Innovative Antibody-Drug Conjugates Show Efficacy Across Advanced Solid Tumors at AACR 2026

The American Association for Cancer Research Annual Meeting 2026 (AACR 2026) in San Diego showcased clinical advancements in the development of antibody-drug conjugates (ADCs). By linking cytotoxic small molecule drugs to monoclonal antibodies, ADCs deliver targeted therapies directly to cancer cells, thereby minimizing systemic toxicity and maximizing therapeutic efficacy. A dedicated clinical trials plenary session highlighted four early-phase studies evaluating innovative ADC monotherapies and synergistic combinations.

The presentations revealed clinical data across various treatment-refractory malignancies, including HER2-expressing solid tumors, advanced nasopharyngeal carcinoma (NPC), platinum-resistant ovarian cancer, and non-squamous non-small cell lung cancer (NSCLC). These investigational agents leverage novel targets and strategic drug combinations to overcome the limitations of standard therapies, offering new treatment avenues for patients facing aggressive and advanced-stage cancers.

Enhancing Tolerability with Trastuzumab Deruxtecan and Olaparib 

Pre-clinical studies show that using poly-ADP ribose polymerase (PARP) inhibitors alongside topoisomerase 1 (Top1) inhibitors works synergistically. Top1 inhibitor creates and stabilizes single-strand DNA breaks during the process of DNA replication, while PARP inhibitor blocks cancer cells from repairing that damage. This combination leads to a highly effective attack on tumors. However, overlapping toxicity to healthy and fast-growing cells, particularly in the bone marrow and digestive system, has long limited the use of this combination.

To solve this tolerability issue, researchers initiated the CTEP 10355 phase 1 trial to test whether delivering the Top1 inhibitor via an ADC could improve tolerability. During AACR 2026, Elizabeth K. Lee from the Dana-Farber Cancer Institute, who is principal investigator of the study, presented the dose-escalation results evaluating the combination of the HER2-targeting ADC trastuzumab deruxtecan (T-DXd), which delivers a Top1 inhibitor directly into tumor cells, and olaparib, an oral targeted PARP inhibitor.

Optimizing Intermittent Dosing for Maximum Efficacy

The trial enrolled 28 participants with HER2-expressing advanced and recurrent solid tumors, including ovarian and uterine cancers. The research team divided patients into three groups to evaluate continuous versus intermittent olaparib dosing schedules alongside standard intervals of T-DXd. Patients in the continuous dosing group (Module 1) and one of the intermittent groups (Module 3) experienced dose-limiting toxicities related to low blood counts, prompting investigators to halt enrollment in those cohorts.

Conversely, Module 2, which administered intermittent olaparib on days 8 through 14 of the treatment cycle, proved highly tolerable by demonstrating reduced hematologic toxicities. For example, patients in Module 2 experienced a 12% rate of grade 3 neutropenia compared to 30% in Module 1. Efficacy data demonstrated clinical activity across all tumor types and HER2 expression levels. The combination therapy achieved a confirmed objective response rate of 46%, including one complete response and 12 partial responses. Moreover, 19 patients were alive and progression-free at six months, and the median progression-free survival was 15.2 months. Based on these results, researchers selected the Module 2 treatment schedule for further evaluation in an ongoing dose expansion study.

A Novel EGFR-Targeted Approach for Nasopharyngeal Carcinoma

Patients with advanced nasopharyngeal carcinoma (NPC) face limited therapeutic options after their disease progresses on standard platinum-based chemotherapy and PD-1 checkpoint inhibitors. To address this need, researchers are evaluating SYS6010, an investigational ADC which consists of a humanized anti-EGFR monoclonal antibody linked to a Top1 inhibitor payload. It was originally designed to treat various advanced EGFR-expressing solid tumors, including NSCLC, breast cancer, head and neck cancer, and colorectal cancer. Following its debut at AACR 2025, the drug returned this year with updated disease-specific data. Haiqiang Mai from the Sun Yat-sen University Cancer Center presented early findings from a phase 1 expansion cohort focusing specifically on the NPC patient population.

The trial enrolled patients to receive intravenous (IV) infusions of SYS6010 at either 4.2 mg/kg or 4.8 mg/kg every three weeks until disease progression or unacceptable toxicity. The drug demonstrated a manageable safety profile, supporting its continued clinical development.

Among the 54 patients evaluable for efficacy, the targeted therapy achieved an objective response rate of 31.5%, which included one complete response in the 4.2 mg/kg dose cohort. The overall disease control rate reached 87%, and patients attained a median progression-free survival of 7.5 months. 

