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

Zwitter, Matjaz; Rossi, Antonio; Di Maio, Massimo; Perme, Maja Pohar; Lopes, Gilberto

doi:10.1515/raon-2017-0029

Figures & Tables

Flow diagram on selection of publications for analysis.

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 1^stline 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 1^stline 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 1^stline 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 1^st 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 1^st 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 1^stline 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

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

Figures & Tables

Figure 1

Figure 2

Randomized trials on intercalated chemotherapy and TKIs for non-small cell lung cancer

Single-arm Phase II trials on intercalated chemotherapy and TKIs for non-small cell lung cancer

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