Evidence from a meta-analysis: is nivolumabneurotoxic in cancer patients?

Figures & data

Table 1 Inclusion and exclusion criteria for study selection in this meta-analysis

Number	Inclusion criteria
1	Randomized Phase II and III studies in patients with solid tumors.
2	The outcome of the study includes neurotoxicities such as fatigue, headache, dysgeusia, vertigo, paresthesia, anxiety or malaise and peripheral neuropathy.
3	Participants received treatment with nivolumab.
4	The RR with a 95% CI of the risk of selected neurotoxicities associated with nivolumab could be obtained from articles directly or calculated based on the figures or tables given in articles or through contacting the authors.
5	For the duplicate articles, only the most complete or the most newly published one was included.
	Exclusion criteria
1	Phase I trials were excluded.
2	The treatments in experimental groups should not include other drugs.

Abbreviations: CI, confidence interval; RR, risk ratio.

Table 2 Baseline characteristics of included studies comparing nivolumab to other drugs

Study	Year	Country	Study type	Treatment arms	Indication	Fatiguea	Headachea	Dysgeusiaa	Vertigoa	Paresthesiaa	Anxiety malaisea	Peripheral neuropathya
Robert et al^Citation12	2015	France	Phase III	Arm A: nivolumab 3 mg/kg of body weight every 2 weeks (206 pts) Arm B: dacarbazine (205 pts)	Stage III or IV unresectable melanoma without a BRAF mutation	41 (20%) versus 30 (14.6%)	9 (4.4%) versus 14 (6.8%)	6 (2.9%) versus 2 (1%)	2 (1%) versus 5 (2.4%)	2 (1%) versus 7 (3.4%)	1 (0.5%) versus 4 (2%)	–
Weber et al^Citation13	2015	USA	Phase III	Arm A: nivolumab 3 mg/kg of body weight every 2 weeks (268 pts) Arm B: investigator choice chemotherapy (102 pts)	Patients with advanced melanoma who progressed after anti-CTLA-4 treatment	67 (25%) versus 35 (34%)	–	–	–	–	–	–
Larkin et al^Citation10	2015	USA	Phase III	945 patients were randomized in a 1:1:1 fashion into: 1) nivolumab 3 mg/kg combined with placebo (316 pts) 2) ipilimumab (3 mg/kg) combined with nivolumab (1 mg/kg) (314 pts) 3) ipilimumab (3 mg/kg) combined with placebo (315 pts)	Advanced melanoma	107 (34.2%) versus 87 (28%)	23 (7.3%) versus 24 (7.7%)	–	–	–	–	–
Borghaei et al^Citation8	2015	USA	Phase III	Arm A: nivolumab 3 mg/kg of body weight every 2 weeks (292 pts) Arm B: docetaxel (290 pts)	Advanced non-squamous cell NSCLC	91 (32%) versus 102 (38%)	29 (10%) versus 32 (12%)	7 (2%) versus 27 (10%)	25 (9%) versus 24 (9%)	12 (4%) versus 23 (9%)	16 (6%) versus 5 (2%)	9 (3%) versus 25 (9%)
Brahmer et al^Citation9	2015	USA	Phase III	Arm A: nivolumab 3 mg/kg of body weight every 2 weeks (131 pts) Arm B: docetaxel (129 pts)	Advanced squamous cell NSCLC	21 (16%) versus 42 (33%)	–	–	2 (2%) versus 7 (5%)	2 (2%) versus 7 (5%)	–	1 (1%) versus 15 (12%)
Motzer et al^Citation11	2015	USA	Phase III	821 patients were randomly assigned (in a 1:1 ratio) to receive 3 mg of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10 mg everolimus tablet orally once daily	Advanced clear-cell renal cell carcinoma for which they had received previous treatment with 1 or 2 regimens of antiangiogenic therapy	134 (33%) versus 134 (34%)	–	11 (3%) versus 51 (13%)	–	–	–	–

Notes:

a Data presented as number of patients with versus number of patients without.

Abbreviations: pts, patients; BRAF, B-Raf; CTLA-4, cytotoxic T lymphocyte antigen-4; NSCLC, non-small-cell lung cancer.

