Analyzing the clinical benefit of newer therapies for advanced or metastatic non-small-cell lung cancer: application of the ESMO-magnitude of clinical benefit scale v1.1

Figures & data

Figure 1. Flow diagram depicting the trial selection process for the review. RCT: randomized controlled trial; ESMO-MCBS: ESMO-Magnitude of Clinical Benefit Scale.

Table 1. Characteristics of the 42 clinical trials included.

Characteristic	N	%
Histology
Squamous NSCLC	4	9.5
Non-squamous NSCLC	15	35.7
Both histology types	23	54.8
Therapy
Cytotoxic	7	16.7
Targetet	23	54.8
Monoclonal antibody	3	7.1
Immunotherapy	9	21.4
Primary endpoint
Overall survival (OS)	12	28.6
Progression-free survival (PFS)	25	59.5
Co-primary endpoints (OS + PFS)	4	9.5
Overall response rate (ORR)	1	2.4
Sample size
Mean	347
Median	387
Range	289−601
Industry sponsorship
Yes	39	92.8
No	3	7.2

Table 2. Characteristics of trials on first-line therapies for advanced NSCLC stratified by histology and their corresponding final ESMO-MCBS scores.

Trial name or first author	Year(s) of publication	Control arm	Experimental arm	Primary outcome (PO)	PO control arm (mo)	PO gain (mo)	PO HR (95%CI)	QoL assessment	Toxicity adjustment or comment	Final score and form	Led to approval^a
SQUAMOUS (SQ) ADVANCED NSCLC
Shukuya T	2015	CsP + DCX	Nedaplatin + DCX	OS	11.4	2.2	0.81 (0.65–1.02)	No	Less grades 3-4 toxic effects. Adj 1	4 (form 2a)	No
SQUIRE	2015	CsP + GEM	CsP + GEM  + Necitumumab	OS	9.9	1.6	0.84 (0.74–0.96)	EQ-5D-3L, LCSS	NA	1 (form 2a)	Yes: 1 L, SQ, EGFR
NON-SQUAMOUS (nSQ) ADVANCED NSCLC
AVAPERL	2013, 2014	Bevacizumab	Bevacizumab + PMX	PFS	3.7	3.7	0.57 (0.44–0.75)	QLQ-LC13, QLQ-C30	NA	2 (form 2 b)	No
PARAMOUNT	2013, 2014	Placebo	PMX	PFS (OS improved)	11	2.9	0.78 (0.64–0.96)	EQ-5D	NA	3 (form 2a)	Yes: maintenance therapy, nSQ
LUX-Lung 3	2013, 2018	CsP + PMX	Afatinib	PFS	6.9	4.2	0.58 (0.43–0.78)	QLQ-LC13, QLQ-C30	Diarrhea G3-4 (0 vs 14.4%). Rash G3-4 (0 vs 16.2%). Adj d	4 (form 2 b)	Yes: 1 L, EGFR
PROFILE 1014	2014, 2018	CbP or CsP + PMX	Crizotinib	PFS (OS improved)	19.2	40.6	0.346 (0.081–0.718)	QLQ-LC13, QLQ-C30, EQ-5D	Adj 1 for QoL	5 (form 2a)	Yes: 1 L, ALK
J025567	2014, 2018	Erlotinib	Bevacizumab  + Erlotinib	PFS	9.7	6.3	0.54 (0.36–0.79)	FACT-L	No OS advantage and not improved QoL (Adj c)	2 (form 2 b)	Yes: 1 L, nSQ
