Molecular profiling of solid tumors is increasingly essential in oncology practice, guiding diagnosis-prognosis and providing patients with access to molecularly matched therapies that can improve outcomes. In this study, 554 patients with advanced solid tumors were evaluated through the POWER (Precision Oncology at Western University) study, a first of its kind Canadian study, designed to prospectively assess the clinical impact of expanded pan-cancer next-generation sequencing (NGS) panel testing on patient management, in real-world oncology practice and evaluate the overall health system impact. The findings reveal that 79% of patients had clinically relevant variants, and nearly 28% experienced changes in treatment eligibility because of the identification of novel druggable mutations. Additionally, the analysis shows that a pan-cancer NGS panel significantly impacted patient management, with 18% of patients receiving access to clinical trials and off-label therapy with expected better outcomes and 19% (31/162) patients, previously tested by tumor-specific panels, experiencing management changes when tested through POWER. This study also highlights the broader health system impact: access to safer treatment options (14.5%), change in management (17.6%), treatment sequence changed (17.3%), and Ministry of Health formulary treatment saved (12.5%). These results underline the benefits of expanded NGS testing over tumor-specific panels in guiding personalized treatment decisions, optimizing patient care, and enhancing health care delivery in oncology.

As bispecific T-cell engagers (TCEs) gain traction in the oncology treatment landscape, cancer centres must develop robust clinical pathways to ensure their safe and efficient delivery. Given the limited experience of the Canadian medical oncology community with TCEs, collecting and publishing early clinical experiences with these novel agents will be essential to inform best practices and support their safe and effective adoption across the broader Canadian oncology community. The approval of tarlatamab, the first-in-class delta-like ligand 3 (DLL3)-targeted TCE for extensive-stage small cell lung cancer (ES-SCLC), underscores the importance of sharing early clinical experience with this agent, particularly given its unique safety profile, specific monitoring requirements, and use in a population that often has multiple comorbidities. Like other TCEs, tarlatamab is associated with cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), adverse events (AEs) that necessitate the development of dedicated protocols by medical oncologists and multidisciplinary inpatient and outpatient clinical teams to ensure prompt recognition and management of these associated toxicities. By sharing insights into administration protocols, dose ramp-up procedures, post-cycle 1 monitoring, and AE management strategies implemented at their centres, early adopters of tarlatamab can help other institutions develop and refine their own protocols more efficiently. Lessons learned during the early implementation phase, including the roles of various healthcare providers and the transition from inpatient to outpatient care, should facilitate the smoother integration of tarlatamab and other TCEs for solid tumours into clinical pathways across Canada.

Immune checkpoint inhibitors (ICI) have improved outcomes for patients with non-small cell lung cancer (NSCLC) and melanoma, yet over half of patients exhibit primary resistance. Fecal microbiota transplantation (FMT) may overcome resistance to anti-programmed cell death protein 1 (PD-1) therapy. The clinical activity and safety of FMT plus anti-PD-1 in NSCLC or anti-PD-1 plus anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) therapy in melanoma have not been evaluated. Here we report results from FMT-LUMINate, a multicenter, open-label, phase 2 trial assessing healthy donor FMT plus anti-PD-1 in NSCLC (n = 20) or anti-PD-1 plus anti-CTLA-4 (dual ICI) in melanoma (n = 20), in the first-line setting. Eligible patients received a single FMT via oral capsules prior to ICI initiation. The primary endpoint was objective response rate (ORR) in NSCLC. Secondary endpoints included ORR in melanoma, safety and donor−host microbiome similarity. In NSCLC, the ORR was 80 NCT04951583 . In a phase 2 trial evaluating healthy donor fecal microbial transplantation plus either anti-PD-1 in patients with non-small cell lung cancer or anti-PD-1 and anti-CTLA-4 in patients with melanoma, encouraging efficacy was seen in both cohorts, with responses linked to significantly greater loss of baseline bacterial species.

