Figure 1
Flow diagram on selection of publications for analysis.
Table 1
Randomized trials on intercalated chemotherapy and TKIs for non-small cell lung cancer
| REFERENCE | TYPE OF TRIAL | # OF PTS | SELECTION OF PATIENTS | TREATMENT REGIMEN(s) | % never-smokers | % EGFR mutant, intercalated arm only | ORR (%) | MEDIAN PFS (months) | MEDIAN OS (months) |
|---|---|---|---|---|---|---|---|---|---|
| Mok 2009 | Randomized | 154 | All histologies, | Arm A (76 pts): | 34% | 28% | Arm A: 35.5% | Arm A: 6.9 m | Arm A: 17.3 m |
| (FASTACT) 26 | Phase 2 | previously untreated | Gem, d 1 & 8 | Arm B: 24.4% | Arm B: 5.5 m | Arm B: 17.7 m | |||
| Cis or Carbo, day 1 | |||||||||
| Erlotinib, d 15-28 | P = 0.12 | P = 0.002 | P: ns | ||||||
| Cycle q 4 weeks | |||||||||
| Arm B (78 pts): | |||||||||
| as above, placebo | |||||||||
| instead of Erlotinib | |||||||||
| 52 | As above, | Arm A (24 pts) | 100% | 49% | Arm A: 45.8% | Arm A: 11.1 m | Not reached | ||
| neversmokers | Arm B (28 pts) | Arm B: 32.1% | Arm B: 6.4 m | ||||||
| Treatment as above | P: not | P = 0.002 | |||||||
| reported | |||||||||
| Hirsch 2011 27 | Randomized Phase 2 | 143 | Positive for EGFR protein expression and/or with high EGFR gene copy number, previously untreated | Arm A (71 pts): Pacli d 1 Carbo d 1 Erlotinib d 2 - 15 Cycle q 3 weeks Arm B (72 pts): Erlotinib | 28% | 10% | Arm A: 22.4% Arm B: 11.6% P = ns | Arm A: 4.6 m Arm B: 2.7 m P = ns | Arm A: 11.4 m Arm B: 16.7 m P = ns |
| Aerts 2012 (NVALT 10) 28 | Randomized Phase 2 | 231 | All histologies Progression after platin-based chemotherapy | Arm A (115 pts): Erlotinib Arm B (116 pts): Doce or Pem, d 1 Erlotinib, d 2 - 16 Cycle q 3 weeks | 7% | 4% | Arm A: 7% Arm B: 13% P = 0.03 | Arm A: 4.9 m Arm B: 6.1 m P = 0.11 | Arm A: 5.5 m Arm B: 7.8 m P = 0.01 |
| Lee 2013 29 | Randomized Phase 2 | 240 | Non-squamous, never-smokers, Progression after 1st line chemotherapy | Arm A (78 pts): Pem d 1 Erlotinib d 2 - 14,Cycle q 3 weeks Arm B (82 pts): Erlotinib continuously Arm C (80 pts): Pem d 1,Cycle q 3 weeks | 100% | 56% | Arm A: 44.7% Arm B: 29.3% Arm C: 10.0% P = 0.001 | Arm A: 7.4 m Arm B: 3.8 m Arm C: 4.4 m P = 0.003 | Arm A: 20.5 m Arm B: 22.8 m Arm C: 17.7 m P = 0.19 |
| Wu Y-L 2013 (FASTACT 2) 30 | Randomized Phase 3 | 451 | All histologies, previously untreated | Arm A (226 pts): Gem, d 1 & 8 Cis or Carbo, d 1 Erlotinib, d 15-28 Cycle q 4 weeks Arm B (225 pts): as above, placebo instead of Erlotinib | 49% | 39% | Arm A: 44% Arm B: 16% P < 0.0001 | Arm A: 7.6 m Arm B: 6.0 m P < 0.0001 | Arm A: 18.3 m Arm B: 15.2 m P = 0.04 |
| 97 | As above, subgroup with activating EGFR mutations | Arm A (49 pts): Arm B (48 pts): Treatment as above | Not separately reported | 100% | Arm A: 84% Arm B: 15% P < 0.0001 | Arm A: 16.8 m Arm B: 6.9 m P < 0.0001 | Arm A: 31.4 m Arm B: 20.6 m P = 0.009 | ||
