Ecaterina Ileana Dumbrava, MD is anAssistant Professor, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.

Dr Dumbrava on Targeting TP53 Y220C Mutations in Solid Tumors With Rezatapopt

"I believe that TP53 is becoming actionable will follow the steps of KRAS and other mutations that were previously considered to be [undruggable]."

Ecaterina Dumbrava, MD, an assistant professor in the Department of Investigational Cancer Therapeutics of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed early findings from the phase 1 PYNNACLE trial (NCT04585750) investigating rezatapopt (PC14586) in patients with solid tumors harboring 

Rezatapopt is a small-molecule reactivator of mutant 

 designed to restore normal p53 function, specifically in tumors with the Y220C substitution—a conformational hotspot mutation associated with p53 protein destabilization and loss of tumor suppressor activity. The PYNNACLE trial enrolled patients with advanced solid tumors harboring this alteration, assessing the agent’s safety, pharmacodynamics, and preliminary efficacy.

In early-phase results, rezatapopt demonstrated encouraging antitumor activity, generating an overall response rate exceeding 40% among patients with 

 Y220C–mutated tumors who did not have co-occurring 

 Y220C may represent a clinically actionable genomic alteration when targeted with mutation-specific agents. Responses were observed across multiple tumor types, reinforcing the potential for a histology-agnostic therapeutic approach.

Dumbrava emphasized the importance of increasing clinical awareness regarding the 

 Y220C mutation, which she said has historically been under-recognized in oncology practice. Despite its relative rarity, the presence of this mutation may guide therapeutic decision-making as targeted options such as rezatapopt become more widely studied and potentially integrated into treatment pathways.

She further noted that the development of rezatapopt parallels the evolution of other targeted therapies, such as those directed against 

 G12C mutations, underscoring a broader shift toward drug development strategies aimed at historically “undruggable” tumor suppressor mutations. As molecular profiling becomes more comprehensive and routinely implemented in clinical care, identifying patients with 

 Y220C mutations may enable enrollment into precision oncology trials and support individualized treatment strategies.

Videos

Ecaterina Dumbrava, MD, discusses early findings of rezatapopt in patients with solid tumors harboring TP53 Y220C mutations.

Ecaterina E Dumbrava, M.D.

"All patients with ovarian cancer have a 

 mutation, so developing drugs that are able to restore the normal TP53 wild type function is essential."

Ecaterina Dumbrava, MD, an associate professor in the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center, discussed the rationale and clinical development of rezatapopt (PC14586), a selective small molecule p53 reactivator being evaluated in the phase 2 PYNNACLE trial (NCT04585750) for patients with ovarian cancer and other solid tumors harboring 

Dumbrava explained that most patients with high-grade serous ovarian cancer harbor 

 mutations; however, effective therapies that restore wild-type p53 function remain lacking. The Y220C variant represents a structurally defined subset of 

 mutations amenable to pharmacologic reactivation, and rezatapopt was designed to bind and stabilize the mutant p53 protein, thereby restoring its native conformation and reactivating tumor-suppressive functions.

The PYNNACLE trial, which builds upon preliminary findings from the phase 1 study of rezatapopt, is enrolling patients with locally advanced or metastatic solid tumors carrying the 

 Y220C mutation, including those with ovarian and endometrial cancers where mutation prevalence is relatively higher. Dumbrava noted that early results from the phase 1 trial supported the biologic activity and tolerability of rezatapopt, prompting further evaluation in a larger, genomically defined cohort.

Patients enrolled in PYNNACLE must have confirmed 

 Y220C-mutant tumors and meet eligibility criteria including adequate organ function and ECOG performance status. The study’s primary end point is objective response rate, with secondary end points including progression-free survival, duration of response, overall survival, and safety profile. The goal is to validate the role of selective p53 reactivation as a targeted therapeutic approach in tumors previously deemed undruggable due to the complexity of p53 inactivation.

 Y220C mutation represents a narrow molecular subset, the approach has broader implications for precision oncology and drug development strategies targeting tumor suppressor gene mutations. The trial’s focus on biomarker-driven patient selection, coupled with a mechanism-based therapeutic approach, reflects a paradigm shift toward individualized treatment strategies in oncology.

If successful, the findings from PYNNACLE could support the clinical utility of rezatapopt and encourage further efforts to expand targeted treatment options for patients with 

Ecaterina Dumbrava, MD, discusses the rationale and clinical development of rezatapopt in ovarian cancer and other solid tumors harboring TP53 Y220C mutations.

Dr Dumbrava on the Rationale for Evaluating Rezatapopt in TP53 Y220C–Mutated Ovarian Cancer

Ecaterina Ileana Dumbrava, MD, an assistant professor in the Department of Investigational Cancer Therapeutics, of the Division of Cancer Medicine, at the University of Texas MD Anderson Cancer Center, discusses the mechanism of action of BDC-1001 in advanced HER2-expressing breast cancer.

BDC-1001, a HER2-targeting TLR7/8 immune-stimulating antibody conjugate (ISAC), is currently being examined in an ongoing phase 1 study, according to Dumbrava. The agent consists of an investigational biosimilar of the humanized monoclonal antibody trastuzumab (Herceptin), which is conjugated to a TLR7/8 agonist with a noncleavable linker that is given systemically, Dumbrava explains.

ISACs, such as BDC-1001, can elicit new immune responses in patients by activating human myeloid antigen–presenting cells while retaining antibody-mediated functions, such as antibody-dependent cellular cytotoxicity and phagocytosis, adds Dumbrava.

Although several treatment advances have been made for patients with HER2-expressing breast cancer, improved targeted approaches are needed to further improve patient outcomes, Dumbrava concludes.

Ecaterina Ileana Dumbrava, MD, discusses the mechanism of action of BDC-1001 in advanced HER2-expressing breast cancer.

Ecaterina Ileana Dumbrava, MD

Articles

Dr Dumbrava on Targeting TP53 Y220C Mutations in Solid Tumors With Rezatapopt

Dr Dumbrava on the Rationale for Evaluating Rezatapopt in TP53 Y220C–Mutated Ovarian Cancer

Dr. Dumbrava on the Mechanism of Action of BDC-1001 in Advanced HER2-Expressing Breast Cancer