Breaking therapeutic barriers in solid tumors: Clinical progress of antibody‑drug conjugate/immune checkpoint inhibitor combinations (Review)

Introduction

Cancer is a major contributor to global mortality (1). It has been estimated that ~20 million new cancer cases and ~9.7 million cancer-related deaths occurred in 2022 worldwide (2). Improvements in cancer treatment outcomes have been achieved through advancements in diverse anticancer therapy (3). Over the last 30 years, the US Food and Drug Administration (FDA) has authorized 120 medications for treating solid tumors (1,4). Among these, immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) and its ligand (PD-L1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) have changed the management of several types of malignancy, including non-small cell lung cancer (NSCLC), melanoma, head and neck cancer and renal cell carcinoma (5).

Unlike chemotherapy, radiotherapy and targeted therapy, which directly kill tumor cells, ICIs exert antitumor effects by inhibiting T cell suppressive signals and activating T cell-mediated cytotoxicity (6). ICIs provide durable clinical responses for patients with cancer and significantly improve their overall survival (OS). However, only a proportion of patients with specific tumor types are initially responsive to ICIs, whereas the majority are intrinsically resistant to these therapies (7,8). To enhance the therapeutic effectiveness of ICIs, scientists have shifted toward exploring multimodal therapeutic approaches (9). Notably, findings from multiple phase III clinical studies have validated the integration of immunotherapeutic agents with conventional chemotherapeutic regimens in various malignancies (10–12). However, this combination strategy also faces limitations such as high toxicity, low compliance and compromised therapeutic efficacy. These challenges underscore the need to identify novel therapeutic partners that synergize with ICIs to optimize outcomes in solid tumor management.

Antibody-drug conjugates (ADCs) represent a targeted therapeutic strategy that combines tumor-specific antibody delivery with precision release of potent cytotoxic payloads, thereby enhancing antitumor efficacy while minimizing systemic toxicity. An ADC is composed of three key elements: A monoclonal antibody (or its fragment), a specialized chemical linker and a highly potent cytotoxic agent (payload) (13). Once the antibodies attach to tumor cell surface antigens, ADCs are engulfed by cellular uptake mechanisms and degraded, releasing their cytotoxic components and resulting in tumor cell death through DNA damage or microtubule disruption (14). In addition, through the ‘bystander effect’, some ADCs with cleavable linkers release their payload across the cell membranes of the target tumor cells, further killing the neighboring tumor cells (15). In recent years, ADCs have become one of the fastest-developing drug classes in cancer treatment, with 15 ADCs being approved (up to March 2023) and a large number of ADCs being undergoing clinical trials (16,17). Several ADCs, such as datopotamab (Dato)-deruxtecan (DXd) and trastuzumab deruxtecan (DS-8201), have demonstrated activity against various types of cancer. Furthermore, growing evidence suggests that ADCs increase the efficacy of immunotherapies (13,18). ADCs are mechanistically designed to minimize off-target toxicities through tumor-selective payload delivery, thereby serving as an optimal therapeutic partner for synergistic combination with ICIs in precision oncology paradigms.

Previous preclinical and clinical observations have validated the enhanced therapeutic potential of combining ICIs with ADCs for various types of malignancies (19,20). The present review aimed to evaluate the clinical data supporting the effectiveness of this combined therapeutic approach.

Rationale for combining ADCs and ICIs

The immunostimulatory effects of ADCs are multifaceted and complex, involving several connected mechanisms that synergistically enhance antitumor immunity (3,21–24). The primary mechanisms (Fig. 1) are as follows: i) ADC-mediated delivery of cytotoxic payloads induces immunogenic cell death (ICD), triggering the release and surface exposure of danger-associated molecular patterns (DAMPs); ii) tumor-associated DAMPs, in combination with direct payload-mediated stimulation, promote dendritic cell (DC) maturation within the tumor microenvironment; iii) payload components facilitate DC migration to lymphoid tissues, enhancing naïve T cell activation, tumor-infiltrating lymphocyte recruitment and immunological memory formation; iv) ADC treatment upregulates key immunoregulatory molecules, particularly PD-L1 and major histocompatibility complex class I, potentially sensitizing tumors to ICIs and v) the antibody component mediates antibody-dependent cellular cytotoxicity, directly engaging innate immune effectors (3,21–24). These immunomodulatory properties position ADCs as rational combination partners for ICIs as they may overcome tumor immune evasion mechanisms while simultaneously exerting direct cytotoxic effects (3,21–24). Preclinical studies have demonstrated superior antitumor efficacy with ADC + ICI combinations compared with ADC or ICI monotherapy, supporting the clinical exploration of this therapeutic strategy (21,24).

Figure 1. Rationale for combining ADCs and ICIs. ADC cytotoxic payloads induce ICD, releasing DAMPs. Combined with direct payload effects, DAMPs drive DCs maturation in tumors. Payloads facilitate DC migration to lymphoid tissues, enhancing T cell activation, tumor infiltration, and immune memory. (4) ADC treatment upregulates PD-L1 and MHC-I, potentially sensitizing tumors to ICIs. (5) The antibody mediates ADCC, activating innate immunity. ICD, immunogenic cell death; DAMP, danger-associated molecular pattern; DC, dendritic cell; TME, tumor microenvironment; MHC I, major histocompatibility complex class I; ADCC, antibody-dependent cellular cytotoxicity; ADC, antibody-drug conjugate; ICI, immune checkpoint inhibitor; TCR,; PD-L1, programmed death ligand-1; NK, Natural killer; FCγRIII, Fcγ receptor III.

Clinical trials of ADCs + ICIs

The preclinical rationale supporting the synergistic interaction between ADCs and ICIs in solid tumor therapy has driven the initiation of clinical trials evaluating the feasibility, safety and antitumor efficacy of ADC + ICI combination regimens. Currently available clinical data of the ADC + ICI combination are reported in Table I. The clinical trials investigating the combination of ADCs + ICIs are summarized in Table SI.

Table I. Results of trials evaluating ADCs in combination with immune checkpoint inhibitors.

Table I.

Results of trials evaluating ADCs in combination with immune checkpoint inhibitors.