The clinical benefit proved even more pronounced among a specific subset of patients who had never received prior EGFR-targeting monoclonal antibodies. In this subgroup, the objective response rate climbed to 42.9% for the 4.2 mg/kg dose group and 50% for the 4.8 mg/kg dose group. Interestingly, the researchers observed that both the objective response rate and the median progression-free survival did not differ significantly between patients with high versus low EGFR expression levels. These preliminary results validate SYS6010 as a therapeutic intervention for advanced NPC.

Targeting CLDN6 in Platinum-Resistant Ovarian Cancer

Patients diagnosed with platinum-resistant ovarian cancer face both a poor prognosis and limited treatment options. To address this challenge, Tao Zhu from the Zhejiang Cancer Hospital presented data on QLS5132, an investigational claudin 6 (CLDN6)-targeting ADC using Top1 as the cytotoxic payload at a drug-to-antibody ratio of 8. According to Zhu, CLDN6 is an ideal therapeutic target for ovarian cancer because cancer cells express this protein at high levels while healthy tissues exhibit minimal cell-surface expression.

The first-in-human phase 1 dose-escalation trial enrolled 28 patients who had been diagnosed with advanced platinum-resistant ovarian cancer and who had experienced progression while on standard therapy. The research team administered QLS5132 by IV infusion every three weeks at dose levels of 1.6 mg/kg, 3.2 mg/kg, 4.8 mg/kg, 5.6 mg/kg, and 6.4 mg/kg. Even though mild treatment-related adverse events such as nausea, anorexia, and weakness occurred in most patients, none of them experienced severe conditions including interstitial lung disease, ocular toxicity, or febrile neutropenia. Additionally, no adverse events led to treatment discontinuation or death.

The clinical efficacy data also proved encouraging. Across all dose levels, 18 evaluable patients experienced an objective response rate of 50% and a disease control rate of 94.4%. When calculated for the 17 patients who had received dose levels of 3.2 mg/kg or higher, the objective response rate and disease control rate rose to 52.9% and 100%, respectively. These responses to QLS5132 occurred regardless of patients’ CLDN6 expression levels at baseline. Zhu suggested this broad clinical activity might result from tumor heterogeneity and a bystander effect resulting in antitumor efficacy even in cells with low or no CLDN6 expression.

Combining ADCs with Immunotherapy for Non-Squamous NSCLC

Patients with advanced non-squamous NSCLC lacking actionable genomic alterations face a difficult treatment landscape once their tumors develop resistance against frontline interventions. During the plenary session, Runbo Zhong from the Shanghai Chest Hospital shared results from the open-label, phase 1 ARTEMIS-101 clinical trial. This multi-center study evaluated the combination of risvutatug rezetecan and adebrelimab in this specific patient population. Risvutatug rezetecan is an investigational ADC that targets the B7-H3 immune checkpoint protein and delivers a cytotoxic Top1 inhibitor. Adebrelimab serves as a fully human anti-PD-L1 monoclonal antibody.

The research team presented data from a subgroup of 40 previously treated patients. These individuals received IV infusions of risvutatug rezetecan alongside adebrelimab every three weeks. The combination therapy maintained a manageable safety profile. While all patients experienced at least one treatment-emergent adverse event, these were primarily hematological toxicities such as decreased white blood cell and neutrophil counts. The researchers observed no adverse events resulting in death.

Among the 34 patients evaluable for efficacy, the combination regimen demonstrated synergistic anti-tumor activity. The treatment showed a confirmed objective response rate of 47.1% and a disease control rate of 94.1%. Also, patients achieved a median progression-free survival of 14.0 months. The clinical responses occurred across various baseline levels of tumor PD-L1 expression. For patients with a tumor proportion score below 1% (meaning less than 1% of the viable tumor cells in a sample expressing the PD-L1 protein), the objective response rate reached 33.3%, while those with a score of 1% or higher achieved an objective response rate of 62.5%. Based on these efficacy signals, developers have initiated a phase 3 study in China to further evaluate this combination therapy for advanced non-squamous NSCLC.

The Future of Targeted Oncology

The early-phase clinical data presented at AACR 2026 underscore the clinical utility of next-generation antibody-drug conjugates. By precisely guiding cytotoxic agents directly into the tumor microenvironment, these investigational therapeutics bypass the historical limitations of traditional systemic chemotherapy. The studies presented this year validate the efficacy of targeting novel tumor-specific cell-surface proteins such as CLDN6 and B7-H3, expanding the therapeutic landscape beyond established markers.

Furthermore, the successful integration of ADCs with immune checkpoint inhibitors and PARP inhibitors highlights a future for combination oncology. These strategic regimens not only amplify anti-tumor activity but also successfully manage overlapping toxicities. As these therapies advance into larger, randomized clinical trials, they pave the way for more durable and personalized treatment options for patients battling refractory solid tumors.

Author

Richard Chau