, dacomitinib, another newer generation EGFR TKI, showed improved OS in comparison with gefitinib in patients with treatment-naïveEGFRexon 19 deletion or exon 21 L858R mutations.³Dacomitinib, 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-sidedP= .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.⁴Shepherd explained that patients with exon 20 insertions had the worst prognoses compared with other more commonEGFRmutations, 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 broaderEGFRpanels, 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 toEGFR. For example, co-mutation ofEGFRandTP53frequently occurs, and may help in predicting which patients will transform to small cell lung cancer (SCLC).

A prospective analysis of 65 patients withEGFR-mutant lung adenocarcinoma that had transformed into SCLCs that were resistant to EGFR TKIs revealed that patients harboring completely inactivatedRB1andTP53had a 43-fold greater risk of transforming to SCLC (relative risk, 42.8; 95% CI, 5.88-311).⁵Shepherd said that by knowing which patients have an increased risk for transformation, these patients can be watched more closely.

TheTP53co-mutation also serves as both a prognostic and predictive biomarker inEGFR-mutant NSCLC as patients withEGFRandTP53co-mutations have a worse prognosis thanTP53wild-type patients and demonstrate worse progression-free survival (PFS) on EGFR TKIs (HR, 1.74;P= .06). Additionally, patients withTP53co-mutations had a shorter time to development of central nervous system metastasis (HR, 1.43;P= .25).⁶

“[Even though] we have no treatment strategy to apply toTP53/EGFR-mutant tumors…we might screen more frequently for brain metastases, we might biopsy earlier for SCLC transformation. We might learn something,” Shepherd noted.

Resistance to EGFR TKIs and Improved Detection

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 withEGFRT790M—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 inEGFRT790M—mutant patients, the AURA3 trial also demonstrated that early clearance of plasmaEGFRmutations could be used as a predictor of response to osimertinib. In an analysis from the AURA3 trial led by Shepherd, patients who demonstrated shedding ofEGFRmutation 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 ofTP53mutations 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.

References

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).