Incidence risk of PD-1/PD-L1 related diarrhea in non-small cell lung cancer (NSCLC) patients: a systematic review and meta-analysis

Figures & data

Figure 1 Study flow diagram of inclusion.

Abbreviations: PD-1, programmed cell death 1; PD-L1, Programmed death-ligand 1; SCLC, small cell lung cancer; NSCLC, non-small cell lung cancer.

Table 1 Basic characteristics of enrolled studies

Name of study	Article source	Drug name	PD-1 or PD-L1	Treatment regimen	Patients	Diarrhea of all grades	Diarrhea of grade 3–5	Previous therapy	Phase	Tumor type
Barlesi F et al,^Citation11 2018	Lancet Oncol	Avelumab	PD-L1	Avelumab vs docetaxel	758	80	5	Yes	III	Stage IIIB or IV or recurrent NSCLC
Socinski MAet al,^Citation12 2018	N Engl J Med	Atezolizumab	PD-L1	Atezolizumab+BCP vs BCP	692	141	13	No	III	Metastatic nonsquamous NSCLC
Hellmann MDet al,^Citation13 2018A	N Engl J Med	Nivolumab	PD-1	Nivolumab vs nivolumab+ipilimumab	299	138	12	No	III	Stage IV or recurrent NSCLC
Hellmann MDet al,^Citation13 2018B	N Engl J Med	Nivolumab	PD-1	Nivolumab vs chemotherapy		99	7	No
Hellmann MDet al,^Citation13 2018C	N Engl J Med	Ipilimumab	CTLA-4	Nivolumab+ipilimumab vs chemotherapy	149	13	No
Paz-Ares L et al,^Citation14 2018	N Engl J Med	Pembrolizumab	PD-1	Pembrolizumab+CP vs placebo +CP	558	148	17	No	III	Squamous NSCLC
Gandhi L et al,^Citation15 2018	N Engl J Med	Pembrolizumab	PD-1	Pembrolizumab+PC vs placebo+PC	616	168	27	No	III	Metastatic nonsquamous NSCLC
Rittmeyer A et al,^Citation16 2017	Lancet	Atezolizumab	PD-L1	Atezolizumab vs docetaxel	1,187	235	15	Yes	III	Squamous or nonsquamous NSCLC
Fehrenbacher L et al,^Citation17 2016	Lancet	Atezolizumab	PD-L1	Atezolizumab vs doctaxel	277	40	NA	Yes	II	Advanced or metastatic NSCLC
Reck M et al,^Citation18 2016	N Engl J Med.	Pembrolizumab	PD-1	Pembrolizumab vs chemotherapy	304	42	8	No	III	Advanced NSCLC
Langer CJ et al,^Citation19 2016	Lancet Oncol	Pembrolizumab	PD-1	Pembrolizumab+PC vs placebo+PC	123	19	1	No	II	Stage IIIB or IV, nonsquamous NSCLC
Herbst RS et al,^Citation20 2016A	Lancet	Pembrolizumab	PD-1	Pembrolizumab 2 vs doctaxel	991	80	9	Yes	II/III	NSCLC
Herbst RS et al,^Citation20 2016B	Lancet	Pembrolizumab	PD-1	Pembrolizumab 10 vs doctaxel	78	7	Yes	II/III
Brahmer J et al,^Citation21 2015	N Engl J Med	Nivolumab	PD-1	Nivolumab vs docetaxel	272	36	3	Yes	III	Advanced squamous NSCLC
Borghaei H et al,^Citation22 2015	N Engl J Med	Nivolumab	PD-1	Nivolumab vs docetaxel	582	84	5	Yes	III	Nonsquamous NSCLC

Abbreviations: NSCLC, non–small cell lung cancer; PD-1, programmed cell death 1; PD-L1, programmed cell death ligand 1; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; SCLC, small cell lung cancer; CP, carboplatin plus paclitaxel; NA, No Available; PC, pemetrexed and a platinum-based drug; chemotherapy, carboplatin plus pemetrexed, cisplatin plus pemetrexed, carboplatin plus gemcitabine, cisplatin plus gemcitabine, or carboplatin plus paclitaxel.

Figure 2 (A): Risk of bias summary: review authors’ judgments about each risk of bias item for each included study. (B): Risk of bias graph: review authors’ judgments about each risk of bias item presented as percentages across all included studies.

Figure 3 Forest plots of the incidence risk for all-grade diarrhea. (A1): OR of diarrhea for all grades in the subgroup analysis (PD-1/PD-L1 vs chemotherapy). (A2): OR of diarrhea for all grades in the subgroup analysis (PD-1/PD-L1 vs docetaxel/combined chemotherapy), the data included were assigned to the corresponding subgroup according to control group (docetaxel or combined chemotherapy). (A3): OR of diarrhea for all grades in the subgroup analysis (PD-1/PD-L1 vs chemotherapy), the data included were assigned to the corresponding subgroup according to the name of PD-1/PD-L1 inhibitor and the control group. (B): OR of diarrhea for all grades in the subgroup analysis (PD-1/PD-L1 + chemotherapy vs chemotherapy).

