Supplementary Table S6 shows co-occurrence of actionable RNA expressions and corresponding protein expressions, and vice versa.

PTEN hamartoma tumour syndrome (PHTS) is characterized by a germline PTEN mutation and a substantial increase in lifetime breast cancer risk to 85% with lower age at first diagnosis. Despite the availability of agents targeting PTEN-regulated PI3K/AKT/mTOR pathway, there are currently no approved treatments for PHTS patients with cancer. This is the first report of a patient with triple-negative metaplastic breast cancer and PHTS in the literature. We present an exceptional response of this aggressive stage IV tumour in a 34-year-old woman with PHTS to treatment with the novel AKT1-3 inhibitor, TAS-117. Despite previous rapid progression and resistance to multi-agent chemotherapy and radiotherapy, disease stabilisation was ongoing at 3.8 years. Cell-free DNA analysis of blood samples at baseline and during treatment with TAS-117 revealed a complete marker response to treatment. Therapy has been well tolerated, and the patient continues the therapy without severe adverse events, dose reduction, or treatment interruptions. These findings support further investigation of targeted interventions for malignancies developing in the context of PHTS.

Abstract BRAF V600 mutant CRC is an aggressive subset with shorter survival. Current BRAF inhibitors (BRAFis) are limited by rapid resistance and side effects. There is a high unmet need in patients who progress on BRAFi-containing regimens. Plixorafenib is a paradox breaker designed to disrupt RAF dimers, selectively inhibiting V600 and non-V600 BRAF alterations without activating the MAPK pathway. PLX120-03, a completed single-arm phase 1/2a study assessed optimal dose, safety, and efficacy of plixorafenib monotherapy in BRAF-altered solid tumors. Preliminary data for the total population were reported previously. In this first disclosure of a prespecified efficacy analysis for BRAF V600 mutated CRC (N=14), median age was 60 years, 57% were female, and 100% were White. Participants (pts) received a median of 2 prior lines of treatment, and one received a prior MAPK inhibitor (MAPKi)-containing regimen. For 13 pts with no prior MAPKi, disease control rate with plixorafenib monotherapy was 62% and median PFS was 3.5 months (mos). There was confirmed PR (ORR 8%) lasting 3.7 mos (treatment duration 6 mos); the MAPKi pretreated pt had PD. Seven pts had SD (treatment duration range: 3.7-28.7 mos) with 4 remaining on treatment ≥6 mos. Clinical benefit correlated with fewer lines of prior therapy. Safety was encouraging and consistent with the total population; TEAEs were primarily low-grade LFT elevations, GI disorders, and fatigue. There were 11 grade 3 TEAEs in 5 pts, 8 unrelated and 3 related (decreased appetite, diarrhea, hyperglycemia), and no discontinuations due to TEAEs. Plasma ctDNA alterations at baseline and subsequent timepoints were analyzed (n=12). Decreases in BRAF variant allele frequency (VAF) and intratumor ERK phosphorylation after administration of plixorafenib were observed, confirming direct PD effects. BRAF VAF decreased throughout treatment and rebounded at PD, matching the dynamics of tumor volume changes. At the end of treatment, we identified lower rates of acquired mutations within the MAPK (KRAS, MAP2K1, MET AMP) and PI3K (PIK3CA, AKT2, AKT3) pathways compared to that for approved BRAFis. NRAS mutations or BRAF exon deletions were not observed. Other acquired mutations found in >2 pt were NF1 (n=2), androgen receptor (AR; n=2), and CDKN2A/B CNV (n=3). In pts who did not respond to plixorafenib, baseline mutations in RTKs, NF1, and PI3K pathway (PTEN, PIK3CA, AKT) were identified and may have contributed to resistance. Plixorafenib monotherapy in heavily pre-treated pts with BRAF V600 mutated CRC demonstrated activity comparable to approved BRAFi monotherapy with a markedly improved safety profile. ctDNA data showed a pattern of resistance distinct from that of approved BRAFis, with lower acquired MAPK pathway and PI3K pathway mutations. These data warrant exploration of combination approaches of plixorafenib with targeted drugs or chemotherapy. Citation Format: Rona Yaeger, Sunil Sharma, Aparna Parikh, Stacie Peacock Shepherd, Manish Monga, Ping Jiang, Jessica Jang, Michael Paz, Frank Tsai, Ulka Vaishampayan, Jordi Rodon. Clinical activity and safety of novel BRAF inhibitor plixorafenib (FORE8394) in BRAF V600-mutated advanced colorectal cancers (CRC) [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 CT154.