Tumor type	Disease status	ADC target	Therapy	Phase	Key efficacy outcomes	Safety	Trial (no.)	(Refs.)
NSCLC	Metastatic	TROP2	SG +	II	ORR, 67% (PD-L1	Manageable; aligned	EVOKE-02	(33)
			pembrolizumab		TPS ≥50%);	with the toxicity of SG	(NCT05186974)
					mPFS,	and pembrolizumab
					13×.1 months
	Advanced or	TROP2	Dato-DXd +	Ib	ORR, 52%; DCR,	Manageable; aligned with	TROPION-Lung02	(30)
	metastatic		pembrolizumab		88%; mPFS,	the known toxicities	(NCT04526691)
					11.1 months	of Dato-DXd and
						pembrolizumab
	Advanced or	TROP2	Dato-DXd +	Ib	ORR, 50.0%; DCR,	Manageable; aligned with	TROPION-Lung04	(41)
	metastatic		durvalumab		92.9%	the known toxicities of	(NCT04612751)
						Dato-DXd and
						durvalumab
	Advanced	TROP2	Sac-TMT +	II	Cohort 1A (Q3W):	Manageable (Gr ≥3	OptiTROP-Lung01	(46)
			KL-A167		ORR, 48.6%; DCR,	TRAEs included	(NCT05353688)
					94.6% and mPFS,	neutropenia, leukopenia,
					15.4 months;	anemia and rash)
					Cohort 1B (Q2W):
					ORR, 77.6%; DCR,
					100%; mPFS, NR
	Advanced or	HER2	T-DXd +	II	HER2-overexpression	ILD risk requires	HUDSON	(60)
	metastatic		durvalumab		cohort: ORR,	monitoring	(NCT03334617)
					26.1%; mPFS,
					2.8 months; mOS,
					9.5 months; HER2-
					mutation cohort:
					ORR, 35%; mPFS
					5.7 months; mOS,
					10.6 months
	Advanced	c-Met	Teliso-V +	I	ORR, 7.4%; mPFS,	Manageable (most	NCT02099058	(90)
			nivolumab		7.2 months	common any-grade
						TRAEs were fatigue
						and peripheral sensory
						neuropathy)
UC	Metastatic	TROP2	SG +	II	ORR, 41%; mPFS,	Manageable (Gr ≥3	TROPHY-	(30)
			pembrolizumab		5.3 months; mOS,	TRAEs included	U-01 trial
					12.7 months	neutropenia,	(NCT03547973)
						leukopenia and anemia)
	Metastatic	TROP2	SG + ipilimumab/nivolumab	I	ORR, 66.6%	Manageable	NCT04863885	(34)
	Metastatic	HER2	T-DXd +	Ib	ORR, 36.7%; mPFS,	Aligned with mono-	DS8201-A-U105	(59)
			nivolumab		6.9 months; mOS,	therapy profiles, ILD/	(NCT03523572)
					11.0 months	pneumonitis risk
						requires monitoring
	Advanced or	HER2	RC48 +	Ib/II	ORR, 73.2%; mPFS,	Manageable (Gr ≥3	RC48-C014	(65)
	metastatic		toripalimab		9.3 months; mOS,	TRAEs included	(NCT04264936)
					33.1 months	increased γ-glutamyl-
						transferase and alanine
						aminotransferase and
						asthenia)
	Advanced or	Nectin-4	EV +	Ib/II	ORR, 64.5 vs. 45.2%	Manageable	EV-103	(75)
	metastatic		pembrolizumab		EV; mDOR, NR vs.		(NCT03288545)
					13.2 months EV
	Advanced or	Nectin-4	EV +	III	mPFS, 12.5 vs.	Gr ≥3 TRAEs,	EV-302	(76)
	metastatic		pembrolizumab		6.3 months chemo-	55.9 vs. 69.5%	(NCT04223856)
					therapy; mOS, 31.5 vs.	chemotherapy
					16.1 months
					chemotherapy
BC	TNBC,	TROP2	Dato-DXd +	Ib/II	ORR, 74%	Favorable safety profile	BEGONIA	(44)
	metastatic		durvalumab				(NCT03742102)
	Advanced	HER2	T-DM1 +	II	PFS 8.2 vs. 6.2 months	More Gr ≥3 AEs	KATE2	(53)
			atezolizumab		T-DM1		(NCT02924883)
	Metastatic	HER2	T-DXd +	Ib	HER2+ cohort: ORR,	Aligned with mono-	DS8201-A-U105	(59)
			nivolumab		65.6%; mPFS,	therapy profiles; ILD/	(NCT03523572)
					11.6 months; mOS,	pneumonitis risk
					NR; HER2-low	requires monitoring
					cohort: ORR, 50.0%;
					mPFS, 7.0 months;
					mOS, 9.5 months
	Advanced or	LIV-1	LV +	Ib/II	ORR, 54%	Tolerated (Gr ≥3 TRAEs	SGNLVA-002	(96)
	metastatic		pembrolizumab			included neutropenia,	(NCT03310957)
						diarrhea, fatigue,
						hypokalemia and
						maculo-papular rash)
SCLC	Extensive	DLL3	Rova-T +	I/II	ORR, 30%	Poor tolerability;	NCT03026166	(100)
	stage		nivolumab ±			requires dose optimization
			ipilimumab
G/GEJ	Advanced	HER2	RC48 +	I	ORR, 43%; mPFS,	Manageable (Gr ≥3	RC48-C013	(64)
			toripalimab		6.2 months; mOS,	TRAEs included neutro-	(NCT04280341)
					16.8 months	penia and leukopenia)
OC	Platinum-	FRα	MIRV +	I	ORR, 43%; mDOR,	Manageable; aligned with	NCT02606305	(82)
	resistant		pembrolizumab		6.9 months; mPFS	monotherapy profiles
					5.2, months
CC	Recurrent or	TF	TV +	Ib/II	ORR, 40.6% (1L);	Manageable	NCT03786081	(94)
	metastatic		pembrolizumab		ORR 35.3% (2L/3L)
Solid	Advanced	MSLN	BMS-986148 +	I/IIa	ORR, 20% (including	Manageable; low-grade	CA008-002	(86)
tumor			nivolumab		mesothelioma/	TRAEs (such as increased	(NCT02341625)
					pancreatic cancer)	AST and ALT levels)

[i] ADC, antibody-drug conjugate; PD-L1, programmed death ligand-1; TPS, tumor proportion score; NSCLC, non-small cell lung cancer; UC, urothelial cancer; TNBC, triple negative breast cancer; G/GEJ, gastric/gastroesophageal junction; OC, ovarian cancer; CC, cervical cancer; TROP2, trophoblast cell surface antigen 2; HER, human epidermal growth factor receptor; DLL3, Δ-like ligand 3; FRα, folate receptor α; MSLN, mesothelin; TF, tissue factor; SG, sacituzumab govitecan; Dato-DXd, datopotamab deruxtecan; Sac-TMT, sacituzumab tirumotecan; Teliso-V, telisotuzumab vedotin; T-DXd, trastuzumab deruxtecan; RC48, disitamab vedotin; EV, enfortumab vedotin; T-DM1, trastuzumab emtansine; LV, lLadiratuzumab vedotin; Rova-T, rovalpituzumab tesirine; MIRV, mirvetuximab soravtansine; TV, tisotumab vedotin; ORR, objective response rate; DCR, disease control rate; mPFS, median progression-free survival; mOS, median overall survival; NR, not reached; ILD, interstitial lung disease; Gr, grade; TRAE, treatment-related adverse event; Q3W, once every 3 weeks; mDOR, median duration of response; AST, aspartate aminotransferase; ALT, alanine aminotransferase; 1L, first-line.

Anti-trophoblast cell surface antigen 2 (TROP2) ADCs in combination with ICIs

TROP2, alternatively termed tumor-associated calcium signal transducer 2, is a cell surface glycoprotein upregulated in multiple malignancies, including NSCLC, breast cancer (BC), urothelial cancer (UC), pancreatic and prostate cancer, and is associated with poor prognosis of patients (25). A clinical study revealed elevated TROP2 levels in ~64% of lung adenocarcinoma cases and 75% of squamous cell carcinoma specimens, highlighting its prevalence in NSCLC subtypes (26). TROP2 is upregulated in all subtypes of BC, with particularly pronounced upregulation observed in triple negative (TN)BC (27). The current clinical pipeline features >20 TROP2-targeting ADCs under active investigation globally, with notable candidates including sacituzumab govitecan (SG; Trodelvy®, Gilead Sciences Inc), Dato-DXd and sacituzumab tirumotecan (Sac-TMT), which exemplify diverse therapeutic strategies in this rapidly evolving field (28).

SG in combination with ICIs

SG represents a novel ADC targeting the TROP2 antigen. This therapeutic agent combines a humanized anti-TROP2 IgG antibody with SN-38, the active metabolite of irinotecan that inhibits topoisomerase I activity (29). SG has shown efficacy and safety in numerous types of solid tumors (29). As of January 2024, SG has been approved by the FDA to treat metastatic (m)TNBC, unresectable locally advanced or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor (HER)2-negative BC and metastatic (m)UC (accelerated approval) (29). According to clinicaltrials.gov, nearly 20 clinical studies (30–32) are currently evaluating the therapeutic potential of SG-ICI combination therapy in various types of solid malignancies, including UC, TNBC and NSCLC.

EVOKE-02 (trial no. NCT05186974) is an ongoing open-label phase II trial assessing SG combined with pembrolizumab (an anti-PD-1 monoclonal antibody) ± carboplatin/cisplatin in metastatic (m)NSCLC lacking actionable genomic alterations (AGAs). In cohort A [PD-L1 tumor proportion score (TPS) ≥50%], SG-pembrolizumab demonstrated promising first-line (1-L) antitumor activity with an overall response rate (ORR) of 67% (95% CI: 47–83) and median progression-free survival (PFS) of 13.1 months [95% CI: 5.5-not reached (NR)] (33). The safety profile was manageable and aligned with the known toxicities of the individual agents (33). The phase III KEYNOTE-D46/EVOKE-03 trial (trial no. NCT05609968) is assessing therapeutic augmentation through SG in addition to pembrolizumab monotherapy in PD-L1-high (TPS ≥50%) mNSCLC. Data from this trial remain undisclosed. Additionally, neoadjuvant SG + pembrolizumab is being investigated in resectable NSCLC through a phase II study (trial no. NCT06055465). For extensive-stage (ES)-SCLC, a regimen combining carboplatin/etoposide with pembrolizumab induction followed by maintenance pembrolizumab plus SG is under evaluation (trial no. NCT06667167).

