Table 1.
Characteristics of the studies included in the pooled analysis to evaluate the effects of single-agent erlotinib, single-agent gefitinib or chemotherapy in patients with EGFR mutation-positive NSCLC (studies not included in the original analysis are highlighted)
| Study | Design | Patients | Treatment | PFS/TTP |
|---|---|---|---|---|
| Erlotinib | ||||
| Ahn et al. [31] | Prospective | n = 24: Korean; ≥1 prior treatment; exon 19 deletion (n = 17); L858R (n = 5); exon 20 mutation (n = 1); exon 18 mutation and exon 19 deletion (n = 1) | Erlotinib 150 mg/day | TTP: 8.6 months |
| Jackman et al. [32] | Ph II, single-arm | n = 9: primarily white; chemo-naїve; ≥70 years; exon 19 deletion (n = 3); L858R (n = 5); L861Q and exon 19 deletion (n = 1) | Erlotinib 150 mg/day | TTP: 13 months |
| Jackman et al. [33] | Ph II, single-arm | n = 33: female; chemo-naїve; adenocarcinoma; EGFR mutations | Erlotinib 150 mg/day | TTP: 12.6 months |
| Miller et al. [34] | Ph II, single-arm | n = 18: BAC and adenocarcinoma, BAC subtype; 0–1 prior treatments; exon 19 or 21 EGFR mutation | Erlotinib 150 mg/day | PFS: 13 months |
| Pirker et al. [35] | Prospective (TRUST study) | n = 11: primarily white; chemo-naïve or previously treated; exon 19 deletion (n = 7); L858R (n = 5) | Erlotinib 150 mg/day | PFS: 405 days |
| Riely et al. [36] | Retrospective | n = 12: primarily white; chemo-naїve or previously treated; exon 19 deletion (n = 8); L858R (n = 4) | Erlotinib 150 mg/day | PFS: 12 months |
| Rosell et al. [37] | Prospective, Ph II | n = 12: Spanish; non-squamous cell carcinoma; exon 19 or 21 EGFR mutation | Erlotinib 150 mg/day | PFS: 13 months |
| Zhou et al. [38] | Retrospective | n = 6: Chinese; ≥1 previous treatment; EGFR mutations | Erlotinib 150 mg/day | TTP: 15.8 months |
| Amann et al. [39] | Retrospective; Ph II single-arm | n = 3: primarily white; mainly chemo-naïve; L858R (n = 3) | Erlotinib 150 mg/day | TTP: 13.1 months |
| Ciuleanu et al. [40] | Ph III; randomized comparison versus chemotherapy (TITAN) | n = 7: predominantly white; previously treated; EGFR mutation | Erlotinib 150 mg/day | PFS: 8.4 months |
| Choi et al. [41] | Retrospective; Ph II; single-arm | n = 21: Korean; chemo-naïve; exon 19 or exon 21 mutation | Erlotinib 150 mg/day | PFS: 11.5 months |
| De Greve et al. [42] | Prospective; Ph II; single-arm (FIELT) | n = 46: Belgian; chemo-naïve; exon 18 (n = 2), exon 19 (n = 27), exon 20 (n = 3), exon 21 (n = 15) | Erlotinib 150 mg/day | PFS rate at 3 months: 83% PFS rate at 6 months: 74% Median TTP not reached: 44+ weeks |
| Fiala et al. [43] | Retrospective | n = 9: Czech; EGFR mutation | Erlotinib 150 mg/day | TTP: 8.4 months |
| Rosell et al. [44] | Ph III; randomized comparison versus chemotherapy (EURTAC) | n = 86: primarily white; chemo-naïve; EGFR mutation | Erlotinib 150 mg/day | PFS: 9.7 months |
| Janne et al. [45] | Ph II; randomized comparison versus erlotinib plus chemotherapy (CALGB30406) | n = 33: primarily white; chemo-naïve; EGFR mutation | Erlotinib 150 mg/day | PFS: 14.1 months |
| Lynch et al. [46] | Ph II; randomized comparison versus erlotinib + bortezomib | n = 4: primarily white; mainly chemo-naïve; EGFR mutations | Erlotinib 150 mg/day | PFS: 4.3 months |
