Lung Cancer
Afatinib in Non-Small Cell Lung Cancer Harboring Uncommon EGFR Mutations Pretreated With Reversible EGFR Inhibitors ¨ DAVID F. HEIGENER,a,* CHRISTIAN SCHUMANN,b,* MARTIN SEBASTIAN,c PARVIS SADJADIAN,d INGO STEHLE,e ANGELA MA¨ RTEN,f ANNE LUERS ,g FRANK GRIESINGER,g,* MATTHIAS SCHEFFLER,h,* FOR THE AFATINIB COMPASSIONATE USE CONSORTIUM (ACUC) a LungenClinic Grosshansdorf, Thoracic Oncology, German Center for Lung Research, Grosshansdorf, Germany; bClinic for Pulmonary, Thoracic Oncology, Sleep and Respiratory Critical Care, Kempten-Oberallgaeu Hospitals GmbH, Immenstadt, Germany; cDepartment of Medicine II, University Hospital Frankfurt, Frankfurt, Germany; dClinic for Hematology, Oncology and Palliative Medicine, Minden, Germany; eDepartment of Internal Medicine V, University Hospital of the Saarland, Homburg, Germany; fBoehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany; gDepartment Hematology and Oncology, Pius-Hospital Oldenburg, University Department of Internal Medicine-Oncology, Medical Campus, University of Oldenburg, Oldenburg, Germany; hDepartment of Internal Medicine I, Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany *Contributed equally.
Disclosures of potential conflicts of interest may be found at the end of this article.
Key Words. Afatinib x Non-small cell lung cancer x ErbB receptors x Epidermal growth factor receptor x Compassionate use trials
ABSTRACT Background. Afatinib, an irreversible ErbB family blocker, is approved for treatment of patients with previously untreated non-small cell lung cancer (NSCLC) harboring activating epidermal growth factor receptor (EGFR) mutations. Efficacy of afatinib in EGFR tyrosine kinase inhibitor-na¨ıve (TKI-na¨ıve) patients with uncommon EGFR mutations (other than exon 19 deletions or exon 21 point mutations) has been reported; however, efficacy in TKI-pretreated patients with uncommon EGFR mutations is unknown. Materials and Methods. In the afatinib compassionate use program (CUP), patients with advanced or metastatic, histologically confirmed NSCLC progressing after at least one line of chemotherapy and one line of EGFR-TKI treatment were enrolled. Demographic data, mutation type, response rates, time to treatment failure (TTF), and safety in patients harboring uncommon EGFR mutations were reported.
Results. In 60 patients (63% female, median age 63 years [range: 30–84 years]), a total of 66 uncommon EGFR mutations including 30 T790M mutations were reported (18.4% and 11%, respectively, of known EGFR mutations within the CUP). Most patients (67%) received afatinib as third- or fourth-line treatment. Median TTF was 3.8 months (range: 0.2 to .24.6 months; p 5 .244) in patients with uncommon mutations compared with 5.1 months (range: 0.1 to .21.1 months) in patients with common mutations (n 5 165). Pronounced activity was observed with E709X mutations (TTF .12 months). No new safety signals were detected. Conclusion. Afatinib is clinically active and well tolerated in many TKI-pretreated NSCLC patients harboring uncommon EGFR mutations. Compared with results reported in TKI-na¨ıve patients, activity was also indicated in patients with T790M and exon 20 insertion mutations. The Oncologist 2015;20:1167–1174
Implications for Practice: This analysis consists of a large database of non-small cell lung cancer patients with uncommon EGFR mutations who were previously treated with reversible EGFR tyrosine kinase inhibitors. Although indirectly assessed, the results indicate that patients with uncommon EGFR mutations can derive benefit from treatment with the irreversible ErbB family blocker afatinib, even in some cases of tumors harboring resistance-mediating exon 20 mutations. In this study, adverse events were modest and consistent with previous reports on afatinib.
INTRODUCTION Treatment with an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is standard in patients with metastatic non-small cell lung cancer (NSCLC) harboring activating EGFR mutations.The two most common EGFR mutations account for ∼90% of all mutation-positive NSCLC cases and are known to
confer sensitivity to EGFR-TKIs: in-frame deletions in exon 19 (Del19) and a point mutation in exon 21 (L858R) [1].The efficacy of first-generation reversible EGFR-TKIs like erlotinib and gefitinib on tumors with uncommon EGFR mutations was reported to be lower than in common mutations [2, 3].
Correspondence: David F. Heigener, M.D., LungenClinic Grosshansdorf GmbH, W¨ohrendamm 80, 22927 Grosshansdorf, Germany. Telephone: 04102-601-2103; E-Mail: [email protected] Received February 25, 2015; accepted for publication July 15, 2015; published Online First on September 9, 2015. ©AlphaMed Press 1083-7159/2015/$20.00/0 http://dx.doi.org/10.1634/theoncologist.2015-0073
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Afatinib is an orally available ErbB family blocker, binding to ErbB1 (EGFR), ErbB2 (HER2) and ErbB4, and inhibiting signaling of all homodimers and heterodimers of these receptors [4, 5]. Due to the acrylamide group in the molecule, the binding is—in contrast to gefitinib and erlotinib—covalent and thus irreversible. Afatinib has shown superior progression-free survival (PFS), overall survival (OS), and patient-reported outcomes compared with standard chemotherapy as first-line treatment of patients with NSCLC harboring common EGFR mutations [6–9]. In preclinical models, afatinib has also shown activity against uncommon EGFR mutations like T790M, which has been associated with acquired resistance to EGFR-TKIs [5, 10]. Treatment options for patients with acquired resistance to gefitinib and erlotinib [11] are urgently needed. To investigate the efficacy and tolerability of afatinib in heavily pretreated patients with uncommon EGFR mutations, a subgroup of appropriate patients enrolled in a compassionate use program (CUP) were selected and analyzed.The results of the whole CUP cohort are published elsewhere [12].
afatinib treatment (if not reported, it was calculated as 7 days after shipment) to end of treatment (if not reported, the date of the last order was used). Significance was determined at p , .05. The database was locked on December 31, 2013, and patients still on treatment were censored. Survival curves were estimated using the Kaplan-Meier method for TTF. A Cox model was applied to estimate hazard ratios and 95% confidence intervals (CIs). Analyses were undertaken using MedCalc version 12.1.4.0 (MedCalc Software, Ostend, Belgium, https:// www.medcalc.org). Patients receiving ,2 months’ targeted therapy before stopping due to progressive disease, death, or switching therapy were classified with a best response of “progressive disease,” whereas patients who were on treatment .4 months were classified with a best response of “stable disease” if not reported differently.
MATERIALS AND METHODS
In total, 66 uncommon mutations in 60 patients were reported (18.4% of all known EGFR mutations in the CUP). Most patients (57%) received a reversible TKI in the second line, with a median treatment duration of 10.0 months (Tables 1, 2). The majority of patients (67%) received afatinib as third- or fourthline treatment, with median treatment duration of 3.6 months. Sixty-three percent were female, and the median age was 63 years, ranging from 30 to 84 years (Tables 1, 2). In some instances, cetuximab was added to afatinib in the course of treatment (n 5 6). Demographics of patients with uncommon EGFR mutations did not differ from the whole CUP population (Tables 1, 2).
Compassionate Use Program The CUP was started in May 2010 to enable access to afatinib for patients with life-threatening disease and no other standard treatment option.Inclusioncriteria for theCUP werebased on the LUX-Lung 1 study comparing afatinib monotherapy with placebo in heavily pretreated patients. LUX-Lung 1 failed to reach its primary endpoint of improving OS but resulted in a doubling of PFS [13]. Patients enrolled in the CUP had advanced NSCLC and were ineligible to participate in another actively accruing afatinib phase III trial, had failed at least one line of cytotoxic chemotherapy, and showed tumor progression after clinical benefit on erlotinib or gefitinib (i.e., stable disease for $6 months, a complete response, or partial response) or the presence of an activating mutation of the EGF/Her receptor family, were aged $18 years, had no further established treatment option available, and had provided written informed consent.The competent authorities (Federal Institute for Drugs and Medical Devices [BfArm]; goverments’ steering committee) were informed, and approval by the ethics committee was given (837.105.10[7114]). The CUP was stopped with market availability of afatinib in the European Medicines Agency region.
Centers and Clinical Data In total, 573 patients were enrolled from 118 centers in Germany, and 546 were treated with afatinib. Physicians were asked to provide age, sex, pretreatments, comorbidities, and mutational status to allow checks for eligibility and to report adverse events including tumor progression. All data were reported anonymously. Physicians who had patients with uncommon mutations were approached after closure of the CUP by the authors to fill in a structured documentation sheet for more information on the mutational status (time of testing, EGFR detection method, response to reversible TKI and to afatinib).
