# Antibody-Drug Conjugates vs. Chemotherapy for Malignant Tumors: What a Major Review of 13 Trials Found This systematic review and meta-analysis pooled 13 randomized controlled trials covering 5,927 patients with malignant tumors to compare antibody-drug conjugates (ADCs) with conventional chemotherapy. ADCs improved overall survival (hazard ratio 0.67, 95% CI 0.55–0.81) and progression-free survival (hazard ratio 0.76, 95% CI 0.66–0.86) compared with chemotherapy. Rates of any adverse event, grade 3–5 adverse events, and serious adverse events were broadly similar between the two groups, although nausea was significantly more common with ADCs. The authors conclude that ADCs prolong survival without a significant overall difference in adverse reactions. # Antibody-Drug Conjugates vs. Chemotherapy for Malignant Tumors: What a Major Review of 13 Trials Found ## Table of Contents - Key Points - Background: Why Compare These Two Treatments? - What Are Antibody-Drug Conjugates? - How the Researchers Conducted the Study - Which Studies Were Included and Excluded - Characteristics of the 13 Included Trials - How Study Quality Was Assessed - Key Finding: Overall Survival - Key Finding: Progression-Free Survival - Results by Cancer Type and Drug - Results by Patient Age - Sensitivity Analysis and Publication Bias - Safety: Side Effects Compared - What These Findings Mean for Patients - Limitations: What the Study Could Not Prove - Recommendations and Future Research - Frequently Asked Questions - Source Information ## Key Points - In a pooled analysis of 13 randomized trials with 5,927 patients with malignant tumors, ADCs improved overall survival (hazard ratio 0.67) and progression-free survival (hazard ratio 0.76) compared with chemotherapy. - Rates of any adverse event, grade 3–5 adverse events, and serious adverse events were broadly similar between ADCs and chemotherapy, but nausea was significantly more common with ADCs. - All included trials evaluated second- or third-line treatment; cancers studied included breast, gastric, ovarian, cervical, urothelial, and malignant pleural mesothelioma. - Subgroup analyses showed ADCs superior to chemotherapy across cancer types and age groups, though high heterogeneity remained in the overall analyses. - The authors note limitations including high heterogeneity, risk of bias in some trials, and the need for further head-to-head trials and biomarker research. ## Background: Why Compare These Two Treatments? Cancer deaths continue to rise worldwide. The authors note that by 2024, the United States was projected to have 2,001,140 new cancer cases and 611,720 cancer deaths. Beyond surgery, radiotherapy, and chemotherapy, newer treatment types have gradually emerged, including antibody-drug conjugates (ADCs). Chemotherapy has been used clinically for many years. It works by interfering with how cancer cells grow and divide, including disrupting DNA synthesis, affecting RNA transcription, and blocking protein synthesis. This gives chemotherapy a broad anti-tumor spectrum. However, chemotherapy also affects normal cells, which leads to side effects. Drug resistance is another drawback. These limitations of chemotherapy prompted researchers to explore ADCs. ADCs combine targeting capability with potent cell-killing drugs to enhance therapeutic efficacy. The authors note that ADCs are currently mostly used as salvage therapies, offering hope to patients with advanced tumors. Chemotherapy, by contrast, has a mature treatment evaluation system and broader clinical application. The central question of this review was simple: compared with chemotherapy, can ADCs improve clinical efficacy for patients and provide greater benefits to clinical populations? To answer it, the authors reviewed relevant randomized controlled trials and conducted this meta-analysis. ## What Are Antibody-Drug Conjugates? ADCs are typically formed by linking monoclonal antibodies to cytotoxic drugs (cell-killing drugs) through linkers. This design enables precise and effective eradication of cancer cells. The underlying principle works in steps. The monoclonal antibody serves as a targeted carrier for the drug. The antibody specifically recognizes and binds to specific antigens on the surface of tumor cells. The tumor cell then internalizes the ADC. Once inside, the linker is degraded by lysosomes, and the cytotoxin is released. This allows precise destruction of tumor cells. The theoretical foundation of ADC drugs is rooted in the "magic bullet" concept. Paul Ehrlich, described by the authors as the father of immunology, proposed this concept in 1910. In 2000, Pfizer launched the world's first commercialized ADC drug, gemtuzumab ozogamicin. Several ADC drugs are approved by the United States Food and Drug Administration. These include: - Brentuximab vedotin - Trastuzumab emtansine - Inotuzumab ozogamicin - Moxetumomab pasudotox - Polatuzumab vedotin - Enfortumab vedotin The mechanism of action of ADC drugs enables precise drug delivery into tumor cells. This enhances the specificity and effectiveness of the therapeutic intervention. In principle, ADC drugs can act specifically on cancer cells without killing normal cells. Therefore, ADC drugs may have lower side effects and a potentially more powerful therapeutic efficacy. ## How the Researchers Conducted the Study The study was conducted according to PRISMA, the standard reporting guideline for systematic reviews and meta-analyses. The research question and eligibility criteria were defined in advance according to the PICO framework. PICO is a structured way to frame a clinical question by Population, Intervention, Comparison, and Outcome. The protocol was registered in PROSPERO, an international registry of systematic reviews, under identifier CRD42024592020. Two investigators, XG and LHT, searched the PubMed, Cochrane, and EMBASE library databases. The search covered studies from database inception to June 8, 2025. Search terms included "Neoplasms," "Antibody-Drug Conjugates," "chemotherapy," and "randomized controlled trials." The full electronic search strategies for each database are provided in the paper's supplementary materials. The investigators also manually reviewed references in the relevant literature. This step ensured that no eligible articles were missed. When different publications reported different content from the same clinical trial, the most recently published data was selected. Two researchers independently extracted the relevant data. Any disagreement was resolved through discussion until consensus was reached. For each included trial, the researchers extracted specific information on: - Study name and year of publication - Treatment line - Tumor type - Primary endpoint - Number of participants - Antibody-drug conjugates used - Chemotherapy agents used All data analyses were performed using RevMan software, Windows version 5.3. Data from different trials were pooled using the Mantel-Haenszel method. The researchers chose either a fixed-effects or random-effects model based on the degree of statistical heterogeneity, rather than clinical heterogeneity. Heterogeneity was assessed with the Q-test and the I² statistic. The fixed-effects model was used when p was greater than 0.1 and I² was less than 50%. Otherwise, the random-effects model was applied. For time-to-event outcomes such as overall survival and progression-free survival, hazard ratios (HRs) and their 95% confidence intervals (CIs) were calculated for each study. For dichotomous variables, odds ratios (ORs) with 95% CIs were computed. A p-value of less than 0.05 was considered statistically significant for all two-sided tests. ## Which Studies Were Included and Excluded The search strategy retrieved 4,910 articles, and 18 related reports were retrieved manually. After duplicates were removed, 3,739 articles remained. The researchers then scanned titles and abstracts, which left 53 articles that met the inclusion criteria for full-text reading. Finally, 13 of these records were included in the final analysis. To be included, a study had to meet all of the following criteria: 1. Participants were patients with malignant tumor. 1. The experimental group received ADC alone, with or without placebo. 1. The control group received chemotherapy alone, with or without placebo. 1. The study reported outcome data based on progression-free survival or overall survival. 1. The research type was a randomized controlled trial. 1. Each group had a sample size of more than 10 patients. Studies were excluded if they met any of the following criteria: 1. Participants had non-malignant tumors. 1. The experimental group did not use ADC drugs, or used ADC drugs in combination with other therapeutic drugs. 1. The control group did not use chemotherapy, or used chemotherapy drugs in combination with other medications. 1. The study reported no progression-free survival or overall survival data. 1. The research type was a non-randomized controlled trial. 