Abstract A053: Specific cancer cell and immune features mediate atezolizumab-regimen clinical benefit in anaplastic thyroid cancer (ATC) independent of BRAF or RAS oncogenic status
Jul 2026· Cancer Research· Vol 86, pp. A053-A053· 0 citations
TL;DR
Specific differentiation and immune activation features are associated with longer OS, whereas mesenchymal, hypoxic, and proliferative programs are associated with shorter OS, whereas mesenchymal, hypoxic, and proliferative programs are associated with shorter OS.
Abstract
Anaplastic thyroid cancer (ATC) is a rare, highly aggressive malignancy, responsible for a disproportionate share of thyroid cancer–related mortality and with limited therapeutic options. We reported results from a phase II trial (NCT03181100) in which ATC pts received atezolizumab plus targeted therapy: BRAF V600E (vemurafenib + cobimetinib) or RAS/NF mutant (cobimetinib). mOS was longer in the BRAF V600E cohort (43 months, 95% CI 16-NE) than the RAS/NF mutant cohort (8.7 months, 95% CI 5.1-37.0), but outcomes overlapped; pts with BRAF V600E had OS as short as 81 days, while pts with RAS/NF mutations had OS up to 1702 days. We sought to identify pre-treatment molecular features associated with OS, independent of oncogene status.
Clinical NGS was performed on all tumors; whole-exome and transcriptome sequencing were available for pretreatment samples (n=14,16). Germline/somatic mutations, copy number alterations, and structural variants were assessed. Differential gene expression (DGE), gene set enrichment, and predefined gene profiles were analyzed. Patients were stratified by OS (>2-year vs <2-year).
Among <2-year OS pts (n=9), 6 were RAS-mutant and 3 BRAF V600E; among >2-year OS pts (n=7), 5 were BRAF V600E and 2 RAS-mutant. Three pts were still alive (3.4–4.3 yrs), 2 BRAF V600E and 1 RAS-mutant. No co-mutations were associated with OS. DGE (≥3-fold) between short (<2-year) and long (>2-year) OS pt tumors showed longer OS tumors to express epithelial/differentiation (e.g., PAX8) and immune activation programs, including antigen presentation (MHC-II) and inflammatory signaling, whereas shorter OS pt tumors were enriched for epithelial-to-mesenchymal transition, hypoxia and oncofetal markers, independent of mutation status. DGE of BRAF V600E-only tumors showed longer OS to be associated with immune and antigen presentation signatures with retained differentiation markers, whereas shorter OS corresponded with increased receptor tyrosine kinase signaling and extracellular matrix remodeling genes. DGE in RAS-mutant-only tumors showed shorter OS to be associated with increased proliferative, angiogenic, and mesenchymal/stromal gene profiles. Longer OS corresponded with higher epithelial/differentiation marker and metabolic/secretory programs. In addition, MAPK/ERK activity was associated with improved OS in BRAF V600E pts, but reduced OS in pts with RAS mutations, consistent with differences in targeted therapy.
Survival in ATC is associated with baseline transcriptional programs rather than driver mutation status alone. Specific differentiation and immune activation features are associated with longer OS, whereas mesenchymal, hypoxic, and proliferative programs are associated with shorter OS. These associations differ by cohort, supporting integrated molecular stratification beyond oncogene status to inform prognosis and therapeutic strategies in ATC.
Brian A. McKinley, Haifeng Zhu, Rare Tumor Initiative Team, Ramona Dadu, Jennifer R. Wang, Naifa L. Busaidy, Sabitha Prabhakaran, P Andrew. Futreal, Maria E. Cabanillas, Scott E. Woodman. Specific cancer cell and immune features mediate atezolizumab-regimen clinical benefit in anaplastic thyroid cancer (ATC) independent of BRAF or RAS oncogenic status [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Breaking Barriers in the Fight against Rare Cancers; 2026 Jul 18-20; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(14_Suppl):Abstract nr A053.