Statistics Descriptive analysis was performed for patient demographics. Time to treatment failure (TTF) was defined from start of
RESULTS Demographics of Patients With Uncommon EGFR Mutations
Uncommon EGFR Mutations A total of 23 uncommon EGFR mutations were detected at time of diagnosis; 15 were reported to be acquired mutations (all T790M), and for the remaining cases, time of detection was not reported. Of the uncommon EGFR mutations detected, 21% were on exon 18, 9% were on exon 19, 55% were on exon 20, and 16% were on exon 21. A total of 30 patients (45% of uncommon mutations) had T790M mutations (18 had T790M plus exon 19, 11 had T790M plus exon 21, and 1 had T790M alone), 10 patients had G719X mutations (3 had G719A, 2 had G719C, 2 had G719S, 1 had G719A plus E709A, 1 had G719C plus E709A, and 1 had G719C plus L861Q), 6 had L861Q mutations (2 alone, 2 plus T790M and each one plus G719C or L858M), 4 had E709X mutations (3 had E709K plus L858R, 1 had E709A plus G719X), and 4 had insertions in exon 20 (1 also had Del19). Further mutations included A702S, A750V, deletion and insertion (delins) exon 19 (n 5 2), G753S, point mutation exon 19, S768I plus V769L, R776H plus L858R, L858M, L858M plus L861Q, G857E, and G861L plus T790M (Fig. 1).
Time to Treatment Failure and Best Response Median TTF for patients with T790M mutations (n 5 30) was 4.4 months (range: 0.4–21.8 months), with 4.4 months (range: 0.8–14.9 months) for patients (n 5 15) with acquired T790M and 4.9 months (range: 0.4–21.8 months) for patients with unknown time of first appearance (n 5 14) or de novo T790M
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Table 1. Patient characteristics Common mutations Characteristics Female, n (%) Male, n (%) Age, median (range) Time between initial diagnosis and enrollment in CUP, months, median (range) Histology, n (%) ADC SCC BAC LCC Metastases, n (%) Known brain metastases Known bone metastases Afatinib treatment line, n (%) Second linea Third line Fourth line Fifth line Sixth to ninth lines
Uncommon mutations (n 5 60)
Del19 (n 5 106)
L858R (n 5 59)
38 (63) 22 (37) 63 (30–84) 22.8 (4.5–120.7)
78 (75) 26 (25) 61 (31–87) 23.2 (8.5–139.3)
43 (73) 16 (27) 68 (46–89) 17.9 (7.3–122.5)
54 (90) 2 (3) 2 (3) 0 (0)
97 (92) 0 (0) 6 (6) 2 (2)
52 (88) 4 (7) 2 (3) 0 (0)
15 (25) 20 (33)
21 (20) 38 (36)
15 (25) 35 (59)
9 (15) 22 (37) 18 (30) 6 (10) 5 (8)
3 (3) 21 (20) 73 (69) 7 (7) 2 (2)
5 (8) 35 (59) 10 (17) 6 (10) 3 (5)
a
Patients ineligible for chemotherapy. Abbreviations: ADC, adenocarcinoma; BAC, bronchioloalveolar carcinoma; CUP, compassionate use program; LCC, large cell carcinoma; SCC, squamous cell carcinoma.
mutation (n 5 1) (p 5 .823). TTF for G719X (n 5 10) was 2.6 months (range: 0.2 to ongoing at 24.6 months); TTF for L861Q (n 5 4) was 3.3 months (range: 1.5–9.9 months); TTF for E709X (n 5 4) was 12.2 months (range: ongoing at 0.8–16.7 months); and TTF for insertion exon 20 (n 5 4) was 6.5 months (range: ongoing at 3.6–9.1 months). Patients with A702S, A750V, delins exon 19, G753S, point mutation exon 19, R776H, S768I, V769L, G857E, G861L, and L858M (n 5 14) had TTF varying from 0.8 to ongoing at 16.8 months. In total, 20 patients (33%) were still on treatment at time of database lock (Table 3). Patients with common EGFR mutations (n 5 165) had a median TTF of 4.9 months (range: 0.1 to ongoing at 21.1 months), 4.6 months in patients with Del19 (n 5 106), and 5.8 months in L858R (n 5 59), compared with patients with uncommon mutations of 3.6 months (range: 0.2 to ongoing at 24.6 months) (Fig. 2). This was not significant. From 58 evaluable cases, 22% (n 5 13) had a partial response (including one mixed response), 47% (n 5 27) had stable disease, and 31% (n 5 18) had progressive disease as best response, with L858M mutations showing the highest percentage of patients with a partial response. T790Mmutated patients responded mostly with stable disease (56%) (Table 4).
Safety Profile The complete safety profile from this CUP is reported elsewhere [12]. The afatinib safety profile was as expected, with diarrhea and skin-related adverse events being the most common; no new safety signals were observed. Afatinib was administered continuously at a starting dose of 50 mg in 38
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patients (63%), 40 mg in 13 patients (22%), and 30 mg in 9 patients (15%). Dose reductions from 50 to 40 mg were observed in 19 patients and to 30 mg in 10 patients.
DISCUSSION To the knowledge of the authors, this study has the largest prospective cohort of patients carrying uncommon EGFR mutations and failing on EGFR-TKI published so far; however, the intention of the CUP was to provide a treatment option for patients for whom no further established therapy was available. Consequently, only a minimal data set was required for inclusion, no structured data collection was rolled out, and no source data verification was performed, limiting the quality and generalizability of the data. The reported incidence of 11% of nonacquired uncommon EGFR mutations is in line with other reports [6, 7, 14, 15]. The data reported so far regarding distribution of uncommon mutations are either from TKI-na¨ıve or mixed populations; therefore, a comparison with this population is not possible. Beau-Faller et al. reported an incidence in TKI-na¨ıve patients of 40% for insertions in exon 20 (ins exon 20) but only 12% complex mutations [14]. Our cohort consists of 63% complex mutations but only 5% ins exon 20, indicating that although complex mutations are acquired during reversible EGFR-TKI treatment, patients with tumors harboring the ins exon 20 mutation were unlikely to be treated in later lines. Yasuda et al. described that the structure of ins exon 20 activates EGFR without increasing its affinity for EGFR-TKIs [16]; however, a certain ins exon 20 mutation (Y764insFQEA) was described to be highly sensitive to EGFR-TKIs in vitro, and ©AlphaMed Press 2015
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Table 2. Prior therapy in patients with uncommon mutations (n 5 60) Treatment line
First Second Third (n 5 60, 100%) (n 5 52, 87%) (n 5 29, 48%)
Chemotherapy, n (%) Platinum 34 (57) doublet Monotherapy 1 (2) Targeted therapy, n (%) Erlotinib 6 (10) Gefitinib 17 (28) Afatinib 0 (0) TKI duration, 6.5 months Others 1 (2)
9 (17)
6 (21)
7 (13)
9 (31)
25 (48) 9 (17) 0 (0) 10.0
8 (28) 3 (10) 1 (3) 14.5
2 (4)
2 (7)
Abbreviation: TKI, tyrosine kinase inhibitor.
Figure 1. Distribution of the 60 rare EGFR mutations. Abbreviation: incl., including.
patients with NSCLC harboring this mutation responded to erlotinib. Because we do not have detailed information on the specific ins exon 20 mutation included in our cohort, we can only speculate whether the observed outcome (TTF 6.5 months) might be due to higher incidence of this responding insertion mutation. In our analysis, afatinib has generally shown efficacy in patients with uncommon EGFR mutations but to a lesser degree compared with patients with common EGFR mutations (3.8 and 5.1 months, respectively). Nonetheless, uncommon mutations were a very heterogeneous group, with E709X mutations and rare mutations on exon19 showing quite a long time to treatment failure (.12 and 6.5 months, respectively) and good response rates, whereas G719X mutations showed less benefit (2.6 months). Only limited data are available on efficacy of reversible EGFR-TKIs on uncommon EGFR mutations, and these data are mostly for TKI-na¨ıve patients. Klughammer et al. reported a TTF of 3.5 months for uncommon EGFR mutations from several trials with erlotinib in TKI-na¨ıve patients [17]. Wu et al.,
excluding de novo T790M and ins exon 20, showed a median PFS of 5.0 months in TKI-na¨ıve patients treated with reversible EGFR-TKIs, driven mainly by G719X and X861X mutations (median PFS 6.0 months), whereas the other uncommon mutations progressed after 1.6 months [18]. In the large first-line studies comparing afatinib with chemotherapy, efficacy has also been reported in a broad variety of uncommon EGFR mutations. In this TKI-na¨ıve cohort, however, de novo T790M and ins exon 20 mutations showed inferior results compared with other uncommon mutations with PFS of 2.9 months (95% CI: 1.2–8.3) for T790M, 2.7 months (95% CI: 1.8–4.2) for ins exon 20, and 10.7 months (95% CI: 5.6–14.7) for other uncommon mutations [19]. G719X and ins exon 20 represent the largest subset in the heterogeneous group of uncommon EGFR mutations; in this subset, different patterns according to treatment line could be seen. In TKI-na¨ıve patients, a median PFS of 1.4 months for ins exon 20 and 8.1 months for G719X have been reported [14]. Data from Wu et al. describing a PFS of 8.1 months for TKI-na¨ıve patients with different stages of NSCLC harboring G719X mutations go into a similar direction [18]. A combined analysis [19] from LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6 showed the same trend—although numerically higher—for afatinib in EGFR-TKI–na¨ıve patients (2.7 months for ins exon 20 and 13.8 months for G719X). The different outcomes depending on EGFR-TKI experience and line of treatment could be interpreted as (a) positive selection of responding mutations (in the case of ins exon 20) and (b) potentially, a process of acquiring additional mutations that negatively affect outcomes. This could not be proven in this cohort because 50% of the patients with G719X mutations were tested for EGFR mutational status prior to treatment with reversible EGFR-TKI, and EGFR testing is unknown for the remaining patients. T790M is a high-profile uncommon EGFR mutation. It can be detected de novo and is responsible for approximately 50% of acquired resistance to reversible EGFR-TKIs [10] due to the fact that these agents show in vitro halfmaximal inhibitory concentration values of roughly 250fold higher for T790M [20] compared with common EGFR mutations, explaining their limited effectiveness. In vitro activity of afatinib on T790M mutations has been shown; however, clinical activity with afatinib monotherapy in patients after reversible EGFR-TKI failure did not meet expectations (PFS 3.3 vs. 1.1 months for placebo and no difference in OS) [13]. The different efficacy of afatinib in the TKI-na¨ıve setting compared with patients with acquired resistance is in line with previously reported results in T790M-positive tumors, indicating that the predictive value of T790M in TKI response is dependent on the time point of the occurrence of the mutation. De novo T790M, together with an activating mutation, has been described by different authors, with an incidence ranging from #1% up to 65% [3, 21–24]. These results were dependent on the sensitivity of the method, with more sensitive methods detecting a higher incidence of de novo T790M. If T790M is detected by conventional methods such as Sanger sequencing, the incidence is ∼1%. The largest series of patients with de novo T790M has been reported by Riely et al.
