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Selection of non-small cell lung cancer patients for intercalated chemotherapy and tyrosine kinase inhibitors

Matjaz Zwitter
Matjaz Zwitter
, 
Antonio Rossi
Antonio Rossi
, 
Massimo Di Maio
Massimo Di Maio
, 
Maja Pohar Perme
Maja Pohar Perme
 and 
Gilberto Lopes
Gilberto Lopes
   | Jul 18, 2017
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Article Category: Review
Published Online: Jul 18, 2017
Page range: 241 - 251
Received: May 03, 2017
Accepted: Jun 09, 2017
DOI: https://doi.org/10.1515/raon-2017-0029
© 2017 Matjaz Zwitter, Antonio Rossi, Massimo Di Maio, Maja Pohar Perme, Gilberto Lopes
This work is licensed under the Creative Commons Attribution 4.0 International License.

Figure 1

Flow diagram on selection of publications for analysis.
Flow diagram on selection of publications for analysis.

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.
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.

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 RandomizedPhase 2 143 Positive for EGFRprotein expressionand/or with highEGFR gene copynumber, previouslyuntreated Arm A (71 pts):Pacli d 1Carbo d 1Erlotinib d 2 - 15Cycle q 3 weeksArm B (72 pts):Erlotinib 28% 10% Arm A: 22.4%Arm B: 11.6%P = ns Arm A: 4.6 mArm B: 2.7 mP = ns Arm A: 11.4 mArm B: 16.7 mP = ns
Aerts 2012(NVALT 10) 28 RandomizedPhase 2 231 All histologiesProgression afterplatin-basedchemotherapy Arm A (115 pts):ErlotinibArm B (116 pts):Doce or Pem, d 1Erlotinib, d 2 - 16Cycle q 3 weeks 7% 4% Arm A: 7%Arm B: 13%P = 0.03 Arm A: 4.9 mArm B: 6.1 mP = 0.11 Arm A: 5.5 mArm B: 7.8 mP = 0.01
Lee 2013 29 RandomizedPhase 2 240 Non-squamous,never-smokers,Progression after 1stline chemotherapy Arm A (78 pts):Pem d 1Erlotinib d 2 - 14,Cycleq 3 weeksArm B (82 pts):Erlotinib continuouslyArm C (80 pts):Pem d 1,Cycle q 3weeks 100% 56% Arm A: 44.7%Arm B: 29.3%Arm C: 10.0%P = 0.001 Arm A: 7.4 mArm B: 3.8 mArm C: 4.4 mP = 0.003 Arm A: 20.5 mArm B: 22.8 mArm C: 17.7mP = 0.19
Wu Y-L 2013(FASTACT 2) 30 RandomizedPhase 3 451 All histologies,previously untreated Arm A (226 pts):Gem, d 1 & 8Cis or Carbo, d 1Erlotinib, d 15-28Cycle q 4 weeksArm B (225 pts):as above, placeboinstead of Erlotinib 49% 39% Arm A: 44%Arm B: 16%P < 0.0001 Arm A: 7.6 mArm B: 6.0 mP < 0.0001 Arm A: 18.3 mArm B: 15.2 mP = 0.04
97 As above, subgroupwith activating EGFRmutations Arm A (49 pts):Arm B (48 pts):Treatment as above Notseparatelyreported 100% Arm A: 84%Arm B: 15%P < 0.0001 Arm A: 16.8 mArm B: 6.9 mP < 0.0001 Arm A: 31.4 mArm B: 20.6 mP = 0.009
Auliac 2014 31 RandomisedPhase 2 147 EGFR wild-type orunknownProgression after 1stline chemotherapy Arm A (73 pts):Doce, d 1Erlotinib, d 2 - 16Cycle q 3 weeksArm B (74 pts):Doce, d 1 7.5% 4% Arm A: 4.4%Arm B: 1.4%P = ns Arm A: 2.2 mArm B: 2.5 mP = ns Arm A: 6.5 mArm B: 8.3 mP = ns
Karavasilis2014 32 RandomizedPhase 2 50 All histologiesPreviously untreated Arm A (25 pts):Doce, d 1Erlotinib, d 9 - 20Arm B (25 pts):Doce, d 1Erlotinib, d 3 - 14ycle q 3 weeks 10% 11% Arm A: 24%Arm B:12% Arm A: 2.9 mArm B: 4.2 m Arm A: 9.9 mArm B: 10.8 m
Mok 2014 33 RandomizedPhase 2 123 Unselected,progression afterplatin-based ChT Arm A (63 pts):Eribulin mesylate, d1Erlotinib, d 2-16Cycle q 3 weeksArm B (60 pts):Eribulin mesylate, d 1and 8Erlotinib, d 15-28Cycle q 4 weeks 24% 28% Arm A: 13%Arm B:17%P = ns Arm A: 3.5 mArm B: 3.8 mP = ns Arm A: 7.6 mArm B: 8.5 mP = ns