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancers with adenocarcinoma being the most common subtype. Patients with stage IV NSCLC typically have poor prognosis. In these patients, identification of actionable genomic alterations allows for the selection of targeted therapy rather than chemotherapy or chemo-immunotherapy. EGFR mutations are a common oncogenic driver in NSCLC and are targetable by tyrosine kinase inhibitors (TKIs). However, most of the studies primarily focus on common mutations, which are exon 19 deletions (Ex19del) and exon 21 (L858R) point mutations, and there is inconsistent data on efficacy in the treatment of patients with uncommon EGFR mutations. Currently, the first-line treatment for patients with common EGFR mutations involves a third-generation TKI, typically osimertinib. This case describes a 66-year-old gentleman with two uncommon EGFR frameshift deletions (E701fs and L702fs). His tumor staging was denoted as cT3N2M1b, stage IVA. The patient demonstrated a radiological and biochemical response to osimertinib as part of the OCELOT clinical trial (supported by a grant from AstraZeneca), with evidence of tumor marker decline and radiographic improvement within two months of osimertinib treatment initiation. This response has been durable with continued radiological stability and biochemical improvement at 11 months and ongoing. This case will help guide management for patients with this uncommon EGFR mutations and contribute to the scarce literature of EGFR frameshift deletions in advanced NSCLC patients.

Adjuvant chemotherapy in stage III colon cancer provides uncertain benefit at the individual level. Circulating tumor DNA (ctDNA) may help refine risk-adjusted treatment selection. In this multicenter, randomized, phase 2/3 trial, patients with stage III colon cancer underwent ctDNA testing 5-6 weeks after surgery and were assigned (1:1) to ctDNA-guided or standard management. In the ctDNA-guided arm, patients negative for ctDNA received de-escalated therapy, whereas ctDNA-positive patients received escalated therapy. Clinicians prespecified the standard regimen. Primary endpoints were 3-year recurrence-free survival (RFS) for ctDNA-negative patients and 2-year RFS for ctDNA-positive patients. Secondary endpoints included treatment-related hospitalization and ctDNA clearance. Among 968 evaluable patients, 702 (72.5%) were ctDNA negative. With a median follow-up of 47 months, ctDNA-negative patients experienced significantly fewer recurrences than ctDNA-positive patients (3-year RFS 87% versus 49%; P < 0.001). In ctDNA-negative patients, de-escalation reduced oxaliplatin use (34.8% versus 88.6%) and hospitalizations (8.5% versus 13.2%) but yielded slightly lower RFS than standard management (85.3% versus 88.1%), not meeting the non-inferiority margin. In ctDNA-positive patients, higher ctDNA burden correlated with recurrence risk (3-year RFS 77% to 23% across quartiles; P < 0.001). Escalated therapy did not improve outcomes over standard management (2-year RFS 51% versus 61%). There was no unexpected toxicity. Persistent ctDNA after treatment predicted markedly worse prognosis (3-year RFS 14% versus 79%). ctDNA is validated as a strong prognostic classifier. ctDNA-guided de-escalation reduced oxaliplatin exposure and adverse events with outcomes approaching standard of care, whereas exploratory chemotherapy intensification conferred no RFS benefit, suggesting a need for novel strategies in ctDNA-positive disease.Australian New Zealand Clinical Trials Registry Identifier: ACTRN12617001566325 .

