Ibiayi Dagogo-Jack

Purpose: MTAP loss co-occurs with actionable genomic alterations in NSCLC and creates vulnerability to protein arginine methyltransferase 5 (PRMT5) inhibition. Estimates of prevalence of MTAP loss rely on next-generation sequencing which can underestimate copy losses. Moreover, the activity of PRMT5 inhibitors in oncogene-driven NSCLC is not well established. Experimental Design: We assessed MTAP expression by immunohistochemistry (IHC) in 243 NSCLCs (n=132 early stage, n=111 metastatic), including 33 specimens with paired lymph nodes. Activity of PRMT5 inhibitor monotherapy and in combination with tyrosine kinase inhibitors (TKIs) was evaluated in MTAP-deleted NSCLC cell lines harboring EGFR or KRAS mutations or ALK rearrangements. Results: Among 243 NSCLC specimens from 240 patients (72% with driver alterations, 90% adenocarcinoma), MTAP loss was identified in 42 (17%) specimens, including 17 (13%) early-stage and 22 (20%) metastatic specimens. MTAP loss occurred in 24% of stage 4 driver-positive NSCLCs versus 14% of driver-negative tumors (p=0.314). Twenty-one (64%) lung-nodal pairs demonstrated concordance; eight cases only exhibited decreased MTAP expression in nodes. Variable sensitivity to PRMT5 inhibitors was observed in 22 MTAP-deleted NSCLC cell lines (9 EGFR-mutant, 7 KRAS-mutant, 6 ALK-rearranged), with responses seen in TKI-sensitive and TKI-resistant lines. SDMA (symmetric dimethylarginine) expression did not predict PRMT5 inhibitor sensitivity. TKI + PRMT5 inhibitor combos had greater activity than monotherapy. Conclusions: MTAP loss occurs in 17% of NSCLC, including 24% of oncogene-driven tumors. PRMT5 inhibitor activity is independent of TKI exposure and SDMA expression and enhanced by TKI therapy. These findings support evaluation of PRMT5 inhibitor + TKIs in oncogene-driven NSCLC.

Purpose: Matching patients with effective targeted therapies requires timely molecular results; however, the challenge today how to embed it into routine clinical workflows in ways that meaningfully affect patient-level treatment decisions. Methods: Building on prior work, the authors systematically reviewed laboratory operations, interdepartmental coordination, and administrative processes from two distinct healthcare settings: a US-based academic tertiary care center and a Canadian community hospital. We identified shared themes, context-specific challenges, and operational elements that distinguished successful integration from assay availability alone. Results: Across both environments, the comparison revealed that rapid testing consistently accelerated treatment decisions and facilitated biomarker-informed patient management, but its successful implementation depended on re-engineering laboratory workflows, aligning personnel competencies, and establishing turnaround time monitoring; technical availability alone did not ensure clinically meaningful rapid testing. While the academic context integrated rapid testing within comprehensive molecular pipelines and research frameworks, the community hospital context focused on pragmatic adoption for frontline care, especially in urgent clinical settings and based on the organization of the Canadian health system. Conclusion: Implementing rapid molecular testing in NSCLC is fundamentally an implementation and systems-engineering challenge rather than a technical challenge. Clinical speed depended more on system design than assay availability alone and is influenced, in part, by the larger national healthcare context. Addressing laboratory, operational, and administrative barriers is essential to ensure that rapid testing improves outcomes. Lessons learned from both academic and community practice provide a practical, implementation-focused roadmap for broader adoption and equity in access to precision oncology.

