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CLLC_v19_i5_COVER.indd 1CLLC_v19_i5_COVER.indd 1 22-08-2018 20:15:1422-08-2018 20:15:14

2020. doi: 10.1016/j.cllc.2020.04.011

Reprinted from Clin Lung Cancer. 2020. doi: 10.1016/j.cllc.2020.04.011Clinical Activity of Afatinib in Patients WithNon—Small-Cell Lung Cancer HarboringUncommon EGFR Mutations: A SpanishRetrospective Multicenter StudyTeresa Moran, Alvaro Taus, Edurne Arriola, Carlos Aguado,Manuel Dómine, Ana Gómez Rueda, Antonio Calles, Susana Cedrés, Nuria Viñolas, Dolores Isla, Ramón Palmero, María Sereno, Victor Diaz, Oscar Juan, Raquel Marsé, Paloma Martín Martorell, José Miguel Sánchez Torres, for the Study Group for the Uncommon EGFR Mutations in Spain

© 2020 Elsevier Inc. All rights reserved.

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Original Study

Clinical Activity of Afatinib in Patients WithNoneSmall-Cell Lung Cancer HarboringUncommon EGFR Mutations: A Spanish

Retrospective Multicenter StudyTeresa Moran,1,2 Alvaro Taus,3,4 Edurne Arriola,3,4 Carlos Aguado,5

Manuel Dómine,6 Ana Gómez Rueda,7 Antonio Calles,8 Susana Cedrés,9

Nuria Viñolas,10 Dolores Isla,11 Ramón Palmero,12 María Sereno,13 Victor Diaz,14

Oscar Juan,15 Raquel Marsé,16 Paloma Martín Martorell,17

José Miguel Sánchez Torres,18 for the Study Group for the Uncommon EGFRMutations in Spain�

AbstractWe report the results of the molecular and clinical characterization and the efficacy of afatinib in a cohort ofpatients with advanced nonesmall-cell lung cancer (NSCLC) patients harboring uncommon epidermal growthfactor receptor (EGFR) mutations in Spanish clinical practice. In patients with uncommon EGFR-mutantNSCLC, the most common mutations occurred on exon 18 in amino acid G719, either alone or in combinationwith another mutation; other uncommon mutations were detected in exons 18, 19, 20, 21, and 22. In clinicalpractice, afatinib was active in patients with uncommon EGFR-mutant NSCLC, particularly in patients withcomplex and single mutations; however, in patients with EGFR ins20 (EGFR exon 20 insertions), treatment withafatinib provided a lower clinical benefit, indicating that further treatment strategies are needed for patientswith this type of uncommon EGFR mutation.Introduction: Uncommon epidermal growth factor receptor (EGFR) mutations (u-EGFRm) are a heterogeneous groupof molecular alterations and have also been reported as comutations with other EGFR mutations (complex mutations)in nonesmall-cell lung cancer (NSCLC). Afatinib has shown activity against some u-EGFRm, and we examined itsefficacy in Spanish clinical practice. Patients and Methods: Data of 67 patients with advanced NSCLC with u-EGFRmtreated with afatinib between 2012 and 2017 at 23 Spanish institutions were reviewed. u-EGFRm were analyzed ascomplex mutations (group A), EGFR exon 20 insertions (ins20; group B), or single mutations (group C). Efficacy wasevaluated in terms of overall survival (OS) and tumor response. Results: Group A complex u-EGFRm consisted of

�Additional members of the study group are listed in the Acknowledgments.

1Medical Oncology Department, Catalan Institute of Oncology and Applied ResearchGroup in Oncology (B-ARGO), Badalona, Spain2Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona (UAB), Bada-lona, Spain3Medical Oncology Department, Hospital del Mar-CIBERONC, Barcelona, Spain4Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute),Barcelona, Spain5Medical Oncology Department, Hospital Clínico San Carlos, Madrid, Spain6Medical Oncology Department, Hospital Universitario Fundación Jiménez Díaz, IIS-FJD, Madrid, Spain7Medical Oncology Department, IRYCIS, Ramón y Cajal University Hospital,Madrid, Spain8Early Drug Development and Phase I Unit, Medical Oncology Department, Institutode Investigación Sanitaria Gregorio Marañón, Hospital General Universitario GregorioMarañón, Madrid, Spain9Medical Oncology Department, Vall d’Hebron Hospital and Institute of Oncology,Barcelona, Spain10Medical Oncology Department, Hospital Clinic i Provincial, Barcelona, Spain

