Efficacy and safety of PD-1/PD-L1 inhibitors in triple-negative breast cancer: a systematic review and meta-analysis

Figures & data

Table 1. Characteristics of included studies.

Trial	Author	Year	Phase	Treatment stage	Experimental	Control	TNM	Treatment arm	Control arm	The dose of anti- PD-1/PD-L1	Duration of anti- PD-1/PD-L1	PD-L1 positive
IMpassion131 [13]	Miles	2021	III	Advanced	431	220	Locally advanced/mTNBC	Atezo + Pac	Placebo + Pac	840mg d1,15 q28d	Until disease progression	45%
KEYNOTE-355 [12]	Javier	2020	III	Advanced	566	281	Locally recurrent inoperable or mTNBC	Pem + NabPac/Pac/ GEM + Cb	Placebo + taxane or GEM-Cb	200mg q3w	Until disease progression	75%
NeoTRIPaPDL1 [21]	Gianni	2019	III	NACT	138	142	T1cN1 T2N1 T3N0 + T3N1,T4 anyN,anyT	Atezo + NabPac + Cb	NabPac + Cb	1200mg d1 q3w	8 cycles	56%
IMpassion031 [22]	Mittendorf	2020	III	NACT	165	168	cT2-cT4/cN0-cN3	Atezo + NabPac + AC	Placebo + NabPac+ AC	840mg q2w + 840mg q2w + 1200mg q3w	12w + 8w + 11cycles	46%
I-SPY2 [23]	Nanda	2020	II	NACT	28	79	II/III	Pem + Pac + AC	Pac + AC	200mg q3w	4 cycles	NA
KEYNOTE-522 [24]	Schmid	2020	III	NACT	784	390	T1cN1-2/T2-4 N0-2	Pem + Pac + Cb + AC/EC	Placebo + Pac + Cb+ AC/EC	200mg q3w	4 cycles + 4 cycles	83%
IMpassion130 [11]	Schmid	2020	III	Advanced	451	451	Locally advanced/mTNBC	Atezo + NabPac	Placebo + NabPac	840mg d1,15 q28d	Until disease progression	41%
GeparNuevo [25]	Loibl	2019	II	NACT	88	86	cT2-cT4a-d	Durva + NabPac + EC	Placebo + NabPac+ EC	1.5g q4w + 1.5g q4w	12w + 4cycles	87%

mTNBC: metastatic triple-negative breast cancer; NACT: neoadjuvant chemotherapy; Atezo: atezolizumab; Pem: pembrolizumab; Durva: durvalumab; NabPac: nab-paclitaxel; Pac: paclitaxel; Cb: carboplatin; GEM: gemcitabine; NVB: vinorelbine; CAPE: Capecitabine; EC: epirubicin + cyclophosphamide; AC: adriamycin + cyclophosphamide; NA: not available; w: week.

Table 2. Pooled the endpoints of efficacy and safety.