Background: Methylthioadenosine phosphorylase (MTAP) loss co-occurs with actionable genomic alterations in non-small cell lung cancer (NSCLC) and creates vulnerability to protein arginine methyltransferase 5 (PRMT5) inhibition. Estimates of prevalence of MTAP loss rely on next-generation sequencing which can underestimate copy losses. Moreover, the activity of PRMT5 inhibitors in oncogene-driven NSCLC is not well established. Methods: We assessed MTAP expression by immunohistochemistry (IHC) in 243 NSCLCs (n=132 early stage, n=111 metastatic), including 33 specimens with paired lymph nodes. Antiproliferative activity of PRMT5 inhibitor monotherapy and in combination with tyrosine kinase inhibitors (TKIs) was evaluated in MTAP-deleted NSCLC cell lines harboring EGFR or KRAS mutations or ALK rearrangements. Results: Among 243 NSCLC specimens from 240 patients (72% with driver alterations, 90% adenocarcinoma), MTAP loss was identified in 43 (18%) specimens from 40 (17%) patients, including 18 (14%) early-stage and 22 (20%) metastatic tumors. MTAP loss occurred in 24% of stage 4 driver-positive NSCLCs versus 14% of driver-negative tumors (p=0.314). Twenty (61%) lung-nodal pairs demonstrated concordance; eight cases only exhibited decreased MTAP expression in nodes. Variable sensitivity to PRMT5 inhibitors was observed in 22 MTAP-deleted NSCLC cell lines (9 EGFR -mutant, 7 KRAS -mutant, 6 ALK -rearranged), with responses seen in TKI-sensitive and TKI-resistant lines. SDMA (symmetric dimethylarginine) expression did not predict PRMT5 inhibitor sensitivity. TKI + PRMT5 inhibitor combos had greater activity than monotherapy. Conclusions: MTAP loss occurs in 1-in-5 oncogene-driven metastatic NSCLCs. PRMT5 inhibitor activity is independent of TKI exposure, driver alteration, and SDMA expression and enhanced by addition of TKI. These findings support clinical evaluation of PRMT5 inhibitor + TKI combinations for advanced NSCLC.

The phase II PHAROS study previously showed that encorafenib plus binimetinib has antitumor activity in patients with BRAF V600E-mutant metastatic non–small cell lung cancer (mNSCLC). In PHAROS, 98 patients (59 treatment-naïve; 39 previously treated) received encorafenib 450 mg once daily and binimetinib 45 mg twice daily. We report updated results from data cutoff of March 14, 2025. The median duration of treatment with both encorafenib and binimetinib was 16.3 months in treatment-naïve and 5.5 months in previously treated patients. After median follow-up for overall survival (OS) of 52.3 months in treatment-naïve patients, mOS was 47.6 months (95% CI, 31.3 to not estimable); 4-year OS probability was 49% (95% CI, 35 to 62). After median follow-up for OS of 48.2 months in previously treated patients, mOS was 22.7 months (95% CI, 14.1 to 32.6); 4-year OS probability was 31% (95% CI, 16 to 47). In treatment-naïve and previously treated groups, 58% and 26% received ≥1 subsequent systemic anticancer treatment, respectively. Safety profile remained consistent with that in previous analyses. Although comparisons across trials should be done cautiously, to our knowledge, encorafenib plus binimetinib was associated with the longest mOS reported to date with targeted treatment in patients with treatment-naïve BRAF V600E-mutant mNSCLC.

ASCO Guidelines provide recommendations with comprehensive review and analyses of the relevant literature for each recommendation, following the guideline development process as outlined in the ASCO Guidelines Methodology Manual . ASCO Guidelines follow the ASCO Conflict of Interest Policy for Clinical Practice Guidelines . Clinical Practice Guidelines and other guidance (“Guidance”) provided by ASCO is not a comprehensive or definitive guide to treatment options. It is intended for voluntary use by clinicians and should be used in conjunction with independent professional judgment. Guidance may not be applicable to all patients, interventions, diseases or stages of diseases. Guidance is based on review and analysis of relevant literature and is not intended as a statement of the standard of care. ASCO does not endorse third-party drugs, devices, services, or therapies and assumes no responsibility for any harm arising from or related to the use of this information. See complete disclaimer in Appendix 1 and 2 (online only) for more . PURPOSE: To provide evidence-based recommendations to practicing physicians and others on the management of pleural mesothelioma (PM). METHODS: ASCO convened an Expert Panel of medical oncology, thoracic surgery, radiation oncology, pathology, cancer genetics, and advocacy experts to conduct an updated literature search, which included systematic reviews, meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational studies published from 2016 through 2024. Outcomes of interest included survival, disease-free or recurrence-free survival, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS: The literature search identified 110 additional relevant studies to inform the evidence base for this guideline. RECOMMENDATIONS: Evidence-based recommendations were developed for surgical cytoreduction, immunotherapy, chemotherapy, pathology, and germline testing in patients with PM. Additional information is available at www.asco.org/thoracic-cancer-guidelines .