11Medical Oncology Department, University Hospital Lozano Blesa, Zaragoza, Spain12Medical Oncology Department, ICO-Duran i Reynalds, L’Hospitalet de Llobregat,Spain13Medical Oncology Department, Hospital Universitario Infanta Sofía, San Sebastiánde los Reyes, Spain14Medical Oncology Department, Hospital Sureste, Madrid, Spain15Medical Oncology Department, Hospital Universitario La Fe, Valencia, Spain16Medical Oncology Department, Son Espases, Palma de Mallorca, Spain17Medical Oncology Department, Hospital Clínico Universitario, Valencia, Spain18Medical Oncology Department, Hospital de la Princesa, Madrid, Spain

Submitted: Feb 3, 2020; Revised: Apr 12, 2020; Accepted: Apr 21, 2020

Address for correspondence: Teresa Moran, MD, PhD, Medical Oncology Depart-ment, Catalan Institute of Oncology, Badalona, Hospital Germans Trias i Pujol,Universitat Autòmoma de Barcelona (UAB), Carretera Canyet s/n, 08916 Badalona,Spain

Fax: (þ34) 93 497 89 50; E-mail contact: mmoran@iconcologia.net

1525-7304/$ - see frontmatter ª 2020 Elsevier Inc. All rights reserved.https://doi.org/10.1016/j.cllc.2020.04.011 Clinical Lung Cancer Month 2020 - 1

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Afatinib in NSCLC

double mutations of G719XþE709F, G719XþS768I, G719XþL861Q, L858RþT790M, L858RþS768I, L858RþS765I,del19þS768I, del19þL747S, or R776CþL861Q. No differences in clinical characteristics were found between groupsA (n ¼ 20), B (n ¼ 23), and C (n ¼ 24). Afatinib was administered as first-line therapy in 80% of patients. Median time ofreceipt of therapy was 4.2 months (range, 2.0e12.9 months). Median OS for the entire cohort was 19.9 months (95%confidence interval, 9.7, 30.1). Hazard ratios for OS were 0.26 (95% confidence interval, 0.10, 0.71; P ¼ .008) and 0.40(95% confidence interval, 0.17, 0.95; P ¼ .037) for groups A and C compared to B, respectively. Response wassignificantly higher in groups A (70%) and C (54%) compared to B (13%; pairwise comparison P < .001 and .008,respectively). Conclusion: In clinical practice, afatinib was active in patients with u-EGFRm NSCLC, particularly incomplex and single mutations. Further strategies are needed for patients with ins20, a subgroup u-EGFRm with alower clinical benefit with afatinib.

Clinical Lung Cancer, Vol. -, No. -, --- ª 2020 Elsevier Inc. All rights reserved.Keywords: Afatinib, EGFR mutations, NSCLC, Retrospective, Uncommon

IntroductionOver 250 alterations have been described in the EGFR gene;

however, short in-frame deletions of amino acids ELREA of exon 19(del19) and the exon 21 L858R point mutation are the mostcommon alterations.1 EGFR del19 and L858R mutations aredetected in approximately 85% to 90% of all the EGFR-mutatedlung adenocarcinomas and are strongly associated with response totyrosine kinase inhibitors (TKIs) targeting EGFR. UncommonEGFR mutations (u-EGFRm) in exons 18 to 21 account for 12% to15% of overall EGFR mutations in nonesmall-cell lung cancer(NSCLC).2-31

EGFR TKIs are the standard therapy in NSCLC patients withcommon EGFR mutations. Uncommon or nonclassical mutation is aheterogeneous group of molecular alterations with variable responsesto EGFR-targeted drugs. Most randomized trials of EGFR TKIs wererestricted to patients with common mutations (del19 and L858R);hence, there are limited prospective data against u-EGFRm.32 Resultsfrom several retrospective studies have identified differing clinicalefficacy from EGFR TKIs in patients with cancers harboring thesemutations.3,13,30,31,33-40 Disease of patients with NSCLC harboring a“single sensitizing uncommon mutation,” such as exon 18 G719X,exon 20 S768I, and exon 21 L861Q, usually responds to treatmentwith EGFR TKI, although the response has been generally inferior tothose harboring common sensitizing mutations.3 In contrast, the denovo exon 20 T790M mutation and exon 20 insertion (ins20)generally predict primary resistance to first- and second-generationEGFR TKIs.3,13,33 u-EGFRm have also been reported as comuta-tions with other EGFR mutations (complex mutations).