3503 Background: Despite adjuvant chemotherapy (ACT) a proportion of patients (pts) with stage III colon cancer (CC) will recur. Most at risk are those with detectable ctDNA, whereas those with undetectable ctDNA have a reduced recurrence risk. The DYNAMIC-III study explored the impact of ACT de-escalation or escalation as informed by post-surgery ctDNA results. Here, we report the primary analysis on the impact of treatment escalation in ctDNA-positive pts. Outcome data for treatment de-escalation in ctDNA-negative pts is immature. Methods: DYNAMIC-III is a multi-center, randomized, phase II/III trial. Eligible pts had resected stage III CC and were fit for ACT. Pts were randomly assigned 1:1 to ctDNA-informed or standard of care (SOC) management. Clinicians nominated the selected SOC ACT regimen prior to randomization. For ctDNA-informed management, a ctDNA-positive result at 5-6 weeks after surgery with a tumor-informed assay prompted an escalation ACT strategy (from single agent fluoropyrimidine [FP] to oxaliplatin-based doublet, from 3 months doublet to 6 months doublet or FOLFOXIRI [clinician choice], or from 6 months doublet to FOLFOXIRI). The primary efficacy endpoint for the ctDNA-positive cohort was 2-year RFS. The target sample size of 250 provided 80% power with 90% confidence to confirm superiority of ctDNA-informed treatment escalation compared to SOC with a HR of 0.746. Results: Of 961 eligible pts randomized between Oct 2017 and Apr 2023, 259 (27%) were ctDNA-positive. Of these, 113 (44%) had clinical low risk disease (non-N2 + non-T4). Median follow-up was 42.2 months (range 0.78 – 63.0). 115 (89%) of 129 ctDNA-informed pts received ACT escalation, with 65 (56%) receiving FOLFOXIRI. Of 130 SOC pts, 14 (11%) and 112 (86%) received single agent FP and oxaliplatin doublet, respectively. 2-year RFS for ctDNA-informed treatment escalation was 52% (90% CI: 44 - 59%) vs 61% (90% CI: 54 - 68%) for SOC (HR 1.11, 90% CI: 0.83 - 1.48; P = 0.6). The 3-year RFS for ctDNA-positive pts receiving FOLFOXIRI and FOLFOX/CAPOX was similar (47% vs 51%, HR 1.09, 90% CI 0.78 to 1.53; P = 0.7). In a pre-specified correlative analysis of all ctDNA positive pts, recurrence risk increased with ctDNA burden, with 3-year RFS of 78%, 63%, 36% and 22% for tumor-derived mutant molecules/mL quartiles < 0.06, 0.06 – 0.17, 0.18 – 1.31, and > 1.31, respectively (P < 0.01). Treatment-related hospitalisation was similar for escalated and SOC pts (OR 1.21, P = 0.58). Analysis of post-ACT ctDNA is underway. Conclusions: In this first randomised study of ctDNA-informed management in stage III CC, we confirm the prognostic significance of detectable ctDNA, with the novel finding of recurrence risk increasing markedly with ctDNA burden. Treatment escalation, including to FOLFOXIRI, did not improve RFS. Future studies in ctDNA positive pts should explore other escalation strategies. Clinical trial information: ACTRN12617001566325 .

Surgery is the primary treatment for early-stage lung cancer. Adjuvant therapy is offered to patients who are at a high risk of recurrence, however, determining the patients that would benefit from additional therapy is often difficult. In this study, we aimed to develop a clinical decision support system (CDSS) for post-surgery lung cancer prognostication integrating a multi-modality deep learning model (DLM). Pre-operative medical images and clinical, surgical, and pathological information were fed into an externally validated DLM. A CDSS was then developed to display the patient information and DLM results for potential clinical use. Four oncologists evaluated each patient’s recurrence probability, their confidence level, and their post-surgery recommendations both with and without the DLM information. The CDSS DLM information demonstrated the potential to improve user prediction performance and confidence. This exploratory study is the first to integrate a multi-modality DLM for prognostication with a CDSS, as well as the first study of clinician attitudes towards CDSSs for lung cancer.