KRAS-mutant NSCLC resistance to MEK inhibitors (MEKi) is related to compensatory upregulation of fibroblast growth factor receptor (FGFR) signaling. Futibatinib is a potent, covalent FGFR1–4 inhibitor approved for locally advanced/metastatic cholangiocarcinoma with FGFR2 fusions. We conducted a bench-to-bedside study evaluating futibatinib plus the MEKi binimetinib preclinically, followed by a Phase Ib trial of patients with advanced cancer. The effect of futibatinib ± MEKi on cell signaling and proliferation of KRASmt NSCLC lines (A549, LU99) were assessed in vitro. In a Phase Ib study, patients with advanced cancer who had exhausted standard therapies received futibatinib QD plus binimetinib BID orally following a “3 + 3” dose-escalation design. Primary objective was to establish the recommended Phase 2 dose (RP2D) based on safety. Secondary endpoints included pharmacokinetics and anti-tumor activity. In vitro, MEKi with futibatinib resulted in additive or synergistic anti-tumor activity in KRASmt NSCLC lines. Twenty-three patients received futibatinib with binimetinib at 4 dose levels. The most prevalent adverse events were reversible retinopathies in 20 patients, including 2 DLTs and limiting dose escalation beyond futibatinib 16 mg QD plus binimetinib 15 mg BID (MTD). There were no relevant drug-drug interactions between binimetinib and futibatinib. One patient harboring an FGFR2 fusion had a partial response. No RP2D could be defined as the MTD was below active dose levels of binimetinib. Despite additive anti-tumor activity for FGFR and MEK inhibition in KRASmt NSCLC lines, the trial was stopped after dose escalation, as no RP2D was identified for futibatinib/binimetinib due to reversible retinopathies. Trial register number. NCT04965818. Trial registration date. 20-September-2021.

Supplementary Figure S2 shows DNA alterations uniquely identified by CGTP. Panel A: Distribution of CGTP-unique DNA alterations Panel B: Number of CGTP-unique DNA alterations across patients Panel C: Actionable CGTP-unique fusion events

Supplementary Table S3 shows treatment status and the expression of ADC targets.

Importance:Immune checkpoint inhibitors (ICIs) have transformed the management of recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), yet most patients eventually develop resistance. Investigational immunotherapy strategies beyond checkpoint blockade are being explored, but their clinical activity and associated biomarkers remain poorly defined. Objective:To evaluate the safety, antitumor activity, and biomarkers associated with novel immunotherapy agents in patients with recurrent or metastatic HNSCC treated in early-phase clinical trials. Design, Setting, and Participants:This retrospective cohort study was conducted at The University of Texas MD Anderson Cancer Center Department of Investigational Cancer Therapeutics and included adult patients (aged ≥18 years) with advanced HNSCC treated with novel immunotherapy agents in early-phase clinical trials between January 1, 2015, and May 31, 2025. Patients were followed up from treatment initiation until disease progression, death, or last clinical contact. Exposure:Treatment with investigational immunotherapy agents administered in early-phase clinical trials. Main Outcomes and Measures:The primary outcomes included treatment-related adverse events, objective response rate (complete or partial response), clinical benefit rate (complete or partial response or stable disease lasting ≥6 months), progression-free survival, and overall survival. Logistic regression was used to evaluate biomarkers associated with the clinical benefit rate, including clinical, genomic, and treatment-related variables, while survival outcomes were estimated using the Kaplan-Meier method. Results:The sample included 158 patients (median [range] age, 60.7 [25.7-84.6] years; 136 male [86.1%]). The oropharynx was the most common primary site (94 patients [59.6%]). Patients had received a median of 3 prior lines (range, 0-8 prior lines) of systemic therapies, and 126 patients (79.7%) had prior ICI exposure. A total of 91 of 153 patients (59.5%) had human papillomavirus-positive tumors, and PD-L1 combined positive score of at least 1 was observed in 67 of 87 patients (77.0%). Most patients received combination immunotherapy (106 [67.1%]), with a median treatment duration of 2.3 months (range, 0.1-19.7 months). Treatment-related adverse effects occurred in 85 patients (53.8%), including grade 3 or higher events in 23 patients (14.6%). The overall response rate was 7.7% (12 patients), and the clinical benefit rate was 16.1% (25 patients). Bispecific antibodies were associated with improved clinical benefit (odds ratio, 1.95; 95% CI, 1.23-4.15), whereas PIK3CA alterations were associated with reduced benefit (odds ratio, 0.03; 95% CI, 0.00-0.51). Median progression-free survival was 2.3 months (95% CI, 2.0-2.9 months) and median overall survival was 8.3 months (95% CI, 7.2-11.0 months). Conclusions and Relevance:This retrospective cohort study of heavily pretreated patients with HNSCC treated in early-phase clinical trials found that novel immunotherapy agents may have manageable toxic effects but modest antitumor activity. Bispecific antibodies may have encouraging activity while genomic alterations may help inform treatment stratification.