Afatinib has shown preclinical activity against u-EGFRm, withdrug concentration causing 50% inhibition values of 0.5 nM inL861Q mutations and 0.7 nM in S768I mutations, similar to thedrug concentration causing 50% inhibition against L858R muta-tions (0.2 nM),22 as well as reduced cell proliferation and inhibitionof EGFR phosphorylation in cells with L858M/L861Q mutationsand L858R mutations.41 The LUX-Lung 2, LUX-Lung 3, andLUX-Lung 6 clinical trials of afatinib permitted enrollment of pa-tients with u-EGFRm.16 Afatinib has shown activity against some u-EGFRm, especially G719X, L747S, L747P, S768I, and L861Q,although other u-EGFRm (ins20, de novo T790M) have a lowerlikelihood of response.4,16,22,42-44

nical Lung Cancer Month 2020

In this study, we examined the molecular and clinicalcharacteristics and efficacy of afatinib in a cohort of patients withadvanced NSCLC patients harboring u-EGFRm in Spanish clinicalpractice.

Patients and MethodsPatients

Medical records of 67 NSCLC patients with u-EGFRm treatedwith afatinib between 2012 and 2017 at 23 Spanish institutionswere reviewed. Data were collected on the clinical and molecularcharacteristics of this patient population and its clinical outcomewith afatinib. All patients provided written informed consent, andapproval was obtained from the institutional review board of ourinstitution (RegTumTor2014).

TreatmentPatients were scheduled to receive afatinib at a standard dose of 40

mg per day orally as per clinical practice. Information on reduceddoses at initiation, if any, was noted. In addition, dose reductions ofafatinib due to related adverse events (AEs) was recorded. Treatmentwas maintained until disease progression, loss of clinical benefit, orunacceptable toxicity. Clinical visits were scheduled as per clinicalpractice at each center, with computed tomographic scans performedto evaluate the radiographic response during treatment performed asper clinical practice every 8 to 12 weeks. All the patients were followeduntil death, withdrawal of consent, or loss to follow-up.

Molecular Analysesu-EGFRm were analyzed according to the following association

criteria: as complex mutations, which consisted of multiplemutations including common and uncommon EGFR mutations(group A), insertions in exon 20 (ins20) (group B), or singlemutations (group C). Information on the different techniques forEGFR mutations detection was collected, reflecting how assessmentof the mutations was carried out in clinical practice.

Statistical AnalysisResults are described in terms of absolute frequencies and per-

centages for qualitative variables and as median (interquartile range)and absolute range for the qualitative variables. Fisher exact test and

Teresa Moran et al

Kruskal-Wallis test were used for the comparison of qualitative andquantitative variables, respectively.

Efficacy data were evaluated in terms of overall response rate(ORR), time receiving treatment, and overall survival (OS). OS wasdefined as the time from diagnosis to death from any cause. Data ofpatients who were still alive at the date of last contact were censored.OS medians and confidence intervals (CIs) were estimated with theKaplan-Meier method. Survival at 12, 18, 24, and 36 months wasestimated. OS was the primary end point, and the log-rank test wasused for its calculation. Additionally, a Cox univariate and multi-variate model was used to estimate the risk of OS (hazard ratio [HR]and 95% CI) according to the type of mutation.

Time receiving treatment was defined as the time from afatinibinitiation to finalization for any reason. Response rate was calculatedaccording to the Response Evaluation Criteria in Solid Tumors(RECIST) 1.1 criteria as complete response, partial response, stabledisease, progressive disease, or not evaluable. Information on AEswas recorded and graded according to the Common TerminologyCriteria for Adverse Events (CTCAE) 4.03 criteria.

Figure 1 Pie Graph Showing Overall Population Disposition and Un

Abbreviation: EGFR ¼ epidermal growth factor receptor.

All statistical calculations were performed by Microsoft Excel2007 (Microsoft, Redmond, WA) and SPSS 20 (IBM, Armonk,NY). Significance was set at P � .05.

ResultsPatients

Sixty-seven patients with advanced NSCLC with u-EGFRmtreated with afatinib were identified. Twenty patients were classifiedas having complex mutations, 23 patients had ins20 mutations, and24 patients had single u-EGFRm. The 20 complex u-EGFRm ingroup A consisted of double mutations of G719XþE709F (n ¼ 1),G719XþS768I (n ¼ 11), G719XþL861Q (n ¼ 1),L858RþT790M (n ¼ 1), L858RþS768I (n ¼ 2), L858RþS765I(n ¼ 1), del19þS768I (n ¼ 1), del19þL747S (n ¼ 1), orR776CþL861Q (n ¼ 1) (Figure 1, Supplemental Table 1 in theonline version). In group C, most mutations were identified in exon18 (n ¼ 17), particularly in G719 (n ¼ 13); mutations were alsofound in exon 19 (n ¼ 3), exon 20 (n ¼ 2), exon 21 (n ¼ 1), andexon 22 (n ¼ 1).