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Table 3. Treatment duration and best response with reversible TKIs and afatinib Uncommon mutation Exon 18 A702S E709K 1 L858R E709A 1 G719A G719A G719C G719S G719C 1 L861Q Exon 19 A750V Delins exon19 Point mut exon19 G753S Exon 20 T790M acquired T790M 1 Del19
n
Reversible TKI treatment duration (months)
Best response to reversible TKI
Afatinib treatment duration (months)
Best response to afatinib
1 3 1 2 2 2 1
2 (G)a 8 (E),a 12 (G), 26 (G)a 12 (E)a ,1 (G), 16 (E) 2 (G),a 4 (G) 10 (E),a 18 (E) 12 (G)a
PDa SD,a SD, CRa PDa PD, SD PDa, NR SDa, SD 1 PRa
0.3a 0.8,a 7.1,b 12.2a 16.7a 6.4,b 24.6b 0.2,a 0.8 2.6,a 10.0 2.3a
PD PR, SD, SD PR SD, SD PD, NR NR, NR PD
2 2 1 1
2 (E),a 18 (E)a 3 (G), 10 (E)a 23 (G) 1 (G)a
PDa, PRa NR, SDa SD PDa
1.8,a 4.4a 8.5, 15.1a 3.5 0.9
SD, NR SD, PR NR PD
1 7
60 (E) 8 (E), 41 (E),a 20 (G), 7 (G), 5 (E), 14 (E), 11 (E) 10(G),8(G)/3(G),19(E),12(E), 18 (E), 9 (E), 21(E), 7 (G)/1 (E)
SD SD, SD,a PR, SD, SD, SD, SD SD, MR/PD, SD, PR, SD, PR, SD, SD SD, SD PR
5.4 0.4, 1.0, 2.3,b 2.5, 3.5, 5.7,b 8.1 0.8, 1.9,b 2.2, 3.8, 5.2,b 10.1, 10.2, 14.9 2.7, 5.6 4.4
SD PD, SD, PD, PD, PD, SD, NR PD, NR, NR, SD, SD, PR, SD, PR PD, SD SD
T790M 1 Del19 acquired
8
T790M 1 exon 19 T790M 1 exon 19 acquired T790M 1 L858R
2 1
9 (E), 6 (G) 13 (E)
4
2.4, 4.9, 7.0, 19.5b
SD, SD, PR, SD
T790M 1 L858R acquired T790M 1 exon 21 T790M 1 exon 21 acquired T790M 1 G861L T790M 1 L861Q acquired Ins exon 20 Ins exon 20 1 Del19 R776H 1 L858R S768I 1 V769L V769L 1 S768I Exon 21 L861Q L861Q 1 L858M G861L 1 T790M L861Q 1 T790M L861Q 1 G719C L858M L858M 1 L861Q G857E
3
6 (G)/30 (E), 15 (E)/7 (E), 32 SD, SD, SD, SD (E), 10 (E)/17 (G) 7 (E), 8 (G)/3 (E), 14 (E) PR, SD/NR, PR
2.8, 3.6, 10.7
SD, SD, PD
1 1
34 (E) 2 (E)
PR PD
21.8 1.5
MR PD
1 1
12 (E) 3 (G)
SD PD
1.5 3.6
PD SD
3 1 1 1 1
3 (E),a 3 (G)/2 (E), 21 (E) 10 (G)/22 (E)a 8 (E) 14 (G)a 14 (G)a
PDa, NR/NR, SD SD/PRa SD SDa SDa
2.7, 3.8, 9.1 6.5b 1.7 2.2 2.2
PD, NR, PR SD PD NR NR
3 1 1 1 1 1 1 1
22 (G), 3 (G), 12 (E) 2 (E)a 12 (E)a 3 (G)a 12 (G)a 6 (G) 2 (E)a 2 (E)
PR, PD, PR NRa SDa PDa 1 PR (G)a SD NRa NR
1.5, 3.6, 4.3 9.9 1.5 3.6 2.3a 16.8b 9.9 2.0
SD, SD, PR PR PD SD PD PR PR PD
a
De novo. Censored. Abbreviations: CR, complete response; Del, deletion; delins, deletion and insertion; (E), erlotinib; (G), gefitinib; ins, insertion; MR, mixed response; mut, mutation; NR, not reported; PD, progressive disease; PR, partial response; SD, stable disease; TKI, tyrosine kinase inhibitor.
b
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Figure 2. Time to treatment failure of common and uncommon EGFR mutations.
Table 4. Best response to afatinib Variable
PR, n (%)
SD, n (%)
PD, n (%)
All (n 5 58) A702S (n 5 1/1) E709X (n 5 4/5) G719X (n 5 7/10) A750V (n 5 1/2) Delins exon 19 (n 5 2/2) G753S (n 5 1/1) Ins exon 20 (n 5 3/4) T790M (n 5 27/31) V769L (n 5 1/1) S768I (n 5 1/1) L861Q (n 5 6/6) L858M (n 5 2/2) G861L (n 5 1/1) R776H (n 5 1/1)
13 (22)
27 (47)
18 (31) 1 (100)
2 (50) 1 (14)
2 (50) 3 (43)
1 (50)
1 (50)
1 (33) 4a (15)
1 (33) 15 (56) 1 (100) 1 (100) 3 (50)
2 (33) 2 (100)
3 (43) 1 (50) 1 (100) 1 (33) 8 (30)
1 (17) 1 (100) 1 (100)
a
Includes one mixed response. Abbreviations: delins, deletion and insertion; ins, insertion; PD, progressive disease; PR, partial response; SD, stable disease.
[25]: 15 patients with de novo T790M were identified and treated with first-line TKI; PFS was 1.5 months and OS was 1.3 years compared with 3.0 years in patients who lacked T790M. Most recently, a Korean group detected T790M by matrix-assisted laser desorption/ionization-time and flight/ mass spectrometry in 31 of 124 patients (25%) and evaluated the impact of the mutation frequency of de novo T790M [26]. With a frequency .3.2%, T790M conferred an inferior outcome to TKI treatment (6.3 vs. 11.5 months). Costa et al. reported an incidence of de novo T790M of 65% in the EURTAC trial, showing a significant difference in outcome in the erlotinib-treated population (PFS was 15.8 months for those without the concomitant T790M mutation compared with 9.7 months for those with the T790M mutation [p , .0185]) but no difference in the chemotherapy group [24]. The largest data set for acquired resistance was published by Oxnard et al. [27]. This group identified 58 patients with
acquired TKI resistance by T790M and compared them with 35 patients with acquired TKI resistance without T790M. In this analysis,T790M conferred better survival and PFS than the lack of T790M, suggesting that T790M indicates a more indolent tumor when observed in the TKI-resistant setting [27]; the data generated in the afatinib CUP program are consistent with these findings. Third-generation EGFR-TKIs are under clinical development addressing T790M more or less exclusively. In phase I trials, AZD9291 and CO-1686 achieved response rates of 61% and 67%, respectively, in pretreated patients with acquired T790M mutations; response rates were 21% and 36%, respectively, in patients with T790Mnegative tumors [28, 29]. Median PFS with AZD9291 and CO-1686, respectively, was 9.6 months and 10.4 months in patients with T790M-positive tumors and 2.8 months and 7.5 months in patients with T790M-negative disease [28, 29]. Based on the current analyses, it seems that no clinical characteristic is associated with uncommon EGFR mutation. There were more male patients in the uncommon mutation group compared with those with common mutations, and a shorter time from initial diagnosis until enrollment for patients with L858R-mutated tumors compared with patients with tumors harboring Del19 mutations. Interestingly, patients with concomitant L858R-mutated tumors had similar treatment duration with afatinib as those with concomitant Del19-positive tumors. This is in contrast to the data from first-line trials in EGFR-mutated patients in which patients with L858R-positive tumors showed a shorter PFS [30]. An explanation could be that the acquired resistance mechanisms of L858R-positive tumors are distinct from those in Del19-positive tumors, rendering the former more prone to respond to afatinib. In this regard, it has been shown that L858R-positive tumors have low-level T790M clones at a higher incidence than Del19-positive tumors. In the analysis of the Korean group [26], 75% of the de novo T790M were within the L858R group; however, only 25% were in the Del19 group.This is in line with Yu et al. [23], who showed that de novo T790M mutations are ∼80% concurrent with L858R and only 20% coexistent with Del19 mutations. Whether this preference of T790M for L858R holds true in the acquired resistance setting is unclear. Data from Griesinger et al. do not indicate a difference in the incidence of acquired T790M between L858R- and Del19-positive disease [31].