| Auliac 2014 31 | Randomised Phase 2 | 147 | EGFR wild-type or unknown Progression after 1st line chemotherapy | Arm A (73 pts): Doce, d 1 Erlotinib, d 2 - 16 Cycle q 3 weeks Arm B (74 pts): Doce, d 1 | 7.5% | 4% | Arm A: 4.4% Arm B: 1.4% P = ns | Arm A: 2.2 m Arm B: 2.5 m P = ns | Arm A: 6.5 m Arm B: 8.3 m P = ns |
| Karavasilis 2014 32 | Randomized Phase 2 | 50 | All histologies Previously untreated | Arm A (25 pts): Doce, d 1 Erlotinib, d 9 - 20 Arm B (25 pts): Doce, d 1 Erlotinib, d 3 - 14 ycle q 3 weeks | 10% | 11% | Arm A: 24% Arm B:12% | Arm A: 2.9 m Arm B: 4.2 m | Arm A: 9.9 m Arm B: 10.8 m |
| Mok 2014 33 | Randomized Phase 2 | 123 | Unselected, progression after platin-based ChT | Arm A (63 pts): Eribulin mesylate, d1 Erlotinib, d 2-16 Cycle q 3 weeks Arm B (60 pts): Eribulin mesylate, d 1 and 8 Erlotinib, d 15-28 Cycle q 4 weeks | 24% | 28% | Arm A: 13% Arm B:17% P = ns | Arm A: 3.5 m Arm B: 3.8 m P = ns | Arm A: 7.6 m Arm B: 8.5 m P = ns |
| Yu 2014 34 | Randomized Phase 2 | 117 | Non-squamous, previously untreated | Arm A (58 pts): Pem, d 1 Cis or Carbo, d 1 Gefitinib, d 3 – 16 Cycle q 3 weeks Arm B (57 pts): As above, no Gefitinib | 58% | 40% | Arm A: 50.0% Arm B: 47.7% P = ns | Arm A: 7.9 m Arm B: 7.0 m P = ns | Arm A: 25.4 m Arm B: 20.8 m P = ns |
| 32 | As above, subgroup with activating EGFR mutations | Arm A: 14 pts Arm B: 18 pts Treatment as above | Not separately reported | 100% | Arm A: 76.9% Arm B: 50.0% P = 0.13 | Arm A: Not reached Arm B: 14.0 m P = 0.017 | Not reached | ||
| Choi 2015 35 | Randomized Phase 2 | 90 | NSCLC, EGFR wild. type or unknown PS 0 – 2, previously untreated | Arm A (44 pts): Pem, d 1 Carbo, d 1 Gefitinib, d 2 – 15 Cycle q 3 weeks x 4 Maintenance Gefitinib Arm B (46 pts): As Arm A, no Gefitinib | 10% | 10% | Arm A: 41.9% Arm B: 39.5% P = ns | Arm A: 4.1 m Arm B: 4.1 m P = ns | Arm A: 9.3 m Arm B: 10.5 m P = ns |
| Juan 2015 36 | Randomized Phase 2 | 68 | All histologies Progression after platin-based chemotherapy | Arm A (33 pts): Doce q 3 weeks Erlotnib, d 2 – 16 Arm B (35 pts): Erlotinib continuously | 6% | 5% | Arm A: 3% Arm B: 9% P = 0.19 | Arm A: 3.0 m Arm B: 2.1 m P = 0.19 | Arm A: 7.5 m Arm B: 5.2 m P = 0.19 |
| Lu 2015 37 | Randomized Phase 3 | 219 | Adenocarcinoma, EGFR unknown, non-smokers, no progression after 2 cycles of gem-carbo | Arm A (109 pts): Gem, d 1 and 8 Carbo, d 1 Gefitinib d 15-25 and maintenance Cycle q 4 weeks x 4 Arm B (110 pts): As above, no Gefitinib | 100% | 72% | Not reported | Arm A: 10 m Arm B: 4.4 m P = 0.001 | Not reported |