common EGFR Mutation Distribution

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Of the 67 patients in the study, all had NSCLC of adenocarci-noma histology; approximately half were male (48%); and medianage was 63 years (range, 43e82 years). A total of 84% of the pa-tients were never/former smokers, 79% of the tumors were classifiedas stage IV at diagnosis, 79% of the patients had an EasternCooperative Oncology Group performance status (ECOG PS) of0 or 1, and 84% had not received prior surgery (Table 1). Infor-mation about metastatic sites was not mandatory for case reportform completion, so it was detailed in a minority of patients (n ¼ 3,exclusive lung M1; n ¼ 4, multiple M1 sites excluding centralnervous system involvement, n ¼ 4, were exclusive brain M1,n ¼ 56, information not specified). EGFR mutations were mostlyidentified by the Cobas EGFR Mutation Test (Roche MolecularSystems, Branchburg, NJ), in 64% of the patients. Other methodsincluded massive sequencing (9%), Sanger PCR (6%), and others(21%). No differences in clinical characteristics were found betweenthe 3 groups.

TreatmentThe median time from diagnosis to initiation of treatment with

afatinib was 1.84 months (interquartile range [IQR], 0.95; 12.4).Afatinib was administered as first-line treatment to 53 patients(80%). The starting dose of afatinib was 40 mg per day in 55 patients(82%), while a reduced dose (30 mg per day) was initially adminis-tered to 12 patients (18%). The reasons for an initial reduced dosewere: ECOG PS 2 in 4 patients, low weight in 4 patients, advancedage in 2 patients, and toxicity due to previous treatments, radio-therapy, comorbidities, and reason unknown in one patient each.

Median time receiving treatment for the overall cohort was 4.2months (IQR 2.0; 12.9); however, patients in groups A and C had alonger time of receipt of treatment: 7.1 months (IQR 2.8; 16.6) and8.0 months (IQR 2.1; 13.2), respectively. Median time receivingtreatment for group B was 3.3 months (IQR 1.9; 4.7).

After discontinuing afatinib, 22 patients received furthertreatment (6 patients in group A, 11 in group B, and 5 in group C),for a median of 4 cycles (range, 1e36 cycles). Treatments includedchemotherapy (platinum and pemetrexed doublet and paclitaxel,carboplatin, and bevacizumab triplet in 54.5% and 13.6% ofpatients, respectively) and other TKIs (9.1% of patients). At thedata cut for the analyses, 22 patients (32.8%) were still receivingtreatment with afatinib, 13 (19.4%) were receiving other treat-ments, 3 (4.5%) had died while receiving a TKI, and 22 (32.8%)had died after disease progression while receiving a TKI, and afurther 7 (10.4%) were lost to follow-up. Twenty-two patients(32.4%) did not receive any subsequent treatment after experi-encing disease progression while receiving afatinib, 9 of whom hadreceived afatinib as a second line after prior chemotherapy. Mainreasons for no further therapy included clinical deterioration andpatient decision.

EfficacyAt the data cutoff for OS analyses, 25 patients (37.3%) had died.

Median OS (mOS) for the overall cohort was 19.9 months (95%CI, 9.7, 30.1), but there was a significant difference according to thetype of u-EGFRm (P ¼ .013) (Figure 2). Patients in group A with amOS of 28.8 months (95% CI, 20.8, 36.8) and in group C with amOS of 19.9 months (95% CI, 10.8, 29.0) had a longer survival

nical Lung Cancer Month 2020

than patients in group B (mOS of 10.7 months; 95% CI, 6.2,15.3). Similarly, the survival at 12 and 18 months was alsoimproved in groups A and C compared to group B. In a univariateanalysis, the HRs for OS were 0.26 (95% CI, 0.10, 0.71; P ¼ .008)and 0.40 (95% CI, 0.17, 0.95; P ¼ .037) for groups A and Ccompared to group B, respectively.

In a multivariate analysis evaluating prior surgery, time receivingtreatment, and time to treatment, time to treatment was identifiedas a potential confounding variable (Supplemental Table 2 in theonline version). A longer time of receipt of treatment was associatedwith a better prognosis (HR, 0.91; 95% CI, 0.86, 0.97; P ¼ .005).In this analysis, the HRs for OS were 0.44 (95% CI, 0.16, 1.24;P ¼ .121) and 0.66 (95% CI, 0.27, 1.61; P ¼ .366) for groups Aand C compared to group B, respectively.