| Okano et al. [47] | Prospective; Ph II; single-arm | n = 10: Japanese; previously treated; EGFR mutation | Erlotinib 150 mg/day | PFS: 418 days (13.75 months) |
| Pallis et al. [48] | Prospective; Ph II; single-arm | n = 9: Greek; chemo-naïve; exon 19 deletion (n = 4); L858R (n = 5) | Erlotinib 150 mg/day | PFS: 12.4 months |
| Puente et al. [49] | Retrospective; single-arm | n = 23: chemo-naïve; EGFR mutation | Erlotinib 150 mg/day | PFS: 11 months |
| Rosell et al. [50] | Prospective; single-arm | n = 217: primarily white; chemo-naïve or previously treated; exon 19 deletion (n = 135); L858R (n = 82) | Erlotinib 150 mg/day | PFS: 14 months |
| Rotella et al. [51] | Retrospective; single-arm | n = 8: previously treated; exon 19 (n = 6); exon 21 (n = 2) | Erlotinib 150 mg/day | PFS: 18 months |
| Spigel et al. [52] | Prospective, ph II | n = 3: primarily white; 1–2 prior treatments; EGFR mutations | Erlotinib 150 mg/day | PFS: 9.23 months |
| Sun et al. [53] | Retrospective; single-arm | n = 35: Korean; mainly previously treated; exon 19 deletion or L858R | Erlotinib 150 mg/day | PFS: 8.0 months |
| Takahashi et al. [54] | Retrospective; Ph II; single-arm | n = 2; Japanese; chemo-naïve or previously treated; exon 19 deletion | Erlotinib 150 mg/day | TTP: Patient 1: 308 days (10.1 months) Patient 2: >973 days (>32 months) |
| Zhou et al. [3] | Ph III; randomized comparison versus carboplatin/gemcitabine (OPTIMAL) | n = 82: Chinese; chemo-naïve; exon 19 deletion (n = 43); L858R (n = 39) | Erlotinib 150 mg/day | PFS: 13.1 months |
| Zhu et al. [55] | Retrospective; single-arm | n = 8: Chinese; chemo-naïve or previously treated; exon 19 deletion (n = 5); L858R (n = 3) | Erlotinib 150 mg/day | PFS: 15.2 months |
| Gefitinib | ||||
| Asahina et al. [56] | Ph II, single-arm | n = 16: Japanese; chemo-naive; exon 19 deletion (n = 13); L858R (n = 3) | Gefitinib 250 mg/day | PFS: 8.9 months |
| Bell et al. [57] | Retrospective (Ph II IDEAL studies) | n = 14: ≥1 previous treatment; exon 19 deletion (n = 11); L858R (n = 2); InsG771 (n = 1) | Gefitinib 250 or 500 mg/day | TTP: 3.8 months |
| Buckingham et al. [58] | Retrospective | n = 17: ≥1 previous treatment; EGFR mutation | Gefitinib 250 mg/day | PFS: 13.6 months |
| Chou et al. [59] | Retrospective | n = 33: Taiwanese; prior platinum therapy; exon 18 substitution (n = 4); exon 19 deletion (n = 11); exon 20 substitution or deletion (n = 4); exon 21 substitution (n = 12); ≥1 mutation (n = 2) | Gefitinib 250 mg/day | PFS: 7.6 months |
| Cortes-Funes et al. [60] | Retrospective | n = 10: Spanish; ≥1 previous treatment; exon 19 deletion (n = 8); L858R (n = 2) | Gefitinib 250 mg/day | TTP: 12.3 months |
| D'Addario et al. [61] | Ph II, single-arm | n = 4: Swiss; chemo-naїve; exon 19 deletion (n = 2); L858R (n = 2) | Gefitinib 250 mg/day | TTP: 7.5 months |
| Dongiovanni et al. [62] | Retrospective | n = 9: Italian; chemo-naїve or previously treated; exon 19 deletion (n = 8); L858R (n = 1) | Gefitinib 250 mg/day | TTP: 14.9 months |
| Fukuoka et al. [63] | Ph III IPASS; randomized comparison with carboplatin/paclitaxel | n = 132: East-Asian; adenocarcinoma; never-smokers; chemo-naїve; EGFR mutation | Gefitinib 250 mg/day | PFS: 9.5 months |