| Michael 2015 38 | Randomized Phase 2 | 54 | All histologies PS 2 or elderly Previously untreated | Arm A (28 pts): Gem d 1 and 8 Erlotinib days 15 – 28 Cycle q 4 weeks Arm B (26 pts): Gem d1 and 8 Cycle q 4 weeks | 15% | 12% | Arm A: 6% Arm B: 23% P: ns | Arm A: 2.5 m Arm B: 1.9 m P: ns | Arm A: 3.9 m Arm B: 4.4 m P: ns |
| Han 2016 39 | Randomized Phase 2 | 121 | Adenocarcinoma, EGFR mutant, previously untreated | Arm A (40 pts): Pem, d1 + maintenance Carbo, d1 for ≤ 6 cycles Gefitinib, d 5-21 + maintenance Cycle q 4 weeks Arm B (40 pts): As above, no Gefitinib Arm C (41 pts): Gefitinib alone | Not reported | 100% | Arm A: 82.5% Arm B: 32.5% Arm C: 65.9% P: 0.04 | Arm A: 18.8 m Arm B: 5.7 m Arm C: 12.0 m P: not reported | Not reached |
| Lara 2016 (SWOG S0709) 40 | Randomized Phase 2 | 59 | PS 2, Proteomics: VeriStrat-good status, previously untreated | Arm A (33 pts): Erlotinib Arm B (26 pts): Pacli d 1 Carbo d 1 Erlotinib d 2 – 16 Cycle q 3 weeks x 4 Maintenance Erlotinib | 20% | 20% | Arm A: 6% Arm B: 23% P = 0.06 | Arm A: 1.6 m Arm B: 4.6 m P = 0.06 | Arm A: 6.0 m Arm B: 11.0 m P = 0.27 |
| Li 2016 41 | Randomized Phase 2 | 79 | Predominantly non- squamous Progression after 1st line chemotherapy | Arm A (27 pts): Pem d 1 Cycle q 3 weeks Arm B (52 pts): Pem d 1 Erlotinib d 2 – 17 Cycle q 3 weeks | Not reported | 19% | Arm A: 10% Arm B: 29% P = 0.17 | Arm A: 2.9 m Arm B: 4.7 m P = 0.26 | Arm A: 8.3 m Arm B: 9.7 m P = 0.28 |
| Lee 2016 42 | Randomized Phase 2 | 76 | Adenocarcinoma, neversmokers, Previously untreated | Arm A (39 pts): Pem d1 Carbo d 1 Gefitinib d 5 - 18 + maintenance Cycle q 3 weeks x max 9 Arm B (37 pts): As arm A, placebo instead of Gefitinib At progression: Gefitinib for arm B | 100% | 42% | Arm A: 79.5% Arm B: 51.4% P = 0.01 | Arm A: 12.8 m Arm B: 7.0 m P = 0.009 | Arm A: 29.2 m Arm B: 20.4 m P = 0.15 |
| 29 | As above, EGFR mutant | Arm A: 15 pts Arm B: 14 pts Treatment as above | 100% | 100 | Arm A: 86.7% Arm B: 42.9% P = 0.01 | Arm A: 13.3 m Arm B: 7.8 m P = 0.08 | Arm A: 26.6 m Arm B: 22.2 m P = ns | ||
| 37 | As above, EGFR wt | Arm A: 22 pts Arm B: 15 pts Treatment as above | 100% | 0 | Arm A: 72.7% Arm B: 57.1% P = ns | Arm A: 6.6 m Arm B: 6.6 m P = 0.08 | Arm A: 29.2 m Arm B: 15.9 m P = 0.09 | ||
| Yoon 201643 | Randomized Phase 2 | 87 | Non-squamous Progression after 1st line chemotherapy | Arm A (57 pts): Pem d 1 Afatinib d 2 – 15 Arm B (30 pts): Pem d 1 | 31% | 31% | Arm A: 31.8 % Arm B: 13.3% P = 0.074 | Arm A: 5.7 m Arm B: 2.9 m P = 0.16 | Arm A: 12.1 m Arm B: 15.6 m P = 0.245 |
[i] Carbo = carboplatin; Cis = cisplatin; Doce = docetaxel; Gem = gemcitabine; ORR = overall response rate; OS = overall survival; Pacli = paclitaxel; PFS = progression-free survival; Pem = pemetrexed; PTS = patient
Table 2
Single-arm Phase II trials on intercalated chemotherapy and TKIs for non-small cell lung cancer
