FDA-Approved ADCs: Breaking New Ground in Breast, Lung, and Gastric Cancer Treatment

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Introduction

FDA-approved ADCs are revolutionizing cancer treatment landscapes, as the fifth most prevalent malignancy globally, gastric cancer ranks as the third leading cause of cancer-related mortality. Antibody-drug conjugates represent a promising approach in targeted cancer therapy, combining the targeted precision of antibodies with potent cytotoxic payloads to selectively attack tumor cells while minimizing off-target effects. By the end of 2022, fifteen ADCs had received regulatory approval for clinical use worldwide, demonstrating their growing importance in oncology.

Recent developments have further accelerated the adoption of approved antibody drug conjugates across multiple cancer types. In July, the U.S. Food and Drug Administration granted breakthrough therapy designation to fam-trastuzumab deruxtecan-nxki (T-DXd) in combination with pertuzumab as a first-line treatment for adult patients with unresectable or metastatic HER2-positive breast cancer. This designation highlights the remarkable clinical outcomes of ADC drugs approved for various cancers, with a pooled overall response rate across all ADCs reaching 33.4%. Furthermore, certain ADCs targeting HER2 have exhibited high drug-antibody ratios and bystander-killing effects, even in HER2 low-expressing tumors, transforming breast cancer management across HER2 subtypes.

This comprehensive review examines the structural components, mechanisms of action, and clinical applications of FDA-approved ADCs in breast, lung, and gastric cancers. Additionally, it explores the challenges and future directions in ADC development, offering graduate-level practitioners evidence-based insights into this rapidly evolving therapeutic approach.

Understanding ADCs: Structure, Mechanism, and Clinical Relevance

Antibody-drug conjugates represent an elegant fusion of targeted antibody therapy and potent cytotoxic agents. These sophisticated biopharmaceuticals consist of three critical components: a tumor-targeting monoclonal antibody, a cytotoxic payload, and a connecting linker [1]. This precise combination enables selective drug delivery to cancer cells, thereby minimizing damage to healthy tissues. Currently, twelve ADCs have received FDA approval, highlighting their growing importance in modern oncology [2].

Monoclonal Antibody Targeting in ADCs

The antibody component serves as the navigation system for ADCs, determining plasma circulation duration, target specificity, and immune functions. Most FDA-approved ADCs employ immunoglobulin G (IgG), particularly IgG1, due to its extended serum half-life and robust Fc-mediated immune functions [3]. These include antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis, and complement-dependent cytotoxicity [3]. Target selection remains crucial for ADC efficacy—ideal antigens are exclusively or preferentially expressed on tumor cell surfaces while sparing normal tissues. HER2 and trophoblast cell surface antigen 2 (TROP2) exemplify such targets in breast cancer due to their overexpression on tumor cells [3].

Cytotoxic Payloads: MMAE, DM1, and SN-38

Payloads in FDA-approved ADCs typically fall into two categories: microtubule-binding agents and DNA-damaging compounds. Auristatins such as monomethyl auristatin E (MMAE) and F (MMAF) disrupt microtubule networks, causing cell cycle arrest and apoptosis [4]. MMAE demonstrates high membrane permeability and exhibits strong bystander effects [5]. Maytansinoid derivatives, such as DM1, inhibit microtubule polymerization, leading to cell death at picomolar concentrations [5]. SN-38, the active metabolite of irinotecan, functions as a topoisomerase I inhibitor, preventing religation of DNA breaks and triggering apoptosis [5]. Notably, deruxtecan (DXd), derived from exatecan, has emerged as another potent topoisomerase I inhibitor causing DNA damage in cancer cells [5].

Linker Chemistry: Cleavable vs Non-cleavable

The linker determines how and when the payload is released from its antibody carrier. Cleavable linkers, used in more than 80% of FDA-approved ADCs [6], release payloads in response to specific tumor conditions:

Acid-labile linkers: Break down in acidic lysosomal environments (pH 4.5-6.0) [7]
Enzyme-cleavable linkers: Utilize cathepsin B and other lysosomal proteases [7]
Reducible linkers: Respond to high intracellular glutathione concentrations [7]

In contrast, non-cleavable linkers require complete antibody degradation within lysosomes for payload release, typically yielding charged metabolites with lower membrane permeability [2]. Despite higher plasma stability and reduced off-target toxicity, non-cleavable linkers generally demonstrate reduced bystander killing effects compared to their cleavable counterparts [2]. T-DM1 remains the only FDA-approved ADC employing a non-cleavable linker [6].

