Abstract CT097: A Phase 1, first-in-human study of the SMARCA2 degrader, PLX-61639, in patients with SMARCA4-mutated, locally advanced or metastatic solid tumors

Cancer Research · 2026-04-17

Abstract Background: SMARCA 4 and SMARCA2 are redundant components of the BAF nucleosome remodeling complex, at least one of which is essential for cell survival. Mutations in the gene encoding SMARCA4, occur in approximately 10 - 15% of epithelial solid tumors, including 10% of NSCLC where they are associated with poor prognosis. Mutations that eliminate SMARCA4 protein or cause Loss of Function (LoF) create a dependency on SMARCA2 for tumor cell survival. PLX-61639 is an oral, monovalent, selective direct degrader of SMARCA2 that has shown anti-tumor activity in SMARCA4-deficient tumor xenografts while sparing SMARCA4 expressing normal tissues. The purpose of this First-in-Humans Phase 1 trial (NCT07284186) is to evaluate the safety and PK of PLX-61639, to define the maximum tolerated or maximum administered dose and recommended expansion dose and to make a preliminary assessment of its anti-tumor activity in patients with relapsed or refractory, SMARCA4-deficient solid tumors. Methods: This is a multi-center, open-label dose escalation study of PLX-61639 conducted in 3 parts: Part 1 Dose Escalation, Part 2 Dose Optimization and Part 3 Expansion. Up to 155 patients will be enrolled across all 3 parts. Eligible patients must have SMARCA4 LoF mutations based on existing genomic profiling or negative IHC staining for SMARCA4 and have failed to respond or have relapsed after standard of care regimens. Patients are required to have adequate liver, bone marrow, coagulation, renal, and cardiopulmonary function, ECOG PS 0 or 1 and measurable disease by RECIST 1.1. Patients with germline SMARCA4 deficiency or tumors with loss of SMARCA2 and SMARCA4 are excluded. Enrolled patients will receive PLX-61639 orally, once daily in 28-day cycles at their assigned dose level until disease progression or unacceptable toxicity. A minimum of 3 patients will be evaluated for Dose-Limiting Toxicity in the first 28-day cycle and the decision to escalate to the next higher dose level, de-escalate or expand at the current dose level will be made by the Safety Review Committee (SRC) using a Bayesian Optimal Interval algorithm. Dose levels that have been deemed tolerated by the SRC will be open for backfill enrollment for patients with NSCLC. Upon completion of Part 1, Part 2 will enroll patients with SMARCA4-deficient NSCLC and randomize patients to one of two dose levels to determine the Recommended Expansion Dose (RED). Part 3 of the trial will comprise an expansion cohort of up to 25 patients with SMARCA4-deficient solid tumors treated at the RED. Key endpoints include the incidence and severity of AEs, including DLTs and anti-tumor activity as measured by RECIST 1.1, volumetric analysis of scans and changes in circulating tumor DNA. This study (NCT7284186) opened for enrollment in December, 2025 and is continuing to enroll. Citation Format: Jorge F. DiMartino, Alexander Spira, Anjali Rohatgi, Muhammad R. Khawaja, Laura Alder, Ibaiyi Dagogo-Jack, Miguel A. Villalona, Drew Rasco, Adam Rock, Afshin Dowlati, Robin Guo. A Phase 1, first-in-human study of the SMARCA2 degrader, PLX-61639, in patients with SMARCA4-mutated, locally advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT097.

Erratum: Prevalence and Clinical Characteristics of Germline Epidermal Growth Factor Receptor Mutations in the Southeastern United States

JCO Precision Oncology · 2026-03-01

CRE26-055: A Novel Case of Immune Checkpoint Inhibitor-Mediated DAT-Negative Autoimmune Hemolytic Anemia

Journal of the National Comprehensive Cancer Network · 2026-03-27 · 1 citations

434P Myeloprotection with trilaciclib prior to first-line chemotherapy in extensive-stage small cell lung cancer: An integrated analysis of clinical trials

ESMO Open · 2026-03-17

Conclusions: Baseline immune and transcriptomic features are linked with durable clinical benefit in ES-SCLC pts treated with chemo-IT and may guide personalized ITbased treatment.