| Han et al. [64] | Retrospective | n = 21: Korean; previously treated; exon 19 deletion (n = 12); L858R (n = 6); G719A (n = 3) | Gefitinib 250 mg/day | TTP: 13.8 months |
| Hirsch et al. [65] | Pooled analysis | n = 43: Italian or US; chemo-naїve or previously treated; exon 21 mutations (n = 31); exon 19 deletions (n = 11); mutations in exons 19 and 21 (n = 1) | Gefitinib 250 or 500 mg/day | PFS: 3 months |
| Ichihara et al. [66] | Retrospective | n = 30: Japanese; chemo-naїve and previously treated; exon 19 deletion (n = 16); L858R (n = 14) | Gefitinib 250 mg/day | PFS: 11.3 months |
| Inoue et al. [67] | Ph II, single-arm | n = 29: Japanese; chemo-naїve; poor performance status; exon 19 deletion (n = 18); L858R (n = 10), L861Q (n = 1) | Gefitinib 250 mg/day | PFS: 6.5 months |
| Inoue et al. [68] | Ph II, non-randomized comparison with standard chemotherapy | n = 16: Japanese; chemo-naїve; exon 19 deletion (n = 9); L858R (n = 7) | Gefitinib 250 mg/day | PFS: 9.7 months |
| Kim et al. [69] | Retrospective | n = 8: Korean; ≥1 previous treatment; exon 19 deletion (n = 5); L858R (n = 1) | Gefitinib 250 mg/day | TTP: 12.6 months |
| Kimura et al. [70] | Prospective, single-arm | n = 9: Japanese; chemo-naїve and previously treated; exon 19 deletion (n = 4); L858R (n = 4); V689L (n = 1) | Gefitinib 250 mg/day | PFS: 6.4 months |
| Kobayashi et al. [71] | Ph III, randomized comparison with carboplatin/paclitaxel | n = 98: chemo-naïve, EGFR mutation | Gefitinib 250 mg/day | PFS: 10.4 months |
| Koyama et al. [72] | Retrospective | n = 18: Japanese; chemo-naїve or previous treatment; G719C (n = 2); G719C and W731R (n = 1); P733S (n = 1); exon 19 deletion (n = 6); V738–I744 ins (n = 2); S768C (n = 1); T790M (n = 1); Q812R (1); V843I (n = 1); L858R (n = 2) | Gefitinib 250 mg/day | Mean TTP: 13.7 months |
| Massarelli et al. [73] | Retrospective | n = 7: Asian or Caucasian; chemo-naїve or previous treatment; exon 19 deletion (n = 6); G719A (n = 1) | Gefitinib 250 mg/day | TTP: 9.3 months |
| Oshita et al. [74] | Retrospective | n = 11: Japanese; ≥1 previous treatment; EGFR mutation | Gefitinib 250 mg/day | PFS: 16 months |
| Pallis et al. [75] | Retrospective | n = 11: Greek; ≥1 previous treatment; exon 19 deletion (n = 6); L858R (n = 3); G719D (n = 1); E746V (n = 1) | Gefitinib 250 mg/day | TTP: 14.7 months |
| Riely et al. [36] | Retrospective | n = 22: primarily white; chemo-naїve or previously treated; exon 19 deletion (n = 15); L858R (n = 7) | Gefitinib 250 mg/day | PFS: 12 months |
| Sequist et al. [76] | Ph II, single-arm | n = 31: primarily non-Asian; chemo-naїve; exon 19 deletion (n = 17); L858R (n = 8); atypical mutation (n = 6) | Gefitinib 250 mg/day | PFS: 9.2 months |
| Shao et al. [77] | Ph II, single-arm | n = 51: Taiwanese; chemo-naїve; EGFR mutation | Gefitinib 250 mg/day | PFS: 8.8 months |
| Shoji et al. [78] | Retrospective | n = 20; Japanese; chemo-naїve and previously treated; exon 19 deletion (n = 10); L858R (n = 8); E709A and G719S (n = 1); L858R and Y725Y (n = 1) | Gefitinib 250 mg/day | PFS: 14 months |
| Sugio et al. [79] | Ph II, single-arm | n = 19: Japanese; exon 19 deletion (n = 7); L858R (n = 10); exon 19 deletion and L858R (n = 1); exon 19 deletion and G796A (n = 1) | Gefitinib 250 mg/day | PFS: 7.1 months |