Mechanism of Action: Internalization and Bystander Effect

Upon binding to target antigens, ADCs undergo receptor-mediated endocytosis, trafficking from early endosomes to late endosomes before fusing with lysosomes [8]. Within this acidic environment, cleavable linkers break down or the entire antibody undergoes degradation, releasing the payload to exert cytotoxic effects [8]. Many ADCs demonstrate bystander killing—a phenomenon in which released payloads diffuse into neighboring cells that lack target antigen expression. This effect proves particularly valuable in tumors with heterogeneous antigen expression or antigenic mutations [8]. Interestingly, the most pronounced bystander activity occurs with topoisomerase I inhibitor payloads, such as deruxtecan [8], whereas ADCs employing MMAF generally lack bystander effects due to the charged structures hindering cellular membrane penetration [8].

Beyond direct cytotoxicity, antibody components can independently inhibit tumor growth through ADCC and other immune-mediated effects, providing complementary antitumor activity [3].

FDA Approved ADCs for Breast Cancer: HER2 and Trop2 Targets

The advent of antibody-drug conjugates has markedly altered treatment paradigms for breast cancer patients. Four FDA-approved ADCs now play pivotal roles in managing various breast cancer subtypes, targeting primarily HER2 and TROP2 receptors with unprecedented precision.

Trastuzumab Emtansine (T-DM1) in HER2+ Breast Cancer

T-DM1 (Kadcyla) made history in 2013 as the first ADC approved for treating HER2-positive metastatic breast cancer following trastuzumab and taxane therapy [3]. This pioneering ADC couples trastuzumab with maytansine-derived DM1 via a stable non-cleavable thioether linker, resulting in a drug-to-antibody ratio (DAR) of 3.5:1 [1]. The EMILIA trial demonstrated T-DM1’s superiority, with a median progression-free survival (PFS) of 9.6 months compared to 6.4 months for lapatinib plus capecitabine [9]. Subsequently, the FDA expanded T-DM1’s approval in 2019 to include early-stage high-risk HER2-positive breast cancer with residual disease after neoadjuvant therapy [3]. In the KATHERINE trial, T-DM1 reduced the risk of invasive disease recurrence by 50%, with 88.3% of patients remaining disease-free at 3 years, compared to 77.0% with trastuzumab [3]. Despite its efficacy, T-DM1 carries black-box warnings for hepatotoxicity, cardiac toxicity, and embryo-fetal toxicity [1].

Trastuzumab Deruxtecan (T-DXd) for HER2-Low and HER2+ Subtypes

T-DXd (Enhertu) represents a significant advancement in ADC design, featuring a cleavable tetrapeptide-based linker and topoisomerase I inhibitor payload with an exceptional DAR of 8:1 [1]. This structural advantage enables T-DXd to effectively target cells with low or heterogeneous HER2 expression through its bystander effect. The DESTINY-Breast04 trial revolutionized breast cancer treatment by demonstrating T-DXd’s efficacy in HER2-low tumors, achieving a median PFS of 8.8 months and an overall survival of 22.9 months—more than double that of physician’s choice chemotherapy [1]. In January 2025, T-DXd received FDA approval for HER2-low or HER2-ultralow breast cancer that progressed on endocrine therapy [8]. The DESTINY-Breast06 trial showed median PFS of 13.2 months with T-DXd versus 8.1 months with chemotherapy [8]. Nonetheless, interstitial lung disease remains a serious concern, occurring in 11.3% of patients [8].

Sacituzumab Govitecan (IMMU-132) in Triple-Negative Breast Cancer

Sacituzumab govitecan (Trodelvy) became the first TROP2-directed ADC approved in 2020 for metastatic triple-negative breast cancer (mTNBC) [10]. This innovative ADC combines a humanized anti-TROP2 monoclonal antibody with SN-38 (the active metabolite of irinotecan) via a hydrolyzable CL2A linker [11]. In the confirmatory ASCENT trial, sacituzumab govitecan demonstrated a median PFS of 5.6 months versus 1.7 months for chemotherapy [12]. The objective response rate reached 35% with sacituzumab govitecan compared to merely 5% with standard chemotherapy [12]. February 2023 brought expanded approval for hormone receptor-positive, HER2-negative breast cancer following endocrine therapy and at least two other treatments in metastatic settings [10]. Common adverse events include neutropenia (64%), diarrhea (62%), and nausea (67%) [11].