Background Anti-epidermal growth factor receptor (EGFR) therapy is a therapeutic option in patients with molecularly selected metastatic colorectal cancer (mCRC). However, the identification of predictive factors represents an unmet need. Patients and methods We conducted a pooled analysis of individual patient data from the CAVE-GOIM (NCT04561336) and CAVE-2 GOIM (NCT05291156) studies to investigate the impact of several clinical variables on rechallenge with cetuximab with and without avelumab in circulating tumor DNA RAS/BRAF/EGFR-extracellular domain wild-type mCRC. Results Overall, 180 patients met the eligibility criteria: 136 received cetuximab–avelumab and 44 cetuximab. In patients receiving cetuximab monotherapy, median progression-free survival (mPFS) was 4.80 months [95% confidence interval (CI) 3.90-5.90] and median overall survival (mOS) 12.9 months (95% CI 11.1-not evaluable). Cetuximab activity was retained regardless of clinical factors. Patients treated with cetuximab–avelumab showed an mPFS of 5.00 months (95% CI 4.30-5.90) and mOS of 15.7 months (95% CI 13.0-19.9). In univariable analysis, a shorter progression-free survival was observed in patients with liver involvement [hazard ratio (HR) 2.19, 95% CI 1.51-3.20, P < 0.001] and anti-EGFR-free interval ≤16 months (HR 1.62, 95% CI 1.13-2.31, P < 0.008). Both variables retained statistical significance in multivariable analysis. In univariable analysis, lower overall survival was observed among patients treated with cetuximab–avelumab with >3 metastatic sites (HR 1.79, 95% CI 1.16-2.77, P < 0.009) and liver (HR 1.82, 95% CI 1.15-2.88, P < 0.011) and peritoneal metastases (HR 1.9, 95% CI 1.23-2.93, P < 0.004). In multivariable analysis, only liver and peritoneal metastases maintained statistical significance. Conclusions Single-agent cetuximab activity is not influenced by clinical factors. In cetuximab–avelumab therapy, the absence of liver metastases and longer anti-EGFR-free interval might represent potential biomarkers.
D. Ciardiello, G. Martini, F. Pietrantonio et al.· ESMO gastrointestinal oncolo...· 0 citations
Purpose: Mutations in BRAF at codons other than V600 (non-V600) and BRAF fusions confer dependence on RAF-MEK-ERK pathway. Subprotocol Z1L (EAY131-Z1L) investigated the clinical activity of ulixertinib (ERK1/2 inhibitor) in patients with tumors harboring these alterations. Patients and Methods: In this single-arm study, patients with BRAF non-V600 mutation or BRAF fusion were given ulixertinib orally, at a dose of 600 mg twice daily, continuously for each 28-day cycle until progression or intolerability. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), 6-month PFS, and overall survival (OS). Results: Among 34 eligible patients, median age was 66.5; 50% were female, 88% were white, 9% black, 3% Asian. ECOG PS 1 in 74% of patients. Median number of prior therapies was 4. Tumor types included multiple gastrointestinal malignancies (n = 16), lung cancer, melanoma (n = 3 each), among others. No patients achieved CR or PR, resulting in ORR = 0%. Stable disease was the best response in 7/26 centrally confirmed cases. Median PFS was 1.7 months (90% CI: 1.1, 2.2), 6-month PFS rate was 5% (90% CI: 0.6%, 17.7%), and median OS was 3.5 months (90% CI: 1.9, 5.4). Twenty patients (57%) had grade 3 toxicities, and one patient (3%) had grade 4 toxicity as their worst toxicity; there were no grade 5 toxicities. Conclusion: Ulixertinib had no demonstrable evidence of clinical activity in this small, heavily pretreated population of patients with tumors harboring BRAF fusions, or with non-V600E, non-V600K BRAF mutations.
Vivek Subbiah, Feng-Min Zhao, R. Kudchadkar et al.· Clinical Cancer Research· 0 citations
BACKGROUND
The standard first-line treatment for advanced EGFR-mutated non-small cell lung cancer (NSCLC) is EGFR tyrosine kinase inhibitors. However, concurrent mutations facilitate resistance evolution in EGFR-mutant lung adenocarcinoma and combination therapies may offer a superior approach. This study explores the efficacy and safety of osimertinib plus anlotinib as first-line treatment for advanced NSCLC with EGFR co-mutations.
MATERIALS AND METHODS
This study prospectively enrolled patients with advanced NSCLC harboring EGFR (19Del/21L858R) mutations and ≥1 mutation in TP53, PIK3CA, or RB1, who had not undergone systemic treatment. Kaplan-Meier survival analysis tested the differences among patients with different concurrent mutations. ctDNA test was administered before and after treatment and its correlation with efficacy.
RESULTS
A total of 38 patients were enrolled, with co-mutations in TP53 (76.3%), PIK3CA (26.3%), and RB1 (2.6%). With a median follow-up of 25.6 months, the median progression-free survival (PFS) was 29.0 months (95% CI,18.6-NR), and 1-year PFS rate was 85% (95% CI, 70.4-94.5%). Objective response rate was 73.7% (95% CI, 56.9-86.3%), and disease control rate was 97.4% (95% CI, 85.8-99.9%). Adverse events of any grade occurred in all patients. Seven (18.4%) patients experienced grade 3 treatment-related adverse events (TRAEs), with no grade 4 TRAEs or treatment-related deaths.