The therapeutic potential of SG combined with ICIs is being actively explored in advanced (a)UC. In the phase II TROPHY-U-01 trial (trial no. NCT03547973) cohort 3, the SG-pembrolizumab combination demonstrated clinically meaningful outcomes in 41 patients with platinum-refractory mUC. With a 14.8-month median follow-up, this regimen achieved an ORR of 41% (95% CI: 26.3–57.9), including 20% complete response (CR), with median PFS and OS reaching 5.3 (95% CI: 3.4–10.2) and 12.7 months [95% CI: 10.7-not estimable (NE)], respectively (30). The SG + pembrolizumab combination demonstrated notable antitumor efficacy and a favorable safety spectrum in chemotherapy-refractory mUC. Concurrently, a phase I/II trial (trial no. NCT04863885) is evaluating a novel triplet regimen combining SG with ipilimumab (CTLA-4 inhibitor) and nivolumab (PD-1 blocker) as 1-L therapy for cisplatin-ineligible mUC. The completed phase I dose-escalation (n=9) established a tolerable safety profile (34). Preliminary efficacy analysis in six response-evaluable patients revealed an ORR of 66.6% (4/6), comprising one CR and three partial responses (PRs), supporting further investigation of this immunotherapeutic combination (34). The clinical investigation of SG combined with ICIs is expanding across UC treatment settings: The SURE trial (trial no. 2020-004844-27) is evaluating neoadjuvant SG with/without pembrolizumab (anti-PD-1) before radical cystectomy in muscle-invasive bladder cancer (MIBC) (35), while PRISMA-1 (trial no. NCT06133517), a phase II trial, assesses perioperative SG combined with zimberelimab (PD-1 inhibitor) and domvanalimab [anti-T cell immunoreceptor with Ig and ITIM (TIGIT)] in patients with platinum-ineligible MIBC. Additionally, the phase II single-arm trial NCT06682728 examines adjuvant SG-nivolumab therapy in patients with high-risk MIBC post curative-intent surgery. In advanced disease, the phase III NCT06524544 trial is prospectively comparing pembrolizumab-SG combination vs. SG monotherapy in locally aUC or mUC.

The therapeutic potential of combining SG with pembrolizumab continues to be evaluated through multiple ongoing clinical investigations in BC, covering various molecular subtypes and treatment contexts (36–38). Current research initiatives include the phase II Saci-IO TNBC study (trial no. NCT04468061) comparing SG-pembrolizumab combination therapy vs. SG monotherapy in PD-L1-negative mTNBC (37), the phase II Saci-IO HR+ investigation (trial no. NCT04448886) examining SG + pembrolizumab vs. single-agent SG in metastatic HR-positive/HER2-negative BC (38) and the phase III ASCENT-04/KEYNOTE-D19 trial (trial no. NCT05382286) evaluating SG-pembrolizumab combination against alternative therapeutic approaches in TNBC (36).

Dato-DXd in combination with ICIs

Dato-DXd, also known as DS-1062a, is an innovative TROP2-targeting ADC constructed through covalent attachment of a humanized anti-TROP2 IgG1 monoclonal antibody to DXd, a highly potent DNA topoisomerase I inhibitory agent. This therapeutic agent maintains a drug-to-antibody ratio (DAR) of 4:1, indicating four cytotoxic payload molecules conjugated per antibody unit (25). Unlike SG, Dato-DXd incorporates a protease-cleavable tetrapeptide-based linker system and employs an enhanced topoisomerase inhibitor payload (>10 times greater than that of SN-38 of SG) (25). In clinical trials, Dato-DXd has displayed notable anticancer efficacy coupled with acceptable safety parameters in a variety of solid tumors, including NSCLC and BC (39,40).

The antitumor potential of Dato-DXd was first demonstrated in NSCLC, notably in the TROPION-Lung01 trial (trial no. NCT04656652), a global phase III study where Dato-DXd significantly improved PFS compared with docetaxel in patients with advanced (a)NSCLC treated with at least one prior therapy (39). Building on this success, clinical trials are now evaluating Dato-DXd combined with ICIs, including pembrolizumab and durvalumab: In the TROPION-Lung02 phase Ib trial (trial no. NCT04526691), Dato-DXd + pembrolizumab achieved an ORR of 52% (22/42), a disease control rate (DCR) of 88% (37/42) and a median PFS of 11.1 months (95% CI: 7.2-NE) in patients with treatment-naïve NSCLC, with efficacy observed across PD-L1 expression levels (41). Safety profiles aligned with the known effects of each agent, showing no new safety signals (41). Similarly, early results from the TROPION-Lung04 phase Ib trial (trial no. NCT04612751) revealed that Dato-DXd/durvalumab (doublet regimen; n=14) yielded an ORR of 50.0% and a DCR of 92.9%, while the addition of carboplatin (triplet regimen; n=13) enhanced efficacy (ORR, 76.9%, DCR: 92.3%) without new safety concerns in patients with untreated aNSCLC without AGAs (42). These promising outcomes have spurred multiple phase III trials investigating Dato-DXd-ICI combinations as 1-L therapy for NSCLC, including TROPION-Lung07 [trial no. NCT05555732; Dato-DXd + pembrolizumab with or without platinum-based chemotherapy in patients with advanced/metastatic (a/m)NSCLC with PD-L1 TPS <50%], TROPION-Lung08 (trial no. NCT05215340; Dato-DXd + pembrolizumab vs. pembrolizumab in aNSCLC with PD-L1 TPS ≥50%) (43), TROPION-Lung10 [trial no. NCT06357533; Dato-DXd + rilvegostomig (a bispecific anti-TIGIT/PD-1 antibody) vs. pembrolizumab in PD-L1-high non-squamous NSCLC without AGAs] and TROPION-Lung12 (trial no. NCT06564844; adjuvant Dato-DXd combined with rilvegostomig vs. standard care in circulating tumor DNA-positive/high-risk stage I NSCLC following complete resection).

Dato-DXd is being developed as a targeted therapy for BC, with TNBC as a key focus. In the ongoing BEGONIA platform study (trial no. NCT03742102), the combination of Dato-DXd and durvalumab has demonstrated promising efficacy in 1-L TNBC treatment. Preliminary data from 27 evaluable patients revealed an ORR of 74% (20/27; 95% CI: 54–89), comprising two CRs and 18 PRs (44). Notably, the regimen exhibited a favorable safety profile with no reported cases of dose-limiting toxicity (DLT) or interstitial lung disease/pneumonitis (44). These results from the BEGONIA trial support further investigation of this combination therapy. A total of three pivotal phase III trials are currently underway to evaluate Dato-DXd + ICIs across different BC treatment settings, including TROPION-Breast03 (trial no. NCT05629585; evaluating Dato-DXd ± durvalumab vs. investigator's choice of therapy in patients with stage I–III TNBC with residual invasive disease post-neoadjuvant treatment), TROPION-Breast04 (trial no. NCT06112379; comparing neoadjuvant Dato-DXd/durvalumab followed by adjuvant durvalumab ± chemotherapy with neoadjuvant pembrolizumab/chemotherapy followed by adjuvant pembrolizumab ± chemotherapy in treatment-naïve TNBC or HR-low/HER2-negative BC) and TROPION-Breast05 (trial no. NCT06103864; investigating Dato-DXd ± durvalumab vs. chemotherapy combined with pembrolizumab in PD-L1-positive TNBC).

Sac-TMT in combination with ICIs

Sac-TMT, also known as SKB264 and MK-2870, is a novel TROP2 ADC that was developed using 2-methylsulfonyl pyrimidine as the linker to conjugate the payload (KL610023), a cytotoxic compound derived from belotecan that serves as a topoisomerase I inhibitor (45).