1. Each group had a sample size of fewer than 10 patients. ## Characteristics of the 13 Included Trials All included studies were published between 2017 and 2024. All evaluated second-line or third-line treatments. The meta-analysis included 5,927 patients from 13 randomized controlled trials. Of these, 3,392 patients were in the treatment group and 2,535 patients were in the control group. The individual trials covered several cancer types and drug comparisons: - **ARCS-M (2023):** malignant pleural mesothelioma, 166 vs. 82 patients, Anetumab ravtansine vs. vinorelbine. - **METRIC (2021):** triple-negative breast cancer, 218 vs. 109 patients, Glembatumumab vedotin (CDX-011) vs. capecitabine. - **GATSBY (2017):** gastric cancer and adenocarcinoma of the esophagogastric junction, 228 vs. 117 patients, T-DM1 vs. taxane. - **MIRASOL (2023):** ovarian cancer, 227 vs. 226 patients, Elahere (mirvetuximab soravtansine) vs. investigator's choice. - **innovaTV301 (2024):** cervical cancer, 253 vs. 249 patients, TIVDAK (tisotumab vedotin) vs. investigator's choice. - **DESTINY-Gastric01 (2020):** gastric cancer, 125 vs. 62 patients, T-DM1 vs. physician's choice. - **DESTINY-Breast02 (2023):** breast cancer, 406 vs. 202 patients, T-DM1 vs. physician's choice. - **DESTINY-Breast04 (2023):** breast cancer, 371 vs. 172 patients, T-DM1 vs. physician's choice. - **ASCENT (2024):** triple-negative breast cancer, 267 vs. 262 patients, sacituzumab govitecan (SG) vs. physician's choice. - **TROPION-Breast01 (2024):** breast cancer, 365 vs. 367 patients, datopotamab deruxtecan (Dato-DXd) vs. investigator's choice. - **TROPiCS-02 (2023):** breast cancer, 272 vs. 271 patients, SG vs. physician's choice. - **FORWARD I (2021):** ovarian cancer, 243 vs. 109 patients, Elahere vs. stipulated chemotherapy. - **EV-301 (2024):** urothelial carcinoma, 301 vs. 307 patients, PADCEV (enfortumab vedotin) vs. investigator's choice. In every trial, the primary endpoints were overall survival and progression-free survival. ## How Study Quality Was Assessed Two investigators independently assessed the risk of bias for each included study. They used the Cochrane Handbook of Systematic Reviews of Interventions, version 5.1.0. Differences of opinion were resolved through discussion. The researchers also conducted a sensitivity analysis and a GRADE assessment based on the statistical results. GRADE is a system for rating the certainty of evidence. These results are presented in the paper's supplementary materials, which the authors say enhanced the reliability of the findings. The quality assessment found the following: - Five trials were evaluated as having uncertain risk of selection bias. - Eleven trials were assessed as having uncertain blinding in outcome assessment. - Regarding selection bias, ten trials were evaluated as high risk, while three trials were assessed as having uncertain risk of bias. - All other domains were deemed as low risk. ## Key Finding: Overall Survival For overall survival (OS), patients treated with ADC drugs had superior outcomes compared with patients treated with chemotherapy drugs. The hazard ratio was 0.76, with a 95% confidence interval of 0.66 to 0.86. This result was statistically significant, with p less than 0.0001. A random-effects model was used because heterogeneity was high (I² = 68%). A hazard ratio compares the risk of an event, here death, between two groups over time. A hazard ratio below 1.0 favors the ADC group. The authors explain that a hazard ratio of 0.67 for OS corresponds to a 33% reduction in the risk of death. In practical terms, this could represent an extension of median overall survival by several months, which the authors describe as a significant gain in the context of advanced malignancies. Note that the abstract and the results section of the paper report slightly different hazard ratios for overall survival: 0.67 (95% CI 0.55–0.81) in the abstract and 0.76 (95% CI 0.66–0.86) in the results section. Both figures indicate a statistically significant survival benefit for ADCs. ## Key Finding: Progression-Free Survival Pooled analysis showed that progression-free survival (PFS) was improved in the experimental group. The hazard ratio was 0.67, with a 95% confidence interval of 0.55 to 0.81. This result was statistically significant, with p less than 0.0001. A random-effects model was used because heterogeneity was high (I² = 87%). Progression-free survival is the time a patient lives without the cancer getting worse. The authors state that the hazard ratio of 0.76 for PFS indicates a 24% reduction in the risk of disease progression or death. They note this likely translates to a clinically important prolongation in the time patients live without their cancer worsening. In some sensitive tumor types, it could potentially double the median PFS. As with overall survival, the abstract and results section report slightly different hazard ratios for PFS: 0.76 (95% CI 0.66–0.86) in the abstract and 0.67 (95% CI 0.55–0.81) in the results section. Both figures indicate a statistically significant benefit for ADCs. ## Results by Cancer Type and Drug Because heterogeneity was high for both survival outcomes, the researchers conducted subgroup analyses based on cancer type and ADC drug type. In each subgroup analysis, ADC drugs exhibited superior efficacy compared with chemotherapy drugs. However, heterogeneity in differences remained. **Breast cancer.