LUX-Lung 6	2014, 2015	CsP + GEM	Afatinib	PFS	5.6	5.4	0.28 (0.20–0.39)	QLQ-LC13, QLQ-C30	Improved (adjustment d)	4 (form 2 b)	Yes: 1 L, EGFR
LUX-Lung 7	2016, 2017	Gefitinib	Afatinib	PFS	10.9	0.1	0.73 (0.57–0.95)	EQ-5D	NA	1 (form 2 b)	Yes: 1 L, EGFR
ASCEND-4	2017	CsP or CbP + PMX	Ceritinib	PFS	8.1	8.5	0.55 (0.42–0.73)	EQ-5D-5L, QLQ-LC13, QLQ-C30, LCSS	Improved QoL. Adj d	4 (form 2 b)	Yes: 2 L, ALK
ARCHER 1050	2017, 2018	Gefitinib	Dacomitinib	PFS (OS improved)	26.8	7.3	0.76 (0.58–0.99)	EQ-5D, QLQ-LC13, QLQ-C30	Increased toxicity	3 (form 2a)	Yes: 1 L, EGFR
FLAURA	2018, 2020	Erlotinib or Gefitinib	Osimertinib	PFS (OS improved)	31.8	6.8	0.80 (0.64–1.00)	No	Improved QoL	4 (form 2a)	Yes: 1 L, EGFR
KEYNOTE-189	2018	CbP or CsP + PMX	CbP or CsP + PMX  + Pembrolizumab	OS	11.3	>3.0	0.49 (0.38–0.64)	No	NA	4 (form 2a)	Yes: 1 L, nSQ
IMpower 150	2018	CbP + PCX  + Bevacizumab	CbP + PCX  + Bevacizumab  + Atezolizumab	OS	14.7	4.5	0.78 (0.64–0.96)	No	NA	3 (form 2a)	Yes: 1 L, nSQ
BOTH SQ and nSQ ADVANCED NSCLC
ATLAS	2013	Bevacizumab maintenance	Bevacizumab  + Erlotinib	PFS	3.7	1.1	0.71 (0.58–0.86)	No	NA	2 (form 2 b)	Yes: 1 L, nSQ
FASTACT-2	2013	CbP or CsP + GEM	CbP or CsP + GEM  + Erlotinib	PFS (OS improved)	15.2	3.1	0.79 (0.64–0.99)	FACT, TOI	Rash G3-4 (0.4% vs 5%). No adjustment	4 (form 2a)	No
OPTIMAL	2015	CbP + GEM	Erlotinib	PFS	4.6	8.5	0.16 (0.10–0.26)	FACT-L, LCS	Improved (adjustment d)	4 (form 2 b)	Yes: 1 L, EGFR
ENSURE	2015	CsP + GEM	Erlotinib	PFS	5.5	5.5	0.34 (0.22–0.51)	No	NA	3 (form 2 b)	Yes: 1 L, EGFR
INFORM	2015	Placebo	Gefitinib	PFS	2.6	2.2	0.42 (0.33–0.55)	FACT-L	Toxic deaths incremental rate = 2% (adj b). Improved QoL (adj d)	3 (form 2 b)	Yes: EGFR
Kubota K	2015	CsP + DCX	CsP + S-1	Non-inferiority	17.1	1.0	1.013 (0.837–1.227)	QLQ-LC13, QLQ-C30	Improved	4 (form 2c)	No
KEYNOTE-024	2016, 2017, 2019	CbP + PMX or CsP + PMX or CbP + GEM or CsP + GEM or CbP + PCX	Pembrolizumab	PFS	14.2	15.8	0.63 (0.47–0.86)	EQ-5D-3L, QLQ-LC13, QLQ-C30	NA	4 (form 2a)	Yes: 1 L, PD-L1 ≥ 50%
ALEX	2017	Crizotinib	Alectinib	PFS	10.4	15.3	0.47 (0.34–0.65)	No	NA	3 (form 2 b)	Yes: 1 L, ALK
Ferry D	2017	CsP 80 mg + GEM	CsP 50 mg + GEM	Non-inferiority	9.5	0.5	1.13 (0.99–1.29)	EQ-5D, QLQ-LC13, QLQ-C30	NA	3 (form 2c)	No
Ouyang X	2018	CsP + VNR	CsP + VNR  + Dulanermin	PFS	3.5	2.9	0.403 (0.318–0.512)	No	NA	3 (form 2 b)	No
ALTA-1L	2018, 2020	Crizotinib	Brigatinib	PFS	11.0	13.0	0.49 (0.35–0.68)	No	NA	3 (form 2 b)	Yes: 1 L, ALK

