Antibody-Drug Conjugates: A Review of Clinical Efficacy and Recent Advances

Antibody-drug conjugates (ADCs) have emerged as a powerful class of targeted cancer therapies, combining the specificity of monoclonal antibodies with the potent cytotoxic activity of small molecule drugs. This article reviews the clinical efficacy and recent advances of several FDA-approved ADCs, highlighting their mechanisms of action, clinical trial results, and safety profiles.

Gemtuzumab Ozogamicin (GO) for Acute Myeloid Leukemia (AML)

Gemtuzumab ozogamicin查看药品详情 (GO), marketed by Pfizer查看公司主页, was the first ADC to receive global market approval. It consists of a humanized monoclonal antibody (mAb) targeting CD33 (搜索)搜索该靶点, linked to a cytotoxic N-acetyl-γ-calicheamicin via a cleavable hydrazone linker. GO is designed for patients with AML. The ADC binds to the CD33 antigen, forming a complex that is internalized into AML cells, leading to cell death. Initially approved in 2000 for CD33-positive AML patients over 60 ineligible for cytotoxic chemotherapy, GO was later withdrawn from the market due to safety concerns identified in the SWOG S0106 study, which revealed a higher fatal induction toxicity rate (5.5%) compared to cytarabine alone (1.4%).

However, subsequent trials, including the ALFA-0701 phase III clinical trial, reevaluated GO at a lower dose (3 mg/m²) in combination with chemotherapy. This study showed manageable safety and therapeutic efficacy, leading to its re-approval by the FDA in 2017. Additional trials like MyloFrance-1 and AML-19 further supported its safety and efficacy. The ALFA-0701 trial demonstrated that adding GO to standard chemotherapy significantly extended event-free survival (EFS) in newly diagnosed de novo AML patients. The AMLSG 09-09 trial showed a significant reduction in the cumulative relapse rate when GO was combined with chemotherapy in patients with NPM1 mutant AML. A retrospective analysis in Poland from 2008 to 2022 involving 35 children with refractory or relapsed AML treated with GO showed a 5-year overall survival (OS) of 37.1% ± 8.7%.

Brentuximab Vedotin (BV) for Hodgkin Lymphoma (HL) and Anaplastic Large Cell Lymphoma (ALCL)

Brentuximab vedotin查看药品详情 (BV), co-developed by Seagen查看公司主页 and Takeda (搜索)搜索该公司, is the second approved ADC drug. It comprises brentuximab, a chimeric IgG1 mAb targeting CD30 (搜索)搜索该靶点, linked to monomethyl auristatin E (MMAE) via a cleavable dipeptide linker. BV targets the CD30 antigen expressed in Hodgkin lymphoma (搜索)搜索该疾病 (HL) and anaplastic large cell lymphoma (搜索)搜索该疾病 (ALCL). A phase I study showed an objective response in 50% of patients with relapsed/refractory CD30-positive hematological malignancies, with a median duration of response (DOR) of at least 9.7 months. A phase II trial demonstrated effectiveness in 75% and 87% of patients with HL and ALCL, respectively.

A phase III study showed significant improvement in mycosis fungoides or primary cutaneous ALCL. In 2018, the FDA approved BV in combination with CHP (cyclophosphamide, doxorubicin, and prednisone) for treating adult patients with previously untreated systemic ALCL or other CD30 (搜索)搜索该靶点-expressing peripheral T-cell lymphomas (PTCL). A real-world study between 2020 and 2022 involving 104 patients with lymphoma receiving BV for the first time showed an objective response rate (ORR) of 64.5%, with 6-month progression-free survival (PFS) and OS rates reaching 77.2% and 90.1%, respectively. In an open-label phase I/II trial, 41 patients with HIV-related HL received BV in combination with doxorubicin, vinblastine, and dacarbazine, with all 37 patients who completed treatment achieving complete response (CR).

Trastuzumab Emtansine (T-DM1) for HER2-Positive Breast Cancer

Trastuzumab emtansine查看药品详情 (T-DM1) is an ADC formed by linking the HER2 (搜索)搜索该靶点-targeting drug trastuzumab with emtansine (DM1) via a thioether linker. Trastuzumab selectively transports DM1 into tumor cells with HER2 overexpression, releasing the drug through endocytosis. The EMILIA phase III clinical trial affirmed the clinical role of T-DM1 in HER2-positive advanced breast cancer. In patients with HER2-positive metastases or advanced breast cancer treated with trastuzumab and paclitaxel, T-DM1 demonstrated enhanced treatment efficacy, a higher safety profile, and fewer adverse effects. The TH3RESA study validated the effectiveness of T-DM1 in breast cancer patients who progressed after second-line and above treatment, showing a significantly improved median PFS and a prolonged median OS.