Trial	Efficacy					Safety
	Endpoints	HR (95%CI)				AEs	Experimental		Control
							Events	Total	Events	Total
IMpassion131 [13]	PFS	0.86(0.7–1.05)				any grade AEs	268	432	116	217
						grade ≥ 3 AEs	49	432	11	217
						hypothyroidism	60	432	12	217
						hyperthyroidism	25	432	0	217
						hepatitis	7	432	2	217
	OS	1.2(0.88–1.43)				infusion reaction	15	432	7	217
						pneumonitis	16	432	3	217
						colitis	3	432	2	217
						Rash	141	432	66	217
						adrenal insufficiency	3	432	0	217
KEYNOTE-355 [12]	PFS	0.82(0.69–0.97)				any grade AEs	554	562	276	281
						grade ≥ 3 AEs	438	562	207	281
						hypothyroidism	87	562	9	281
						hyperthyroidism	27	562	3	281
						anemia	275	562	129	281
						neutropenia	231	562	107	281
						fatigue	160	562	83	281
						colitis	10	562	4	281
						pneumonitis	14	562	0	281
						elevated transaminase	115	562	46	281
						skin reactions	10	562	1	281
NeoTRIPaPDL1 [21]	pCR	Experimental		Control		grade ≥ 3 AEs	107	138	98	140
		Events	Total	Events	Total
		60	138	58	142	serious AEs	25	138	8	140
IMpassion031 [22]	EFS	0.76(0.4–1.44)				grade ≥ 3 AEs	103	164	101	167
						serious AEs	50	164	30	167
						hypothyroidism	11	164	2	167
						hyperthyroidism	5	164	0	167
						anemia	63	164	64	167
						neutropenia	59	164	59	167
						vomiting	58	164	51	167
	OS	0.69(0.25–1.87)				infusion reaction	17	164	11	167
						hepatitis	2	164	1	167
						fatigue	59	164	64	167
						cough	35	164	32	167
						Rash	46	164	42	167
						diarrhea	68	164	74	167
						sensory neuropathy	54	164	45	167
	pCR	Experimental		Control		stomatitis	39	164	29	167
		Events	Total	Events	Total	pneumonitis	2	164	2	167
		95	165	69	168	colitis	1	164	1	167
						adrenal insufficiency	0	164	1	167
						pyrexia	34	164	21	167
						elevated transaminase	33	164	26	167
						headache	41	164	35	167
I-SPY2 [23]	EFS	0.65(0.23-1.85)				–
	pCR	Experimental		Control
		Events	Total	Events	Total
		17	28	17	79
KEYNOTE-522 [24]	EFS	0.63(0.43–0.93)				any grade AEs	777	781	389	389
						grade ≥ 3 AEs	633	781	295	389
						hypothyroidism	107	781	13	389
						hyperthyroidism	36	781	4	389
						anemia	430	781	215	389
	OS	0.72(0.51–1.02)				neutropenia	365	781	183	389
						vomiting	199	781	85	389
						infusion reaction	132	781	43	389
						fatigue	321	781	147	389
						Rash	170	781	59	389
	pCR	Experimental		Control		adrenal insufficiency	18	781	0	389
						skin reactions	34	781	4	389
		Events	Total	Events	Total	sensory neuropathy	154	781	82	389
		260	401	103	201	diarrhea	230	781	92	389
						elevated transaminase	199	781	96	389
IMpassion130 [11]	PFS	0.8(0.69–0.92)				any grade AEs	450	453	428	437
						grade ≥ 3 AEs	230	453	190	437
						hypothyroidism	63	453	16	437
						serious AEs	105	453	81	437
						anemia	126	453	118	437
						neutropenia	97	453	68	437
						vomiting	89	453	75	437
						fatigue	212	453	195	437
	OS	0.86(0.72–1.02)				sensory neuropathy	72	453	52	437
						Rash	78	453	73	437
						pneumonitis	23	453	7	437
						headache	108	453	95	437
						pyrexia	88	453	48	437
						cough	114	453	85	437
						diarrhea	147	453	152	437
						elevated transaminase	45	453	43	437
GeparNuevo [25]	pCR	Experimental		Control		serious AEs	30	92	29	82
		Events	Total	Events	Total	hypothyroidism	7	92	2	82
		47	88	38	86	hyperthyroidism	9	92	1	82
						anemia	87	92	79	82
						neutropenia	71	92	67	82
						vomiting	12	92	11	82
						infusion reaction	3	92	1	82
						fatigue	70	92	68	82
						hepatitis	1	92	0	82
						stomatitis	15	92	14	82
						skin reactions	45	92	39	82
						sensory neuropathy	76	92	69	82
						Rash	21	92	22	82
						pneumonitis	1	92	1	82
						headache	38	92	28	82
						pyrexia	16	92	12	82
						cough	25	92	15	82
						diarrhea	26	92	34	82

AEs: adverse events; pCR: pathological complete response; OS: overall survival; PFS: progress free survival; EFS: event free survival; HR: hazard ratio; CI: confidence interval.