CONCLUSION In summary, afatinib is clinically active in many TKIpretreated patients with NSCLC harboring uncommon EGFR mutations. Pronounced activity was observed with E709X mutations (TTF .12 months). In comparison with results reported in TKI-na¨ıve patients, our data also indicate activity in patients with tumors carrying T790M and ins exon 20 mutations.
ACKNOWLEDGMENTS Editorial assistance, supported financially by Boehringer Ingelheim, was provided by Katie McClendon, of GeoMed, an Ashfield company, part of UDG Healthcare PLC, prior to
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submission of this article. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development, and approved the final version. Study group members were A. Abdollahi, A. Ammon, S.P. Aries, C. Arntzen, H.J. Achenbach, D. Atanackovic, A. Atmaca, N. Basara, D. Binder, B. Borchard, M. Bos, W. Brugger, S. Budweiser, K. Conrad, K. Corduan, D. Cortes-Incio, B. Dallmeier, C. Denzlinger, H.G. Derigs, N. Dickgreber, I. Dittrich, T. D¨ull, W. Engel-Riedel, M. Faehling, A. Fertl, J.R. Fischer, D. Fleckenstein, G. Folprecht, A. Forstbauer, Y. France, N. Frickhofen, S. Fr¨uhauf, M. Gardizi, T. Gauler, C. Gessner,W. Gleiber, E. G¨okkurt, M. G¨orner, C. Grah, J. Greeve, J. Greiner, F. Griesinger, C. Groh´e, W. Gr¨uning, D. Guggenberger, S. G¨utz, C. Hannig, D. Heigener, M. Heilmann, B. Heinrich, G. Hense, M. Hoiczyk, R.M. Huber, G. Illerhaus, G. Jacobs, P. Jung, K.O. Kambartel, L. Kayikci, J. Kern, J. Kersten, M. Kiehl, M. Kimmich, J. Kisro, H. Knipp, Y.D. Ko, J.U. Koch, C.H. Koehne, J. Kollmeier, A. Kommer, W. K¨orber, K. Kratz-Albers, G. Krause, R. Kr¨ugel, E. Laack, R. Leistner, U. Liebers, M. Lommatzsch, C. Maintz, C. Mozek, A. Matzdorff, M. Mohr, W. Neumeister, ¨ H. Nolte, T. Overbeck, M. Ostreicher, J. Panse, T. Pelzer, K. Peters, M. Planker, A. Reissig, M. Ritter, A. Rittmeyer, S. R¨osel, P. Sadjadian, B. Sandritter, M. Schatz, M. Scheffler, G. Schmid-Bindert, A. Schmittel, C.P. Schneider, W. SchneiderKappus, F. Schneller, E. Schorb, J. Schreiber, F. Sch¨uler, M. Schuler, A. Schulz-Abelius, C. Schumann, W. Sch¨utte, S. Sch¨utz, M. Sch¨utz, M. Sebastian, M. Serke, D. Spissinger, W. Spengler, H. Staiger, U. Steffen, I. Stehle, H. Steiniger, K. Stengele, S. Steppert, J. St¨ohlmacher-Williams, T. Strapatsas,
B. Sulzbach, A. Tessmer, M. Thomas, B. Th¨oming, D. Ukena, B. Wagner, T. Wagner, D. Wagner-Hug, H. Wahn, T. Wehler, R. Wiewrodt, C. Witt, M. Wohlleber, J. Wolf, M. Wolf, K. Wricke, O. Zaba, I. Zander.
AUTHOR CONTRIBUTIONS Conception/Design: David F. Heigener, Angela M¨arten, Frank Griesinger Provision of study material or patients: David F. Heigener, Anne L¨uers, Frank Griesinger Collection and/or assembly of data: David F. Heigener, Christian Schumann, Martin Sebastian, Parvis Sadjadian, Ingo Stehle, Anne L¨uers, Frank Griesinger, Matthias Scheffler Data analysis and interpretation: David F. Heigener, Christian Schumann, Angela M¨arten, Frank Griesinger Manuscript writing: David F. Heigener, Christian Schumann, Martin Sebastian, Parvis Sadjadian, Ingo Stehle, Angela M¨arten, Anne L¨uers, Frank Griesinger, Matthias Scheffler Final approval of manuscript: David F. Heigener, Christian Schumann, Martin Sebastian, Parvis Sadjadian, Ingo Stehle, Angela M¨arten, Anne L¨uers, Frank Griesinger, Matthias Scheffler
DISCLOSURES David F. Heigener: Boehringer Ingelheim, Hoffmann-La Roche, Lilly (C/A), Boehringer Ingelheim, Roche, Pfizer (RF), Lilly, Astra Zeneca, Hoffman La Roche, Boehringer Ingelheim, Bristol-Myers Squibb (H); Martin Sebastian: Boehringer Ingelheim, Pfizer, Roche, Astra Zeneca, Teva, Novartis (C/A), Boehringer Ingelheim, Pfizer, Roche, Novartis (H); Parvis Sadjadian: Roche (C/A), Roche, Boehringer Ingelheim (H); Ingo Stehle: Lilly, Boehringer Ingelheim, GlaxoSmithKline (C/A); Angela M¨arten: Boehringer Ingelheim (E); Anne L¨uers: Boehringer Ingelheim, Novartis (C/A); Frank Griesinger: Boehringer Ingelheim (C/A, H); Matthias Scheffler: Boehringer Ingelheim, Novartis, Bristol-Myers Squibb (C/A). The other author indicated no financial relationships. (C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/ inventor/patent holder; (SAB) Scientific advisory board
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5. Solca F, Dahl G, Zoephel A et al. Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker. J Pharmacol Exp Ther 2012;343:342–350.
11. Jackman D, Pao W, Riely GJ et al. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J Clin Oncol 2010;28: 357–360.
6. Sequist LV, Yang JC, Yamamoto N et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013;31: 3327–3334.
12. Schuler M, Fischer JR, Groh´e C et al. Experience with afatinib in patients with non-small cell lung cancer progressing after clinical benefit from gefitinib and erlotinib. The Oncologist 2014;19: 1100–1109.
7. Wu YL, Zhou C, Hu CP et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): An open-label, randomised phase 3 trial. Lancet Oncol 2014;15:213–222.
13. Miller VA, Hirsh V, Cadranel J et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): A phase 2b/3 randomised trial. Lancet Oncol 2012;13:528–538.
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16. Yasuda H, Park E, Yun CH et al. Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer. Sci Transl Med 2013;5: 216ra177. 17. Klughammer B, Spleiss O. PP 71 ‘Other’ (nonactivating, non-T790M) EGFR mutations and their clinical implications collected from various Tarceva trials in NSCLC. Eur J Cancer 2011;47(suppl 4): S20–S21. doi:10.1016/S0959-8049(11)72665-X. 18. Wu JY, Yu CJ, Chang YC et al. Effectiveness of tyrosine kinase inhibitors on “uncommon” epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer. Clin Cancer Res 2011;17:3812–3821. 19. Yang JCH, Sequist LV, Geater SL et al. Clinical activity of afatinib in patients with advanced nonsmall-cell lung cancer harbouring uncommon EGFR mutations: A combined post-hoc analysis of LUXLung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol 2015;16:830–838. 20. Cross DAE, Ashton SE, Ghiorghiu S et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors
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1174 in lung cancer. Cancer Discov 2014;4:1046– 1061. 21. Su KY, Chen HY, Li KC et al. Pretreatment epidermal growth factor receptor (EGFR) T790M mutation predicts shorter EGFR tyrosine kinase inhibitor response duration in patients with nonsmall-cell lung cancer. J Clin Oncol 2012;30:433– 440. 22. Fujita Y, Suda K, Kimura H et al. Highly sensitive detection of EGFR T790M mutation using colony hybridization predicts favorable prognosis of patients with lung cancer harboring activating EGFR mutation. J Thorac Oncol 2012;7:1640–1644. 23. Yu HA, Arcila ME, Hellmann MD et al. Poor response to erlotinib in patients with tumors containing baseline EGFR T790M mutations found by routine clinical molecular testing. Ann Oncol 2014;25:423–428. 24. Costa C, Molina MA, Drozdowskyj A et al. The impact of EGFR T790M mutations and BIM mRNA
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non-small cell lung cancer (NSCLC). Presented at: European Society for Medical Oncology 2014 Congress; September 26–30, 2014; Madrid, Spain. 29. Soria J-C, Sequist L, Goldman J et al. Interim phase 2 results with the irreversible, mutant selective, EGFR inhibitor rociletinib (CO-1686). Presented at: EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics; November 18–21, 2014; Barcelona, Spain. 30. Sebastian M, Schmittel A, Reck M. First-line treatment of EGFR-mutated nonsmall cell lung cancer: Critical review on study methodology. Eur Respir Rev 2014;23:92–105. 31. Griesinger F, Halbfass V, Conradi I et al. Acquired resistance in NSCLC with EGFR mutation treated with TKIs: Single center experience and treatment outcome. J Thorac Oncol 2013;8:P2.06– 035.