CONCLUSION
Osimertinib plus anlotinib shows promising efficacy and manageable toxicity as first-line treatment for advanced NSCLC with EGFR co-mutations (ChiCTR2300070023).
CLINICAL TRIAL REGISTRATION
This study was registered in the Chinese Clinical Trial Registry (ChiCTR) under the registration number ChiCTR2300070023 on March 31, 2023 (https://www.chictr.org.cn).
Xiaojun Yang, Qin-Quan Tan, Shiyuan Chen et al.· The Oncologist· 0 citations
Background Osimertinib is the standard first-line treatment for non-small cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) mutation. Erlotinib plus an angiogenesis inhibitor (erlotinib+A) has demonstrated efficacy in controlling malignant pleural effusion (MPE) through reduction of vascular permeability; however, no clinical trials have directly compared its MPE control efficacy with that of osimertinib. This study aimed to compare the efficacy of osimertinib vs. erlotinib+A in controlling MPE in patients with EGFR-mutant NSCLC. Methods This multicenter retrospective cohort study analyzed longitudinal medical records of patients with advanced or recurrent EGFR-mutant NSCLC presenting with MPE at treatment initiation who received osimertinib or erlotinib+A at 14 institutions in Japan between November 2009 and October 2023. Patients with squamous cell carcinoma were excluded. The primary endpoint was time to MPE recurrence [MPE-progression-free survival (PFS)]. Secondary endpoints included PFS, overall survival (OS), and adverse events (AEs) graded according to the Common Terminology Criteria for Adverse Events (CTCAE). Multivariable Cox proportional hazards regression served as the primary analysis, with propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) utilized for sensitivity analyses. Results Among 421 patients (median age, 73 years; 65% female; 66% never-smokers; 99% adenocarcinoma), 373 received osimertinib and 48 received erlotinib+A. In the multivariable Cox regression analysis, no significant differences were observed between the osimertinib and erlotinib+A groups in MPE-PFS [adjusted hazard ratio (HR): 0.79; 95% confidence interval (CI): 0.54–1.15; P=0.22], PFS (adjusted HR: 0.87; 95% CI: 0.60–1.25; P=0.45), or OS (adjusted HR: 0.95; 95% CI: 0.63–1.44; P=0.83). However, a significant interaction between the treatment regimen and EGFR mutation type was identified (P=0.004 for MPE-PFS). Subgroup analysis demonstrated that osimertinib was significantly superior to erlotinib+A in patients with EGFR exon 19 deletions (MPE-PFS: adjusted HR: 0.38; 95% CI: 0.21–0.67; P<0.001), whereas no difference was observed in those with L858R mutations. Grade ≥3 AEs were more frequent in the erlotinib+A group (38% vs. 21%, P=0.02), whereas osimertinib was associated with a higher incidence of all-grade interstitial pneumonia (21% vs. 6%, P=0.01). Conclusions Osimertinib showed comparable efficacy to erlotinib+A in MPE control with a more favorable safety profile. Subgroup analysis suggested a particular benefit in patients harboring EGFR exon 19 deletions, highlighting the potential importance of mutation subtype-based treatment selection. Given the retrospective design and potential for residual confounding, prospective validation is warranted.