Figure 1. Forest plots for outcomes in early triple-negative breast cancer. (A) OR for PCR (before sensitivity analysis), (B) OR for PCR (after sensitivity analysis), (C) Subgroup analysis for PCR according to different PD-L1 status (positive versus negative), (D) Subgroup analysis for PCR according to different types of interventions (anti PD1 versus anti PD-L1), (E) HR for EFS, (F) HR for OS.

Figure 2. Forest plots for outcomes in advanced triple-negative breast cancer. (A) HR for PFS, (B) HR for OS.

Table 3. Pooled odds ratio for toxicities in early triple-negative breast cancer.

Toxicity	No. of included studies	Heterogeneity		OR (95%CI)	p Value
		I^2 (%)	p
Grade ≥ 3 AEs	3	0	0.66	1.31 (1.05–1.64)	0.02
Serious AEs	3	74	0.02	1.80 (0.86–3.77)	0.12
Hypothyroidism	3	0	0.87	4.59 (2.73–7.72)	<0.00001
Hyperthyroidism	3	0	0.76	5.76 (2.38–13.95)	0.0001
Anemia	3	0	0.86	0.99 (0.80–1.22)	0.89
Neutropenia	3	0	0.77	0.98 (0.79–1.20)	0.81
Fatigue	3	18	0.29	1.04 (0.85–1.28)	0.69
Vomiting	3	0	0.88	1.21 (0.95–1.53)	0.12
Hepatitis	2	0	0.89	2.28 (0.33–15.59)	0.40
Infusion reaction	3	0	0.91	1.66 (1.19–2.30)	0.003
Stomatitis	2	0	0.36	1.29 (0.83–2.01)	0.26
Diarrhea	3	73	0.02	0.93 (0.58–1.51)	0.77
Pneumonitis	2	0	0.94	0.97 (0.19–4.87)	0.97
Rash	3	38	0.20	1.33 (1.03–1.70)	0.03
Cough	2	0	0.41	1.31 (0.85–2.01)	0.22
Headache	2	0	0.85	1.30 (0.87–1.92)	0.20
Pyrexia	2	0	0.45	1.59 (0.98–2.56)	0.06
Sensory Neuropathy	3	0	0.41	1.01 (0.79–1.29)	0.93
Skin reactions	2	82	0.02	2.02 (0.49–8.34)	0.33
Adrenal insufficiency	2	73	0.05	2.71 (0.04–166.23)	0.64
Elevated transaminase	2	0	0.40	1.10 (0.86–1.42)	0.46

AEs: adverse events; OR: odds ratio; CI: confidence interval.

Table 4. Pooled odds ratio for toxicities in advanced triple-negative breast cancer.

Toxicity	No. of included studies	Heterogeneity		OR (95%CI)	p Value
		I^2 (%)	p
Any grade AEs	3	0	0.49	1.48 (1.09–2.02)	0.01
Grade ≥ 3 AEs	3	31	0.24	1.39 (1.15–1.70)	0.0009
Hypothyroidism	3	8	0.34	4.05 (2.82–5.82)	<0.00001
Hyperthyroidism	2	32	0.23	7.86 (2.65–23.29)	0.0002
Anemia	2	0	0.70	1.09 (0.88–1.33)	0.43
Neutropenia	2	24	0.25	1.27 (1.02–1.59)	0.04
Fatigue	2	0	0.51	1.03 (0.84–1.26)	0.77
Colitis	2	0	0.64	1.09 (0.41–2.88)	0.87
Pneumonitis	3	0	0.53	3.77 (1.91–7.43)	0.0001
Rash	2	0	0.79	1.07 (0.84–1.37)	0.58
Elevated transaminase	2	0	0.37	1.18 (0.89–1.57)	0.26

AEs: adverse events; OR: odds ratio; CI: confidence interval.

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