The best response in the overall cohort was 2 complete responsesand 28 partial responses, for an ORR of 45% and a disease controlrate of 67% (Table 2). The response differed significantly accordingto the mutation profile (P ¼ .001). Response to afatinib wassignificantly higher in groups A (70%) and C (54%) compared togroup B (13%; pairwise comparison P < .001 and .008, respec-tively). There was no significant difference between patients withcomplex mutations and patients with single mutations (P ¼ .419).The disease control rate was 85%, 48%, and 75%, in groups A, B,and C, respectively.

SafetyToxicities were reported in 38 patients (57%), with 4 patients

reporting grade 3 AEs (Table 3). The most common AEs reportedwere diarrhea in 22 patients (33%), rash in 18 patients (27%), andnailtoxicity in 12 patients (18%). The grade 3AEswere diarrhea, reportedin 1 patient; rash, reported in 2 patients; nail toxicity, reported in 1patient; and asthenia, reported in 2 patients. Sixteen patients (24%)required a dose reduction during treatment with afatinib as a result ofdiarrhea in 8 patients, rash in 5 patients, stomatitis or nail toxicity in 4patients each, and asthenia in 3 patients.

DiscussionIn the cohort of Spanish, mainly white, patients with u-EGFRm

NSCLC, the most common mutations occurred on exon 18 inamino acid G719, either alone or in combination with anothermutation, such as S768I. In clinical practice, afatinib was active inpatients with u-EGFRm NSCLC, particularly in patients withcomplex and single mutations. We cannot fully exclude that thebenefit in patients in group A may be driven by the patients withdel19 and L858R (25% in this group); however, our data areconsistent with other series of patients harboring double u-EGFRmcontaining both del19 and L8585R mutations and with betteroutcomes with erlotinib and gefitinib compared to those patientswith single u-EGFRm.8,9,11 However, in the subgroup of patientswith the u-EGFRm ins20, treatment with afatinib provided a lowerclinical benefit. Our result confirm prior results that have beenlargely demonstrated mostly with first-generation TKIs, indicatingthat further treatment strategies are needed for patients with thistype of u-EGFRm.

This study reflects clinical practice use of afatinib for the treat-ment of patients with u-EGFRm and as such has several limitationsthat should be considered. For example, several different methods

Table 1 Baseline Clinical, Demographic, and Molecular Data

Characteristic Variable Overall (N [ 67) Group A (N [ 20) Group B (N [ 23) Group C (N [ 24) P

Age (y) Median (range) 63.8 (28e84) 63 (43e82) 64.3 (28e84) 63.5 (38e78) .802

Sex Male 32 (47.8) 10 (50.0) 14 (60.9) 8 (33.3) .174

Female 35 (52.2) 10 (50.0) 9 (39.1) 16 (66.7)

Race Other 3 (4.5) 1 (5.0) 1 (4.3) 1 (4.2) 1.000

White 64 (95.5) 19 (95.0) 22 (95.7) 23 (95.8)

Tobacco exposure None 31 (46.3) 8 (40.0) 9 (39.1) 14 (58.3) .504

Former 25 (37.3) 7 (35.0) 10 (43.5) 8 (33.3)

Current 11 (16.4) 5 (25.0) 4 (17.4) 2 (8.3)

Detection method Sanger PCR 4 (6.0) 0 0 4 (16.7) .071a

Cobas 43 (64.2) 12 (60.0) 18 (78.3) 13 (54.2)

Massive sequencing 6 (9.0) 2 (10.0) 1 (4.3) 3 (12.5)

Others 5 (7.5) 4 (20.0) 0 1 (4.2)

Sanger/PCR plus others 9 (13.4) 2 (10.0) 4 (17.4) 3 (12.5)

Stage IV disease at diagnosis No 14 (20.9) 2 (10.0) 4 (17.4) 8 (33.3) .172

Yes 53 (79.1) 18 (90.0) 19 (82.6) 16 (66.7)

Prior surgery No 56 (83.6) 19 (95.0) 20 (87.0) 17 (70.8) .097a

Yes 11 (16.4) 1 (5.0) 3 (13.0) 7 (29.2)

ECOG PS 0e1 53 (79,1) 17 (85.0) 17 (73.9) 18 (75.0) .750

2e3 14 (20.9) 3 (15.0) 5 (21.7) 6 (25.0)

First-line afatinib No 14 (20.9) 3 (15.0) 5 (21.7) 5 (20.8) .860

Yes 53 (79.1) 17 (85.0) 17 (73.9) 19 (79.2)

Time to treatment (months) Median (IQR) [range] 1.84 (0.95; 12.4) [0.20e75.4] 1.81 (1.05; 5.21) [0.20e47.8] 2.07 (0.99; 9.93) [0.50e23.0] 1.69 (0.66; 16.6) [0.20e75.4] .908