Abbreviation: RE, random effect; PD-1, programmed cell death 1; PD-L1, programmed cell death ligand 1;.

Figure 4 Forest plots of the incidence risk for grade 1–2 diarrhea. (A1): OR of diarrhea for grade 1–2 in the subgroup analysis (PD-1/PD-L1 vs chemotherapy) (A2): OR of diarrhea for grade 1–2 in the subgroup analysis (PD-1/PD-L1 vs docetaxel/combined chemotherapy), the data included were assigned to the corresponding subgroup according to control group (docetaxel or combined chemotherapy). (A3): OR of diarrhea for grade 1–2 in the subgroup analysis (PD-1/PD-L1 vs chemotherapy), the data included were assigned to the corresponding subgroup according to the name of PD-1/PD-L1 inhibitor and the control group. (B): OR of diarrhea for grade 1–2 in the subgroup analysis (PD-1/PD-L1 + chemotherapy VS chemotherapy).

Abbreviation: PD-1, programmed cell death 1; PD-L1, programmed cell death ligand 1; RE, random effect.

Figure 5 Forest plots of the incidence risk for grade 3–5 diarrhea. (A1): OR of diarrhea for grade 3–5 in the subgroup analysis (PD-1/PD-L1 vs chemotherapy) (A2): OR of diarrhea for grade 3–5 in the subgroup analysis (PD-1/PD-L1 vs docetaxel/combined chemotherapy), the data included were assigned to the corresponding subgroup according to control group (docetaxel or combined chemotherapy). (A3): OR of diarrhea for grade 3–5 in the subgroup analysis (PD-1/PD-L1 vs chemotherapy), the data included were assigned to the corresponding subgroup according to the name of PD-1/PD-L1 inhibitor and the control group. (B): OR of diarrhea for grade 3–5 in the subgroup analysis (PD-1/PD-L1 + chemotherapy vs chemotherapy).

Abbreviation: PD-1, programmed cell death 1; PD-L1, programmed cell death ligand 1; RE, random effect.

Figure S1 Funnel plots of the incidence risk for all-grade diarrhea. (A1): Funnel plots of diarrhea for all grades in the subgroup analysis (PD-1/PD-L1 vs chemotherapy). (A2): Funnel plots of diarrhea for all grades in the subgroup analysis (PD-1/PD-L1 vs docetaxel/combined chemotherapy), the data included were assigned to the corresponding subgroup according to control group (docetaxel or combined chemotherapy). (A3): Funnel plots of diarrhea for all grades in the subgroup analysis (PD-1/PD-L1 vs chemotherapy), the data included were assigned to the corresponding subgroup according to the name of PD-1/PD-L1 inhibitor and the control group. (B): Funnel plots of diarrhea for all grades in the subgroup analysis (PD-1/PD-L1 + chemotherapy vs chemotherapy).

Abbreviation: PD-1, programmed cell death 1; PD-L1, programmed cell death ligand 1; OR, odds ratio; RR, risk ratio.

Figure S2 Funnel plots of the incidence risk for grade 1–2 diarrhea. (A1): Funnel plots of diarrhea for grade 1–2 in the subgroup analysis (PD-1/PD-L1 vs chemotherapy). (A2): Funnel plots of diarrhea for grade 1–2 in the subgroup analysis (PD-1/PD-L1 vs docetaxel/combined chemotherapy), the data included were assigned to the corresponding subgroup according to control group (docetaxel or combined chemotherapy).(A3): Funnel plots of diarrhea for grade 1–2 in the subgroup analysis (PD-1/PD-L1 vs chemotherapy), the data included were assigned to the corresponding subgroup according to the name of PD-1/PD-L1 inhibitor and the control group. (B): Funnel plots of diarrhea for grade 1–2 in the subgroup analysis (PD-1/PD-L1 + chemotherapy vs chemotherapy).

Abbreviation: PD-1, programmed cell death 1; PD-L1, programmed cell death ligand 1; OR, odds ratio; RR, risk ratio.

Figure S3 Funnel plots of the incidence risk for grade 3–5 diarrhea. (A1): Funnel plots of diarrhea for grade 3–5 in the subgroup analysis (PD-1/PD-L1 vs chemotherapy). (A2): Funnel plots of diarrhea for grade 3–5 in the subgroup analysis (PD-1/PD-L1 vs docetaxel/combined chemotherapy), the data included were assigned to the corresponding subgroup according to control group (docetaxel or combined chemotherapy). (A3): Funnel plots of diarrhea for grade 3–5 in the subgroup analysis (PD-1/PD-L1 VS chemotherapy), the data included were assigned to the corresponding subgroup according to the name of PD-1/PD-L1 inhibitor and the control group. (B): Funnel plots of diarrhea for grade 3–5 in the subgroup analysis (PD-1/PD-L1 + chemotherapy vs chemotherapy).

Abbreviation: PD-1, programmed cell death 1; PD-L1, programmed cell death ligand 1; OR, odds ratio; RR, risk ratio.

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