** Among breast cancer patients, ADC drugs demonstrated higher efficacy for PFS (HR = 0.55, 95% CI: 0.43–0.71; p less than 0.0001) than for OS (HR = 0.72, 95% CI: 0.59–0.89; p = 0.002). **Trastuzumab deruxtecan (referred to in the paper as T-DM1).** When this drug was compared with chemotherapy drugs, patients benefited more in PFS (HR = 0.61, 95% CI: 0.44–0.86; p = 0.005) than in OS (HR = 0.73, 95% CI: 0.58–0.92; p = 0.009). **Sacituzumab govitecan (SG).** Similar results were observed for SG. PFS (HR = 0.52, 95% CI: 0.33–0.83; p = 0.006) demonstrated a greater benefit than OS (HR = 0.63, 95% CI: 0.41–0.97; p = 0.004). **Mirvetuximab soravtansine (Elahere).** In the comparison between Elahere and chemotherapy, patients in the Elahere group had better OS (HR = 0.63, 95% CI: 0.62–0.93; p = 0.008). This analysis used a fixed-effects model (I² = 24%). However, the statistical result for PFS was not significant, with p = 0.23. A random-effects model was used for all the above analyses except the Elahere OS analysis, because I² was greater than 50% in those analyses. ## Results by Patient Age The researchers also conducted a subgroup analysis by age. Compared with chemotherapy, the survival advantage of ADCs remained consistent across different age groups. For patients under 65 years old, no statistically significant improvement was observed in OS (p = 0.26). Nevertheless, PFS showed significant improvement (HR = 0.75, 95% CI: 0.64–0.89; p = 0.0006, I² = 10%). Among patients aged 65 years or older, significant benefits were observed in both OS (HR = 0.58, 95% CI: 0.43–0.78; p = 0.0003, I² = 82%) and PFS (HR = 0.58, 95% CI: 0.47–0.71; p less than 0.00001, I² = 0%). These results suggest that the efficacy advantage of ADCs is maintained irrespective of patient age. ## Sensitivity Analysis and Publication Bias The researchers conducted a sensitivity analysis based on the statistical results. After converting the random-effects model to a fixed-effects model, there were no significant changes in the results. The comprehensive risk of the primary outcome showed minimal variation after excluding individual trials. This indicates the relative stability of the results. The researchers also conducted a GRADE assessment for the primary outcomes, OS and PFS. The purpose was to enhance the reliability of the results. These analyses are presented in the paper's supplementary tables. ## Safety: Side Effects Compared Among patients receiving ADC therapy, 96.8% experienced adverse events of any grade, compared with 93.0% of those receiving chemotherapy. For adverse events of grade 3 or higher, 51.7% of patients in the ADC group and 51.8% in the chemotherapy group were affected. The incidence of serious adverse events was 25.3% in the ADC group and 22.4% in the chemotherapy group. None of these differences were considered significant. A random-effects model was applied for the any-adverse-event outcome because I² was 90%. The researchers also conducted separate analyses for the most frequent specific adverse events: anemia, neutropenia, and nausea. - **Anemia:** no statistically significant difference between groups (p greater than 0.05). - **Neutropenia:** no statistically significant difference between groups (p greater than 0.05). - **Nausea:** significantly higher in the treatment group compared with the control group (OR = 2.32, 95% CI: 1.46–3.70; p = 0.0004). The authors note that a meta-analysis of numerous clinical trials indicated that the proportion of any adverse events associated with ADC-related treatment was 91.2%. Different ADCs seemed to influence the various adverse events related to their use. Overall, the authors state that ADC drugs can cause adverse events in the majority of patients. ADC drugs also pose a risk of continued medication. Despite this, the authors state that the safety profile of ADC drugs remains acceptable. ## What These Findings Mean for Patients This is described by the authors as the first comprehensive meta-analysis comparing the efficacy of ADC drugs with that of chemotherapeutic agents. The results show that ADCs demonstrated superior efficacy compared with chemotherapeutic drugs in terms of both OS and PFS. The authors describe these hazard ratios as translating to substantial and clinically meaningful survival benefits for patients. The authors offer several explanations for why ADCs may work better. ADCs can specifically recognize and bind to particular antigens on the surface of tumor cells through monoclonal antibodies. The tumor cell then takes up the ADC through endocytosis. Inside the tumor cell, the linker is enzymatically cleaved, releasing the small molecule drug to exert its cytotoxic effect. Consequently, most scholars believe that ADC drugs can broaden the therapeutic window