Time receiving treatment(months)

Median (IQR) [range] 4.18 (2.04; 12.9) [0.56e36.3] 7.11 (2.78; 16.6) [0.79e26.0] 3.36 (1.97; 4.70) [0.66e23.3] 7.99 (2.11; 13.2) [0.56e36.3] .080a

Data are presented as n (%) unless otherwise indicated. Group A indicates complex mutations; group B, ins20 (EGFR exon 20 insertions); and group C, single mutations.Abbreviations: ECOG PS ¼ Eastern Cooperative Oncology Group performance status; IQR ¼ interquartile range.aStatistically significant. Tests were Kruskal-Wallis and log-rank test, as appropriate, and otherwise Fisher exact test.

Teresa

Moran

etal

ClinicalLungCancer

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Afatinib in NSCLC

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were used to detect mutations in EGFR, with different sensitivities.Approximately one fifth of the patients had ECOG PS > 1, whichis more representative of a population treated outside a clinical trial;however, it is also indicative of a population that has a worseprognosis. The size of the study is also a limitation, but it isindicative of the small patient population and is within the range ofother studies of patients with u-EGFRm NSCLC.16,40,42,45

No new safety signals were identified in our study that weredifferent to what has been reported with afatinib. Similarly, thenumber of patients requiring an afatinib dose reduction or initiationat a lower dose were also comparable to data reported in clinicaltrials. Efficacy data demonstrated that dose reduction led to adecrease incidence in AEs without jeopardizing efficacy.46 However,whether dose reduction in our cohort of patients could have had anydifferential outcome is uncertain.

Figure 2 Kaplan-Meier Curve for Overall Survival

Overall CohortN=67n (%)

Group AComplex mutatio

n=20n (%)

Median OS (95% CI) 19.9 (9.75, 30.1) 28.8 (20.8, 36.8

Survival at 12 months 65.1% 83.5%

Survival at 18 months 52.1% 83.5%

Survival at 24 months 37.5% 62.6%

Survival at 36 months 25.8% 31.3%

*Log -rank test.

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Afatinib was initially approved in 2013 in the United States forthe first-line treatment of patients with metastatic NSCLC withexon 19 deletions or exon 21 L858R substitutions and in Europefor EGFR TKIenaive patients with locally advanced or metastaticNSCLC with activating EGFR mutations, including both commonand uncommon mutations. In January 2018, the US Food andDrug Administration expanded the frontline indication for afatinibto include the treatment of patients with metastatic NSCLC whosetumors harbor the following u-EGFRm: L861Q, G719X, and/orS768I. The expanded approval was based on findings from 32patients with nonresistant u-EGFRm enrolled onto the phase 2LUX-Lung 2 trial and the randomized phase 3 trials LUX-Lung 3and LUX-Lung 6.16 ORR was 66% (95% CI, 47, 81), with aresponse lasting � 12 months in 52% of those with responseand � 18 months in 33% of those with response.47

nsGroup B

Ins 20n=23n (%)

Group CSingle mutations

n=24n (%) p-value*

) 10.7 (6.2, 15.3) 19.9 (10.8, 29.0) 0.013

39.6% 77.7%

24.7% 53.9%

35.9%

Table 2 Best Tumor Response

Responsea Overall (N [ 67) Group A (N [ 20) Group B (N [ 23) Group C (N [ 24) P

Complete response 2 (3.0) 1 (5.0) 0 1 (4.2) .001b

Partial response 28 (41.8) 13 (65.0) 3 (13.0) 12 (50.0)

Stable disease 16 (23.9) 3 (15.0) 8 (34.8) 5 (20.8)

Progressive disease 13 (19.4) 0 10 (43.5) 3 (12.5)

Not evaluable 8 (11.9) 3 (15.0) 2 (8.7) 3 (12.5)

Pairwise comparisonversus:

Group A <.001b .419

Group B .008b

Data are presented as n (%) unless otherwise indicated. Group A indicates complex mutations; group B, ins20 (EGFR exon 20 insertions); and group C, single mutations.aPatients with nonevaluable data were not included in the statistical analysis.bStatistically significant.

Teresa Moran et al

An open-label phase 3b trial recently evaluated afatinib inpatients with EGFR TKIenaive locally advanced/metastaticNSCLC in conditions similar to real-world practice.45 Interimoutcomes revealed that 84 (18%) of 479 enrolled patients had u-EGFRm (62 single u-EGFRm and 22 in combination with commonmutations), including ins20 (37 patients, 44% of u-EGFRm),T790M (12 patients, 14%), G719S/A/C (12 patients, 14%),L861Q (10 patients, 12%), S768I (9 patients, 11%), and othermutations (18 patients, 21%). The study did not report outcomesaccording to different u-EGFRm; however, for the whole u-EGFRmsubgroup, efficacy outcomes were worse than in commonmutations, likely due to outcomes in patients with ins20, repre-senting half the subgroup population.

