Frances A. Shepherd, MD
In a keynote deal with by Frances A. Shepherd, MD, FRCPC, OOnt, OC, throughout the 19th Annual Worldwide Lung Most cancers Congress, Shepherd expressed that EGFR-mutant non–small cell lung most cancers (NSCLC) is a mannequin for a way far the sector of lung most cancers has progressed prior to now decade, thanks largely to molecular pathologists. “Our translational research has really been translated into standard of care,” mentioned Shepherd, the Scott Taylor Chair in Lung Most cancers Analysis on the Princess Margaret Most cancers Centre, and the professor of drugs on the College of Toronto. “We’ve learned so much and our translational molecular pathologists have helped us so much.”Broader EGFR Testing May Information Therapy DecisionsIt has turn out to be normal of take care of sufferers with NSCLC harboring EGFR mutations to be handled with an EGFR tyrosine kinase inhibitor (TKI) within the first-line setting, as EGFR-targeted therapies have proven superiority over chemotherapy on this affected person inhabitants.Current developments have additionally proven that elevated info from the pathologist concerning particular EGFR mutations may also help oncologists resolve which EGFR inhibitor to provide every affected person.The second-generation EGFR inhibitor afatinib (Gilotrif) was authorized in 2013 for the remedy of sufferers with metastatic NSCLC with exon 19 deletions or exon 21 L858R substitutions. The approval was expanded in January 2018 to incorporate unusual EGFR alterations, together with L861Q, G719X, and/or S768I based mostly on outcomes from the LUX Lung trials.Afatinib demonstrated important profit over chemotherapy in sufferers with exon 19 deletions in pooled analyses from the LUX Lung three and 6 trials. Within the LUX Lung three trial, the median total survival (OS) was 33.three months with afatinib in contrast with 21.1 months with pemetrexed/cisplatin chemotherapy (HR, Zero.54; 95% CI, Zero.36-Zero.79; P = .0015), and in LUX Lung 6, the median OS was 31.Four months with afatinib versus 18.Four months with gemcitabine/cisplatin (HR, Zero.64; 95% CI, Zero.44-Zero.94; P = .Zero23).1 Within the LUX Lung 7 trial, nonetheless, sufferers with EGFR-mutant superior NSCLC demonstrated modest improved survival with afatinib in contrast with gefitinib (Iressa). Sufferers with exon 19 deletions, particularly, had a median OS of 30.7 months in contrast with 26.Four months with gefitinib (HR, Zero.83; 05% CI, Zero.58-1.17; P = .2841).2 Though the OS profit was not discovered to be statistically important and the toxicity profile of afatinib is harder, Shepherd famous that in match sufferers with exon 19 deletions, she is going to prescribe afatinib. For much less match sufferers, she really helpful gefitinib.In up to date outcomes from the ARCHER 1050 trial offered lately on the 2018 ASCO Annual Assembly, dacomitinib, one other newer era EGFR TKI, confirmed improved OS as compared with gefitinib in sufferers with treatment-naïve EGFR exon 19 deletion or exon 21 L858R mutations.three Dacomitinib, which was granted a precedence evaluate by the FDA in April 2018 for this setting, demonstrated a median OS of 34.1 months in contrast with 26.Eight months with gefitinib (HR, Zero.760; 95% CI, Zero.582-Zero.993; 2-sided P = .0438). The OS profit was significantly important amongst sufferers with exon 21 L858R mutations particularly, with a median OS of 32.5 months with dacomitinib versus 23.2 months with gefitinib (HR, Zero.707; 95% CI, Zero.478-1.045; P = .0805).Responses to afatinib had been additionally seen in sufferers who had level mutations or duplications in exons 18 by 21 within the LUX Lung trials. Of 38 sufferers on this group, 27 sufferers responded to remedy and demonstrated a median OS of 19.Four months (95% CI, 16.Four-26.9), whereas sufferers with exon 20 insertions (n = 23) had a median OS of 9.2 months (95% CI, Four.1-14.2) and solely 2 sufferers had goal responses.Four Shepherd defined that sufferers with exon 20 insertions had the worst prognoses in contrast with different extra widespread EGFR mutations, and most of those insertions weren’t attentive 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 mentioned.Don’t Cease Testing at One MutationShepherd added that it could be vital to additionally know of