The interim findings from the OptiTROP-Lung01 phase II trial (trial no. NCT05353688) evaluating Sac-TMT + KL-A167 (a fully humanized PD-L1-targeting monoclonal antibody) for aNSCLC have been reported (46). The aforementioned study enrolled patients with treatment-naïve aNSCLC without AGAs, administering either Sac-TMT (5 mg/kg) once every 3 weeks (Q3W) + KL-A167 (1,200 mg Q3W; cohort 1A) or Sac-TMT (5 mg/kg) once every 2 weeks (Q2W) with KL-A167 (900 mg Q2W; cohort 1B). Cohort 1A and 1B demonstrated clinically meaningful efficacy with a manageable safety profile in this patient population. After median follow-up durations of 14.0 (cohort 1A) and 6.9 months (Cohort 1B), the following outcomes were observed: Cohort 1A achieved an ORR of 48.6% (18/37), DCR of 94.6% and median PFS of 15.4 months (95% CI: 6.7-NE), with a 6-month PFS rate of 69.2%; Cohort 1B showed superior outcomes with ORR of 77.6% (45/58), DCR of 100% and median PFS not yet reached, accompanied by a 6-month PFS rate of 84.6% (46). Notably, the Q2W regimen demonstrated enhanced clinical activity compared with the Q3W schedule. Based on these results, the Q2W administration schedule has been selected for further clinical investigation (46).

Other ongoing clinical trials are evaluating Sac-TMT combined with ICIs. MK-2870-010 (trial no. NCT06312176), a phase III randomized open-label study, compares Sac-TMT monotherapy and combination with pembrolizumab vs. physician's choice therapy in HR+/HER2− BC. TroFuse-011 (MK-2870-011; trial no. NCT06841354) examines Sac-TMT with or without pembrolizumab vs. clinician-determined therapy for treatment-naïve TNBC with low PD-L1 expression [combined positive score <10]. MK-2870-012 (trial no. NCT06393374), a phase III adjuvant trial, compares Sac-TMT combined with pembrolizumab against physician-selected therapy for patients with TNBC who failed to achieve pathological CR following neoadjuvant therapy. MK-2870-023 (trial no. NCT06422143), a phase III trial, tests pembrolizumab with carboplatin/taxane induction followed by pembrolizumab ± maintenance Sac-TMT in 1-L treatment of metastatic squamous NSCLC. TroFuse-007 (trial no. NCT06170788), a phase III study, compares 1-L Sac-TMT/pembrolizumab vs. pembrolizumab monotherapy in patients with NSCLC with PD-L1 high expression (TPS ≥50%).

Anti-human epidermal growth factor receptor 2 (HER2) ADCs in combination with ICIs

HER2, a tyrosine kinase receptor within the EGFR/ErbB family, is a transmembrane glycoprotein encoded by the ERBB2 gene (47). Clinically, HER2 upregulation has been extensively documented in multiple malignancies, notably BC, NSCLC, UC and gastric and ovarian cancer, with its aberrant expression associated with aggressive tumor phenotypes and adverse clinical outcomes (48,49). To address this therapeutic challenge, novel HER2-targeted ADCs have emerged as a transformative strategy in the treatment of HER2-positive cancer (50,51). Representative agents in this class include trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (DS-8201), disitamab vedotin (RC48) and trastuzumab rezetecan (SHR-A811) (50,51).

T-DM1 in combination with ICIs

T-DM1 (Kadcyla®) is the first approved anti-HER2 ADC. It comprises an anti-HER2 antibody trastuzumab conjugated via a non-cleavable linker to the highly potent cytotoxin DM1, with an average DAR of 3.5 (52). Clinical investigations evaluating T-DM1 combined with ICIs predominantly focus on HER-positive BC (53–55).

The phase II KATE2 trial (trial no. NCT02924883) assessed T-DM1 with atezolizumab vs. T-DM1 alone in pretreated HER2-positive advanced (a)BC (53). Despite preclinical rationale, the combination failed to demonstrate significant clinical benefits: PFS showed no significant improvement (8.2 vs. 6.2 months; HR, 0.82, 95% CI: 0.55–1.23, P=0.33), while exhibiting increased AEs (53). Notably, exploratory analyses revealed a PFS and OS trend favoring PD-L1-positive subgroups, prompting the phase III KATE3 trial (trial no. NCT04740918) to evaluate this combination in PD-L1-positive, unresectable locally advanced/metastatic HER2-positive BC.

The phase Ib GO29381 trial (trial no. NCT02605915), which demonstrated acceptable tolerability of T-DM1-atezolizumab in early/advanced HER2-positive BC, alongside evidence of adaptive immune activation (54). Patients with mBC who received T-DM1 + atezolizumab achieved a combined ORR of 35% (54). The ongoing ASTEFANIA trial (trial no. NCT04873362) further investigates this combination in patients with HER2-positive BC with residual invasive disease post-neoadjuvant therapy (56).

Pembrolizumab represents another ICI candidate for T-DM1 combination strategies. The phase Ib KEYNOTE-358 trial (trial no. NCT03032107) explored T-DM1 + pembrolizumab in taxane/trastuzumab-pretreated HER2-positive BC, reporting a 20% ORR and median PFS of 9.6 months with manageable toxicity (55).

T-DXd in combination with ICIs

T-DXd, also known as DS-8201, represents an ADC composed of a HER2-targeted monoclonal antibody conjugated to a topoisomerase I inhibitor payload, with a high DAR of ~8. T-DXd has shown a lower risk of disease progression or death vs. T-DM1 in patients with pretreated HER2-positive mBC (57), and greater improvements in PFS and OS vs. chemotherapy in HER2-low mBC (58). Given its superior efficacy profile, T-DXd is currently being investigated in combination with ICIs in multiple clinical trials to evaluate potential synergistic antitumor effects (59–61).

DS8201-A-U105 (NCT03523572), a phase Ib clinical trial, investigated the therapeutic combination of T-DXd and nivolumab in individuals diagnosed with HER2-expressing mBC and mUC (59). The safety profile of this regimen aligned with the established safety characteristics of T-DXd monotherapy (59). Confirmed ORRs were 65.6 (21/32; 95% CI: 46.8–81.4) in HER2-positive mBC (cohort 1), 50.0 (8/16; 95% CI: 24.7–75.3) in HER2-low mBC (cohort 2) and 36.7% (11/30; 95% CI: 19.9–56.1) in HER2-high mUC (cohort 3). Median PFS was 11.6 months (95% CI: 6.9-NR) in cohort 1, 7.0 months (95% CI: 2.3–10.8) in cohort 2 and 6.9 months (95% CI: 2.7–14.4) in cohort 3. Median OS was NR in cohort 1 (95% CI: 20.8-NR), 9.5 months (95% CI: 2.7-NR) in cohort 2 and 11.0 months (95% CI: 7.2-NR) in cohort 3. These results underscore the promising antitumor activity of T-DXd + nivolumab across HER2-expressing mBC and mUC (59). Furthermore, a phase II trial (trial no. NCT05480384) is currently evaluating this combination in patients with HER2-high esophagogastric adenocarcinoma who have undergone chemoradiation followed by esophagectomy.

Durvalumab, a key PD-L1 inhibitor, has been extensively explored in combination with T-DXd across various solid tumors (60–62). The HUDSON platform study (trial no. NCT03334617) investigated therapeutic combinations for patients with NSCLC experiencing disease progression following ICI therapy, including T-DXd + durvalumab (60). This regimen demonstrated manageable safety and clinical activity in NSCLC with HER2 upregulation or activating mutations. Among HER2-high patients (n=23), the ORR was 26.1% (80% CI: 14.3–41.3), while HER2-mutated patients (n=20) achieved a higher ORR of 35% (80% CI: 20.7–51.8). Median PFS was 2.8 months (80% CI: 2.2–5.5) in the upregulated group vs. 5.7 months (80% CI: 5.5–6.5) in the mutation cohort. Median OS was 9.5 months (80% CI: 6.6–12.4) for HER2-high patients compared with 10.6 months (80% CI: 8.9-NR) in the mutation group (60). The phase Ib DESTINY-Lung03 trial (trial no. NCT04686305) extends this strategy to 1-L HER2-positive aNSCLC with T-DXd/durvalumab ± chemotherapy. In BC, early results from BEGONIA Arm 6 (trial no. NCT03742102) demonstrated 100% ORR (4/4) in HER2-low TNBC with T-DXd/durvalumab (61). Exploratory trials DESTINY-Breast07 (trial no. NCT04538742) and -Breast08 (trial no. NCT04556773) systematically assess T-DXd/durvalumab combinations in HER2-positive and HER2-low subtypes. For inflammatory BC, a rare and aggressive BC subtype, where PD-L1 expression is prevalent and 80% of cases demonstrate HER2 alterations (40% positive, 40% low) (62), the phase II TRUDI trial (trial no. NCT05795101) examined neoadjuvant T-DXd/durvalumab in HER2-expressing cases. Gastrointestinal malignancy represents an emerging focus, with the phase II EPOC2003 trial (trial no. NCT05034887) investigating neoadjuvant T-DXd + capecitabine/durvalumab in HER2-positive gastric cancer. The DESTINY-Gastric-03 study (trial no. NCT04379596) further explored T-DXd/durvalumab combinations for advanced HER2-expressing gastric/gastroesophageal junction (G/GEJ) cancer and esophageal adenocarcinoma.