For Further Reading: Martin Schuler, J¨urgen R. Fischer, Christian Grohe´ et al. Experience With Afatinib in Patients With Non-Small Cell Lung Cancer Progressing After Clinical Benefit From Gefitinib and Erlotinib. The Oncologist 2014;19:1100–1109. Implications for Practice: This analysis of a large cohort of patients treated mainly in the community oncology setting confirms the activity of afatinib, an irreversible ErbB family blocker, in heavily pretreated metastatic non-small cell lung cancer. In particular, patients with tumors harboring somatic EGFR mutations derive a clinical meaningful benefit from afatinib, despite progressing on prior treatments with reversible EGFR inhibitors gefitinib or erlotinib. In some patients receiving multiple EGFR-targeting lines, the second and third lines provided prolonged disease control. Maintaining ErbB blockade by afatinib is an attractive strategy in EGFR-dependent lung cancer with acquired resistance to gefitinib or erlotinib.
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Afatinib in Non-Small Cell Lung Cancer Harboring Uncommon EGFR Mutations Pretreated With Reversible EGFR Inhibitors ¨ DAVID F. HEIGENER,a,* CHRISTIAN SCHUMANN,b,* MARTIN SEBASTIAN,c PARVIS SADJADIAN,d INGO STEHLE,e ANGELA MA¨ RTEN,f ANNE LUERS ,g FRANK GRIESINGER,g,* MATTHIAS SCHEFFLER,h,* FOR THE AFATINIB COMPASSIONATE USE CONSORTIUM (ACUC) a LungenClinic Grosshansdorf, Thoracic Oncology, German Center for Lung Research, Grosshansdorf, Germany; bClinic for Pulmonary, Thoracic Oncology, Sleep and Respiratory Critical Care, Kempten-Oberallgaeu Hospitals GmbH, Immenstadt, Germany; cDepartment of Medicine II, University Hospital Frankfurt, Frankfurt, Germany; dClinic for Hematology, Oncology and Palliative Medicine, Minden, Germany; eDepartment of Internal Medicine V, University Hospital of the Saarland, Homburg, Germany; fBoehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany; gDepartment Hematology and Oncology, Pius-Hospital Oldenburg, University Department of Internal Medicine-Oncology, Medical Campus, University of Oldenburg, Oldenburg, Germany; hDepartment of Internal Medicine I, Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany *Contributed equally.
Disclosures of potential conflicts of interest may be found at the end of this article.
Key Words. Afatinib x Non-small cell lung cancer x ErbB receptors x Epidermal growth factor receptor x Compassionate use trials
ABSTRACT Background. Afatinib, an irreversible ErbB family blocker, is approved for treatment of patients with previously untreated non-small cell lung cancer (NSCLC) harboring activating epidermal growth factor receptor (EGFR) mutations. Efficacy of afatinib in EGFR tyrosine kinase inhibitor-na¨ıve (TKI-na¨ıve) patients with uncommon EGFR mutations (other than exon 19 deletions or exon 21 point mutations) has been reported; however, efficacy in TKI-pretreated patients with uncommon EGFR mutations is unknown. Materials and Methods. In the afatinib compassionate use program (CUP), patients with advanced or metastatic, histologically confirmed NSCLC progressing after at least one line of chemotherapy and one line of EGFR-TKI treatment were enrolled. Demographic data, mutation type, response rates, time to treatment failure (TTF), and safety in patients harboring uncommon EGFR mutations were reported.
Results. In 60 patients (63% female, median age 63 years [range: 30–84 years]), a total of 66 uncommon EGFR mutations including 30 T790M mutations were reported (18.4% and 11%, respectively, of known EGFR mutations within the CUP). Most patients (67%) received afatinib as third- or fourth-line treatment. Median TTF was 3.8 months (range: 0.2 to .24.6 months; p 5 .244) in patients with uncommon mutations compared with 5.1 months (range: 0.1 to .21.1 months) in patients with common mutations (n 5 165). Pronounced activity was observed with E709X mutations (TTF .12 months). No new safety signals were detected. Conclusion. Afatinib is clinically active and well tolerated in many TKI-pretreated NSCLC patients harboring uncommon EGFR mutations. Compared with results reported in TKI-na¨ıve patients, activity was also indicated in patients with T790M and exon 20 insertion mutations. The Oncologist 2015;20:1167–1174
Implications for Practice: This analysis consists of a large database of non-small cell lung cancer patients with uncommon EGFR mutations who were previously treated with reversible EGFR tyrosine kinase inhibitors. Although indirectly assessed, the results indicate that patients with uncommon EGFR mutations can derive benefit from treatment with the irreversible ErbB family blocker afatinib, even in some cases of tumors harboring resistance-mediating exon 20 mutations. In this study, adverse events were modest and consistent with previous reports on afatinib.
INTRODUCTION Treatment with an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is standard in patients with metastatic non-small cell lung cancer (NSCLC) harboring activating EGFR mutations.The two most common EGFR mutations account for ∼90% of all mutation-positive NSCLC cases and are known to
confer sensitivity to EGFR-TKIs: in-frame deletions in exon 19 (Del19) and a point mutation in exon 21 (L858R) [1].The efficacy of first-generation reversible EGFR-TKIs like erlotinib and gefitinib on tumors with uncommon EGFR mutations was reported to be lower than in common mutations [2, 3].
Correspondence: David F. Heigener, M.D., LungenClinic Grosshansdorf GmbH, W¨ohrendamm 80, 22927 Grosshansdorf, Germany. Telephone: 04102-601-2103; E-Mail: [email protected] Received February 25, 2015; accepted for publication July 15, 2015; published Online First on September 9, 2015. ©AlphaMed Press 1083-7159/2015/$20.00/0 http://dx.doi.org/10.1634/theoncologist.2015-0073
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Afatinib is an orally available ErbB family blocker, binding to ErbB1 (EGFR), ErbB2 (HER2) and ErbB4, and inhibiting signaling of all homodimers and heterodimers of these receptors [4, 5]. Due to the acrylamide group in the molecule, the binding is—in contrast to gefitinib and erlotinib—covalent and thus irreversible. Afatinib has shown superior progression-free survival (PFS), overall survival (OS), and patient-reported outcomes compared with standard chemotherapy as first-line treatment of patients with NSCLC harboring common EGFR mutations [6–9]. In preclinical models, afatinib has also shown activity against uncommon EGFR mutations like T790M, which has been associated with acquired resistance to EGFR-TKIs [5, 10]. Treatment options for patients with acquired resistance to gefitinib and erlotinib [11] are urgently needed. To investigate the efficacy and tolerability of afatinib in heavily pretreated patients with uncommon EGFR mutations, a subgroup of appropriate patients enrolled in a compassionate use program (CUP) were selected and analyzed.The results of the whole CUP cohort are published elsewhere [12].
afatinib treatment (if not reported, it was calculated as 7 days after shipment) to end of treatment (if not reported, the date of the last order was used). Significance was determined at p , .05. The database was locked on December 31, 2013, and patients still on treatment were censored. Survival curves were estimated using the Kaplan-Meier method for TTF. A Cox model was applied to estimate hazard ratios and 95% confidence intervals (CIs). Analyses were undertaken using MedCalc version 12.1.4.0 (MedCalc Software, Ostend, Belgium, https:// www.medcalc.org). Patients receiving ,2 months’ targeted therapy before stopping due to progressive disease, death, or switching therapy were classified with a best response of “progressive disease,” whereas patients who were on treatment .4 months were classified with a best response of “stable disease” if not reported differently.
MATERIALS AND METHODS
In total, 66 uncommon mutations in 60 patients were reported (18.4% of all known EGFR mutations in the CUP). Most patients (57%) received a reversible TKI in the second line, with a median treatment duration of 10.0 months (Tables 1, 2). The majority of patients (67%) received afatinib as third- or fourthline treatment, with median treatment duration of 3.6 months. Sixty-three percent were female, and the median age was 63 years, ranging from 30 to 84 years (Tables 1, 2). In some instances, cetuximab was added to afatinib in the course of treatment (n 5 6). Demographics of patients with uncommon EGFR mutations did not differ from the whole CUP population (Tables 1, 2).