3044 Background: Stereotactic ablative radiotherapy (SABR) is the preferred curative treatment for inoperable patients with stage I/IIA non–small-cell lung cancer (NSCLC). In cases where the tumor is inaccessible or biopsy carries a high risk of complications, SABR is offered even in the absence of a tissue diagnosis, based on a high likelihood of malignancy as calculated by validated predictive models. In these situations, a blood based liquid biopsy detecting circulating tumor DNA (ctDNA) can serve as an aide to confirm malignancy and allow molecular testing. However, low ctDNA yield in early stage NSCLC presents a challenge for diagnosis. This study hypothesizes that ctDNA detection rates will improve by combining assessment of pre- and post-SABR plasma samples. Methods: This is a multi-institutional study including two cohorts: 1) patients with suspected stage I/IIA NSCLC, with a pretreatment likelihood of malignancy of ≥60% on Herder or Brock models, and 2) patients with biopsy-proven NSCLC. SABR was delivered according to standard guidelines. Plasma was collected for ctDNA analysis before and 24-72 hours following the first fraction of SABR. SHIELDING ULTRA MRD panel of hotspot regions in 2365 cancer-related genes with ultra-high sensitivity was used for ctDNA analysis (mutation + fragment profile + CNV). In this pre-planned interim analysis, we report on the secondary objective: to assess the impact of SABR on detection rates of ctDNA. Results: Paired plasma samples (pre- and post-SABR) were tested for 69 patients. After quality control analysis, 66 paired samples were analyzed and included in this interim analysis. The median age was 76 years (range, 56-89) and 36 (54%) were male. The median concentration of circulating free DNA (ng/mL) did not increase from pre- (5.5, inter quartile range (IQR): 3.3-8.1) to post-SABR (5.7, IQR: 4.1-7.6) (P=0.82). The ctDNA detection rate in pre-SABR samples was 22.7% versus 27.3% in post-SABR samples (Table). Interestingly, in 10 patients (15.2%), ctDNA became detectable in post-SABR samples and in 7 patients (10.6%) the ctDNA was no longer detectable in the post-SABR samples. The ctDNA remained undetectable in 41 patients (62.1%). 37.9% of patients had detectable ctDNA either before or after SABR. Conclusions: The diagnostic yield of ctDNA for confirming malignancy in early stage NSCLC is improved by testing both the pre- and the post-SABR samples, collected within 24-72 hours after the first fraction of SABR. This approach may improve the diagnostic rates of liquid biopsies for patients with presumed NSCLC undergoing SABR, warranting further investigation of ctDNA detection before and shortly after treatment. Clinical trial information: NCT05921474 . ctDNA detection rates (N=66). Pre-SABR Post-SABR n (%) detected detected 8 (12.1%) not detected detected 10 (15.2%) detected not detected 7 (10.6%) not detected not detected 41 (62.1%)

Background:Chemoimmunotherapy is the standard treatment for patients with metastatic esophageal squamous cell carcinoma (ESCC), for which 5-fluorouracil (5-FU) is commonly part of the chemotherapy regimen. Given that 5-FU has a mean cardiotoxicity risk of approximately 5%, raltitrexed has often been used as an alternative in patients with a history of fluoropyrimidine-associated cardiotoxicity or significant coronary artery disease (CAD). We report the first case, to our knowledge, of the use of raltitrexed in place of 5-FU in combination with pembrolizumab and platinum-based chemotherapy for the treatment of metastatic esophageal cancer in a patient with CAD. Case Description:A 75-year-old gentleman with preexisting multivessel CAD was diagnosed with metastatic gastroesophageal junction (GEJ) squamous cell carcinoma (SCC) after presenting to medical attention with a 2-month history of worsening chest pain in addition to progressive dysphagia associated with weight loss. Following initial treatment with palliative locoregional radiotherapy to the lower mediastinum, GEJ, and upper abdomen, the decision was made to proceed with palliative systemic therapy. Considering his significant cardiac history, 5-FU was replaced with raltitrexed and combined with carboplatin and pembrolizumab. After a total of 10 months of treatment, the patient presented to hospital with recurrent chest pain and was diagnosed with a non-ST-elevation myocardial infarction (NSTEMI). Despite radiographic evidence of stability of his malignancy on systemic therapy, he was not considered to be a candidate for cardiac intervention. He was thus transitioned to a comfort-focused care approach and passed away shortly thereafter, with the cause of death being acute coronary syndrome. Conclusions:Although the patient unfortunately passed away prematurely due to preexisting CAD, there was no evidence of disease progression in the 10 months that he received treatment. In addition to an encouraging progression-free survival (PFS), the patient reported an overall improvement in quality of life while on therapy with no signals of toxicity from raltitrexed or immunotherapy. Overall, the present case demonstrates that chemotherapy in combination with immunotherapy for the treatment of advanced esophageal cancer appears to be safe and effective when raltitrexed is substituted for 5-FU, which is of particular relevance due to the many overlapping characteristics of patients with cardiac pathology and esophageal cancer.