Table 3 The statistical methods used in this meta-analysis and their explanation

Statistical means	Goals and usages	Explanation
Labbe plot	To evaluate heterogeneity between the included studies	In Labbe figure, if the points basically present as a linear distribution, it can be taken as an evidence of homogeneity.
Cochran’s Q test	To evaluate heterogeneity between the included studies	Cochran’s Q test is an extension to the McNemar test for related samples that provides a method for testing for differences between 3 or more matched sets of frequencies or proportions. Heterogeneity was also considered significant if P<0.05 using the Cochran’s Q test.
I^2 index test	To evaluate heterogeneity between the included studies	The I^2 index measures the extent of true heterogeneity dividing the difference between the result of the Q test and its degrees of freedom (k – 1) by the Q value itself and multiplied by 100. I^2 values of 25%, 50% and 75% were used as evidence of low, moderate and high heterogeneity, respectively.
Sensitivity analysis	To examine the stability of the pooled results	A sensitivity analysis was performed using the one-at-a-time method, which involved omitting one study at a time and repeating the meta- analysis. If the omission of one study significantly changed the result, it implied that the result was sensitive to the studies included.
Contour-enhanced funnel plot	Publication bias test	Visual inspection of the contour-enhanced funnel plots was used to assess potential publication bias. Asymmetry in the plots, which may be due to studies missing on the left-hand side of the plot that represents low statistical significance, suggested publication bias. If studies were missing in the high statistical significance areas (on the right-hand side of the plot), the funnel asymmetry was not considered to be due to publication bias.

Figure 1 Literature search and selection of articles.

Note: Adapted from Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009) Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. Creative Commons license and disclaimer available from: http://creativecommons.org/licenses/by/4.0/legalcode.²⁰
Abbreviation: PRISMA, Preferred Reporting Items for Systematic Reviews.

Table 4 Jadad quality assessment of the included studies

Study	Year	Country	Study type	Randomization	Blinding	An account of all patients	Overall score
Robert et al^Citation12	2015	France	Phase III	2	2	1	5
Weber et al^Citation13	2015	USA	Phase III	2	0	1	3
Larkin et al^Citation10	2015	USA	Phase III	2	2	1	5
Borghaei et al^Citation8	2015	USA	Phase III	2	0	1	3
Brahmer et al^Citation9	2015	USA	Phase III	2	0	1	3
Motzer et al^Citation11	2015	USA	Phase III	2	0	1	3

Figure 2 Labbe plots, sensitivity analysis plots and contour-enhanced funnel plots of the included studies focusing on the risk of selected neurotoxicity associated with the PD-1 inhibitor nivolumab.

Notes: Labbe plots concerned fatigue (A), headache (B), dysgeusia (C), vertigo (D), paresthesia (E) and anxiety or malaise (F), respectively. Sensitivity analysis concerned fatigue (G), headache (H), dysgeusia (I), vertigo (J) and paresthesia (K). Contour-enhanced funnel plots concerned fatigue (L), headache (M), dysgeusia (N), vertigo (O) and paresthesia (P). Sensitivity analysis was performed using the one-at-a-time method (G–K).
Abbreviation: PD-1, programmed death-1.

Figure 3 Forest plots (individual and pooled effects with 95% CI) regarding the risk of selected neurotoxicity of fatigue (A, random-effects model), headache (B, fixed-effects model), dysgeusia (C, random-effects model), vertigo (D, fixed-effects model), paresthesia (E, fixed-effects model), anxiety or malaise (F, random-effects model) and peripheral neuropathy (G, random-effects model) associated with nivolumab versus controls.

Abbreviations: RR, risk ratio; CI, confidence interval; df, degree of freedom; M–H, Mantel–Haenszel.

RobertCLongGVBradyBNivolumab in previously untreated melanoma without BRAF mutationN Engl J Med2015372432033025399552

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WeberJSD’AngeloSPMinorDNivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trialLancet Oncol201516437538425795410

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LarkinJChiarion-SileniVGonzalezRCombined nivolumab and ipilimumab or monotherapy in untreated melanomaN Engl J Med2015373233426027431

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BorghaeiHPaz-AresLHornLNivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancerN Engl J Med2015373171627163926412456

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BrahmerJReckampKLBaasPNivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancerN Engl J Med201537312313526028407

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MotzerRJEscudierBMcDermottDFNivolumab versus everolimus in advanced renal-cell carcinomaN Engl J Med20153731803181326406148

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MoherDLiberatiATetzlaffJAltmanDGThe PRISMA Group2009Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statementPLoS Med67e100009719621072

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