SYD985 and ARX788: Emerging HER2-Targeted ADCs

ARX788, a next-generation site-specific ADC, employs EuCODETM technology, creating a stable oxime bond between trastuzumab and the proprietary MMAF payload AS269 [13]. Phase III data showed ARX788 significantly improved PFS (11.3 months versus 8.2 months with lapatinib/capecitabine) [13]. Its unique structure allows potent activity in both HER2-positive and HER2-low tumors [1]. Meanwhile, trastuzumab duocarmazine (SYD985) couples trastuzumab with duocarmycin via a cleavable linker with a DAR of 2.8:1 [1]. Despite promising efficacy in the TULIP trial, ocular toxicities affected 78.1% of patients, preventing FDA approval [14]. Another recent addition is datopotamab deruxtecan (Dato-DXd), a TROP2-directed ADC approved for hormone receptor-positive, HER2-negative breast cancer, demonstrating a median PFS of 6.9 months versus 4.9 months with chemotherapy [2].

FDA Approved ADCs in Lung Cancer: Targeting Trop2 and HER3

Recent breakthroughs in antibody-drug conjugate technology have opened promising avenues for treating non-small cell lung cancer (NSCLC), especially for patients with limited therapeutic options after disease progression on standard treatments.

Datopotamab Deruxtecan (Dato-DXd) in NSCLC

On June 23, 2025, the FDA granted accelerated approval to datopotamab deruxtecan (DATROWAY) for adult patients with locally advanced or metastatic EGFR-mutated NSCLC who previously received EGFR-directed therapy and platinum-based chemotherapy [5]. This approval followed Priority Review and Breakthrough Therapy Designation based on combined results from TROPION-Lung05 and TROPION-Lung01 trials. In these studies, Dato-DXd demonstrated a confirmed objective response rate of 45% (95% CI: 35-54%), with complete responses in 4.4% of patients, and a median duration of response of 6.5 months (95% CI: 4.2-8.4) [5].

As a specifically engineered TROP2-directed ADC, Dato-DXd consists of a humanized anti-TROP2 monoclonal antibody linked to a potent topoisomerase I inhibitor payload via a plasma-stable, cleavable linker [15]. Although the TROPION-Lung01 trial did not show statistically improved overall survival in the general population (12.9 months versus 11.8 months with docetaxel), the prespecified nonsquamous NSCLC subgroup demonstrated a 2.3-month improvement (14.6 months versus 12.3 months) [15]. Common adverse reactions included stomatitis (55.2%), nausea (37.8%), and alopecia (20.3%) [16].

Patritumab Deruxtecan (HER3-DXd) for EGFR-Mutant NSCLC

HER3-DXd, another innovative ADC, combines a fully human HER3-targeting monoclonal antibody with a topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker [17]. In the phase 2 HERTHENA-Lung01 trial, HER3-DXd showed a confirmed ORR of 28.4% with a median duration of response of 6.0 months and a median progression-free survival of 5.5 months in previously treated EGFR-mutated NSCLC patients [6].

The subsequent phase 3 HERTHENA-Lung02 trial compared HER3-DXd to platinum-based chemotherapy, demonstrating modest yet statistically superior PFS (5.8 versus 5.4 months; HR 0.77; p=0.011) [17]. Notably, HER3-DXd achieved a 35.2% ORR compared to 25.3% with chemotherapy [17]. However, the lack of an overall survival benefit led to the withdrawal of its biologics license application [18]. Despite this setback, HER3-DXd showed promising activity against brain metastases, with a 36.7% confirmed CNS ORR in patients with nonirradiated brain lesions [6].

TROP2 Expression in Lung Adenocarcinoma

TROP2 protein expression at any level appears in 82% to 90% of NSCLC tumors across various sample sets [7], making it an attractive therapeutic target. Expression patterns remain consistent between adenocarcinoma and squamous cell carcinoma histologies [7]. In fact, 92% of adenocarcinoma and 91% of squamous cell carcinoma specimens show some level of TROP2 expression (H-score > 0) [7].

Significantly, TROP2 overexpression correlates with poor prognosis in NSCLC, particularly in lung adenocarcinoma [19]. A recent study found that TROP2 overexpression was present in 77% of patients with intensity 1/2 staining and in 35% with ≥25% positive tumor cells [19]. This overexpression associates with several aggressive features, including advanced pathological stage, larger tumor size, and specific genetic profiles [19].

FDA Approved ADCs in Gastric Cancer: HER2 and CLDN18.2 Targets

Gastric cancer treatment has evolved with the advent of FDA-approved ADCs targeting two primary biomarkers: HER2 and Claudin 18.2. These targeted therapies offer new hope for patients with limited treatment options.