| REFERENCE | # OF PTS | SELECTION OF PATIENTS | TREATMENT REGIMEN(s) | % never-smokers | % EGFR mutant | ORR (%) | MEDIAN PFS (months) | MEDIAN OS (months) |
|---|---|---|---|---|---|---|---|---|
| Oshita 2010 44 | 16 | Unselected, previously untreated | Pacli d 1 Irino d 1 Gefitinib d 8-14 Cycle q 3 weeks | Not reported | 25% | 43.8% | Not reported | 18.1 m |
| Sangha 2011 45 | 39 | All histologies Progression after 1st line chemotherapy | Doce d 1 Erlotinib days 2 – 16 Cycle q 3 weeks | 28% | 19% | 28.2% | 4.1 m | 18.2 m |
| Minami 2013 46 | 27 | Non-squamous Progression after 1st line chemotherapy | Pem, d 1 Erlotinib, d 2 – 16 Cycle q 3 weeks | 22% | 4% | 11.1% | 2.8 m | 15.8 m |
| Yoshimura 2013 47 | 27 | Activating EGFR mutations, Progression after TKI | Pem, d 1 Erlotinib or Gefitinib, days 2 – 16 Cycle q 3 weeks | 78% | 100% | 25.9% | 7.0 m | 11.4 m |
| Kim 2014 48 | 17 | Non-squamous, EGFR wt, progression after 1st line ChT | Pem d 1 Erlotinib d 2-15 | 27% | 0% | 27.0% | 2.5 m | 6.7 m |
| Fang 2014 49 | 57 | Unselected, progression after platin-based ChT | Gem, d 1 and 8 Cis, d 1-3 Gefitinib, d 10 - 24 Cycle q 4 weeks | 37% | 40% | 11% | 10 m | 15.2 m |
| Yang 2014 50 | 29 | Adenocarcinoma, non-smokers, EGFR unknown, previously untreated | Pacli, d1 Carbo, d1 Gefitinib, d 8 – 17 + maintenance Cycle q 3 weeks | 100% | 73% | 74.1% | 16 m | Not reached |
| Zwitter 2014 51 | 15 | Adenocarcinoma, light/never smokers, EGFR wild-type or unknown Previously untreated | Gem d 1 and 4 Cis d 2 Erlotinib d 5 – 15 Cycle q 3 weeks x 4 – 6 Maintenance Erlotinib | 100% | 5% | 33% | 6.0 m | 7.6 m |
| Yoshimura 2015 52 | 26 | Activating EGFR mutations Previously untreated | Pem d 1 Gefitinib d 2-16 | 46% | 100% | 84.6% | 18.0 m | 32.0 m |
| Yu 2015 53 | 42 | Mostly adenocarcinoma Progression after response to TKI | Pem, d 1 or Pem + Platin, d 1 TKI (Erlotinib or Gefitinib), d 6 – 21 Cycle q 3 weeks | 71% | 61% | 23.8% | 8.0 m | 11.0 m |
| Zwitter 2016 (ITAC 2) 54 | 38 | Activating EGFR mutations Previously untreated | Gem d 1 and 4 Cis d 2 Erlotinib d 5 – 15 Cycle q 3 weeks x 4 – 6 Maintenance Erlotinib | 63% | 100% | 84.2% | 23.4 m | 38.3 m |
[i] Carbo = carboplatin; Cis = cisplatin; Doce = docetaxel; Gem = gemcitabine; Irino = irinotecan; ORR = overall response rate; OS = overall survival; Pacli = paclitaxel; PFS = progression-free survival; Pem = pemetrexed; PTS = patient
Figure 2
Correlation between median PFS and proportion of patients with non-squamous histology (A), proportion of never-smokers (B) and proportion of EGFR mutant patients (C). Black solid marks and black solid lines are for 1st line treatment; red hollow marks and red interrupted lines for 2nd line treatment. Bubble size corresponds to the number of patients in a trial.