| Sunaga et al. [80] | Ph II, single-arm | n = 21: Japanese; chemo-naїve or previously treated; exon 19 deletion (n = 17); L858R (n = 4) | Gefitinib 250 mg/day | PFS: 12.9 months |
| Sutani et al. [81] | Ph II, single-arm | n = 27: Japanese; 0–1 previous treatments; exon 19 deletion; L858R, L861Q | Gefitinib 250 mg/day | TTP: 9.4 months |
| Takano et al. [82] | Retrospective | n = 85: Japanese; chemo-naїve or previously treated; exon 19 deletion (n = 49); L858R (n = 36) | Gefitinib 250 mg/day | PFS: 9.2 months |
| Tamura et al. [83] | Ph II, single-arm | n = 28: Japanese; 0–2 previous treatments; exon 19 deletion (n = 14); L858R (n = 14) | Gefitinib 250 mg/day | PFS: 11.5 months |
| Varella-Garcia et al. [84] | Retrospective | n = 27: Japanese; chemo-naїve or previously treated; EGFR mutations | Gefitinib 250 mg/day | TTP: 10.2 months |
| Xu et al. [85] | Retrospective | n = 32: Chinese; chemo-naїve and previous treatment; exon 19 deletion (n = 11); exon 19 – not deletion (n = 6); L858R (n = 6); exon 18 mutation (n = 6); exon 20 mutation (n = 2); exon 23 mutation (n = 1) | Gefitinib 250 mg/day | TTP: 15 months |
| Zhang et al. [86] | Retrospective | n = 12: Chinese; ≥1 previous treatment; exon 19 deletion (n = 4); L858 (n = 8) | Gefitinib 250 mg/day | PFS: 10 months |
| Asami et al. [87] | Prospective; Ph II; single-arm | n = 17: Japanese; exon 19 deletion (n = 7); L858R (n = 10) | Gefitinib 250 mg/day | PFS: 12.9 months |
| Azuma et al. [88] | Retrospective | n = 47: Japanese; chemo-naїve or previously treated; exon 19 deletion (n = 27); L858R (n = 20) | Gefitinib 250 mg/day | PFS: 6.7 months |
| Chen et al. [89] | Prospective, single-arm | n = 26: Chinese; chemo-naїve; EGFR mutation | Gefitinib 250 mg/day | PFS: 9.0 months |
| Chen et al. [90] | Prospective, Ph II; randomized comparison of gefitinib ± tegafur/uracil | n = 16: Taiwanese or Chinese; previously treated; exon 19 deletion (n = 12); L858R (n = 4) | Gefitinib 250 mg/day | PFS: 7.6 months |
| Douillard et al. [7] | Ph III INTEREST study; randomized, comparison with docetaxel | n = 19: primarily white; prior platinum chemotherapy; EGFR mutation | Gefitinib 250 mg/day | PFS: 7.0 months |
| Giovannetti et al. [91] | Retrospective, single-arm | n = 9: Italian; chemo-naїve or previously treated; exon 19 deletion (n = 7); L858R (n = 2) | Gefitinib 250 mg/day | TTP: 9.0 months |
| Inoue et al. [92] | Prospective; Ph II; single-arm (NEJ003) | n = 31: Japanese; chemo-naїve; EGFR mutation | Gefitinib 250 mg/day | PFS: 13.6 months |
| Lee et al. [93] | Ph III; randomized comparison with cisplatin/gemcitabine (First-SIGNAL) | n = 27: Korean; chemo-naïve; EGFR mutation | Gefitinib 250 mg/day | PFS: 7.9 months |
| Kim et al. [94] | Prospective; Ph II; single-arm | n = 45: Korean; chemo-naïve; exon 19 deletion (n = 29); L858R (n = 15); L861Q (n = 1) | Gefitinib 250 mg/day | PFS: 398 days (13.1 months) |
| Maemondo et al. [10] | Ph III; randomized comparison with carboplatin/paclitaxel (NEJSG002) | n = 114: Japanese; chemo-naïve; exon 19 deletion (n = 58); L858R (n = 49); Other (n = 7) | Gefitinib 250 mg/day | PFS: 10.8 months |
| Masago et al. [95] | Retrospective; single-arm | n = 47; Japanese; chemo-naїve or previously treated; EGFR mutation | Gefitinib 250 mg/day | PFS: 342 days (11.3 months) |