Compassionate Use Program The CUP was started in May 2010 to enable access to afatinib for patients with life-threatening disease and no other standard treatment option.Inclusioncriteria for theCUP werebased on the LUX-Lung 1 study comparing afatinib monotherapy with placebo in heavily pretreated patients. LUX-Lung 1 failed to reach its primary endpoint of improving OS but resulted in a doubling of PFS [13]. Patients enrolled in the CUP had advanced NSCLC and were ineligible to participate in another actively accruing afatinib phase III trial, had failed at least one line of cytotoxic chemotherapy, and showed tumor progression after clinical benefit on erlotinib or gefitinib (i.e., stable disease for $6 months, a complete response, or partial response) or the presence of an activating mutation of the EGF/Her receptor family, were aged $18 years, had no further established treatment option available, and had provided written informed consent.The competent authorities (Federal Institute for Drugs and Medical Devices [BfArm]; goverments’ steering committee) were informed, and approval by the ethics committee was given (837.105.10[7114]). The CUP was stopped with market availability of afatinib in the European Medicines Agency region.
Centers and Clinical Data In total, 573 patients were enrolled from 118 centers in Germany, and 546 were treated with afatinib. Physicians were asked to provide age, sex, pretreatments, comorbidities, and mutational status to allow checks for eligibility and to report adverse events including tumor progression. All data were reported anonymously. Physicians who had patients with uncommon mutations were approached after closure of the CUP by the authors to fill in a structured documentation sheet for more information on the mutational status (time of testing, EGFR detection method, response to reversible TKI and to afatinib).
Statistics Descriptive analysis was performed for patient demographics. Time to treatment failure (TTF) was defined from start of
RESULTS Demographics of Patients With Uncommon EGFR Mutations
Uncommon EGFR Mutations A total of 23 uncommon EGFR mutations were detected at time of diagnosis; 15 were reported to be acquired mutations (all T790M), and for the remaining cases, time of detection was not reported. Of the uncommon EGFR mutations detected, 21% were on exon 18, 9% were on exon 19, 55% were on exon 20, and 16% were on exon 21. A total of 30 patients (45% of uncommon mutations) had T790M mutations (18 had T790M plus exon 19, 11 had T790M plus exon 21, and 1 had T790M alone), 10 patients had G719X mutations (3 had G719A, 2 had G719C, 2 had G719S, 1 had G719A plus E709A, 1 had G719C plus E709A, and 1 had G719C plus L861Q), 6 had L861Q mutations (2 alone, 2 plus T790M and each one plus G719C or L858M), 4 had E709X mutations (3 had E709K plus L858R, 1 had E709A plus G719X), and 4 had insertions in exon 20 (1 also had Del19). Further mutations included A702S, A750V, deletion and insertion (delins) exon 19 (n 5 2), G753S, point mutation exon 19, S768I plus V769L, R776H plus L858R, L858M, L858M plus L861Q, G857E, and G861L plus T790M (Fig. 1).
Time to Treatment Failure and Best Response Median TTF for patients with T790M mutations (n 5 30) was 4.4 months (range: 0.4–21.8 months), with 4.4 months (range: 0.8–14.9 months) for patients (n 5 15) with acquired T790M and 4.9 months (range: 0.4–21.8 months) for patients with unknown time of first appearance (n 5 14) or de novo T790M
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Table 1. Patient characteristics Common mutations Characteristics Female, n (%) Male, n (%) Age, median (range) Time between initial diagnosis and enrollment in CUP, months, median (range) Histology, n (%) ADC SCC BAC LCC Metastases, n (%) Known brain metastases Known bone metastases Afatinib treatment line, n (%) Second linea Third line Fourth line Fifth line Sixth to ninth lines
Uncommon mutations (n 5 60)
Del19 (n 5 106)
L858R (n 5 59)
38 (63) 22 (37) 63 (30–84) 22.8 (4.5–120.7)
78 (75) 26 (25) 61 (31–87) 23.2 (8.5–139.3)
43 (73) 16 (27) 68 (46–89) 17.9 (7.3–122.5)
54 (90) 2 (3) 2 (3) 0 (0)
97 (92) 0 (0) 6 (6) 2 (2)
52 (88) 4 (7) 2 (3) 0 (0)
15 (25) 20 (33)
21 (20) 38 (36)
15 (25) 35 (59)
9 (15) 22 (37) 18 (30) 6 (10) 5 (8)
3 (3) 21 (20) 73 (69) 7 (7) 2 (2)
5 (8) 35 (59) 10 (17) 6 (10) 3 (5)
a
Patients ineligible for chemotherapy. Abbreviations: ADC, adenocarcinoma; BAC, bronchioloalveolar carcinoma; CUP, compassionate use program; LCC, large cell carcinoma; SCC, squamous cell carcinoma.
mutation (n 5 1) (p 5 .823). TTF for G719X (n 5 10) was 2.6 months (range: 0.2 to ongoing at 24.6 months); TTF for L861Q (n 5 4) was 3.3 months (range: 1.5–9.9 months); TTF for E709X (n 5 4) was 12.2 months (range: ongoing at 0.8–16.7 months); and TTF for insertion exon 20 (n 5 4) was 6.5 months (range: ongoing at 3.6–9.1 months). Patients with A702S, A750V, delins exon 19, G753S, point mutation exon 19, R776H, S768I, V769L, G857E, G861L, and L858M (n 5 14) had TTF varying from 0.8 to ongoing at 16.8 months. In total, 20 patients (33%) were still on treatment at time of database lock (Table 3). Patients with common EGFR mutations (n 5 165) had a median TTF of 4.9 months (range: 0.1 to ongoing at 21.1 months), 4.6 months in patients with Del19 (n 5 106), and 5.8 months in L858R (n 5 59), compared with patients with uncommon mutations of 3.6 months (range: 0.2 to ongoing at 24.6 months) (Fig. 2). This was not significant. From 58 evaluable cases, 22% (n 5 13) had a partial response (including one mixed response), 47% (n 5 27) had stable disease, and 31% (n 5 18) had progressive disease as best response, with L858M mutations showing the highest percentage of patients with a partial response. T790Mmutated patients responded mostly with stable disease (56%) (Table 4).
Safety Profile The complete safety profile from this CUP is reported elsewhere [12]. The afatinib safety profile was as expected, with diarrhea and skin-related adverse events being the most common; no new safety signals were observed. Afatinib was administered continuously at a starting dose of 50 mg in 38
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patients (63%), 40 mg in 13 patients (22%), and 30 mg in 9 patients (15%). Dose reductions from 50 to 40 mg were observed in 19 patients and to 30 mg in 10 patients.
DISCUSSION To the knowledge of the authors, this study has the largest prospective cohort of patients carrying uncommon EGFR mutations and failing on EGFR-TKI published so far; however, the intention of the CUP was to provide a treatment option for patients for whom no further established therapy was available. Consequently, only a minimal data set was required for inclusion, no structured data collection was rolled out, and no source data verification was performed, limiting the quality and generalizability of the data. The reported incidence of 11% of nonacquired uncommon EGFR mutations is in line with other reports [6, 7, 14, 15]. The data reported so far regarding distribution of uncommon mutations are either from TKI-na¨ıve or mixed populations; therefore, a comparison with this population is not possible. Beau-Faller et al. reported an incidence in TKI-na¨ıve patients of 40% for insertions in exon 20 (ins exon 20) but only 12% complex mutations [14]. Our cohort consists of 63% complex mutations but only 5% ins exon 20, indicating that although complex mutations are acquired during reversible EGFR-TKI treatment, patients with tumors harboring the ins exon 20 mutation were unlikely to be treated in later lines. Yasuda et al. described that the structure of ins exon 20 activates EGFR without increasing its affinity for EGFR-TKIs [16]; however, a certain ins exon 20 mutation (Y764insFQEA) was described to be highly sensitive to EGFR-TKIs in vitro, and ©AlphaMed Press 2015
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Table 2. Prior therapy in patients with uncommon mutations (n 5 60) Treatment line
First Second Third (n 5 60, 100%) (n 5 52, 87%) (n 5 29, 48%)
Chemotherapy, n (%) Platinum 34 (57) doublet Monotherapy 1 (2) Targeted therapy, n (%) Erlotinib 6 (10) Gefitinib 17 (28) Afatinib 0 (0) TKI duration, 6.5 months Others 1 (2)
9 (17)
6 (21)
7 (13)
9 (31)
25 (48) 9 (17) 0 (0) 10.0
8 (28) 3 (10) 1 (3) 14.5
2 (4)
2 (7)
Abbreviation: TKI, tyrosine kinase inhibitor.