The KATHERINE study indicated that the T-DM1 group exhibited an improved 3-year disease-free survival (DFS) rate and a significantly reduced risk of recurrence or death in adjuvant therapy for residual invasive HER2 (搜索)搜索该靶点-positive early breast cancer. The ATEMPT trial revealed that the 3-year invasive DFS for T-DM1 reached 97.8%, with patients experiencing less neuropathy and alopecia than those treated with paclitaxel plus trastuzumab in stage I HER2-positive breast cancer. A phase I trial investigating the combination of T-DM1 and metronomic temozolomide in 12 patients with HER2-positive breast cancer and brain metastases indicated low-grade toxicity and potential activity in the secondary prevention of HER2-positive brain metastases.

Inotuzumab Ozogamicin (InO) for Acute Lymphoblastic Leukemia (ALL)

Inotuzumab ozogamicin查看药品详情 (InO) is an ADC drug created by conjugating the human IgG4 mAb targeting CD22 (搜索)搜索该靶点 with the cytotoxic chemotherapeutic drug calicheamicin. The binding of InO to CD22-expressing tumor cells initiates endocytosis of the InO-CD22 complex, leading to hydrolysis of the N-acetyl-γ-khakimycin dimethylhydrazide junction, inducing double-stranded DNA breaks, cell cycle arrest, and cell death. A phase III trial of InO in relapsed/refractory ALL showed significantly higher CR rates, lower disease burden in remission, and longer duration of remission compared to standard chemotherapy. A multicenter phase III trial indicated a higher CR or CR with incomplete hematologic recovery rate in the InO group compared to the standard-of-care (SoC) group, with a median OS of 7.7 months in the InO group and 6.2 months in the SoC group.

In a phase II trial, InO was investigated as a monotherapy in pediatric patients with relapsed/refractory ALL, revealing a 1-year EFS rate of 36.7% and an OS rate of 55.1%. A multicenter study focusing on low-dose post-transplant InO for preventing relapse in ALL reported a 1-year non-relapse mortality rate of 5.6%, a PFS of 89%, and an OS of 94%. A phase II study investigating InO for the palliation of measurable residual disease in ALL indicated a 69% response rate, leading to measurable residual disease negativity, with a 2-year relapse-free survival rate of 54% and a 2-year OS rate of 60%.

Moxetumomab Pasudotox (MP) for Hairy Cell Leukemia (HCL)

Moxetumomab pasudotox查看药品详情 (MP), developed by AstraZeneca查看公司主页, is a recombinant immunotoxin comprising moxetumomab targeting CD22 (搜索)搜索该靶点 and a 38 kDa fragment of pseudomonas exotoxin A. It is utilized for treating adult patients with relapsed/refractory hairy cell leukemia (搜索)搜索该疾病 (HCL) who have not responded to at least two systemic therapies. The FDA approval of MP relies on data from the phase III clinical study, Study 1053, which revealed that MP monotherapy achieved an ORR of 75%, a CR of 41%, and a durable CR of 30%.

Polatuzumab Vedotin (PV) for Diffuse Large B-Cell Lymphoma (DLBCL)

Polatuzumab vedotin查看药品详情 (PV), developed by Genentech查看公司主页, is an ADC composed of the antibody CD79b (搜索)搜索该靶点 linked to MMAE. It received initial approval for the treatment of adult patients with relapsed/refractory diffuse large B-cell lymphoma (搜索)搜索该疾病 (DLBCL) who have undergone at least two prior therapies in conjunction with bendamustine and rituximab (BR). The approval was based on findings from the GO29365 phase Ib/II clinical study, which demonstrated a higher CR rate in the BR with PV group compared to the BR alone group (40.0% vs. 17.5%). The phase III POLARIX study further demonstrated PV as an effective option for treating patients with relapsed/refractory DLBCL, showing that PV in combination with rituximab plus cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) significantly improved PFS compared to R-CHOP.

Enfortumab Vedotin (EV) for Urothelial Carcinoma (UC)

Enfortumab vedotin查看药品详情 (EV) is an ADC that combines a human antibody against Nectin-4 (搜索)搜索该靶点 with the cytotoxic MMAE. In the phase I dose-escalation study EV-101, results from the study involving 112 patients with mUC treated with single-agent EV showed an investigator-assessed confirmed ORR of 43%, with a DOR lasting 7.4 months. The median OS was 12.3 months, and the 1-year OS rate reached 51.8%. In a two-cohort, single-arm, phase II study (EV-201) involving 125 patients with metastatic UC, a final ORR of 44%, a CR rate of 12%, and a median DOR of 7.6 months were confirmed. The EV-301 trial further showcased the ability of EV to prolong the OS of patients compared to standard chemotherapy, with a 30% reduction in the risk of death (HR 0.70, 95% CI 0.58–0.85).

The FDA granted breakthrough therapy designation to the combination of EV with pembrolizumab (EV + P), approving it as a first-line treatment for patients with la/mUC who are not suitable for cisplatin. In a phase II trial study, cisplatin-ineligible patients received treatment with EV + P, leading to demonstrated tumor shrinkage in a majority of the patients. In another study involving patients with la/mUC ineligible for cisplatin therapy, EV + P demonstrated a high confirmed ORR and a persistent response as first-line therapy.