Prevalence and Clinical Characteristics of Germline Epidermal Growth Factor Receptor Mutations in the Southeastern United States

JCO Precision Oncology · 2026-01-01

PURPOSE Up to 1% of patients with non–small cell lung cancer harbor germline epidermal growth factor receptor ( EGFR ) mutations, although they remain poorly described in unselected, noncancer populations. We sought to characterize the prevalence of germline EGFR mutations in Southeastern United States. METHODS We assessed the prevalence of EGFR mutations in unselected cohorts of individuals enrolled in the Duke CATHeterization GENetics, gnomAD, UK Biobank, and All of Us studies. We additionally performed comprehensive chart review for patients evaluated at the Duke Cancer Institute with germline EGFR mutations. RESULTS We found the prevalence of germline EGFR T790M to be >1 in 3,000 individuals in the Duke catchment area. This prevalence was 7.5 times greater than the national All of Us cohort, 3.7 times greater than the international gnomAD cohort, and 55.8 times greater than the UK Biobank cohort. The Southeastern region also contained the highest proportion of T790M carriers in the All of Us cohort. Twenty-eight individuals with suspected germline EGFR mutations were identified in our institutional cohort. The majority of these patients did not have a history of smoking, had multiple lung nodules at the time of diagnosis, and had a family history of cancer. Forty-five percent of patients had a diagnosis of a second primary malignancy. CONCLUSION Our analysis represents the largest study to date assessing the prevalence of germline EGFR mutations from both patients with lung cancer and unselected cohorts of individuals and presents evidence for increased prevalence of EGFR T790M mutations within the Southeastern United States. Given the high prevalence and documented hereditary risk of germline EGFR mutations, future studies investigating the role of familial testing and screening in these individuals is warranted.

Broadening clinical trial inclusivity of patients with lung cancer and brain metastases utilizing the Graded Prognostic Assessment (GPA): A call to action

Lung Cancer · 2026-02-10

Quantitative HER2 tissue and plasma profiling predicts the activity of trastuzumab deruxtecan for breast cancer

npj Precision Oncology · 2026-03-13

Trastuzumab deruxtecan (T-DXd) is commonly used for treating metastatic breast cancer (MBC); however, traditional HER2 immunohistochemistry has largely failed to predict T-DXd activity. We reviewed survival outcomes and tested the reliability of multiple HER2 quantitative assays in predicting T-DXd's performance among 191 patients with MBC. We demonstrate that T-DXd's activity varies depending on the temporal evolution of HER2 immunohistochemical expression, with the longest activity observed among patients with HER2-positive disease or maintaining HER2-low disease across primary and metastatic settings. Quantitative HER2 assessment on pre-T-DXd samples showed that time-to-next treatment progressively increased by High Sensitivity-HER2 quartiles, Reverse Phase Protein Array HER2 quartiles, HER2DX ERBB2 mRNA scores and plasma-based DNADX HER2 signature tertiles (all with log-rank p < 0.05). Conversely, HER2 immunohistochemical subtypes showed limited predictive value for clinical outcomes. Additionally, elevated TOPO1 expression was associated with worse outcomes with T-DXd in HER2-negative breast cancer, suggesting potential relevance for payload-related markers in predicting T-DXd performance.

Neoadjuvant, Perioperative, and Adjuvant Immunotherapy in Early-Stage Surgically Resectable Non-Small Cell Lung Cancer: Updates and Future Perspectives.

Preprints.org · 2025-05-05

Historically, systemic therapy for resectable non-small cell lung cancer (NSCLC) has been associated with modest impact in overall survival. Current treatment options for early-stage resectable NSCLC include use of neoadjuvant, adjuvant, and perioperative immunotherapy in combination with chemotherapy. In this review, we will explore current treatment paradigms and emerging opportunities for improved survival outcomes in using immunotherapeutic approaches in the treatment of early-stage resectable NSCLC.

Given TKIs With High CNS Penetrance, Systemic Therapy Should Be Administered Before Radiation Therapy for CNS Metastases

Journal of Thoracic Oncology · 2025-12-01

Management outcomes for biopsy-proven radiation necrosis in patients with brain metastases in the era of immune-checkpoint blockade

Journal of Neuro-Oncology · 2025-06-16