Figure 1. Distribution of the 60 rare EGFR mutations. Abbreviation: incl., including.
patients with NSCLC harboring this mutation responded to erlotinib. Because we do not have detailed information on the specific ins exon 20 mutation included in our cohort, we can only speculate whether the observed outcome (TTF 6.5 months) might be due to higher incidence of this responding insertion mutation. In our analysis, afatinib has generally shown efficacy in patients with uncommon EGFR mutations but to a lesser degree compared with patients with common EGFR mutations (3.8 and 5.1 months, respectively). Nonetheless, uncommon mutations were a very heterogeneous group, with E709X mutations and rare mutations on exon19 showing quite a long time to treatment failure (.12 and 6.5 months, respectively) and good response rates, whereas G719X mutations showed less benefit (2.6 months). Only limited data are available on efficacy of reversible EGFR-TKIs on uncommon EGFR mutations, and these data are mostly for TKI-na¨ıve patients. Klughammer et al. reported a TTF of 3.5 months for uncommon EGFR mutations from several trials with erlotinib in TKI-na¨ıve patients [17]. Wu et al.,
excluding de novo T790M and ins exon 20, showed a median PFS of 5.0 months in TKI-na¨ıve patients treated with reversible EGFR-TKIs, driven mainly by G719X and X861X mutations (median PFS 6.0 months), whereas the other uncommon mutations progressed after 1.6 months [18]. In the large first-line studies comparing afatinib with chemotherapy, efficacy has also been reported in a broad variety of uncommon EGFR mutations. In this TKI-na¨ıve cohort, however, de novo T790M and ins exon 20 mutations showed inferior results compared with other uncommon mutations with PFS of 2.9 months (95% CI: 1.2–8.3) for T790M, 2.7 months (95% CI: 1.8–4.2) for ins exon 20, and 10.7 months (95% CI: 5.6–14.7) for other uncommon mutations [19]. G719X and ins exon 20 represent the largest subset in the heterogeneous group of uncommon EGFR mutations; in this subset, different patterns according to treatment line could be seen. In TKI-na¨ıve patients, a median PFS of 1.4 months for ins exon 20 and 8.1 months for G719X have been reported [14]. Data from Wu et al. describing a PFS of 8.1 months for TKI-na¨ıve patients with different stages of NSCLC harboring G719X mutations go into a similar direction [18]. A combined analysis [19] from LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6 showed the same trend—although numerically higher—for afatinib in EGFR-TKI–na¨ıve patients (2.7 months for ins exon 20 and 13.8 months for G719X). The different outcomes depending on EGFR-TKI experience and line of treatment could be interpreted as (a) positive selection of responding mutations (in the case of ins exon 20) and (b) potentially, a process of acquiring additional mutations that negatively affect outcomes. This could not be proven in this cohort because 50% of the patients with G719X mutations were tested for EGFR mutational status prior to treatment with reversible EGFR-TKI, and EGFR testing is unknown for the remaining patients. T790M is a high-profile uncommon EGFR mutation. It can be detected de novo and is responsible for approximately 50% of acquired resistance to reversible EGFR-TKIs [10] due to the fact that these agents show in vitro halfmaximal inhibitory concentration values of roughly 250fold higher for T790M [20] compared with common EGFR mutations, explaining their limited effectiveness. In vitro activity of afatinib on T790M mutations has been shown; however, clinical activity with afatinib monotherapy in patients after reversible EGFR-TKI failure did not meet expectations (PFS 3.3 vs. 1.1 months for placebo and no difference in OS) [13]. The different efficacy of afatinib in the TKI-na¨ıve setting compared with patients with acquired resistance is in line with previously reported results in T790M-positive tumors, indicating that the predictive value of T790M in TKI response is dependent on the time point of the occurrence of the mutation. De novo T790M, together with an activating mutation, has been described by different authors, with an incidence ranging from #1% up to 65% [3, 21–24]. These results were dependent on the sensitivity of the method, with more sensitive methods detecting a higher incidence of de novo T790M. If T790M is detected by conventional methods such as Sanger sequencing, the incidence is ∼1%. The largest series of patients with de novo T790M has been reported by Riely et al.
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Table 3. Treatment duration and best response with reversible TKIs and afatinib Uncommon mutation Exon 18 A702S E709K 1 L858R E709A 1 G719A G719A G719C G719S G719C 1 L861Q Exon 19 A750V Delins exon19 Point mut exon19 G753S Exon 20 T790M acquired T790M 1 Del19
n
Reversible TKI treatment duration (months)
Best response to reversible TKI
Afatinib treatment duration (months)
Best response to afatinib
1 3 1 2 2 2 1
2 (G)a 8 (E),a 12 (G), 26 (G)a 12 (E)a ,1 (G), 16 (E) 2 (G),a 4 (G) 10 (E),a 18 (E) 12 (G)a
PDa SD,a SD, CRa PDa PD, SD PDa, NR SDa, SD 1 PRa
0.3a 0.8,a 7.1,b 12.2a 16.7a 6.4,b 24.6b 0.2,a 0.8 2.6,a 10.0 2.3a
PD PR, SD, SD PR SD, SD PD, NR NR, NR PD
2 2 1 1
2 (E),a 18 (E)a 3 (G), 10 (E)a 23 (G) 1 (G)a
PDa, PRa NR, SDa SD PDa
1.8,a 4.4a 8.5, 15.1a 3.5 0.9
SD, NR SD, PR NR PD
1 7
60 (E) 8 (E), 41 (E),a 20 (G), 7 (G), 5 (E), 14 (E), 11 (E) 10(G),8(G)/3(G),19(E),12(E), 18 (E), 9 (E), 21(E), 7 (G)/1 (E)
SD SD, SD,a PR, SD, SD, SD, SD SD, MR/PD, SD, PR, SD, PR, SD, SD SD, SD PR
5.4 0.4, 1.0, 2.3,b 2.5, 3.5, 5.7,b 8.1 0.8, 1.9,b 2.2, 3.8, 5.2,b 10.1, 10.2, 14.9 2.7, 5.6 4.4
SD PD, SD, PD, PD, PD, SD, NR PD, NR, NR, SD, SD, PR, SD, PR PD, SD SD
T790M 1 Del19 acquired
8
T790M 1 exon 19 T790M 1 exon 19 acquired T790M 1 L858R
2 1
9 (E), 6 (G) 13 (E)
4
2.4, 4.9, 7.0, 19.5b
SD, SD, PR, SD
T790M 1 L858R acquired T790M 1 exon 21 T790M 1 exon 21 acquired T790M 1 G861L T790M 1 L861Q acquired Ins exon 20 Ins exon 20 1 Del19 R776H 1 L858R S768I 1 V769L V769L 1 S768I Exon 21 L861Q L861Q 1 L858M G861L 1 T790M L861Q 1 T790M L861Q 1 G719C L858M L858M 1 L861Q G857E
3
6 (G)/30 (E), 15 (E)/7 (E), 32 SD, SD, SD, SD (E), 10 (E)/17 (G) 7 (E), 8 (G)/3 (E), 14 (E) PR, SD/NR, PR
2.8, 3.6, 10.7
SD, SD, PD
1 1
34 (E) 2 (E)
PR PD
21.8 1.5
MR PD
1 1
12 (E) 3 (G)
SD PD
1.5 3.6
PD SD
3 1 1 1 1
3 (E),a 3 (G)/2 (E), 21 (E) 10 (G)/22 (E)a 8 (E) 14 (G)a 14 (G)a
PDa, NR/NR, SD SD/PRa SD SDa SDa
2.7, 3.8, 9.1 6.5b 1.7 2.2 2.2
PD, NR, PR SD PD NR NR
3 1 1 1 1 1 1 1
22 (G), 3 (G), 12 (E) 2 (E)a 12 (E)a 3 (G)a 12 (G)a 6 (G) 2 (E)a 2 (E)
PR, PD, PR NRa SDa PDa 1 PR (G)a SD NRa NR
1.5, 3.6, 4.3 9.9 1.5 3.6 2.3a 16.8b 9.9 2.0
SD, SD, PR PR PD SD PD PR PR PD
a
De novo. Censored. Abbreviations: CR, complete response; Del, deletion; delins, deletion and insertion; (E), erlotinib; (G), gefitinib; ins, insertion; MR, mixed response; mut, mutation; NR, not reported; PD, progressive disease; PR, partial response; SD, stable disease; TKI, tyrosine kinase inhibitor.
b
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Figure 2. Time to treatment failure of common and uncommon EGFR mutations.
Table 4. Best response to afatinib Variable
PR, n (%)
SD, n (%)
PD, n (%)
All (n 5 58) A702S (n 5 1/1) E709X (n 5 4/5) G719X (n 5 7/10) A750V (n 5 1/2) Delins exon 19 (n 5 2/2) G753S (n 5 1/1) Ins exon 20 (n 5 3/4) T790M (n 5 27/31) V769L (n 5 1/1) S768I (n 5 1/1) L861Q (n 5 6/6) L858M (n 5 2/2) G861L (n 5 1/1) R776H (n 5 1/1)
13 (22)
27 (47)
18 (31) 1 (100)
2 (50) 1 (14)
2 (50) 3 (43)
1 (50)
1 (50)
1 (33) 4a (15)
1 (33) 15 (56) 1 (100) 1 (100) 3 (50)
2 (33) 2 (100)
3 (43) 1 (50) 1 (100) 1 (33) 8 (30)
1 (17) 1 (100) 1 (100)
a
Includes one mixed response. Abbreviations: delins, deletion and insertion; ins, insertion; PD, progressive disease; PR, partial response; SD, stable disease.