Additional ICIs under evaluation in T-DXd-based combination therapy for solid tumors include pembrolizumab, rilvegostomig and volrustomig. The phase Ib DS8201-A-U106 trial (trial no. NCT04042701) evaluates T-DXd + pembrolizumab in aBC, mBC or NSCLC. In HER2-positive G/GEJ cancer, the phase III DESTINY-Gastric05 study (trial no. NCT06731478) compares 1-L T-DXd + chemotherapy ± pembrolizumab vs. chemotherapy + trastuzumab ± pembrolizumab. Rilvegostomig, a bispecific antibody targeting PD-1 and TIGIT receptors, is designed to enhance antitumor activity beyond PD-(L)1 inhibition (63). The phase III ARTEMIDE-Gastric01 trial (trial no. NCT06764875) is assessing the efficacy and safety of rilvegostomig combined with fluoropyrimidine and T-DXd vs. trastuzumab, chemotherapy and pembrolizumab as 1-L treatment for HER2-positive gastric cancer. The phase III DESTINY-Biliary Tract Cancer-01 trial (trial no. NCT06467357) is evaluating the efficacy and safety of T-DXd with rilvegostomig or T-DXd monotherapy vs. gemcitabine + cisplatin and durvalumab in patients with advanced treatment-naïve HER2-expressing biliary tract cancer. Volrustomig, an investigational bispecific antibody targeting PD-1 and CTLA-4 receptors, is being studied in combination with T-DXd in DESTINY-Lung03 Arm 3 (trial no. NCT04686305) for HER2-high NSCLC and DESTINY-Gastric03 Arm 3 (trial no. NCT04379596) for gastric cancer.

RC48 in combination with ICIs

RC48, a humanized HER2-targeting ADC approved in China, underwent assessment in the RC48-C013 phase I study (trial no. NCT04280341) exploring its synergistic effects with PD-1 inhibitor toripalimab for advanced HER2-positive G/GEJ cancer and other types of solid neoplasms. Among 56 enrolled patients (30 with G/GEJ cancer; 26 with other tumors), no DLT occurred (64). In the G/GEJ cancer cohort, the validated ORR was 43% (12/28; 95% CI: 25–63%), with a median PFS of 6.2 months (95% CI: 4.0–6.9) and median OS of 16.8 months (95% CI: 7.2-NE). Among patients with G/GEJ treated with RP2D (n=24), ORR was 50% (11/22; 95% CI: 28–72%) (64). Clinical benefit was observed across HER2 expression levels: HER2-positive patients (n=9) achieved an ORR of 56% (5/9; 95% CI: 21–86%), median PFS of 7.8 months (95% CI: 0.9-NE) and median OS NR (95% CI: 4.3-NE), while HER2-low patients (n=13) showed an ORR of 46% (6/13; 95% CI: 19–75%), median PFS of 5.1 months (95% CI: 1.2–6.9) and median OS of 14.0 months (95% CI: 5.1-NE). Antitumor activity was also observed in other types of malignancies, including BC (ORR: 38%, 5/13) and endometrial carcinoma (1/1) (64). The RC48-C013 trial results demonstrated that the combination of RC48 and toripalimab exhibits tolerable safety characteristics while displaying promising therapeutic activity in previously treated individuals diagnosed with HER2-positive or low HER2 expression levels in G/GEJ cancers.

The phase Ib/II RC48-C014 trial (trial no. NCT04264936) evaluated RC48 combined with toripalimab in 41 patients with locally aUC or mUC, including 61% treatment-naïve individuals, demonstrating a manageable safety profile and promising antitumor activity with a confirmed ORR of 73.2%, median PFS of 9.3 months and median OS of 33.1 months (65). The aforementioned trial demonstrated that patients with mUC may benefit from RC48 + toripalimab regardless of treatment line and HER2 and PD-L1 expression. A multicenter real-world study (n=36) observed a longer median PFS with RC48 + ICIs vs. RC48 monotherapy (8.5 vs. 5.4 months), though statistical significance was not achieved due to limited sample size (66).

Ongoing trials exploring RC48-ICI combinations include RC48-C024 (trial no. NCT06227117; neoadjuvant RC48 + toripalimab in HR-negative/HER2-low BC), RC48-C025 (trial no. NCT06389006; neoadjuvant RC48 + toripalimab in HR-positive/HER2-low BC), RC48-C025 (trial no. NCT06178159; neoadjuvant RC48 + pertuzumab ± toripalimab in HER2-positive BC), RC48-C027 (trial no. NCT05980481; RC48 + toripalimab + chemotherapy/trastuzumab in HER2-positive G/GEJ cancer), RC48-C035 [trial no. NCT06221748; RC48 + cadonilimab, PD-1/CTLA-4 bispecific antibody (67)] in 2-L HER2-positive G/GEJ cancer], RC48-C016 (trial no. NCT05302284; RC48 + toripalimab vs. chemotherapy in 1-L HER2-positive UC) and RC48-C030 [trial no. NCT06155396; RC48 + zimberelimab (an anti-PD-1) in platinum-resistant HER2-positive cervical cancer (CC)].

SHR-A811 in combination with ICIs

SHR-A811, an investigational HER2-targeted ADC, combines a humanized monoclonal antibody with a cleavable tetrapeptide linker and DNA topoisomerase I inhibitor, demonstrating preliminary antitumor efficacy and a favorable safety profile in HER2-mutant NSCLC (68). Its therapeutic potential is being explored through combination studies with adebrelimab, a novel anti-PD-L1 antibody, across multiple clinical trials targeting diverse malignancies: Ongoing investigations include SHR-A1811-II-203 (trial no. NCT05482568; HER2-positive NSCLC), SHR-A1811-II-202 (trial no. NCT05353361; HER2-positive BC), BC-MUL-IIT-ADC-SHR1316 (trial no. NCT06433609; HER2-negative aBC), BC-NEO-IIT-SHR-A1811-SHR1316 (trial no. NCT06340230; neoadjuvant therapy for HR-positive/HER2-low BC), NCC4483 (trial no. NCT06411457; HER2-low mBC) and SHR-A1811-Ib/II-205 (trial no. NCT05671822; HER2-expressing G/GEJ cancer).

Anti-nectin cell adhesion molecule-4 (nectin-4) ADCs in combination with ICIs

Nectin-4, also known as poliovirus receptor-related protein 4, is a transmembrane glycoprotein belonging to the immunoglobulin-like nectin family that serves key functions in cellular homeostasis and developmental regulation through its involvement in intercellular adhesion, proliferation, differentiation, migration and immune-modulatory signaling pathways (69). Notably, nectin-4 overexpression exhibits oncogenic properties, promoting tumor progression and invasive behavior in UC and other malignancies (70). This tumor-selective expression pattern and functional contribution to carcinogenesis have established nectin-4 as a biologically rational molecular target for ADC therapeutics (71).