Personalized cancer treatment depends on the accurate and timely detection of the patient tumor variants. LBx enables minimally invasive tumor mutation profiling. We report results of a pan-Canadian LBx program for patients with advanced solid tumors. Plasma samples were tested at Imagia Canexia Health accredited laboratory using the clinically validated Follow It 38-gene panel. A proprietary platform was used to identify clinically relevant variants in the circulating tumor DNA and report results following accepted international guidelines on clinical significance. A total of 4229 eligible patients submitted samples for LBx testing, and reports for 97% of them were delivered within ~8 days. More than 80% of Canadian oncologists from >150 institutions across 12 provinces (11% from rural centers) participated in the project. The patient cohort consisted mostly of advanced or metastatic lung, breast, and colon cancers. ctDNA mutations were detected in >50% of cases, and clinical trials were recommended for 76% of all participants. Health economics modeling analysis found that Follow It® in combination with tissue biopsy was cost-saving and resulted in an additional 0.1138 QALYs gained relative to tissue biopsy alone. The successful pan-Canadian implementation of a cost-effective, robust LBx testing program demonstrated its sustained demand and feasibility, and its potential economic and health benefits.

The management strategies in resectable non-small cell lung cancer (NSCLC) have changed over the last few years. Despite advancements in surgical techniques and conventional chemotherapy, patients with resectable NSCLC remained at high risk of future recurrence. Clinical trials have demonstrated improvements in response rates, pathological outcomes, and survival with the perioperative approach. Considering the findings of these landmark trials, there is a pressing need to contextualize and incorporate these global developments into the national practice framework. This review outlines key developments from recent clinical trials, with a focus on perioperative strategies in early-stage operable NSCLC from a Canadian perspective. We discuss the integration of checkpoint inhibitors in the perioperative setting for patients without actionable genomic alterations, adjuvant targeted therapies for EGFR and ALK mutant disease, and emerging tools such as ctDNA based minimal residual disease monitoring. The article also addresses the practical challenges of implementing these advances within the Canadian healthcare system, including systemic therapy approvals, barriers, and importance of multidisciplinary care to guide clinicians in optimizing patient outcomes.

Liquid biopsy (LB) is a useful tool in patients with advanced non-small cell lung cancer (aNSCLC) to detect actionable molecular alterations and thereby allow genotype-matched therapies. Currently, LB is recommended for individuals diagnosed with aNSCLC who have an insufficient tissue sample or difficult-to-reach tumour tissue. Despite the potential advantages of LB, its incorporation into the standard diagnostic work-up for all newly diagnosed patients with aNSCLC is lacking. Our study aimed to evaluate whether addition of plasma circulating tumor DNA (ctDNA) next generation sequencing (NGS) testing early in the diagnostic work-up for patients with aNSCLC can improve the time to molecular results and treatment initiation. This was a single-centre quality improvement initiative with two cohorts of patients. Patients in the ‘ctDNA cohort’ had plasma ctDNA testing in addition to the standard diagnostic work-up. The ‘reference cohort' was a parallel group of patients who had the standard work-up (no LB). Tissue biopsy and reflex tissue NGS testing were done in both cohorts. ctDNA testing shortened the time to molecular results in the ctDNA cohort compared to the reference cohort (median, 14 vs 35 days; p = 0.01), the time from first respirology/thoracic surgery consult to molecular results (median, 22 vs 48 days respectively; p = 0.01), and the time from medical oncology consultation to initiation of first-line treatment (median, 12 vs 22 days; p = 0.01). In conclusion, in a publicly funded and single-payer healthcare system, ctDNA testing as part of the standard work-up for patients with aNSCLC provides molecular results significantly faster than tissue-based testing and shortens the time to treatment initiation.