Trastuzumab Deruxtecan (T-DXd) in HER2+ Gastric Cancer

T-DXd received FDA approval for HER2-positive gastric cancer following convincing results from the DESTINY-Gastric01 trial. This study demonstrated the superior efficacy of T-DXd compared to the physician’s choice of chemotherapy, achieving an objective response rate of 51% versus 14% [20]. Most impressively, median overall survival reached 12.5 months with T-DXd compared to 8.4 months with standard chemotherapy [20]. The recent DESTINY-Gastric04 trial solidified T-DXd’s position as a second-line therapy by showing a median overall survival of 14.7 months, compared to 11.4 months with ramucirumab plus paclitaxel [21]. Consequently, T-DXd has become the first HER2-directed medicine to demonstrate survival improvement in second-line metastatic HER2-positive gastric cancer [4].

Disitamab Vedotin (RC48) for HER2-Expressing GC

Disitamab vedotin, an ADC comprising hertuzumab coupled with monomethyl auristatin E via a cleavable linker, received approval in China for third-line treatment of HER2-overexpressing gastric cancer [22]. RC48 demonstrates efficacy in both HER2-positive and HER2-low-expressing tumors through its excellent bystander effect [22]. In combination with toripalimab (anti-PD-1), RC48 achieved a 43% objective response rate and median progression-free survival of 6.2 months in pretreated HER2-expressing gastric cancer [23]. Moreover, RC48 plus camrelizumab and S-1 in the neoadjuvant setting yielded an 80% objective response rate, with 25% achieving a pathological complete response [24].

CMG901 and EO-3021: CLDN18.2-Targeted ADCs

Claudin 18.2 has emerged as an exciting target with zolbetuximab-clzb becoming the first FDA-approved CLDN18.2-directed therapy in October 2024 [25]. CMG901, a first-in-class ADC targeting CLDN18.2 linked to MMAE, showed promising results with a 28% objective response rate and a median duration of response of 7.2 months in advanced gastric cancer [26]. The KYM901 trial demonstrated that CMG901 achieved a 33% confirmed objective response rate with a 70% disease control rate [27]. Likewise, EO-3021, another CLDN18.2/MMAE ADC, demonstrated a 47.1% objective response rate in gastric cancer patients with acceptable toxicity, primarily nausea (42.4%) and vomiting (36.4%) [28].

Challenges and Future Directions in ADC Development

Despite therapeutic advances, FDA-approved ADCs face substantial hurdles that limit long-term efficacy. Understanding these challenges directs future development pathways.

Drug Resistance Mechanisms: Antigen Loss and Efflux Pumps

Decreased cell-surface antigen expression remains a primary resistance mechanism, reducing antibody binding and diminishing ADC effectiveness [29]. For instance, HER2 downregulation occurs at both the protein and RNA levels upon chronic T-DM1 exposure [30]. Elevated drug transporters, particularly MDR1 and MRP1, facilitate the efflux of payload out of cancer cells [29]. Additionally, alterations in vesicle transport and antibody trafficking hinder proper internalization and processing [29].

Toxicity Management: Hematologic and Hepatic Effects

FDA-approved ADCs frequently cause grade ≥3 hematologic toxicities:

Neutropenia (31.2%) [31]
Thrombocytopenia (22.6%) [31]
Lymphopenia (21.0%) [31]

Treatment-related deaths occur in approximately 1.3% of patients, primarily from respiratory complications [32]. Hepatotoxicity manifests as sinusoidal obstruction syndrome, especially following allogeneic stem cell transplantation after inotuzumab ozogamicin therapy (27% incidence) [33].

Sequential ADC Therapy and Combination Strategies

Changing payload mechanisms proves crucial when sequencing multiple ADCs. The objective response rate increases from 5.3% when using similar payloads to 22.6% when switching payload types between first and second ADCs [3]. T-DM1 followed by T-DXd demonstrated superior progression-free survival compared to T-DM1 followed by disitamab vedotin (5.37 vs 3.30 months) [3].

Ongoing Trials Expanding ADC Indications

Dual-payload ADCs entering early-phase trials aim to overcome resistance and tumor heterogeneity [34]. Novel combinations, such as patritumab deruxtecan with PARP inhibitors, exploit synergy between topoisomerase I inhibitors and DNA repair inhibition [9]. Biomarker-driven enrollment and adaptive trial designs now help sponsors improve response rates across solid tumors [34].

Conclusion

Antibody-drug conjugates have emerged as powerful therapeutic modalities, transforming treatment paradigms across breast, lung, and gastric cancers. The marriage of targeted antibodies with potent cytotoxic payloads allows these innovative biopharmaceuticals to deliver highly concentrated doses directly to malignant cells while sparing healthy tissue. This precision approach has yielded remarkable clinical outcomes, particularly in patients with limited therapeutic options or refractory disease.