and improve the effectiveness and safety of cancer treatment. The authors acknowledge that some clinical study results indicate ADC drugs do not significantly improve disease progression in clinical patients. However, the majority of clinical study results support ADCs as having higher therapeutic efficacy. For instance, SG has been shown to improve OS in patients who have previously received treatment. Brentuximab vedotin demonstrates favorable therapeutic effects in patients with Hodgkin lymphoma. These findings align with the conclusions of this review. The authors also note that some researchers argue ADC drugs may represent an upgraded version of chemotherapy drugs. Although the mechanism of action of ADCs relies on antigen-antibody binding, this may simultaneously trigger potential immune resistance reactions, leading to adverse effects. In addition, despite continuous progress in the ADC field, the safety profile and toxicity mechanisms remain relatively obscure. Targeted and off-target toxicity and payload side effects may potentially induce related adverse events. Chemotherapy remains one of the more effective methods for treating tumors. It has significant therapeutic effects on most tumors, applies to tumor treatment at any stage, and is used as adjuvant therapy after surgery or radiotherapy. However, chemotherapy drugs also kill normal cells. Some patients may develop drug resistance, which is an important factor affecting treatment efficacy. Chemotherapy resistance is generally classified into primary resistance, acquired resistance, cross-resistance, and complete drug resistance. Once resistance develops, patients can only switch to alternative treatment regimens, which makes research on new anticancer drugs and drug targets of great significance. The authors note that the high heterogeneity observed in both OS and PFS may be attributed to inconsistencies in the chemotherapy agents, ADC drugs, and doses used across trials. ## Limitations: What the Study Could Not Prove The authors identify several limitations and areas needing further research. High heterogeneity was present in both primary analyses: I² was 68% for overall survival and 87% for progression-free survival. Subgroup analyses reduced but did not eliminate this heterogeneity. The authors attribute the remaining heterogeneity to differences in chemotherapy agents, ADC drugs, and doses across trials. Several trials had quality concerns. Ten trials were evaluated as high risk for selection bias, and eleven trials had uncertain blinding in outcome assessment. These factors may affect the reliability of the pooled results. The authors state that further well-designed, head-to-head randomized controlled trials are needed. These trials should directly compare ADC therapy with standard chemotherapy regimens, especially within specific cancer subtypes and molecular contexts. The review also could not address several questions. The authors note that future studies should focus on identifying predictive biomarkers, such as tumor antigen expression levels and mechanisms of drug resistance. Such biomarkers would help stratify patients who are most likely to benefit from ADCs. In addition, more research is needed to evaluate the economic impact and cost-effectiveness of ADCs relative to conventional chemotherapy. ## Recommendations and Future Research Based on this review, the authors make several recommendations for future research and clinical practice: 1. Conduct further well-designed, head-to-head randomized controlled trials that directly compare ADC therapy with standard chemotherapy regimens. 1. Focus these trials on specific cancer subtypes and molecular contexts, since treatment effects varied by cancer type and drug. 1. Identify predictive biomarkers, such as tumor antigen expression levels and mechanisms of drug resistance, to better stratify patients who are most likely to benefit from ADCs. 1. Evaluate the economic impact and cost-effectiveness of ADCs relative to conventional chemotherapy, which the authors say will be crucial for guiding clinical decisions. For patients, the key message is that ADCs prolonged both overall survival and progression-free survival compared with chemotherapy in this pooled analysis of 13 trials and 5,927 patients. The overall rates of adverse events, grade 3–5 adverse events, and serious adverse events were similar between the two treatment types. Nausea, however, was significantly more common with ADCs. Patients considering ADC therapy should discuss the specific drug, the cancer type, and the expected side-effect profile with their treatment team. ## Frequently Asked Questions ### What are antibody-drug conjugates (ADCs)? ADCs are treatments that link a monoclonal antibody to a cell-killing drug. The antibody binds to specific