Two Novel Tumor-Agnostic Trials Target HER2-Positive Cancers and p53 Mutations at ESMO 2024
核心洞察
Dr. Vivek Subbiah presented two groundbreaking tumor-agnostic trials at ESMO 2024, representing different approaches to biomarker-driven cancer treatment beyond traditional anatomical classifications.
The DiscovHER PAN-206 trial evaluates zanidatamab in HER2 (搜索)-positive solid tumors across three cohorts, including breast cancer patients who progressed after trastuzumab deruxtecan treatment.
The first-in-human GUARDIAN-101 trial tests CLSP-1025, a novel T-cell engager targeting the previously "undruggable" p53 R175H mutation using innovative diabody technology.
Dr. Vivek Subbiah, Chief of Early-Phase Drug Development at Sarah Cannon Research Institute (搜索), presented two pivotal tumor-agnostic therapy trials at the European Society for Medical Oncology (ESMO) conference, showcasing the evolution of precision cancer medicine beyond traditional anatomical classifications. These trials represent different facets of biomarker-driven treatment strategies that could transform how oncologists approach cancer care across multiple tumor types.
Expanding HER2-Targeted Therapy Beyond Biliary Cancer
The DiscovHER PAN-206 trial (NCT06695845) explores new applications for zanidatamab (Ziihera), a dual HER2 (搜索)-targeted bispecific antibody already approved by both the FDA and European Medicines Agency for HER2-positive biliary tract cancer. This Phase 2 trial addresses a critical unmet need for patients experiencing toxicities from current HER2-targeted therapies.
"Today, we have an antibody drug conjugate approved for all HER2 (搜索)-positive cancers that are IHC3+ immunohistochemistry," Subbiah explained, referring to trastuzumab deruxtecan (Enhertu). "But one of the main challenges of an antibody drug conjugate that we are seeing are toxicities, chronic toxicities, and also pneumonitis and interstitial lung disease. And so, we are looking for other options for patients who have lung disease, and better tolerated options."
The trial evaluates three distinct cohorts of patients with previously treated HER2 (搜索)+/IHC3+ tumors. Cohort 1 enrolls patients with locally advanced, unresectable, or metastatic solid tumors excluding biliary tract cancer, with no prior HER2-targeting therapy permitted. Cohort 2 focuses on breast cancer patients who have progressed after trastuzumab deruxtecan treatment, representing what Subbiah calls "an unmet need." Cohort 3 applies similar criteria to patients with gastroesophageal adenocarcinoma.
Zanidatamab's unique mechanism involves binding to two distinct sites on HER2 (搜索), promoting receptor crosslinking and driving multiple antitumor mechanisms. This approach leads to degradation of HER2 cell surface expression, limits HER2 signaling pathways, and produces immune-mediating effects through a single therapy.
Targeting the "Undruggable" p53 Mutation
The first-in-human GUARDIAN-101 trial (NCT06778863) represents a more revolutionary approach, testing CLSP-1025, developed by Clasp Therapeutics (搜索). This therapy targets the R175H mutation in p53, the most common p53 mutation found across various solid tumors, which has long been considered "undruggable."
"Making p53 targetable and actionable would be a huge milestone in cancer treatment, on part with the groundbreaking ability to finally target KRAS," Subbiah noted. "It was considered as one of the undruggable genes. Now we drug KRAS."
CLSP-1025 uses diabody technology to create a T-cell engager that selectively binds HLA-presented peptides only to oncogenic driver mutations. The therapy requires patients to have both the R175H mutation and the HLA-A*02:01 antigen, but Subbiah indicated this will still encompass sizable numbers across many common cancers.
The diabody technology functions similarly to bispecific antibodies but is engineered "for absolute tumor specificity and immune synapse mimicry." On one side, the therapy binds perfectly with p53 R175H and the peptide HLA complex on tumor cells, while on the other side, it binds with CD3 (搜索) on T cells, "resulting in a potent, selective T-cell–mediated tumor killing." Preclinical studies have been described as "exceptional."
Addressing Molecular Inequity in Cancer Care
These trials exemplify Subbiah's broader vision for eliminating "molecular inequity" in cancer treatment. He argues that the traditional approach of studying one tumor type at a time fails to serve patients with rare cancers who harbor actionable biomarkers.
"I personally believe that every drug that is a precision medicine, a drug that is a biomarker-targeted drug should be developed across multiple tumor types," Subbiah stated. "Why? Because if we don't develop drugs based in a biomarker fashion, in all cancers, patients with rare cancers may not have access to drugs."
He illustrated this point with ALK (搜索) fusions: "We have 6 drugs approved in non–small cell lung cancer that are ALK-fusion positive. But think about that patient with ovarian cancer or a patient with prostate cancer who has an ALK fusion—they don't have a drug approved in the real world; unless a drug is FDA approved, you may not have access to the drugs."
The Future of Tumor-Agnostic Medicine
The concept builds on the FDA's first tumor-agnostic approval in May 2017 for pembrolizumab (Keytruda) in patients with microsatellite-instability–high (MSI-H) or mismatch-repair–deficient (dMMR) solid tumors. Today, there are 10 such approvals, but Subbiah believes this number will expand dramatically.
"Cancer is a genomically driven disease, and tumor-agnostic therapies and tumor-agnostic treatment is a different way we think about drug development and cancers," he explained. The approach "transcends the anatomical location" because "this makes more sense" given cancer's genomic nature.
Better biomarkers and artificial intelligence are accelerating this shift, making trials faster and more cost-effective. As Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Center, noted during ESMO's opening press conference: "We want to stop really treating, let's say, lung cancer, per se, per organ. And when I go back to the biology, I personally believe we are ready. It's there."
Subbiah predicts dozens more tumor-agnostic therapies could receive approval over the next 25 years, fundamentally changing how oncologists approach precision medicine and ensuring equitable access to life-saving treatments across all cancer types.