Throughout this review, we examined how the structural components—antibodies, linkers, and payloads—collectively determine the efficacy and toxicity profiles of ADCs. FDA-approved ADCs targeting HER2, TROP2, HER3, and CLDN18.2 have demonstrated substantial survival benefits and response rates across multiple cancer types. Trastuzumab deruxtecan stands out as a versatile agent with unprecedented activity in HER2-low breast cancer and improved outcomes in gastric malignancies. Additionally, newer agents like datopotamab deruxtecan offer hope for previously undertreated populations with metastatic lung cancer.

Despite these advances, several challenges persist. Antigen downregulation, drug efflux mechanisms, and off-target toxicities continue to limit long-term efficacy. Consequently, researchers now focus on developing dual-payload ADCs, optimizing drug-antibody ratios, and exploring rational combination strategies with immunotherapies and targeted agents. The sequential use of ADCs with different payload mechanisms represents another promising approach to overcoming resistance.

The field continues to evolve rapidly, with over 100 ADCs currently in clinical development. Furthermore, biomarker-driven patient selection will likely enhance response rates and minimize unnecessary toxicities. Though certain adverse events remain clinically challenging, improved management strategies and predictive biomarkers may eventually mitigate these concerns.

ADCs undoubtedly occupy a central position in modern oncology. Their unique ability to deliver cytotoxic payloads precisely to tumor cells fundamentally changes how clinicians approach treatment sequencing and combination strategies. As research progresses and newer-generation ADCs enter clinical practice, we anticipate further refinements in dosing, scheduling, and patient selection—ultimately leading to improved outcomes across various malignancies.

Key Takeaways

FDA-approved ADCs are revolutionizing cancer treatment by combining targeted antibodies with potent cytotoxic payloads, achieving remarkable clinical outcomes across breast, lung, and gastric cancers.

ADCs deliver precision therapy: These “smart bombs” target tumor cells specifically while sparing healthy tissue, achieving 33.4% pooled response rates across all approved ADCs.
HER2-low breast cancer breakthrough: Trastuzumab deruxtecan transformed treatment by effectively targeting previously “undruggable” HER2-low tumors with 8.8-month median progression-free survival.
TROP2 emerges as key target: Sacituzumab govitecan and datopotamab deruxtecan target TROP2, expressed in 82-90% of lung cancers and overexpressed in triple-negative breast cancer.
Resistance requires strategic sequencing: Switching payload mechanisms between ADCs increases response rates from 5.3% to 22.6%, making treatment sequencing crucial for long-term success.
Toxicity management is critical: Grade ≥3 hematologic toxicities affect 31% of patients, with treatment-related deaths in 1.3%, requiring careful monitoring and supportive care.

The future of ADC therapy lies in dual-payload designs, biomarker-driven patient selection, and rational combination strategies with immunotherapies to overcome resistance mechanisms and improve patient outcomes.

Frequently Asked Questions:

FAQs

Q1. What are antibody-drug conjugates (ADCs) and how do they work in cancer treatment? Antibody-drug conjugates are precision cancer therapies that combine a targeted antibody with a potent cytotoxic payload, thereby delivering targeted treatment. They work by delivering highly concentrated doses of medication directly to cancer cells while minimizing damage to healthy tissue.

Q2. Which cancers have FDA-approved ADCs shown promise in treating? FDA-approved ADCs have demonstrated significant efficacy in treating breast cancer (including HER2-positive and HER2-low subtypes), non-small cell lung cancer, and gastric cancer. They target specific proteins like HER2, TROP2, and Claudin 18.2.

Q3. What are some of the main challenges associated with ADC therapy? Key challenges include drug resistance mechanisms like antigen loss and increased drug efflux, managing toxicities (especially hematologic and hepatic effects), and optimizing sequential ADC therapy to overcome resistance.

Q4. How effective is trastuzumab deruxtecan (T-DXd) in treating HER2-low breast cancer? Trastuzumab deruxtecan has shown remarkable efficacy in HER2-low breast cancer, achieving a median progression-free survival of 8.8 months, which is more than double that of standard chemotherapy. This breakthrough has expanded treatment options for patients who were previously difficult to treat.

Q5. What are some emerging strategies to improve ADC efficacy? Emerging strategies include developing dual-payload ADCs to overcome resistance, using biomarker-driven patient selection to enhance response rates, and exploring combination therapies with immunotherapies and other targeted agents. Researchers are also optimizing drug-antibody ratios and sequencing strategies to enhance the effectiveness of these treatments.