antigens on tumor cells, which then take in the ADC and release the drug inside. This design aims to target cancer cells more precisely than conventional chemotherapy, which affects normal cells too. ### How much did ADCs improve survival compared with chemotherapy? In a pooled analysis of 13 randomized trials with 5,927 patients, ADCs improved overall survival (hazard ratio 0.67, 95% CI 0.55–0.81) and progression-free survival (hazard ratio 0.76, 95% CI 0.66–0.86) compared with chemotherapy. Both results were statistically significant, though the article notes slightly different hazard ratios in the abstract and results sections. ### What does a hazard ratio of 0.67 mean for overall survival? A hazard ratio compares the risk of death between two groups over time. A value below 1.0 favors the ADC group. A hazard ratio of 0.67 corresponds to a 33% reduction in the risk of death, which could mean extending median overall survival by several months in advanced malignancies. ### Are the side effects of ADCs worse than chemotherapy? In the pooled trials, rates of any adverse event, grade 3–5 adverse events, and serious adverse events were broadly similar between ADCs and chemotherapy. However, nausea was significantly more common with ADCs (odds ratio 2.32, 95% CI 1.46–3.70). Anemia and neutropenia showed no significant difference between groups. ### Who was included in the trials of ADCs versus chemotherapy? The 13 randomized trials included 5,927 patients with malignant tumors, all receiving second-line or third-line treatment. Cancers studied included breast, gastric, ovarian, cervical, urothelial, and malignant pleural mesothelioma. Each group had more than 10 patients, and trials compared ADC alone (with or without placebo) to chemotherapy alone. ### Did the benefit of ADCs vary by cancer type or patient age? Subgroup analyses found ADCs superior to chemotherapy across cancer types and age groups, though heterogeneity remained. For example, in breast cancer, progression-free survival improved more than overall survival. Patients aged 65 or older showed significant benefits in both overall and progression-free survival, while those under 65 had significant improvement only in progression-free survival. ### What are the limitations of this review? The review had high heterogeneity for overall survival (I²=68%) and progression-free survival (I²=87%), possibly due to differences in drugs and doses across trials. Ten trials had high risk of selection bias, and eleven had uncertain blinding. The authors call for further head-to-head trials and research into predictive biomarkers and cost-effectiveness. ### If I have an advanced malignant tumor and my doctor recommends chemotherapy, when should I seek a second opinion about whether an antibody-drug conjugate is an option? Across 13 trials and 5,927 patients, ADCs improved overall survival and progression-free survival compared with chemotherapy, with broadly similar rates of serious adverse events, though nausea was more common with ADCs. Because effects varied by cancer type and drug, a review of your pathology and prior treatments can clarify which options apply. Diagnostic Detectives Network provides independent expert second opinions. ## Source Information **Original article title:** Comparative efficacy of antibody-drug conjugates and chemotherapy for malignant tumors: a systematic review and meta-analysis. **Authors:** Gao X, Tao L, Hao W, Wu X, Zhu F, Lv S, Zhang Y. **Author affiliations:** School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China; Lanxi Hospital of Traditional Chinese Medicine, Jinhua, China; School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China **Journal:** Frontiers in Oncology, volume 15, article 1697340 **Publication details:** Received 02 September 2025; revised 19 November 2025; accepted 12 December 2025; published 09 January 2026 **DOI:** 10.3389/fonc.2025.1697340 **Systematic Review Registration:** PROSPERO, identifier CRD42024592020 (http://www.crd.york.ac.uk/PROSPERO) **Funding and access:** This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). *This patient-friendly article is based on peer-reviewed research. It restructures one published systematic review and meta-analysis for a patient audience. All figures and findings come from the original paper. Patients should discuss any treatment decisions with their own medical team.* --- Publisher: Diagnostic Detectives Network (https://diagnosticdetectives.com) — independent multi-expert medical second opinions, worldwide, private-pay. Author byline: Anton Titov, MD, PhD. Contact: https://diagnosticdetectives.com/pages/contact Canonical page: https://diagnosticdetectives.com/products/antibody-drug-conjugates-vs-chemotherapy-for-malignant-tumors-what-a-major-review-of-13-trials-found