Recent reports have shown better activity of afatinib than otherEGFR TKIs, including osimertinib in u-EGFRm L747P orL747S.43,44 In our study, there was one patient with u-EGFRmL747P with a partial response as a best response, who receivedafatinib for 10 months and was still receiving treatment at data

Table 3 Safety and Tolerability of Afatinib

AE All AEs Grade 1

All subjects (n ¼ 67)

Any AE reported 38 (56.7) 23 (34.

Diarrhea 22 (32.8) 13 (19.

Rash 18 (26.9) 6 (9.0

Nail toxicity 12 (17.9) 2 (3.0

Stomatitis 10 (14.9) 5 (7.5

Asthenia 5 (7.5) 2 (3.0

Other cutaneous AEsa 4 (6.0) 4 (6.0

Dose reduction during therapy(n ¼ 16, 23.8%)

Diarrhea 8 (50.0) —

Rash 5 (31.2) —

Stomatitis 4 (25.0) —

Nail toxicity 4 (25.0) —

Asthenia 3 (18.7) —

Data are presented as n (%) unless otherwise indicated.Abbreviation: AE ¼ adverse event.aIncludes pruritus and xerostomia.

cutoff. One patient with L747S also had a partial response, receivedafatinib for 4.1 months, and was also still receiving afatinib at datacutoff. In a phase 2 study in 36 patients with NSCLC with EGFRmutations other than del19, L858R, T790M, or ins20, patientsreceived osimertinib 80 mg once daily as first-line treatment in 61%of patients.48 The most common mutations were in exon 18 inG719 (19 patients, 53%), followed by L861Q (9 patients, 25%)and S7681 (8 patients, 22%). In the overall cohort, ORR was 50%and disease control rate was 89%, with higher efficacy in patientswith L861Q (ORR of 78%) or G719 (ORR of 53%) mutationsthan patients with S768I mutations (38%). Although cross-trialcomparisons should be made with caution, osimertinib appearedto demonstrate a similar benefit, specially in patients with L861Qand G719X mutations, with an overall lower toxicity and withpromising results in central nervous system metastases control.Considering the cumulative evidence of osimertinib-related AEs andits acceptable toxicity profile in this trial, these results make osi-mertinib of special interest in this population. Osimertinib could

AE Grade 2 AE Grade 3 AE

3) 25 (37.3) 4 (6.0)

4) 8 (11.9) 1 (1.5)

) 10 (14.9) 2 (3.0)

) 9 (13.4) 1 (1.5)

) 5 (7.5) 0

) 1 (1.5) 2 (3.0)

) 0 0

2 (12.5) 6 (37.5)

2 (12.5) 3 (18.7)

3 (18.7) 1 (6.3)

2 (12.5) 2 (12.5)

0 3 (18.7)

Clinical Lung Cancer Month 2020 - 7

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8 - Cli

thus be proposed in patients harboring L861Q and G719X muta-tions, or other single or complex u-EGFRm, and specially in thosepatients with central nervous system involvement. Still, osimertinibcould play a role as a subsequent therapeutic line after afatinib inthose patients who develop T790M-acquired resistance, although ithas been reported a lower incidence of such mechanism in patientswith u-EGFRm.49 Other possible strategies that can be suggested aspotentially active for patients with u-EGFRm include the combi-nation of osimertinib plus antiangiogenics, such as bevacizumab(NCT03133546), or TKI plus chemotherapy, although these stra-tegies have not been formally tested in this population.

Approximately 4% to 10% of EGFR mutations are ins20mutations.50 There are no approved targeted agents, but there areseveral agents being investigated specifically in patients with ins20 inEGFR or human epidermal growth factor receptor 2 (HER2), suchas poziotinib and TAK-788, with some promising results.51-56

However, their overall efficacy results are in line with thegenerally poor results in this population with ins20, similar to theresults of the present study. A clinical trial with osimertinib is alsoongoing in this patient population (NCT03191149). Thus, effec-tive treatments are eagerly awaited for patients with ins20, for whomthere is a high unmet need.

ConclusionAfatinib was highly active in patients with complex and single u-

EGFRm, particularly in patients with mutations in G719 eitheralone or with a comutation, such as S768I. Further treatmentstrategies are needed for patients with ins20.

Clinical Practice Points

� We conducted a real-world analysis of patients with u-EGFRmNSCLC.