Yu 2014 34 RandomizedPhase 2 117 Non-squamous,previously untreated Arm A (58 pts):Pem, d 1Cis or Carbo, d 1Gefitinib, d 3 – 16Cycle q 3 weeksArm B (57 pts):As above, no Gefitinib 58% 40% Arm A: 50.0%Arm B: 47.7%P = ns Arm A: 7.9 mArm B: 7.0 mP = ns Arm A: 25.4mArm B: 20.8 mP = ns
32 As above, subgroupwith activating EGFRmutations Arm A: 14 ptsArm B: 18 ptsTreatment as above Notseparatelyreported 100% Arm A: 76.9%Arm B: 50.0%P = 0.13 Arm A:Not reachedArm B: 14.0 mP = 0.017 Not reached
Choi 2015 35 RandomizedPhase 2 90 NSCLC, EGFR wild.type or unknownPS 0 – 2, previouslyuntreated Arm A (44 pts):Pem, d 1 Carbo, d 1Gefitinib, d 2 – 15Cycle q 3 weeks x 4Maintenance GefitinibArm B (46 pts):As Arm A, no Gefitinib 10% 10% Arm A: 41.9%Arm B: 39.5%P = ns Arm A: 4.1 mArm B: 4.1 mP = ns Arm A: 9.3 mArm B: 10.5 mP = ns
Juan 2015 36 RandomizedPhase 2 68 All histologiesProgression afterplatin-basedchemotherapy Arm A (33 pts):Doce q 3 weeksErlotnib, d 2 – 16Arm B (35 pts):Erlotinib continuously 6% 5% Arm A: 3%Arm B: 9%P = 0.19 Arm A: 3.0 mArm B: 2.1 mP = 0.19 Arm A: 7.5 mArm B: 5.2 mP = 0.19
Lu 2015 37 RandomizedPhase 3 219 Adenocarcinoma,EGFR unknown,non-smokers, noprogression after 2cycles of gem-carbo Arm A (109 pts):Gem, d 1 and 8Carbo, d 1Gefitinib d 15-25 andmaintenanceCycle q 4 weeks x 4Arm B (110 pts):As above, no Gefitinib 100% 72% Not reported Arm A: 10 mArm B: 4.4 mP = 0.001 Not reported
Michael2015 38 RandomizedPhase 2 54 All histologiesPS 2 or elderlyPreviously untreated Arm A (28 pts):Gem d 1 and 8Erlotinib days 15 – 28Cycle q 4 weeksArm B (26 pts):Gem d1 and 8Cycle q 4 weeks 15% 12% Arm A: 6%Arm B: 23%P: ns Arm A: 2.5 mArm B: 1.9 mP: ns Arm A: 3.9 mArm B: 4.4 mP: ns
Han 2016 39 RandomizedPhase 2 121 Adenocarcinoma,EGFR mutant,previously untreated Arm A (40 pts):Pem, d1 +maintenanceCarbo, d1 for ≤ 6 cyclesGefitinib, d 5-21 +maintenanceCycle q 4 weeksArm B (40 pts):As above, no GefitinibArm C (41 pts):Gefitinib alone Notreported 100% Arm A: 82.5%Arm B: 32.5%Arm C: 65.9%P: 0.04 Arm A: 18.8 mArm B: 5.7 mArm C: 12.0 mP: notreported Not reached
Lara 2016(SWOGS0709) 40 RandomizedPhase 2 59 PS 2, Proteomics:VeriStrat-goodstatus, previouslyuntreated Arm A (33 pts):ErlotinibArm B (26 pts):Pacli d 1Carbo d 1Erlotinib d 2 – 16Cycle q 3 weeks x 4Maintenance Erlotinib 20% 20% Arm A: 6%Arm B: 23%P = 0.06 Arm A: 1.6 mArm B: 4.6 mP = 0.06 Arm A: 6.0 mArm B: 11.0 mP = 0.27
Li 2016 41 RandomizedPhase 2 79 Predominantly non-squamousProgression after 1stline chemotherapy Arm A (27 pts):Pem d 1Cycle q 3 weeksArm B (52 pts):Pem d 1Erlotinib d 2 – 17Cycle q 3 weeks Notreported 19% Arm A: 10%Arm B: 29%P = 0.17 Arm A: 2.9 mArm B: 4.7 mP = 0.26 Arm A: 8.3 mArm B: 9.7 mP = 0.28
Lee 2016 42 RandomizedPhase 2 76 Adenocarcinoma,neversmokers,Previously untreated Arm A (39 pts):Pem d1Carbo d 1Gefitinib d 5 - 18 +maintenanceCycle q 3 weeks xmax 9Arm B (37 pts):As arm A, placeboinstead of GefitinibAt progression: Gefitinibfor arm B 100% 42% Arm A: 79.5%Arm B: 51.4%P = 0.01 Arm A: 12.8 mArm B: 7.0 mP = 0.009 Arm A: 29.2 mArm B: 20.4 mP = 0.15
29 As above, EGFRmutant Arm A: 15 ptsArm B: 14 ptsTreatment as above 100% 100 Arm A: 86.7%Arm B: 42.9%P = 0.01 Arm A: 13.3 mArm B: 7.8 mP = 0.08 Arm A: 26.6 mArm B: 22.2 mP = ns
37 As above,EGFR wt Arm A: 22 ptsArm B: 15 ptsTreatment as above 100% 0 Arm A: 72.7%Arm B: 57.1%P = ns Arm A: 6.6 mArm B: 6.6 mP = 0.08 Arm A: 29.2 mArm B: 15.9 mP = 0.09
Yoon 201643 RandomizedPhase 2 87 Non-squamousProgression after 1stline chemotherapy Arm A (57 pts):Pem d 1Afatinib d 2 – 15Arm B (30 pts):Pem d 1 31% 31% Arm A: 31.8 %Arm B: 13.3%P = 0.074 Arm A: 5.7 mArm B: 2.9 mP = 0.16 Arm A: 12.1 mArm B: 15.6 mP = 0.245

