Pembrolizumab in gestational trophoblastic neoplasia: Systematic review and meta-analysis with sub-group analysis of potential prognostic factors

Barcellos, Marcio; Braga, Antonio; Rech, Matheus Machado; Oliveira, Solange Artimos de; Madi, Jose Mauro; Sun, Sue Yazaki; Rezende Filho, Jorge de; Elias, Kevin M.; Horowitz, Neil S.; Berkowitz, Ross S.

doi:10.1016/j.clinsp.2025.100583

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Original articles • Clinics 80 • 2025 • https://doi.org/10.1016/j.clinsp.2025.100583 linkcopy

Pembrolizumab in gestational trophoblastic neoplasia: Systematic review and meta-analysis with sub-group analysis of potential prognostic factors

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Objective: To assess the performance of pembrolizumab for the treatment of Gestational Trophoblastic Neoplasia (GTN).

Methods: The Medical Subject Headings related to immunotherapy/pembrolizumab and GTN were used alone or in combination to retrieve relevant articles. The authors searched in EMBASE, MEDLINE/PubMed, Elsevier’s Scopus, and Web of Science until November/2024. The authors included any randomized controlled trials, cohort studies, case series, and case reports focusing on pembrolizumab treatment in GTN. Meta-analysis of proportions was carried out employing a random-effects model. The meta-analysis employed the inverse variance method, with the arcsine link function for the analysis of proportional data. All analyses were performed using Stata 18. For all analyses, a p-value < 0.05 indicated statistical significance. This study was registered on PROSPERO (CRD42023493329).

Results: A total of 550 studies were identified after a literature search among which 15 original studies were included in the systematic review and in the meta-analysis. Pembrolizumab induced complete sustained remission in 71.59% (95% CI 53.27-84.78%; I² = 0.00%, H² = 1.00, p = 0.90) of cases. The subgroups metaanalysis showed pembrolizumab had similar performance, regardless of age (< 40 vs. ≥ 40-years-old, p = 0.38), GTN histopathology (Placental Site Trophoblastic Tumor [PSTT], Epithelioid Trophoblastic Tumor [ETT]/ noninvasive mole/others versus invasive mole/choriocarcinoma, p = 0.48), time from diagnosis to the beginning of immunotherapy (< 4 vs. ≥ 4-years, p = 0.84), pembrolizumab combined with chemotherapy (yes vs. no, p = 0.66).

Conclusions: Pembrolizumab seems an effective treatment for patients with high-risk GTN with chemoresistant or relapsed disease, including cases of PSTT/ETT, notwithstanding patient age, time to initiate immunotherapy and whether or not it was associated with chemotherapy.

Keywords:
Gestational trophoblastic neoplasia; Choriocarcinoma; Immunotherapy; PD-1/PD-L1 inhibitors; Pembrolizumab

Study	Year	Country	Remission	Age	Origin of GTN	Histopathology	Time to initiate Im (weeks)	FIGO score	hCG pre Im	Im + Ch	Indication for Im	Number of previous Ch lines	Number of consolidation cycles
Ghorani et al.	2017	UK	Yes	42	-	Choriocarcinoma	36	17	80	No	Relapse	6	5
		Sweden	Death	52	-	Mixed PSTT⁶/ ETT⁷	192	8	2468	No	Relapse	2	*
			Yes	48	-	PSTT⁶	132	20	73	No	Resistance	4	5
			Yes	37	-	Choriocarcinoma	7	6	118	No	Relapse	6	5
Huang et al.	2017	US	Yes	26	AD	Choriocarcinoma	6	18	700	No	Resistance	3	2a
Choi et al.	2019	South	Yes	39	-	PSTT	37	15	67	No	Resistance	3	13
Choi et al.	2019	Korea	Yes	26	-	ETT	73	14	57	No	Resistance	2	4b
Clair et al.	2020	US	Yes	30	CHM	Choriocarcinoma	35	1	4527	No	Relapse	6	Not reported
Goldfarb et al.	2020	US	Progression	50	-	Choriocarcinoma	39	-	480	No	Relapse	6	3
Pisani et al.	2021	Malta	Yes	49	AD	ETT	204	-	0	No	First line	0	Not reported
Bell et al.	2021	US	Yes	47	-	ETT	156	-	9	No	Resistance	1	c
Porter et al.	2021	US/UK	Yes	34	AD	PSTT	7	-	55	Yes	Resistance	2	Not reportedd
Polnaszek et al.	2021	US	Yes	23	Abortion	PSTT	2	-	440	No	First line	0	0e
Paspalj et al.	2022	Austria	Yes	31	AD	Choriocarcinoma	10	10	2115	No	Resistance	3	3
Wong et al.	2022	US	Yes	44	-	Choriocarcinoma	-	13	26	No	Relapse	3	f
Braga et al.	2023	Brazil	Yes	26	CHM	-	22	5	17,000	No	Relapse	3	3
Braga et al.			Yes	29	CHM	Invasive mole	21	2	-	No	Relapse	4	5
			Yes	41	Abortion	-	14	8	-	No	Resistance	3	3
Lehmann et al.	2023	Austria	Yes	32	AD	Choriocarcinoma	140	5	2598	Yes	Relpase	3	12
Niimi et al.	2023	Japan	Progression	38	Abortion	Choriocarcinoma	25	6	48,000	No	Resistance	6	*
Helbig et al.	2023	Germany	Yes	46	AD	ETT	11	-	7	No	Relapse	1	Not reported

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Faculdade de Medicina / USP Rua Dr Ovídio Pires de Campos, 225 - 6 and., 05403-010 São Paulo SP - Brazil, Tel.: (55 11) 2661-6235 - São Paulo - SP - Brazil
E-mail: clinics@hc.fm.usp.br

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[TFN1] Im, Immunotherapy; FIGO, International Federation of Gynecologists and Obstetricians; hCG, Human Chorionic Gonadotropin (UI/L); Ch, Chemotherapy; AD, After Delivery; PSTT, Placental Site Trophoblastic Tumor; ETT, Epithelioid Trophoblastic Tumor.

[TFN2] ^*
Not applicable as there was no remission.

[TFN3] ^a
Need to reduce the dosage of the 2 consolidation cycles of pembrolizumab in 50% due to toxicity.

[TFN4] ^b
The institution’s tumor board decided to continue treatment with pembrolizumab, even after remission.

[TFN5] ^c
The authors did not specify the number of pembrolizumab cycles until remission and consolidation cycles. However, after 29 cycles of pembrolizumab, with remission for 12-months, the patient continued immunotherapy.

[TFN6] ^d
Although the number of consolidation chemotherapy cycles with pembrolizumab was not reported, the authors reported that they used, in addition to pembrolizumab, 5 consolidation cycles with the EP/EMA regimen, replacing cisplatin to carboplatin in the last cycle due to toxicity (thrombocytopenia, ototoxicity and tinnitus). Finally, the authors reported that she is still on consolidation treatment with pembrolizumab.

[TFN7] ^e
This patient was scheduled for 4 pembrolizumab consolidation cycles, which were not administered once the patient became pregnant.

[TFN8] ^f
The patient achieves remission after 2 cycles of pembrolizumab (followed by 5 consolidation cycles). However, she relapsed after 6 months and was again treated with pembrolizumab. The report was unclear but suggested that the patient achieved remission after 4 further cycles of pembrolizumab, followed by 21 consolidation cycles. The patient was still undergoing consolidation chemotherapy at the time of publication of the case report, with no evidence of disease and with normal hCG levels after 2-months of the end of immunotherapy.