T. Hata, T. Yamada, Koji Mikami et al.· Translational Lung Cancer Re...· 0 citations
Abstract Background SMARCB1-deficient renal medullary carcinoma (RMC) is a highly aggressive renal cell carcinoma (RCC) that predominantly affects young individuals of African descent harboring sickle hemoglobinopathies (Msaouel et al. Clin Cancer Res 2018, PMID: 29440190). All cases are defined by loss of the SMARCB1 tumor suppressors, and most patients present with metastatic disease, with median overall survival of approximately 24 months (Lebenthal et al. Eur Urol Oncol 2025, PMID: 39013742). Unlike other RCCs, RMC is refractory to anti-angiogenic and mTOR-directed therapies as well as immune checkpoint inhibitors (Msaouel P. Future Oncol. 2026, PMID: 41777050). Cytotoxic chemotherapy yields responses in ∼29% of patients which are durable in less than 5% of patients, underscoring the urgent need for novel strategies. Our integrated molecular profiling of RMC tissues identified TROP2 as upregulated at the RNA and protein levels. RMC additionally shows marked upregulation of topoisomerases that buffers the replication stress induced by SMARCB1 loss, providing a distinctive mechanistic rationale for a topoisomerase 1-targeting payload in this disease. Supporting this, we clinically repurposed the first-generation TROP2 antibody-drug conjugate (ADC) sacituzumab govitecan in four heavily pretreated patients with RMC, with one patient achieving a partial response and two patients maintaining stable disease with symptom improvement (Msaouel et al. Cell Rep Med 2025, PMID: 41172996). Sacituzumab tirumotecan is a next-generation ADC comprising a humanized anti-TROP2 IgG1 monoclonal antibody conjugated via a stable linker to the topoisomerase 1 inhibitor KL610023, with a drug-antibody ratio of 7.4. We hypothesize that sacituzumab tirumotecan will produce a potent and durable antitumor response in patients with RMC who develop progressive disease on at least one prior line of therapy. Methods This is a phase II, single-arm, open-label, investigator-initiated study (NCT07438626). Eligible patients have locally advanced or metastatic SMARCB1-deficient RMC (or unclassified RCC with medullary phenotype) confirmed by expert pathology, progression on ≥ 1 prior line of therapy, ECOG PS 0-1, age ≥18 years, measurable disease per RECIST 1.1, and adequate organ function. Participants receive sacituzumab tirumotecan 4 mg/kg IV on days 1, 15, and 29 of each 42-day cycle until disease progression, unacceptable toxicity, or completion of 78 doses (∼3 years). Figure 1 presents the study schema. Up to 20 patients will be enrolled under a Bayesian framework with simultaneous monitoring of toxicity via the Bayesian Optimal Phase 2 (BOP2) design and of two efficacy endpoints—objective response rate (ORR) at any time and disease control rate (DCR) at 18 weeks per RECIST 1.1—via the time-to-event Bayesian Optimal Phase 2 (TOP) design. The regimen will be deemed promising if ORR is > 15% or DCR at 18 weeks is > 15%, with 71.4% power to detect a true ORR or DCR of 30% at a type I error rate of 15%. Interim safety and futility monitoring will occur after 10 patients. Secondary endpoints include overall survival, progression-free survival, duration of response, and grade ≥3 adverse events (CTCAE v6.0). Exploratory analyses will evaluate baseline tumor TROP2 expression as a potential biomarker of response. Longitudinal blood and optional tumor biopsies will be obtained for cytokine and immune-cell profiling, spatial transcriptomics, and TROP2 IHC to characterize mechanisms of response and resistance. These will be directly compared with analogous datasets from our prior RMC trials and preclinical models to enable cross-trial and cross-species biomarker integration in this rare disease. Results Significance and Vision: STaRMC is the first clinical trial of a TROP2-directed ADC specifically designed for RMC. Clinical and translational signals will (1) validate TROP2 as a therapeutic target in RMC, (2) establish ADCs as a new therapeutic class for this near-uniform fatal disease, and (3) inform combinatorial strategies and expansion to other SMARCB1-deficient malignancies. Conclusions N/A DOD CDMRP Funding Yes25 Figure
P. Msaouel, Rebecca S. Slack-Tidwell, R. Sheth et al.· The Oncologist· 0 citations
Background The Echinoderm microtubule-associated protein-like 4 (EML4) - Anaplastic lymphoma kinase (ALK) gene fusion represents a significant driver mutation in non-small cell lung cancer (NSCLC). Among the over 20 identified EML4-ALK variant subtypes, the V5' variant occurs relatively infrequently, constituting merely 4% of cases. Currently, the clinicopathological features and prognostic implications associated with this particular variant remain poorly characterized in the literature. Case summary We report the case of a 38-year-old man diagnosed with stage IV lung adenocarcinoma carrying the EML4-ALK V5' fusion variant, who received first-line treatment with iruplinalkib at a dose of 180 mg once daily. After 6.3 months of therapy, the patient developed a substantial malignant pleural effusion. Consequently, the treatment regimen was switched to lorlatinib 100 mg once daily combined with intrathoracic infusion chemotherapy. However, no significant improvement in the malignant pleural effusion was observed. We thereafter modified the therapeutic strategy to include lorlatinib-based targeted therapy combined with a dual-agent chemotherapy regimen consisting of cisplatin and pemetrexed, along with bevacizumab for anti-angiogenic therapy. Following this adjustment, the patient’s malignant pleural effusion showed marked remission. Conclusion For patients with NSCLC harboring the EML4-ALK V5' fusion variant who have developed resistance to second-generation tyrosine kinase inhibitors (TKIs), switching to third-generation TKI lorlatinib in combination with chemotherapy and anti-angiogenic treatment may serve as a potential therapeutic option for overcoming acquired resistance and curbing rapid disease progression.
Mengqing Cao, Shumin Li, Linfeng Cao et al.· Frontiers in Pharmacology· 0 citations
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