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,previouslyuntreated Pacli d 1Irino d 1Gefitinib d 8-14Cycle q 3 weeks Not reported 25% 43.8% Not reported 18.1 m
Sangha 2011 45 39 All histologiesProgressionafter 1st linechemotherapy Doce d 1Erlotinib days 2 – 16Cycle q 3 weeks 28% 19% 28.2% 4.1 m 18.2 m
Minami 2013 46 27 Non-squamousProgressionafter 1st linechemotherapy Pem, d 1Erlotinib, d 2 – 16Cycle q 3 weeks 22% 4% 11.1% 2.8 m 15.8 m
Yoshimura 2013 47 27 Activating EGFRmutations,Progression afterTKI Pem, d 1Erlotinib or Gefitinib, days 2 – 16Cycle q 3 weeks 78% 100% 25.9% 7.0 m 11.4 m
Kim 2014 48 17 Non-squamous,EGFR wt,progression after 1stline ChT Pem d 1Erlotinib d 2-15 27% 0% 27.0% 2.5 m 6.7 m
Fang 2014 49 57 Unselected,progression afterplatin-based ChT Gem, d 1 and 8Cis, d 1-3Gefitinib, d 10 - 24Cycle q 4 weeks 37% 40% 11% 10 m 15.2 m
Yang 2014 50 29 Adenocarcinoma,non-smokers,EGFR unknown,previouslyuntreated Pacli, d1Carbo, d1Gefitinib, d 8 – 17 +maintenanceCycle q 3 weeks 100% 73% 74.1% 16 m Not reached
Zwitter 2014 51 15 Adenocarcinoma,light/neversmokers, EGFRwild-type orunknownPreviouslyuntreated Gem d 1 and 4Cis d 2Erlotinib d 5 – 15 Cycle q 3 weeks x 4 – 6Maintenance Erlotinib 100% 5% 33% 6.0 m 7.6 m
Yoshimura 2015 52 26 Activating EGFRmutationsPreviouslyuntreated Pem d 1Gefitinib d 2-16 46% 100% 84.6% 18.0 m 32.0 m
Yu 2015 53 42 MostlyadenocarcinomaProgression afterresponse to TKI Pem, d 1 or Pem +Platin, d 1TKI (Erlotinib or Gefitinib),d 6 – 21Cycle q 3 weeks 71% 61% 23.8% 8.0 m 11.0 m
Zwitter 2016 (ITAC 2) 54 38 Activating EGFRmutationsPreviouslyuntreated Gem d 1 and 4Cis d 2Erlotinib d 5 – 15Cycle q 3 weeks x 4 – 6 Maintenance Erlotinib 63% 100% 84.2% 23.4 m 38.3 m
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