Trastuzumab Deruxtecan (T-DXd) for HER2-Positive Breast Cancer and Other Solid Tumors

Trastuzumab deruxtecan查看药品详情 (T-DXd) is an ADC that combines trastuzumab with an exatecan derivative (a topoisomerase I inhibitor). In an open-label phase I trial, results revealed a confirmed objective response in 66 out of 111 patients with advanced solid tumors expressing HER2 (搜索)搜索该靶点, with disease control confirmed in 104 out of 111 patients. In the phase II DESTINY-Breast01 trial, T-DXd demonstrated sustained antitumor activity in patients with HER2-positive metastatic breast cancer who had previously received ≥ 2 anti-HER2 treatments, including T-DM1. In DESTINY-Breast02, a randomized phase III trial, the median PFS was 17.8 months in the T-DXd group compared to 6.9 months in the treatment of the physician’s choice group. In the DESTINY-Breast03 phase III trial, T-DXd demonstrated a significant improvement in OS compared to T-DM1 in HER2-positive metastatic breast cancer patients.

Sacituzumab Govitecan (SG) for Triple-Negative Breast Cancer (TNBC) and Urothelial Carcinoma (UC)

Sacituzumab govitecan查看药品详情 (SG) comprises an anti-Trop-2 (搜索)搜索该靶点 antibody, a SN-38 payload, and a CL2A linker. In a single-arm trial, SG was administered to 108 patients with metastatic TNBC who had undergone at least two anticancer treatments before, revealing a median DOR of 7.7 months, PFS of 5.5 months, and OS of 13.0 months. The TROPiCS-02 study, a randomized phase III trial, evaluated the efficacy of SG in patients with pretreated, endocrine-resistant hormone receptor-positive, HER2 (搜索)搜索该靶点-negative metastatic breast cancer, showing a significantly longer median OS in the SG group (14.4 months) compared to the chemotherapy group (11.2 months). SG received FDA approval as a second-line treatment for patients with la/mUC who had previously received platinum and PD-1/PD-L1 inhibitors. In the IMMU-132-01 trial, among the 45 patients with mUC, the ORR was 31%.

Disitamab Vedotin (RC48) for Gastric Cancer (GC) and Urothelial Carcinoma (UC)

Disitamab vedotin查看药品详情 (RC48), developed by RemeGen查看公司主页, comprises a novel humanized HER2 (搜索)搜索该靶点 antibody, a histone-cleavable linker, and MMAE. In a single-arm Phase II clinical trial, which enrolled 125 patients with HER2-positive locally advanced or metastatic GC previously treated with second-line or higher regimens, the study reported an ORR of 24.8%, a PFS of 4.1 months, and an OS of 7.9 months. In a phase II clinical study (RC48-C005), 43 patients with HER2-positive la/mUC that had progressed after at least one prior systemic chemotherapy were enrolled, demonstrating an ORR of 51.2%, a DCR of 90.7%, a median PFS of 6.9 months, and an OS of 13.9 months.

Loncastuximab Tesirine (LT) for Large B-Cell Lymphoma (LBCL)

Loncastuximab tesirine查看药品详情 (LT) is an ADC with a CD19 (搜索)搜索该靶点-targeting mechanism. In a single-arm, phase II clinical trial evaluating LT monotherapy in patients with relapsed/refractory DLBCL (LOTIS-2), the ORR was 48.3%, with a median DOR of 10.3 months, a median PFS of 4.9 months, and a median OS of 9.9 months.

Tisotumab Vedotin (TV) for Cervical Cancer

Tisotumab vedotin查看药品详情 (TV) contains a fully human mAb targeting TF that is conjugated with MMAE. InnovaTV 204 was a multicenter, single-arm, phase II study in which a total of 101 patients with r/mCC received at least one intravenous injection of TV. The results showed an ORR of 24%, a DCR of 72%, and a median OS of 12.1 months.

Mirvetuximab Soravtansin (MIRV) for Ovarian Cancer

Mirvetuximab soravtansin (搜索)搜索该药品 (MIRV) employs a FRα-targeted antibody linked to a microtubule inhibitor. In a phase I expansion clinical trial, 46 patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer and positive FRα expression were administered MIRV once every 3 weeks at a dose of 6.0 mg/kg. Results revealed a confirmed ORR of 26%, a median PFS of 4.8 months, and a median DOR of 19.1 weeks. In a global, open-label, controlled trial, the MIRV group exhibited a median PFS of 5.62 months compared to 3.98 months in the chemotherapy group. The ORR in the MIRV group was significantly higher (42.3% vs. 15.9%), and the median OS in the MIRV group was 16.46 months, while in the chemotherapy group, it was 12.75 months.