Supplementary Figure S4 the correlation between treatment status and expression of ADC targets.

PURPOSE:Comprehensive genomic profiling has prognostic and predictive value for patients with pancreatic adenocarcinoma (PAAD). EXPERIMENTAL DESIGN:We reviewed clinical and molecular data from 4,009 samples from patients who had undergone the BostonGene Tumor Portrait test between October 28, 2021, and October 8, 2024, and 2,181 samples from the BostonGene PAAD meta-cohort, collected from various data hosts and processed by BostonGene automated pipelines. RESULTS:In this high-purity PAAD cohort, 24% harbor homozygous methylthioadenosine phosphorylase (MTAP) deletion, and the co-occurrence of Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations and MTAP loss was common (18.9% of all PAADs). This association identified a subgroup with worse survival outcomes. MTAP-deficient tumors harbor more fibrotic, less immune-enriched microenvironments and have shorter survival. Within the comutated tumors, the most frequently detected KRAS variants were G12D, G12V, and G12R, with the last one slightly more related to immune-enriched tumor microenvironment features than the other KRAS variants. CONCLUSIONS:Comprehensive genomic profiling is essential for patients with PAAD and carries both prognostic and predictive values. MTAP loss in KRAS-mutant PAAD represents a subgroup of immune-excluded PAADs with a poor prognosis.

PURPOSE:Fibroblast activation protein (FAP) is an attractive target for radiopharmaceutical therapy. Phase I of the LuMIERE study (ClinicalTrials.gov, NCT04939610) investigated the safety of [177Lu]Lu-FAP-2286 (177Lu-FAP-2286) in heavily pretreated patients with advanced solid tumors and identified the recommended phase II dosage (RP2D). PATIENTS AND METHODS:LuMIERE is a prospective, open-label, nonrandomized, phase I/II, multicenter study. Phase I followed a Bayesian optimal interval design evaluating four escalating activity levels of 177Lu-FAP-2286 (3.70, 5.55, 7.40, and 9.25 GBq). Patients were selected by positive [68Ga]Ga-FAP-2286 (68Ga-FAP-2286, also known as [68Ga]Ga-HKG301) PET/CT imaging on all target lesions [maximum standardized uptake value (SUVmax) ≥1.5× SUVmean of mediastinal blood pool]. 177Lu-FAP-2286 was administered intravenously every 6 weeks for ≤6 cycles. The primary endpoint was dosage-limiting toxicities (DLT) and treatment-emergent adverse events (TEAE). RESULTS:Of 35 patients imaged with 68Ga-FAP-2286, 27 received 177Lu-FAP-2286 (3.70 GBq, n = 3; 5.55 GBq, n = 6; 7.40 GBq, n = 7; 9.25 GBq, n = 11). Two DLTs were observed: one patient who received 5.55 GBq of 177Lu-FAP-2286 experienced grade 4 lymphopenia, and one patient who received 9.25 GBq experienced grade 3 hemoptysis; these were the only treatment-related grade ≥3 TEAEs. All-cause grade ≥3 TEAEs were reported for 11 patients (40.7%). The RP2D for 177Lu-FAP-2286 monotherapy was determined to be 9.25 GBq. Preliminary Response Evaluation Criteria in Solid Tumors efficacy findings demonstrated a partial response in 1 patient and stable disease in 10 patients (maintained for at least two assessments in 6 patients). CONCLUSIONS:177Lu-FAP-2286 was well tolerated in patients with advanced solid tumors. The safety and preliminary efficacy findings support its continued development in phase II.

