Editor's Note: At the 2024 ESMO Conference, the Phase 1a/1b study of the novel drug GQ1005, led by Dr. Biyun Wang from Fudan University Shanghai Cancer Center, was showcased as a poster presentation, garnering significant attention. This study not only confirmed the efficacy and safety of GQ1005 in HER2-low breast cancer and HER2-positive gastric cancer but also laid a solid foundation for its future clinical applications. We invited Dr. Biyun Wang to delve into the background, study design, preliminary efficacy, and safety data of the GQ1005 Phase 1a/1b study, while also discussing its promising future in combination therapies.
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Oncology Frontier: The GQ1005 Phase 1a/1b study was presented as a poster at the ESMO conference. Could you introduce the background of this study and explain what makes GQ1005 unique in the field of anticancer drugs?
Dr. Biyun Wang: In this year’s ESMO conference, we reported the preliminary results of GQ1005 in treating advanced/metastatic HER2-low breast cancer and HER2-positive gastric cancer. GQ1005 is a novel ADC (antibody-drug conjugate) that uses a new integrative enzymatic site-specific conjugation technology to covalently attach DXd to a HER2-targeting antibody. The antibody and payload of GQ1005 are similar to those of the approved drug T-DXd (DS-8201). What sets GQ1005 apart is its proprietary enzyme-based site-specific conjugation technology, along with a stable cleavable linker, which ensures high drug stability, balancing efficacy and safety. This allows it to achieve a tumor-killing effect comparable to T-DXd in localized tumors.
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Oncology Frontier: Could you elaborate on the design of this study and how GQ1005 performed in patients with HER2-low breast cancer and HER2-positive gastric cancer?
Dr. Biyun Wang: As of May 10, 2024, 188 patients with HER2-expressing/mutated advanced/metastatic solid tumors had received at least one dose of GQ1005. This included 104 breast cancer cases, 28 gastric cancer cases, 50 non-small cell lung cancer (NSCLC) cases, 3 colorectal cancer cases, 2 bladder cancer cases, and 1 bile duct cancer case. The median drug exposure was 84 days (range: 21–466 days). We assessed the safety and efficacy in both the dose-escalation and expansion phases.
In the Phase 1a dose-escalation study, GQ1005 was administered every 3 weeks (Q3W) at doses ranging from 2 to 8.4 mg/kg. No dose-limiting toxicities (DLT) were observed during this phase.
In the Phase 1b dose-expansion study, more than half of the patients had undergone three or more lines of therapy. The enrolled patients were categorized into four cohorts based on tumor type and HER2 expression: HER2-high breast cancer, HER2-low breast cancer, HER2 exon 19/20 mutated NSCLC, and HER2-expressing (IHC 2+/3+) gastric cancer. The recommended dose for the expansion phase was 7.2 mg/kg.
At this conference, we reported the preliminary results of GQ1005 in HER2-low breast cancer and HER2-positive gastric cancer. Among the 29 evaluable HER2-low breast cancer patients, the objective response rate (ORR) was 27.6%, and the disease control rate (DCR) was 69.0%. The median progression-free survival (mPFS) was 10.4 months, with a median duration of response (mDOR) of 11.9 months. The 6-month PFS rate was 68.39%.
In the 15 evaluable HER2-positive gastric cancer patients, the ORR was 33.3%, and the DCR was 80%. The 6-month PFS rate was 70.0%. The adverse event (AE) profile was consistent across cohorts, with only one case of interstitial lung disease (ILD) in each cohort.
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Oncology Frontier: What challenges did you face during the study, and how was patient safety managed with GQ1005?
Dr. Biyun Wang: The safety profile of GQ1005 in this Phase 1 trial was quite favorable. Besides the typical interstitial lung toxicity associated with ADCs, no significant ocular or peripheral nerve toxicities, which could impact quality of life, were observed. For lung toxicity, we implemented timely monitoring and management, preventing severe consequences for the patients.
Among the patients treated with GQ1005, 33 (17.6%) experienced grade 3 or higher treatment-related toxicities. The main adverse events included gastrointestinal toxicity, hematologic toxicity, and elevated liver enzymes. No new safety signals were identified. Overall, GQ1005 demonstrated a good safety profile with relatively few adverse events.
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Oncology Frontier: What are your future research directions for GQ1005, and what do you see as its clinical potential?
Dr. Biyun Wang: Based on current data, we believe the safety and efficacy of GQ1005 are reliable. In terms of future research, I think we can take inspiration from the research path of T-DXd, which has explored combination therapies with other drugs. For example, T-DXd has been studied in combination with pertuzumab, small-molecule TKIs, and other agents in HER2-positive breast cancer patients. In the future, it may also be explored in combination with other targeted therapies, immunotherapies, or even chemotherapy.
Similarly, GQ1005 holds great potential for combination therapies in the future, which could further enhance patient outcomes.
Fudan University Shanghai Cancer Center, Department of Oncology
Director of the Breast and Urological Tumor Division, Chief Physician, Master’s Supervisor
Board Member of the Chinese Society of Clinical Oncology (CSCO)
Chair of the CSCO Youth Committee
Executive Committee Member and Secretary-General of the CSCO Patient Education Expert Committee
Member of the CSCO Breast Cancer Expert Committee
Vice Chair and Secretary-General of the Shanghai Anti-Cancer Association’s Cancer Rehabilitation and Palliative Care Committee
Standing Member of the Shanghai Anti-Cancer Association’s Breast Cancer Committee
Standing Director of the Shanghai Anti-Cancer Association’s Youth Council