Enfortumab vedotin (EV), an ADC targeting nectin-4, received regulatory approval from FDA in 2019 as 2L therapy for aUC (72). Building upon the established therapeutic roles of EV (73) and pembrolizumab (74) in UC management, clinical rationale supports their combination as 1-L treatment for a/mUC. The EV-103 phase Ib/II trial (trial no. NCT03288545) cohort K demonstrated superior efficacy of EV-pembrolizumab combination vs. EV alone in cisplatin-ineligible patients with treatment-naïve aUC or mUC, achieving significantly higher ORR (64.5 vs. 45.2%) and prolonged duration of response [median duration of response (DOR) NR vs. 13.2 months] (75). These findings were corroborated in the key phase III EV-302 trial (trial no. NCT04223856), where EV-pembrolizumab combination nearly doubled median PFS (12.5 vs. 6.3 months; HR 0.45, 95% CI: 0.38–0.54, P<0.00001) and OS (31.5 vs. 16.1 months; HR 0.47, 95% CI: 0.38–0.58, P<0.00001) compared with platinum-based chemotherapy, while demonstrating improved safety (grade ≥3 TRAEs: 55.9 vs. 69.5%) (76). These transformative outcomes have established this combination as the 1-L standard of care for aUC or mUC. An extensive clinical development program continues to evaluate EV–ICI combinations across genitourinary malignancies: NEPTUNE (trial no. NCT06356155; neoadjuvant EV-pembrolizumab in cisplatin-eligible upper tract UC), PEVRAD (trial no. NCT05879653; EV-pembrolizumab with radiotherapy for MIBC), EV-303 (trial no. NCT03924895; perioperative EV-pembrolizumab in cisplatin-ineligible MIBC), EV-304 (trial no. NCT04700124; perioperative EV-pembrolizumab vs. neoadjuvant cisplatin-gemcitabine in cisplatin-eligible MIBC), REPRINT (trial no. NCT06302569; EV-pembrolizumab in collecting duct/renal medullary carcinoma), MK-3475-04C (trial no. NCT06483334; Sac-TMT + EV ± pembrolizumab in aUC) and VOLGA [trial no. NCT04960709; perioperative EV + durvalumab ± tremelimumab (a CTLA-4 monoclonal antibody) in cisplatin-ineligible MIBC].

9MW2821, a novel nectin-4-targeting ADC with an enzyme-cleavable valine-citrulline linker conjugated to monomethyl auristatin E (MMAE) payload (77), has demonstrated clinically meaningful antitumor activity in multiple advanced malignancies in a phase I/II trial (78). Initial efficacy data revealed ORR of 62.2% (95% CI: 44.8–77.5%; n=37) in UC, 37.8% (95% CI: 23.8–53.5%; n=45) in CC, 29.6% (95% CI: 13.8–50.2%; n=27) in esophageal carcinoma (EC) and 43.9% (95% CI: 19.8–70.1%; n=16) in TNBC, establishing its broad therapeutic potential (78). Building on this rationale and preclinical synergy between ADCs and ICIs, 1-L 9MW2821 is being investigated in combination with PD-1 inhibitors in for solid tumors such as UC and TNBC through multiple registered trials: 9MW2821-CP203 (trial no. NCT06823427; 9MW2821 + toripalimab vs. 9MW2821 monotherapy in UC), 9MW2821-2023-CP104 (trial no. NCT06079112; 9MW2821 + toripalimab in UC), 9MW2821-CP205 (trial no. NCT06492005; 9MW2821 + PD-1 inhibitor in TNBC) and 9MW2821-CP302 (trial no. NCT06592326; 9MW2821-toripalimab vs. chemotherapy in UC).

SHR-A2102, another investigational nectin-4-targeting ADC, is composed of three functional elements: A fully humanized IgG1 monoclonal antibody directed against nectin-4, an enzymatically cleavable linker and a topoisomerase I inhibitor payload. Its clinical development program currently evaluates SHR-A2102-adebrelimab combination in solid malignancies, such as SHR-A2102-201 (trial no. NCT06417554; dose-escalation study of SHR-A2102 ± adebrelimab in advanced solid tumors), SHR-A2102-205 (trial no. NCT06512051; SHR-A2102-adebrelimab ± chemotherapy in NSCLC), SHR-A2102-206 [trial no. NCT06589778; SHR-A2102-adebrelimab + SHR-8068 (an anti-CTLA-4 antibody) in NSCLC], SHR-A2102-207 (trial no. NCT06639347; SHR-A2102-adebrelimab + SHR-8068 in aUC) and SHR-A2102-303 (trial no. NCT06879145; perioperative SHR-A2102-adebrelimab in MIBC).

Anti-folate receptor α (FRα) ADCs in combination with ICIs

FRα is a transmembrane glycoprotein that facilitates the unidirectional transport of folate into cells. It has been reported that FRα is upregulated in epithelial tumors, particularly high-grade serous ovarian cancer (79). The accessibility of this cell surface marker makes it a promising candidate for ADC therapeutic approaches when combined with ICIs (80).

Mirvetuximab soravtansine (MIRV), also known as IMGN853, is an ADC that combines a FRα-targeting antibody with a cleavable linker and the maytansinoid DM4 cytotoxic agent (79). In November 2022, MIRV obtained FDA authorization for managing FRα-expressing, platinum-resistant epithelial ovarian carcinoma, fallopian tube malignancies or primary peritoneal cancer in patients having undergone 1–3 previous lines of systemic therapy (81). A phase Ib clinical trial (trial no. NCT02606305) is investigating MIRV combined with pembrolizumab for platinum-resistant ovarian cancer (PROC) treatment. In the dose-escalation part (n=14), MIRV + pembrolizumab demonstrated favorable tolerability and durable antitumor activity, with a confirmed ORR of 43%, median DOR of 6.9 months and a median PFS of 5.2 months (82). The results prompted an extended trial phase to assess the therapeutic potential and safety profile of the MIRV-pembrolizumab regimen in PROC. However, the data regarding the expansion cohort have not been published. In addition to PROC, MIRV-pembrolizumab combination is also under investigation in patients with microsatellite stable (MSS) recurrent or persistent endometrial cancer (trial no. NCT03835819), with the hypothesis that addition of MIRV may improve the low response to immunotherapy in MSS endometrial cancer (83).

Anti-mesothelin (MSLN) ADCs in combination with ICIs

MSLN, a glycosylphosphatidylinositol-anchored protein located on the cell surface, is involved in cell adhesion (84). Its expression is limited in normal tissue but significantly upregulated in ~30% of cancer cases (85). Numerous MSLN-directed ADCs are under clinical development including BMS-986148. CA008-002 (trial no. NCT02341625), a phase I/IIa clinical study, evaluates the tolerability and therapeutic potential of BMS-986148 as monotherapy or combined with nivolumab for treating advanced-stage solid malignancy (86). The safety profile of BMS-986148 in combination with nivolumab is manageable, with the most common TRAEs being low grade (86). Notably, among 30 patients treated with this combination, six (20%) achieved a confirmed PR, including four with pleural mesothelioma, one with non-pleural mesothelioma and one with pancreatic cancer. These preliminary clinical data suggest that the BMS-986148 + nivolumab regimen exhibits clinically meaningful antitumor activity in a small cohort of patients with mesotheliomas and pancreatic malignancy (86). The response profile supports the need for further investigation in expanded clinical trials to evaluate the therapeutic potential and underlying mechanism of action (86).

Alongside BMS-986148, the MSLN-targeting ADC anetumab ravtansine (BAY 94-9343) has disclosed phase I/II clinical trial data evaluating its therapeutic efficacy in combination with pembrolizumab (trial no. NCT03126630) in patients with pleural mesothelioma that expressed mesothelin. Although the combination therapy with anetumab ravtansine and pembrolizumab demonstrated a prolonged median PFS compared with pembrolizumab monotherapy (12.2 vs. 3.9 months, respectively), the intergroup difference failed to reach statistical significance, potentially due to limited statistical power from an underpowered study population (87).

RC88 is another investigational ADC targeting MSLN (88). The safety, clinical pharmacology and efficacy of intravenous RC88 combined with sintilimab is currently under evaluation in a phase I/II trial (trial no. NCT05804526).

Combinations of ICIs and ADCs targeting other antigens

The tyrosine kinase receptor c-Met is predominantly found on epithelial and endothelial cell membranes. Dysregulated c-Met signaling pathways are frequently observed in NSCLC cases and associated with unfavorable clinical outcomes (89). A phase Ib study (trial no. NCT02099058) evaluated the safety and efficacy of novel anti-c-Met ADC telisotuzumab vedotin (Teliso-V) combined with nivolumab in c-Met positive aNSCLC (90). The results showed that the combination therapy with Teliso-V + nivolumab demonstrated a favorable safety profile; however, the antitumor activity of this combination in c-Met positive patients was limited (ORR, 7.4%; median PFS 7.2 months) (90). More studies are needed to detect the efficacy of this combination in NSCLC. RC108 is another anti-c-Met ADC targeting c-Met-positive advanced malignant solid tumors. A phase I clinical trial (trial no. NCT05821933) is currently evaluating the safety and efficacy profile of RC108 in combination with furmonertinib, with or without toripalimab, in patients with EGFR-mutated NSCLC exhibiting MET expression who experienced disease progression following prior EGFR tyrosine kinase inhibitor therapy.