Comprehensive, multiplexed RNA sequencing (RNA-seq) is increasingly being incorporated into molecular tumour-profiling assays owing to overall cost-effectiveness related to enhanced detection of clinically actionable biomarkers. RNA-seq assays are now quite robust, with turnaround times of a few weeks and reasonable costs that support integration into routine clinical workflows. In this Perspective, we propose a framework for incorporating RNA levels and other RNA-seq data into precision oncology that considers RNA levels of oncogenes, tumour suppressors and diverse therapeutic targets, as well as multigene diagnostic, prognostic and predictive signatures; chimeric gene fusion transcripts; splice variants; RNA-based variant and/or mutation calling; and oncoviral gene expression; among other factors. Additionally, we provide a list of genes representing the current actionable transcriptome focused on the predictive utility of RNA-level overexpression of oncogenes and underexpression of tumour-suppressor genes. This list also includes cell-surface targets, given that RNA profiling has demonstrated that many tumour types have clinically relevant expression levels of such targets. The RNA expression levels of certain genes might also be associated with biological features such as homologous recombination deficiency and DNA mismatch repair defects. Taken together, comprehensive RNA profiling can help to identify additional actionable alterations beyond those detected via DNA sequencing and overcome the challenges faced by conventional low-plex assays (such as immunohistochemistry and in situ hybridization), thereby enhancing therapeutic opportunities for personalized cancer care. RNA sequencing (RNA-seq) is increasingly being integrated into molecular tumour profiling but remains underutilized for clinical decision-making. This Perspective presents a framework for assessing the therapeutic, diagnostic and prognostic actionability of RNA-seq findings as well as an ‘actionable transcriptome’ list to help guide the application of RNA-seq findings in oncology practice.

Abstract Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with specific genomic alterations. Results in a cohort of pts with solid tumors with NTRK1/2/3 amp treated with L are reported. Methods: Eligible pts had measurable disease, ECOG performance status (PS) 0-2, adequate organ function, and no remaining standard treatment (tx) options. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Amp cut-offs were defined per NGS providers. Tumors must not have had NTRK fusions. L dosing was one 100 mg capsule or oral solution twice daily until disease progression or unacceptable toxicity. Primary endpoint was disease control (DC) per investigator defined as objective response (OR) or stable disease (SD) of at least 16+ weeks (wks) duration (SD16+) per RECIST v1.1. Simon 2-stage design tested the null DC rate of 20% vs. 45% (power = 0.85, α=0.10). If ≥2 of 8 pts in stage 1 had DC, 13 more pts were enrolled; otherwise, the cohort was closed for futility. Secondary endpoints were OR, progression-free survival (PFS), overall survival (OS), duration of response and SD, and safety. Results: 8 pts with solid tumors (breast [n=3], soft tissue sarcoma [n=2], head and neck [n=1], non-small cell lung cancer (LC) [n=1], small cell LC [n=1]) with NTRK1 amp (n=5), NTRK2 amp (n=1), NTRK1 amp and mutation (mut) (n=1), and NTRK1 amp and NTRK3 mut (n=1) were enrolled. All pts were evaluable for efficacy. Table shows demographics and outcomes. SD16+ was observed in 1 pt with myxoliposarcoma and NTRK1 amp for a DC rate of 13% (1-sided 90% CI, 1 to 100) and an OR rate of 0% (95% CI, 0 to 37). Duration of SD in 1 pt was 24 wks. The null DC rate was not rejected (p=0.83). No pts had grade 3-5 tx-related adverse or serious adverse events. Conclusions: L did not meet prespecified criteria to declare a signal of activity in pts with solid tumors with NTRK amp. Citation Format: Jordi Rodon, Michael Rothe, Elizabeth Garrett-Mayer, Nithin Rohatgi, Alvaro G. Menendez, Leighton A. Elliott, Andrew Gregory, Abigail Gregory, Dominique C. Hinshaw, Gina N. Grantham, Susan Halabi, Richard L. Schilsky. Larotrectinib (L) in patients (pts) with solid tumors with NTRK1/2/3 amplification (amp): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study [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 CT206.

Supplementary Table S1 shows reasons for inability to perform CGTP.