� Afatinib was active in patients with u-EGFRm NSCLC.� Best outcomes with afatinib were observed in complex or singleu-EGFRm.

� Strategies are needed for patients with ins20, for whom there is ahigh unmet need.

AcknowledgmentsSupported in part by Boehringer Ingelheim for statistical analysis

and editorial assistance. The authors thank Aurora O’Brate foreditorial assistance.

The following investigators participated in the study as part of theStudy Group for the Uncommon EGFR Mutations in Spain:Georgia Anguera (Hospital de Sant Pau i Santa Creu, Barcelona,Spain); Joaquim Bosch (ICO-Girona, Girona, Spain); Luis Cabezón(Hospital Universitario de Torrejón, Madrid, Spain); Silvia Catot(Fundació Althaia, Manresa, Barcelona, Spain); Alex Martinez (Valld’Hebron Hospital and Institute of Oncology, Barcelona, Spain);Silvia Muñoz (Hospital de Granollers, Barcelona; Spain); andInmaculada Ramos (Hospital Virgen de la Victoria, Málaga, Spain).

DisclosureT.M. has received personal fees from Boehringer Ingelheim for

lecture speaking. A.T. reports personal fees and nonfinancial sup-port from Roche and Boehringer-Ingelheim; nonfinancial support

nical Lung Cancer Month 2020

from Lilly; and personal fees from BMS, MSD, and Pfizer. E.A.reports personal fees and nonfinancial support from BMS; personalfees from AstraZeneca; grants, personal fees, and nonfinancialsupport from Roche; personal fees and nonfinancial support fromMSD; personal fees from Lilly; grants and personal fees from Pfizer;and personal fees from Boehringer Ingelheim. C.A. reports personalfees from Boehriger Ingelheim, Roche, AstraZeneca, MSD, andNovartis; and nonfinancial support from Boehriger Ingelheim,Roche, and Novartis. A.C. reports personal fees from BoehrigerIngelheim, Roche, AstraZeneca, MSD, Pfizer, BMS, Lilly, andNovartis. The other authors have stated that they have no conflict ofinterest.

Supplemental DataSupplemental tables accompanying this article can be found in

the online version at https://doi.org/10.1016/j.cllc.2020.04.011.

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Supplemental Data

Supplemental Table 1 Numbers of Uncommon EGFR Mutations in Each Group

Site MutationGroup A(N [ 20)

Group B(N [ 23)

Group C(N [ 24)

G719þS768 G719XþS768I 11

Other G719SþE709F 1

G719XþL861Q 1

L858RþT790M 1

L858RþS768I 2

L858RþS765I 1

Del19þS786I 1

Del19þL747S 1

R776CþL861Q 1

ins20 ins20 NE 19

V769_D770 1

D770_N771 1

ins20þdel19 2

G719 (exon 18) G719 NE 1

G719A 2

G719X 9

G719S 1

Other exon 18 E709A 1

F723I 1

Exon 18 NE 2

Exon 19 Delþins19 1

L747S 1

L747P 1

S768 (exon 20) S768I 1

Other exon 20 T790M 1

L861 (exon 21) L861Q 1

Exon 22 Exon 22 NE 1

Data are presented as n (%) unless otherwise indicated. Group A indicates complex mutations; group B, ins20 (EGFR exon 20 insertions); and group C, single mutations.Abbreviations: EGFR ¼ epidermal growth factor receptor; NE ¼ not evaluable.

- Clinical Lung Cancer Month 2020

Supplemental Table 2 Multivariate Analyses for Time to Overall Survival

Analysis Group A (N [ 20) Group B (N [ 23) Group C (N [ 24)

Univariate

HR (95% CI); P 0.26 (0.10, 0.71) .008 1 0.40 (0.17, 0.95) .037

Adjusted models

HR (95% CI); P 0.26 (0.10, 0.69) .007 1 0.43 (0.18, 1.02) .055

Surgery 0.55 (0.19, 1.62) .277

HR (95% CI); P 0.44 (0.16, 1.24) .121 1 0.66 (0.27, 1.61) .366

Time receiving treatment 0.91 (0.86, 0.97) .005

HR (95% CI); P 0.26 (0.1, 0.72) .009 1 0.4 (0.16, 0.98) .045

Time to treatment 1 (0.97, 1.03) .971

Group A indicates complex mutations; group B, ins20 (EGFR exon 20 insertions); and group C, single mutations.Abbreviations: CI ¼ confidence interval; HR ¼ hazard ratio.

Teresa Moran et al

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This e-print is distributed with the support of Boehringer Ingelheim

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