| Mitsudomi et al. [9] | Ph III; randomized comparison with cisplatin/docetaxel (WJTOG3405) | n = 86: Japanese; chemo-naïve; exon 19 deletion (n = 50); L858R (n = 36) | Gefitinib 250 mg/day | PFS: 9.2 months (8.4 months in stage IIIB/IV) |
| Moiseyenko et al. [96] | Prospective; single-arm | n = 25: Russian; chemo-naïve; exon 19 deletion (n = 17); L858R (n = 8) | Gefitinib 250 mg/day | PFS: 8.0 months |
| Park et al. [97] | Prospective, Ph II, single-arm | n = 3: Korean; previously treated; exon 19 deletion (n = 2); L858R (n = 1) | Gefitinib 250 mg/day | PFS: 5.8 months |
| Sun et al. [53] | Retrospective; single-arm | n = 42: Korean; mainly previously treated; exon 19 deletion or L858R | Gefitinib 250 mg/day | PFS: 11.9 months |
| Sun et al. [15] | Ph III; randomized comparison with icotinib (ICOGEN) | n = 39: Chinese; previously treated; EGFR mutation | Gefitinib 250 mg/day | PFS: 158 days |
| Uruga et al. [98] | Retrospective; single-arm | n = 9: Japanese; chemo-naїve or previously treated; exon 19 deletion (n = 6); L858R (n = 3) | Gefitinib 250 mg/day | PFS: 396 days |
| Wu et al. [99] | Retrospective; single-arm | n = 272: Taiwanese; chemo-naїve or previously treated; exon 19 deletion (n = 106); L858R (n = 114); other (n = 52) | Gefitinib 250 mg/day | PFS: 7.8 months |
| Wu et al. [100] | Retrospective; single-arm | n = 32: Chinese; previously treated; exon 19 deletion or L858R | Gefitinib 250 mg/day | PFS: 8.0 months |
| Yamaguchi et al. [101] | Retrospective; single-arm | n = 16: Japanese; chemo-naїve or previously treated; exon 19 deletion (n = 4); L858R (n = 8); exon 19 deletion + L858R (n = 4) | Gefitinib 250 mg/day | PFS: 246 days(8.1 months) |
| Yoshida et al. [102] | Prospective | Japanese; chemo-naïve (n = 23); exon 19 deletion or L858R Japanese; previously treated (n = 15); exon 19 deletion or L858R | Gefitinib 250 mg/day | PFS: 7.8 months PFS: 6.5 months |
| Chemotherapy | ||||
| Bell et al. [57] | Retrospective (Ph III INTACT studies; randomized comparison with gefitinib) | n = 9: primarily white; chemo-naїve; exon 19 deletion; L858R; other mutations | Paclitaxel/carboplatin or gemcitabine/cisplatin | PFS: 6.7 months |
| Eberhard et al. [103] | Retrospective (Ph III TRIBUTE study; randomized comparison with erlotinib plus carboplatin/paclitaxel) | n = 14: primarily white; chemo-naїve; exon 19 deletion; L858R; other mutations | Carboplatin/paclitaxel | TTP: 6.6 months |
| Fukuoka et al. [63] | Ph III; randomized comparison with gefitinib (IPASS) | n = 129: East-Asian; adenocarcinoma; never-smokers; chemo-naїve; EGFR mutation | Carboplatin/paclitaxel | PFS: 6.3 months |
| Inoue et al. [68] | Ph II; non-randomized comparison with gefitinib | n = 9: Japanese; chemo-naїve; exon 19 deletions (n = 8); L858R (n = 1) | Standard chemotherapy | PFS: 7.6 months |
| Lee et al. [104] | Retrospective | n = 17: Korean; chemo-naїve; patients receiving platinum-based chemotherapy; EGFR mutation | Platinum-based chemotherapy | TTP: 8 months paclitaxel, 9.7 months; gemcitabine, 7.4 months |
| Tambo et al. [105] | Retrospective | n = 26: Japanese; chemo-naïve; EGFR mutations | Chemotherapy | PFS: 8.4 months |