NA: not applicable; adj: adjustment; HR: hazard ratio; MCBS: magnitude of clinical benefit scale; QoL: quality of life; PFS: progression-free survival; OS: overall survival; 1 L: first-line setting; 2 L: second or subsequent line of therapy; CbP: carboplatin; CsP: cisplatin; GEM: gemcitabine; PCX: paclitaxel; PMX: pemetrexed; DCX: docetaxel; rmhTNF: recombinant mutated human tumor necrosis factor.

^a Trials that led to approval are those which appear alongside the ‘EPAR’ for EMA or the ‘Label’ for FDA approvals. Indication for use in advanced NSCLC setting is also reported.

References of the clinical trials included are available online as Supplementary material.

Table 3. Trials that show disparity between the ESMO-MCBS score based on the lower limit of the 95% confidence interval of hazard ratio (final score) and the reported or point estimate hazard ratio ESMO-MCBS score.

Analyzed treatment(s)	Setting	Primary outcome (PO)	PO HR (95%CI)	Toxicity adjustment/comment	Final score and form	HR point estimate MCBS
Bevacizumab + Erlotinib	First-line, SQ and nSQ	PFS	0.71 (0.58–0.86)	–	2 (form 2 b)	1
PMX	First-line, nSQ, maintenance	PFS (OS improved)	0.78 (0.64–0.96)	–	3 (form 2a)	1
CbP or CsP  + GEM + Erlotinib	First-line, SQ and nSQ	PFS (OS improved)	0.79 (0.64–0.99)	Rash G3-4 (0.4% vs 5%). No adjustment	4 (form 2a)	2
Nedaplatin + DCX	First-line, SQ	OS	0.81 (0.65–1.02)	Less G3-4 toxic effects. Adjustment 1	4 (form 2a)	2
Afatinib	First-line, nSQ	PFS	0.73 (0.57–0.95)	–	1 (form 2 b)	1
Dacomitinib	First-line, nSQ	PFS (OS improved)	0.76 (0.58–0.99)	–	3 (form 2a)	1
Osimertinib	First-line, nSQ	PFS (OS improved)	0.80 (0.64–1.00)	Improved QoL	4 (form 2a)	1
CbP + PCX + Bevacizumab  + Atezolizumab	First-line, nSQ	OS	0.78 (0.64–0.96)	–	3 (form 2a)	1
CsP/CbP + DCX  + rmhTNF	Second or subsequent line, SQ and nSQ	OS	0.75 (0.63–0.89)	Less G3-4 nausea and vomiting	5 (form 2a)	2
Atezolizumab	Second or subsequent line, SQ and nSQ	OS	0.73 (0.53–0.99)	–	3 (form 2a)	1
Atezolizumab	Second or subsequent line, SQ and nSQ	OS	0.75 (0.64–0.89)	Improved	5 (form 2a)	2
Anlotinib	Second or subsequent line, SQ and nSQ	OS	0.68 (0.54–0.87)	Improved	4 (form 2a)	3

NA: not applicable; HR: hazard ratio; MCBS: magnitude of clinical benefit scale; QoL: quality of life; PFS: progression-free survival; OS: overall survival; CbP: carboplatin; CsP: cisplatin; GEM: gemcitabine; PCX: paclitaxel; DCX: docetaxel; rmhTNF: recombinant mutated human tumor necrosis factor.

Table 4. Trials showing discrepancies in applying the ESMO framework when compared with the ESMO-MCBS scorecards and reasons for discrepancy.

Analyzed treatment(s)	Setting	Primary outcome (PO)	PO HR (95%CI)	Toxicity adjustment/comment	Final score and form	ESMO-MCBS scorecard value	Reason(s) for discrepancy
Afatinib	First-line, nSQ	PFS	0.58 (0.43–0.78)	Diarrhea G3-4 (0 vs 14.4%); rash G3-4 (0 vs 16.2%)	4 (form 2 b)	4	Analyzed studies
Crizotinib	First-line, nSQ	PFS (OS improved)	0.35 (0.08–0.72)	Improved QoL (adj 1)	5 (form 2a)	4	Analyzed studies and toxicity adjustment
Bevacizumab  + Erlotinib	First-line, nSQ	PFS	0.54 (0.36–0.79)	No OS advantage and not improved QoL (adj c)	2 (form 2 b)	3	Analyzed studies and QoL adjustment
Pembrolizumab	First-line, SQ and nSQ	PFS	0.63 (0.47–0.86)	EQ-5D-3L VAS differences show no statistical significance	4 (form 2a)	5	Toxicity/QoL adjustment
Nivolumab	Second or subsequent line, SQ	OS	0.62 (0.47–0.80)	Improved QoL	5 (form 2a)	5	Analyzed studies
Nivolumab	Second or subsequent line, nSQ	OS	0.75 (0.63–0.91)	Improved QoL	5 (form 2a)	5	Analyzed studies
Crizotinib	Second or subsequent line, SQ and nSQ	PFS	0.49 (0.37–0.64)	Improved QoL	4 (form 2 b)	4	Analyzed studies
DCX + Ramucirumab	Second or subsequent line, SQ and nSQ	OS	0.86 (0.75–0.98)	NA	1 (form 2a)	1	Analyzed studies
Pembrolizumab 10 mg/Kg	Second or subsequent line, SQ and nSQ, PDL1 ≥ 1%	OS	0.61 (0.49–0.75)	No statistically significant differences observed in the adverse events included on the ESMO-MCBS form	4 (form 2a)	5	Toxicity adjustment
Osimertinib	Second or subsequent line, SQ and nSQ	PFS	0.30 (0.23–0.41)	Improved QoL	4 (form 2 b)	4	Analyzed studies
Lorlatinib	Second or subsequent line, SQ and nSQ	ORR	NA	Selected cohort included EXP2-5 groups	3 (form 3)	3	Cohort selection

NA: not applicable; adj: adjustment; QoL: quality of life; PFS: progression-free survival; OS: overall survival; HR: hazard ratio; MCBS: magnitude of clinical benefit scale; VAS: visual analogue scale.

Data availability statement

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.