[25]: 15 patients with de novo T790M were identified and treated with first-line TKI; PFS was 1.5 months and OS was 1.3 years compared with 3.0 years in patients who lacked T790M. Most recently, a Korean group detected T790M by matrix-assisted laser desorption/ionization-time and flight/ mass spectrometry in 31 of 124 patients (25%) and evaluated the impact of the mutation frequency of de novo T790M [26]. With a frequency .3.2%, T790M conferred an inferior outcome to TKI treatment (6.3 vs. 11.5 months). Costa et al. reported an incidence of de novo T790M of 65% in the EURTAC trial, showing a significant difference in outcome in the erlotinib-treated population (PFS was 15.8 months for those without the concomitant T790M mutation compared with 9.7 months for those with the T790M mutation [p , .0185]) but no difference in the chemotherapy group [24]. The largest data set for acquired resistance was published by Oxnard et al. [27]. This group identified 58 patients with
acquired TKI resistance by T790M and compared them with 35 patients with acquired TKI resistance without T790M. In this analysis,T790M conferred better survival and PFS than the lack of T790M, suggesting that T790M indicates a more indolent tumor when observed in the TKI-resistant setting [27]; the data generated in the afatinib CUP program are consistent with these findings. Third-generation EGFR-TKIs are under clinical development addressing T790M more or less exclusively. In phase I trials, AZD9291 and CO-1686 achieved response rates of 61% and 67%, respectively, in pretreated patients with acquired T790M mutations; response rates were 21% and 36%, respectively, in patients with T790Mnegative tumors [28, 29]. Median PFS with AZD9291 and CO-1686, respectively, was 9.6 months and 10.4 months in patients with T790M-positive tumors and 2.8 months and 7.5 months in patients with T790M-negative disease [28, 29]. Based on the current analyses, it seems that no clinical characteristic is associated with uncommon EGFR mutation. There were more male patients in the uncommon mutation group compared with those with common mutations, and a shorter time from initial diagnosis until enrollment for patients with L858R-mutated tumors compared with patients with tumors harboring Del19 mutations. Interestingly, patients with concomitant L858R-mutated tumors had similar treatment duration with afatinib as those with concomitant Del19-positive tumors. This is in contrast to the data from first-line trials in EGFR-mutated patients in which patients with L858R-positive tumors showed a shorter PFS [30]. An explanation could be that the acquired resistance mechanisms of L858R-positive tumors are distinct from those in Del19-positive tumors, rendering the former more prone to respond to afatinib. In this regard, it has been shown that L858R-positive tumors have low-level T790M clones at a higher incidence than Del19-positive tumors. In the analysis of the Korean group [26], 75% of the de novo T790M were within the L858R group; however, only 25% were in the Del19 group.This is in line with Yu et al. [23], who showed that de novo T790M mutations are ∼80% concurrent with L858R and only 20% coexistent with Del19 mutations. Whether this preference of T790M for L858R holds true in the acquired resistance setting is unclear. Data from Griesinger et al. do not indicate a difference in the incidence of acquired T790M between L858R- and Del19-positive disease [31].
CONCLUSION In summary, afatinib is clinically active in many TKIpretreated patients with NSCLC harboring uncommon EGFR mutations. Pronounced activity was observed with E709X mutations (TTF .12 months). In comparison with results reported in TKI-na¨ıve patients, our data also indicate activity in patients with tumors carrying T790M and ins exon 20 mutations.
ACKNOWLEDGMENTS Editorial assistance, supported financially by Boehringer Ingelheim, was provided by Katie McClendon, of GeoMed, an Ashfield company, part of UDG Healthcare PLC, prior to
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submission of this article. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development, and approved the final version. Study group members were A. Abdollahi, A. Ammon, S.P. Aries, C. Arntzen, H.J. Achenbach, D. Atanackovic, A. Atmaca, N. Basara, D. Binder, B. Borchard, M. Bos, W. Brugger, S. Budweiser, K. Conrad, K. Corduan, D. Cortes-Incio, B. Dallmeier, C. Denzlinger, H.G. Derigs, N. Dickgreber, I. Dittrich, T. D¨ull, W. Engel-Riedel, M. Faehling, A. Fertl, J.R. Fischer, D. Fleckenstein, G. Folprecht, A. Forstbauer, Y. France, N. Frickhofen, S. Fr¨uhauf, M. Gardizi, T. Gauler, C. Gessner,W. Gleiber, E. G¨okkurt, M. G¨orner, C. Grah, J. Greeve, J. Greiner, F. Griesinger, C. Groh´e, W. Gr¨uning, D. Guggenberger, S. G¨utz, C. Hannig, D. Heigener, M. Heilmann, B. Heinrich, G. Hense, M. Hoiczyk, R.M. Huber, G. Illerhaus, G. Jacobs, P. Jung, K.O. Kambartel, L. Kayikci, J. Kern, J. Kersten, M. Kiehl, M. Kimmich, J. Kisro, H. Knipp, Y.D. Ko, J.U. Koch, C.H. Koehne, J. Kollmeier, A. Kommer, W. K¨orber, K. Kratz-Albers, G. Krause, R. Kr¨ugel, E. Laack, R. Leistner, U. Liebers, M. Lommatzsch, C. Maintz, C. Mozek, A. Matzdorff, M. Mohr, W. Neumeister, ¨ H. Nolte, T. Overbeck, M. Ostreicher, J. Panse, T. Pelzer, K. Peters, M. Planker, A. Reissig, M. Ritter, A. Rittmeyer, S. R¨osel, P. Sadjadian, B. Sandritter, M. Schatz, M. Scheffler, G. Schmid-Bindert, A. Schmittel, C.P. Schneider, W. SchneiderKappus, F. Schneller, E. Schorb, J. Schreiber, F. Sch¨uler, M. Schuler, A. Schulz-Abelius, C. Schumann, W. Sch¨utte, S. Sch¨utz, M. Sch¨utz, M. Sebastian, M. Serke, D. Spissinger, W. Spengler, H. Staiger, U. Steffen, I. Stehle, H. Steiniger, K. Stengele, S. Steppert, J. St¨ohlmacher-Williams, T. Strapatsas,
B. Sulzbach, A. Tessmer, M. Thomas, B. Th¨oming, D. Ukena, B. Wagner, T. Wagner, D. Wagner-Hug, H. Wahn, T. Wehler, R. Wiewrodt, C. Witt, M. Wohlleber, J. Wolf, M. Wolf, K. Wricke, O. Zaba, I. Zander.
AUTHOR CONTRIBUTIONS Conception/Design: David F. Heigener, Angela M¨arten, Frank Griesinger Provision of study material or patients: David F. Heigener, Anne L¨uers, Frank Griesinger Collection and/or assembly of data: David F. Heigener, Christian Schumann, Martin Sebastian, Parvis Sadjadian, Ingo Stehle, Anne L¨uers, Frank Griesinger, Matthias Scheffler Data analysis and interpretation: David F. Heigener, Christian Schumann, Angela M¨arten, Frank Griesinger Manuscript writing: David F. Heigener, Christian Schumann, Martin Sebastian, Parvis Sadjadian, Ingo Stehle, Angela M¨arten, Anne L¨uers, Frank Griesinger, Matthias Scheffler Final approval of manuscript: David F. Heigener, Christian Schumann, Martin Sebastian, Parvis Sadjadian, Ingo Stehle, Angela M¨arten, Anne L¨uers, Frank Griesinger, Matthias Scheffler
DISCLOSURES David F. Heigener: Boehringer Ingelheim, Hoffmann-La Roche, Lilly (C/A), Boehringer Ingelheim, Roche, Pfizer (RF), Lilly, Astra Zeneca, Hoffman La Roche, Boehringer Ingelheim, Bristol-Myers Squibb (H); Martin Sebastian: Boehringer Ingelheim, Pfizer, Roche, Astra Zeneca, Teva, Novartis (C/A), Boehringer Ingelheim, Pfizer, Roche, Novartis (H); Parvis Sadjadian: Roche (C/A), Roche, Boehringer Ingelheim (H); Ingo Stehle: Lilly, Boehringer Ingelheim, GlaxoSmithKline (C/A); Angela M¨arten: Boehringer Ingelheim (E); Anne L¨uers: Boehringer Ingelheim, Novartis (C/A); Frank Griesinger: Boehringer Ingelheim (C/A, H); Matthias Scheffler: Boehringer Ingelheim, Novartis, Bristol-Myers Squibb (C/A). The other author indicated no financial relationships. (C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/ inventor/patent holder; (SAB) Scientific advisory board
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For Further Reading: Martin Schuler, J¨urgen R. Fischer, Christian Grohe´ et al. Experience With Afatinib in Patients With Non-Small Cell Lung Cancer Progressing After Clinical Benefit From Gefitinib and Erlotinib. The Oncologist 2014;19:1100–1109. Implications for Practice: This analysis of a large cohort of patients treated mainly in the community oncology setting confirms the activity of afatinib, an irreversible ErbB family blocker, in heavily pretreated metastatic non-small cell lung cancer. In particular, patients with tumors harboring somatic EGFR mutations derive a clinical meaningful benefit from afatinib, despite progressing on prior treatments with reversible EGFR inhibitors gefitinib or erlotinib. In some patients receiving multiple EGFR-targeting lines, the second and third lines provided prolonged disease control. Maintaining ErbB blockade by afatinib is an attractive strategy in EGFR-dependent lung cancer with acquired resistance to gefitinib or erlotinib.
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