| Ciuleanu et al. [40] | Ph III; randomized comparison versus erlotinib (TITAN) | n = 4: predominantly white; previously treated; EGFR mutation | Docetaxel or pemetrexed (single-agent) | PFS: 9.9 months |
| Douillard et al. [7] | Ph III; randomized comparison with gefitinib (INTEREST) | n = 19; primarily white; prior platinum chemotherapy; EGFR mutation | Docetaxel | PFS: 4.1 months |
| Rosell et al. [44] | Ph III; randomized comparison versus erlotinib (EURTAC) | n = 87: primarily white; chemo-naïve; EGFR mutation | Platinum-based chemotherapy | PFS: 5.2 months |
| Kalikaki et al. [106] | Retrospective; single-arm | n = 9; Greek; chemo-naïve; EGFR mutation | Chemotherapy | TTP: 6.1 months |
| Kim et al. [107] | Retrospective | n = 67: Korean; chemo-naïve; EGFR mutation | Platinum-based chemotherapy | PFS: 7.1 months |
| Lin et al. [108] | Retrospective; single-arm | n = 56: East-Asian; chemo-naïve; primarily exon 19 deletion or L858R | Predominantly platinum-based chemotherapy | PFS: 6.1 months |
| Maemondo et al. [10] | Ph III; randomized comparison with gefitinib (NEJSG002) | n = 114: Japanese; chemo-naïve; exon 19 deletion (n = 59); L858R (n = 48); other (n = 7) | Carboplatin/paclitaxel | PFS: 5.4 months |
| Matsumoto et al. [109] | Retrospective; single-arm | n = 26: Japanese; chemo-naïve; EGFR mutation | Chemotherapy (50% platinum doublet, 50% non-platinum) | PFS: 6.9 months |
| Mitsudomi et al. [9] | Ph III; randomized comparison with gefitinib (WJTOG3405) | n = 86: Japanese; chemo-naïve; exon 19 deletion (n = 37); L858R (n = 49) | Cisplatin/docetaxel | PFS: 6.3 months (5.3 months in stage IIIB/IV) |
| Sun et al. [53] | Retrospective; single-arm | n = 67: Korean; chemo-naïve; exon 19 deletion or L858R | Chemotherapy | PFS: 5.1 months |
| Wu et al. [99] | Retrospective; single-arm | n = 93: Taiwanese; previously treated; exon 19 deletion (n = 43); L858R (n = 37); other (n = 13) | Pemetrexed monotherapy | PFS: 3.9 months |
| Wu et al. [100] | Retrospective; single-arm | n = 55: Chinese; chemo-naïve; exon 19 deletion (n = 32); L858R (n = 21); exon 19 deletion and L858R (n = 2) | Predominantly platinum-based chemotherapy | PFS: 4 months |
| Yoshida et al. [102] | Prospective | Japanese; chemo-naïve (n = 25) or previously treated (n = 20); exon 19 deletion or L858R | Cytotoxic chemotherapy | PFS: chemo-naïve: 5.1 months; previously treated: 4.0 months |
| Zhou et al. [3] | Ph III; randomized comparison versus erlotinib (OPTIMAL) | n = 72: Chinese; chemo-naïve; exon 19 deletion (n = 39); L858R (n = 33) | Carboplatin/gemcitabine | PFS: 4.6 months |
| Afatinib | ||||
| Yang et al. [110] | Ph II; randomized, single-arm | n = 129; Taiwanese and US; chemo-naïve, or one previous line of chemotherapy; exon 19 deletion (n = 52); L858R (n = 54); other (n = 23) | Afatinib 40 mg or 50 mg/day | PFS: 14 months |
| Icotinib | ||||
| Ren et al. [16] | Ph I; single-arm | n = 7: Chinese; previously treated; exon 19 deletion (n = 3); L858R (n = 4) | Icotinib (varied dose and schedule) | PFS: 141 days (4.6 months) |
| Sun et al. [15] | Ph III; randomized comparison with gefitinib (ICOGEN) | n = 27: Chinese; previously treated; EGFR mutation | Icotinib 125 mg three times/day | PFS: 198 days (6.5 months) |
Ph: phase, BAC: bronchioloalveolar carcinoma.