Background:Docetaxel, following progression on immunotherapy and platinum-based chemotherapy, remains the standard of care for advanced non-small-cell lung cancer (NSCLC) but offers limited promise. Antibody-drug conjugates (ADCs) may improve outcomes in this population. Objectives:Data from the literature, mainly randomized controlled trials (RCTs), have shown discrepancies. This report evaluates the efficacy and safety of ADCs versus docetaxel in previously treated advanced NSCLC. Design:The systematic review and meta-analysis was conducted focusing on phase II/III RCTs to synthesize available evidence regarding efficacy outcomes and safety of ADCs compared to docetaxel. Data resources and methods:Databases (PubMed (MEDLINE), EMBASE, and Cochrane Library), clinical trial registries, and proceedings of global oncology conferences from January 2015 to November 2024 were screened comparing ADC versus docetaxel. Two researchers independently completed data retrieval and screening work using Covidence. The Cochrane Risk of Bias Tool (RoB 2.0) was used to assess the methodological quality of the included RCTs. The primary outcomes include progression-free survival (PFS) and overall survival (OS), while the secondary outcomes include objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). The pooled hazard ratios (HRs) and odds ratios (ORs) were meta-analyzed using the appropriate generic variance and Mantel-Haenszel methods. Random-effect models were used to compute pooled estimates. Results:Of the 212 records screened, three RCTs involving 1597 patients were included. ADCs did not significantly improve PFS (pooled HR: 0.91, 95% CI: 0.73-1.13). For OS, the pooled HR was 0.88 (95% CI: 0.78-1.00, p = 0.06), reflecting a borderline significant trend favoring ADCs, with negligible heterogeneity (I 2 = 0%). Furthermore, subgroup analysis demonstrated a significant OS benefit in the nonsquamous cohort (HR: 0.85, 95% CI: 0.74-0.98, p = 0.03). In addition, no difference was observed in ORR (OR: 1.16, 95% CI: 0.54-2.51) and DCR (OR: 1.39, 95% CI: 0.75-2.57). Grade ⩾ 3 treatment-related AEs were significantly lower (pooled OR: 0.49, 95% CI: 0.26-0.90, p = 0.02) with ADCs, despite high heterogeneity (I 2 = 87%). Conclusion:Overall, there was no difference between the docetaxel and the ADC treatment arms; however, our findings report a significant survival benefit in the subgroup of patients with nonsquamous NSCLC pathology treated with ADCs compared to docetaxel with a manageable safety profile. Further research is needed to address heterogeneity, refine patient selection, and obtain more mature survival data with predictive biomarkers.

Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small-cell lung cancer (NSCLC) accounting for the majority of the cases. Despite advancements in targeted therapies and immunotherapies, many patients still rely on chemotherapy, highlighting the need for innovative treatment strategies. Bispecific antibodies (bsAbs), which feature two distinct binding sites capable of targeting different antigens, have emerged as a promising therapeutic approach, particularly in combination with chemotherapy. This review explores the scientific evolution and clinical application of bsAbs in NSCLC, focusing on their synergistic potential with chemotherapy. BsAbs, such as amivantamab, which targets EGFR and MET, have demonstrated significant efficacy in clinical trials, particularly in patients with EGFR mutations. The combination of bsAbs with chemotherapy enhances immune-mediated tumor destruction by modulating the tumor microenvironment and overcoming resistance mechanisms. Recent clinical trials have shown improved progression-free survival and overall survival when bsAbs such as amivantamab are combined with chemotherapy, underscoring their potential to transform NSCLC treatment. Many other clinical trials are underway that are evaluating newer bsAbs, such as ivonescimab, which targets PD1 and VEGF. This review also discusses ongoing clinical trials investigating various bsAbs targeting EGFR, PD-1, PD-L1, HER2, and other pathways, highlighting the future directions of bsAb-based therapies. As the field evolves, bsAbs are poised to become a cornerstone of multimodal NSCLC treatment, offering more effective and personalized therapeutic options for patients with advanced disease.