co-mutations along with EGFR. For instance, co-mutation of EGFR and TP53 incessantly happens, and should assist in predicting which sufferers will remodel to small cell lung most cancers (SCLC).A potential evaluation of 65 sufferers with EGFR-mutant lung adenocarcinoma that had remodeled into SCLCs that had been immune to EGFR TKIs revealed that sufferers harboring utterly inactivated RB1 and TP53 had a 43-fold larger threat of remodeling to SCLC (relative threat, 42.Eight; 95% CI, 5.88-311).5 Shepherd mentioned that by figuring out which sufferers have an elevated threat for transformation, these sufferers may be watched extra carefully.The TP53 co-mutation additionally serves as each a prognostic and predictive biomarker in EGFR-mutant NSCLC as sufferers with EGFR and TP53 co-mutations have a worse prognosis than TP53 wild-type sufferers and exhibit worse progression-free survival (PFS) on EGFR TKIs (HR, 1.74; P = .06). Moreover, sufferers with TP53 co-mutations had a shorter time to improvement of central nervous system metastasis (HR, 1.43; P = .25).6“[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 famous.Resistance to EGFR TKIs and Improved DetectionShepherd mentioned that molecular pathologists are much more vital in figuring out mechanisms of resistance to EGFR TKI remedy. “Resistance, this is where molecular pathologists have to be our friends for sure,” she commented.Though T790M is the most typical resistance mutation, showing in roughly 60% of sufferers, it’s removed from the one mechanism of resistance. Nevertheless, third-generation EGFR TKIs have proven sensitivity to T790M, and osimertinib (Tagrisso) was granted FDA approval in 2017 for the remedy of sufferers with EGFR T790M–mutant NSCLC who progressed on an EGFR TKI, based mostly on outcomes from the section III AURA3 trial.Along with demonstrating a PFS profit for osimertinib over chemotherapy in EGFR T790M–mutant sufferers, the AURA3 trial additionally demonstrated that early clearance of plasma EGFR mutations could possibly be used as a predictor of response to osimertinib. In an evaluation from the AURA3 trial led by Shepherd, sufferers who demonstrated shedding of EGFR mutation within the peripheral blood had worse PFS in contrast with nonshedders (Eight.three vs 14.Zero months) and worse goal response charges (68% vs 75%).7Additional genomic aberrations is also discovered within the peripheral blood, and Shepherd famous that there was no enchancment in PFS with the detection of TP53 mutations in plasma (HR, 1.17; 86% CI, Zero.78-1.76).“Technology has advanced so much that we can even do next-generation sequencing on little peripheral blood sample,” Shepherd commented.
Yang JC, Wu YL, Schuler M, et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung three and LUX-Lung 6): evaluation of total survival information from two randomised, section three trials. Lancet Oncol. 2015;16(2):141-151. doi: 10.1016/S1470-2045(14)71173-Eight.
Paz-Ares L, Tan EH, O’Byrne Okay, et al. Afatinib versus gefitinib in sufferers with EGFR mutation-positive superior non-small-cell lung most cancers: total survival information from the section IIb LUX-Lung 7 trial. Ann Oncol. 2017;28(2):270-277. doi: 10.1093/annonc/mdw611.
Mok T, Cheng Y, Zhou X, et al. Dacomitinib (daco) versus gefitinib (gef) for first-line remedy of superior NSCLC (ARCHER 1050): Closing total survival (OS) evaluation. J Clin Oncol. 2018;36(suppl; abstr 9004).
Yang JCH, Sequist LV, Geater SL, et al. Scientific exercise of afatinib in sufferers with superior non-small-cell lung most cancers harbouring unusual EGFR mutations: a mixed post-hoc evaluation of LUX-Lung 2, LUX-Lung three, and LUX-Lung 6. Lancet Oncol. 2015;16(7):830-838. doi: 10.1016/S1470-2045(15)00026-1.
Lee JK, Lee J, Kim S, et al. Clonal historical past 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.
Labbé C, Cabanero M, Korpanty GJ, et al. Prognostic and predictive results of TP53 co-mutation in sufferers with EGFR-mutated non-small cell lung most cancers (NSCLC). Lung Most cancers. 2017;111:23-29. doi: 10.1016/j.lungcan.2017.06.Zero14.
Shepherd FA, Papadimitrakopoulou V, Mok T, et al. Early clearance of plasma EGFR mutations as a predictor of response to osimertinib within the AURA3 trial. J Clin Oncol. 2018;36(suppl; abstr 9027).
Frances A. Shepherd, MD