Tissue factor (TF) is synthesized by vascular-associated cells, including adventitial fibroblasts surrounding blood vessels and epithelial cells lining body surfaces. This protein serves a key function in maintaining hemostatic balance (91). Elevated TF expression has been observed in various malignancies such as BC, prostate cancer, CC and colorectal and pancreatic cancer. Tisotumab vedotin (TV) is an investigational ADC composed of an anti-TF mAb conjugated to MMAE via a protease cleavable linker (92). Supported by findings from a phase II clinical study (trial no. NCT03438396), TV has received its first approval in the USA for managing adult patients with recurrent or metastatic cervical carcinoma showing disease progression following chemotherapy (93). TV + pembrolizumab is under evaluation for the treatment of recurrent or mCC in a multi-cohort phase Ib/II trial (trial no. NCT03786081). The preliminary results showed that ORR was 40.6% (13/32; 95% CI: 23.7–59.4) with 1-L TV + pembrolizumab (arm E) and 35.3% (12/34; 95% CI: 19.7–53.5) with 2/3-L TV + pembrolizumab (arm F) (94). Furthermore, the combination of TV and pembrolizumab demonstrated manageable safety. Grade ≥3 AEs (≥15%) reported in arm F were anemia; no grade ≥3 AE (≥15%) in arm E was reported (94).

Zinc transporter ZIP6 (LIV-1), a member of the zinc transporter protein family localized in cellular membranes, exhibits elevated expression in TNBC as documented in prior research (95). Ladiratuzumab vedotin (LV) is a promising investigational ADC directed against LIV-1. LV +pembrolizumab has been evaluated as 1-L treatment for patients with unresectable local advanced or mTNBC in the phase Ib/II SGNLVA-002 study (trial no. NCT03310957). The preliminary results of this study showed that LV + pembrolizumab were clinically active and generally well tolerated for advanced or mTNBC in 1-L setting. Of the 26 evaluable patients, the confirmed ORR was 54% (95% CI: 33.4–73.4) (96). The aforementioned findings suggest that the combination of LV and pembrolizumab warrants further investigation in TNBC.

Δ-like ligand 3 (DLL3), a Notch signaling ligand, serves a critical role in regulating the proliferation, development and metastasis of cancer cells. Studies have shown that DLL3 is significantly upregulated on the surface of SCLC cells, making it an attractive and specific target for SCLC therapy (97,98). Rovalpituzumab tesirine (Rova-T) is an ADC specifically targeting DLL3, demonstrating promising antitumor activity in patients with DLL3-expressing tumors, accompanied by a manageable safety profile (99). The antitumor activity of Rova-T with nivolumab in the presence or absence of ipilimumab, was evaluated in a phase I/II study involving patients with previously treated ES-SCLC: The combination of Rova-T with nivolumab, with or without ipilimumab, demonstrated promising antitumor activity in heavily pretreated patients with ES-SCLC. Specifically, an ORR of 30% (12/40) was observed in patients with ES-SCLC receiving Rova-T in combination with either nivolumab alone (27.6%; 8/29) or nivolumab + ipilimumab (36.4%; 4/11) (100). However, the combination of Rova-T with nivolumab ± ipilimumab was not well tolerated at the evaluated dose levels and administration schedules (100). The safety profile of the Rova-T and nivolumab combination indicates that dose and schedule optimization of this combination should be investigated.

B7 homolog 3 protein (B7-H3) belongs to the B7 superfamily of immunomodulatory molecules. B7-H3 is expressed on antigen-presenting cells; however, its expression is limited or undetectable in most normal tissue (101). By contrast, B7-H3 is upregulated in numerous types of solid cancers, including prostate cancer, NSCLC, SCLC and BC (102). Ifinatamab deruxtecan (I-DXd), also known as DS-7300, is an innovative ADC comprising a B7-H3-targeting monoclonal antibody conjugated to DXd (103). NCT06362252 is a study aiming to evaluate the safety and efficacy of I-DXd in combination with atezolizumab with or without carboplatin in patients with ES-SCLC in the 1-L setting. The aforementioned study is currently in the patient recruitment phase. BGB-C354 is another ADC targeting B7-H3. A phase I trial (trial no. NCT06422520) is ongoing to evaluate the preliminary antitumor activity and safety of BGB-C354 in combination with the anti-PD-1 monoclonal antibody tislelizumab in patients with advanced solid tumors.

B7 homolog 4 protein (B7-H4) belongs to the B7 immune checkpoint. It is a type I transmembrane protein that exhibits relatively low expression in normal healthy tissues but is highly expressed in a number of solid tumors including breast, ovarian, lung and pancreatic cancer (104). Several B7-H4-targeted ADCs are under clinical development, such as AZD8205, XMT-1660, BG-C9074 and HS-20089. The combination of AZD8205 and rilvegostomig as a potential treatment for advanced or metastatic solid tumors is under evaluation in a phase I/IIa study (trial no. NCT05123482). BG-C9074, a promising ADC targeting B7-H4, is currently being evaluated in a phase I clinical trial in combination with tislelizumab in patients with advanced solid tumors (trial no. NCT06233942).

HER3, belonging to the EGFR tyrosine kinase receptor family, demonstrates elevated expression in multiple carcinoma types such as breast, head and neck, pulmonary, colorectal, prostatic and gynecological malignancy (105). Due to its ubiquitous presence in tumors and efficient internalization by cancer cells following antibody binding, HER3 has emerged as an attractive target for cancer treatment, particularly in the development of ADCs (106). SHR-A2009 represents an innovative ADC incorporating a fully humanized anti-HER3 IgG1 monoclonal antibody, a cleavable peptide-based linker and a DNA topoisomerase I inhibitor payload, which has a tolerable safety profile and encouraging antitumor activity in patients with heavily pretreated advanced solid tumors (107). SHR-A2009 + adebrelimab is planned to be evaluated in a phase Ib/II trial for patients with advanced solid tumors, including NSCLC (trial no. NCT06092268). Patritumab deruxtecan, also known as HER3-DXd, is another investigational HER3-targeted ADC. The combination of patritumab deruxtecan and pembrolizumab is being investigated in the 1-L setting for NSCLC (trial no. NCT06731907), as well as in the neoadjuvant setting for TNBC or HR-low/HER2-negative BC (trial no. NCT06797635).

Claudin-18 isoform 2 (CLDN18.2), a key member of the tight junction protein family, has emerged as a promising tumor-associated antigen (TAA) for ADC therapeutic targeting (108). CLDN18.2 is highly and stably expressed in multiple solid tumors, including gastric and pancreatic ductal adenocarcinoma, EC, NSCLC and colorectal and hepatocellular carcinoma (108,109). AZD0901 (CMG901) is a first-in-class CLDN18.2 ADC with a humanized anti-CLDN18.2 antibody linked to microtubule-disrupting agent MMAE (110). The phase I trial of AZD0901 demonstrated that AZD0901 exhibits promising anti-tumor activity in patients with advanced (a)G/GEJ cancer, along with a manageable safety profile (110). A phase II trial (trial no. NCT05702229) is currently evaluating the combination of AZD0901 with rilvegostomig, volrustomig or AZD7789 [a bispecific antibody targeting PD-1 and T cell immunoglobulin and mucin domain 3) (111)] in patients with advanced unresectable or metastatic (m)G/GEJ cancer. LM-302 represents a novel MMAE-conjugated ADC targeting CLDN18.2. A phase I/II clinical trial (trial no. NCT05188664) is currently investigating the safety, tolerability, pharmacokinetic profile, immunogenicity and preliminary efficacy of LM-302 combined with toripalimab in patients with advanced solid tumors. In parallel, RC118 has emerged as another CLDN18.2-targeting ADC under clinical development. A phase I/II trial (trial no. NCT06038396) is actively evaluating the efficacy and safety profile of RC118 + toripalimab for patients with CLDN18.2-positive, locally advanced unresectable or metastatic malignant solid tumors.

EGFR belongs to the ErbB family of tyrosine kinase receptors, serving a pivotal role in regulating cell proliferation, differentiation, migration and survival, as well as adhesion (112). EGFR is reported to be upregulated in various solid tumors, including squamous cell carcinoma of the head and neck (SCCHN), nasopharyngeal carcinoma (NPC) and colorectal cancer (112). MRG003 is a novel ADC with an anti-EGFR humanized monoclonal antibody conjugated with MMAE via a valine-citrulline linker (112). Preliminary data from a phase I/II trial (trial no. NCT05688605) demonstrated favorable tolerability and encouraging antitumor activity of the MRG003 and pucotenlimab (an anti-PD-1 mAb) combination in patients with NPC and SCCHN. Notably, the regimen exhibited significant clinical efficacy in patients with NPC who had previously progressed following PD-1 inhibitor therapy (113). In the phase I cohort, the ORR and DCR were 63.0% (95% CI: 42.4–80.6) and 88.9% (95% CI: 70.8–97.7), respectively (113). In the phase II study, among nine evaluable patients with EGFR-positive NPC who progressed following 1-L treatment with PD-1 + platinum-based chemotherapy, the combination achieved two CR, five PR and two cases of stable disease, yielding an ORR of 77.8% (95% CI: 40.0–97.2) and a DCR of 100% (95% CI: 66.4–100) (113). The phase II study is ongoing. Furthermore, the combination of MRG003 and pucotenlimab is also being investigated as a neoadjuvant therapy for locally advanced EGFR-positive head and neck squamous cell carcinoma in an ongoing phase II trial (trial no. NCT06530914).

Receptor tyrosine kinase-like orphan receptor 2 (ROR2) has been validated as a TAA of notable therapeutic relevance across multiple types of cancer types with substantial unmet medical needs, positioning it as an attractive molecular target for cancer therapy (114). Ozuriftamab vedotin (BA3021) is a conditionally active biological agent (CAB) anti-ROR2 ADC employing a cleavable linker to conjugate MMAE (115). The ongoing BA3021-001 trial (NCT03504488) is a phase I/II study designed to evaluate the safety and antitumor efficacy of BA3021 as both monotherapy and in combination therapy with nivolumab for patients with selected advanced solid tumors, including NSCLC and melanoma.

Anexelokto (AXL), a receptor tyrosine kinase upregulated in numerous types of solid and hematological malignancy, drives tumor progression and is associated with poor clinical outcomes (116). Mecbotamab vedotin (BA3011), a CAB anti-AXL ADC, is under investigation as a therapeutic agent for advanced solid tumors. The BA3011-002 trial (trial no. NCT04681131), an ongoing phase II study, aims to assess the efficacy and safety of BA3011 as monotherapy or in combination with nivolumab for patients with AXL-expressing mNSCLC.

Fibronectin (FN) is a ubiquitously expressed, high-molecular weight, extracellular matrix glycoprotein. The extra domain B splice variant of FN (EDB + FN) is a novel therapeutic target that is upregulated in the TME of numerous types of solid tumor, with restricted expression in normal tissue (117). PYX-201 is an investigational ADC consisting of a site-specific engineered EDB + FN-targeting monoclonal antibody conjugated to vc0101, a microtubule depolymerizing agent with potent anti-mitotic and cytotoxic properties (117). PYX-201-102 (trial no. NCT06795412) is an ongoing phase I/II trial to evaluate the safety, tolerability and preliminary efficacy of PYX-201 in combination with pembrolizumab in participants with advanced solid tumors.

Integrin β-6 (IB6), a tumor-associated transmembrane protein, serves as a key mediator in disease progression and metastatic potential (118). Sigvotatug vedotin (SV), also known as SGN-B6A, is an IB6-directed ADC, which demonstrated promising efficacy against NSCLC in the phase I study SGNB6A-001 (trial no. NCT04389632) (119). Due to these encouraging results, a phase III trial is ongoing to compare the combination treatment (SV + pembrolizumab) vs. pembrolizumab alone in patients with NSCLC with high levels of PD-L1 (trial no. NCT06758401).

Conclusion

The combination of ADCs with ICIs represents a paradigm shift in cancer therapeutics, offering synergistic mechanisms to overcome intrinsic resistance and enhance antitumor immunity. Clinical evidence underscores the potential of this combination strategy in numerous types of solid tumor, driven by the ability of ADC to induce ICD, remodel the TME and amplify ICI-mediated immune cell activation. The direct comparison of ADC-ICI combination efficacy against ADC or ICI monotherapy is critical for contextualizing findings. However, clinical investigation of ADC-ICI combinations remains largely limited to early-phase trials. To date, two head-to-head trials (trial nos. NCT02924883 and NCT03288545) have compared ADC-ICI combination therapy with ADC monotherapy. Robust clinical trial evidence directly comparing combination regimens with respective monotherapies remains insufficient to draw definitive conclusions.

BC, particularly HER2-positive and TNBC, NSCLC and urothelial carcinoma represent the most extensively studied malignancies in ADC-ICI combination trials. Up to April 2025, urothelial carcinoma remains the only tumor type with a fully approved ADC-ICI combination (EV + pembrolizumab) (120). Promising ADC-ICI combinations for other solid tumors, including BC (trial nos. NCT05382286, NCT05633654, NCT06103864 and NCT05629585), NSCLC (trial nos. NCT05609968, NCT05555732 and NCT05215340) and G/GEJ cancer (trial nos. NCT06731478 and NCT05980481), have advanced to phase III trials.

The comprehensive review by Wei et al (121) provided analysis of the additive or synergistic potential between ADCs and various classes of oncology therapeutics, including immunotherapy. However, the aforementioned study had limited coverage of the specific mechanistic underpinnings, efficacy profiles and safety considerations associated with ADC-immunotherapy combinations. Clinical evidence supporting this particular combinatorial strategy lacks comprehensiveness. Similarly, Fong et al (122) summarized preclinical and clinical advancements for ADCs in oncology but did not specifically concentrate on combination therapies involving ADCs and other agents. The present review aimed to provide an exclusive and systematic focus on combinations of ADCs with ICIs (120,121) and evaluation of the clinical evidence for this promising therapeutic approach. The present review provided an antigen-focused clinical update concerning ADC-ICI combinations.

A key challenge in combining ADC and ICI therapies lies in managing overlapping AEs. For example, diarrhea or pneumonitis are shared as AEs by both immunotherapy and some ADCs; therefore, their incidence rate may increase when combined (123). Therefore, future studies should concentrate on enhancing the specificity, efficacy and safety profiles of ADCs and ICIs.

The advent of next-generation PD-1/PD-L1 agents, particularly bifunctional molecules and bispecific antibodies (PD-1/CTLA-4, PD-1/VEGF, PD-1/TIGIT and PD-1/LAG-3 bispecifics), may expand the clinical indications of immune checkpoint blockade. By simultaneously targeting PD-(L)1 and other key molecules involved in immune regulation, bispecific antibodies offer a multifaceted approach to enhance antitumor immune responses (124). Several bispecific antibodies, notably ivonescimab (PD-1/VEGF bispecific), exhibit superior therapeutic efficacy compared with conventional PD-(L)1 monoclonal antibodies such as pembrolizumab (125). Therefore, bispecific antibodies targeting the PD-1/PD-L1 signaling pathway may serve as superior alternatives to PD-(L)1 monoclonal antibodies when combined with ADCs in cancer treatment regimens.

Next-generation ADCs have emerged as innovative therapeutic modalities addressing limitations of conventional ADC platforms through novel engineering strategies (125). Bispecific ADCs demonstrate enhanced tumor selectivity and internalization efficiency via dual epitope/target engagement mechanisms (126), with >10 candidates currently in clinical development. Dual-payload ADCs represent a paradigm shift approach, employing synergistic combinations of distinct cytotoxic agents on a single antibody scaffold to overcome resistance mechanisms (127). These advanced ADC platforms, when strategically combined with ICIs, may present promising multimodal therapeutic strategies for optimizing tumor targeting while minimizing systemic toxicity through enhanced payload delivery and conditional activation mechanisms.

Supplementary Material

Supporting Data

Acknowledgements

Not applicable.

Funding

The present study was supported by the Science and Technology Project of Southwest Medical University (grant no. 2020ZRQNA004).

Availability of data and materials

Not applicable.

Authors' contributions

YZ, RD and YD conceived the study and wrote the manuscript. LC and ZZ revised the manuscript. RD reviewed and edited the manuscript. All authors have read and approved the final manuscript. Data authentication is not applicable.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References