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.

Objectives: Despite a good response to first-line chemotherapy, small-cell lung cancer (SCLC) has high relapse rates and a poor prognosis. We conducted a systematic review and meta-analysis to assess the role of immune checkpoint inhibitors (ICIs) in the treatment of extended stage SCLC (ES-SCLC), in different lines of therapy. Methods: Medline (PubMed), EMBASE, and Cochrane Library databases between January 2010 and March 2025 and conference proceedings between 2018 and 2025 were searched for RCTs assessing ICIs versus chemotherapy in patients with ES-SCLC. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints included objective response rate (ORR) and grade 3+ adverse events. Pooled hazard ratios (HR) for OS and PFS were meta-analyzed using the generic inverse variance method, and random-effect models were used to compute pooled estimates. Subgroup analyses compared survival by line of therapy, sex, age, and ECOG status. Results: ICIs decreased risk of death by 19% (HR: 0.81, 95% CI: 0.76-0.86). OS benefit was regardless of age, sex, or ECOG, but only in first-line treatment. ICIs decreased the risk of disease progression by 22% (HR: 0.78, 95% CI: 0.67-0.91), with PFS benefit restricted to first-line treatment with a detrimental effect in the second line. ICIs improved ORR (OR: 0.79, 95% CI: 0.66-0.95), but were associated with increased grade 3+diarrhea (OR: 3.63, 95% CI: 1.46-9.02). Conclusions: ICIs conferred efficacy benefits and an acceptable safety profile in the treatment of patients with ES-SCLC in the first-line, but should not be used in the second-line as single agents. Biomarkers predicting long-term benefit are needed to further improve outcomes.

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.

BACKGROUND:Acute kidney injury (AKI) is a known immune-related adverse event of cancer immune checkpoint inhibitor (ICI) therapy. Further population-based data on AKI incidence, risk factors and practice patterns post-ICI therapy are needed. METHODS:We measured the cumulative incidence of AKI among advanced cancer patients while receiving ICI therapy and non-ICI systemic therapy in Ontario, Canada (2012-18). An increase in serum creatinine was used to define AKI and graded according to event severity. Time to event modeling was used to compare the risk of developing AKI, pre-disposing factors and survival outcomes. RESULTS:We studied 16 425 patients with advanced cancer receiving either ICI or non-ICI systemic therapy. Among 4380 patients receiving ICI therapy, the overall crude 4-year incidence of AKI (any stage) was 29% and severe AKI (stage ≥2) was 7%. Characteristics associated with a higher risk of AKI included male sex, genitourinary (versus other) malignancy, the presence of hypertension, diabetes or chronic kidney disease, and prescription of a non-steroidal anti-inflammatory drug. The risk of experiencing AKI was significantly lower among patients treated with ICI versus non-ICI systemic therapy [adjusted hazards ratio (aHR) 0.80, 95% confidence interval (CI) 0.74-0.86, P-value <.0001]. Among the 587 patients who experienced an AKI and were both alive and discontinued ICI therapy within 30 days, 54 (9%) were re-challenged with ICI in the following 6 months and 24 (44%) had a recurrent AKI event. Patients who were re-challenged with ICI therapy had improved overall survival as compared with patients that received other non-ICI systemic therapy (aHR 0.38, 95% CI 0.22-0.67, P-value <.001). CONCLUSION:Our real-world study demonstrates a modest risk for severe AKI among cancer patients receiving ICI therapy, lower than with exposure to other systemic cancer therapies. Among patients who developed AKI and stopped ICI therapy, re-challenge was uncommon but may warrant consideration for select patients.

OBJECTIVES:Despite a good response to first-line chemotherapy, small-cell lung cancer (SCLC) has high relapse rates and a poor prognosis. We conducted a systematic review and meta-analysis to assess the role of immune checkpoint inhibitors (ICIs) in the treatment of extended stage SCLC (ES-SCLC), in different lines of therapy. METHODS:Medline (PubMed), EMBASE, and Cochrane Library databases between January 2010 and March 2025 and conference proceedings between 2018 and 2025 were searched for RCTs assessing ICIs versus chemotherapy in patients with ES-SCLC. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints included objective response rate (ORR) and grade 3+ adverse events. Pooled hazard ratios (HR) for OS and PFS were meta-analyzed using the generic inverse variance method, and random-effect models were used to compute pooled estimates. Subgroup analyses compared survival by line of therapy, sex, age, and ECOG status. RESULTS:ICIs decreased risk of death by 19% (HR: 0.81, 95% CI: 0.76-0.86). OS benefit was regardless of age, sex, or ECOG, but only in first-line treatment. ICIs decreased the risk of disease progression by 22% (HR: 0.78, 95% CI: 0.67-0.91), with PFS benefit restricted to first-line treatment with a detrimental effect in the second line. ICIs improved ORR (OR: 0.79, 95% CI: 0.66-0.95), but were associated with increased grade 3+diarrhea (OR: 3.63, 95% CI: 1.46-9.02). CONCLUSIONS:ICIs conferred efficacy benefits and an acceptable safety profile in the treatment of patients with ES-SCLC in the first-line, but should not be used in the second-line as single agents. Biomarkers predicting long-term benefit are needed to further improve outcomes.

Trials have shown that FMT plus immune checkpoint inhibitors (ICI) could improve ⍺PD-1 response in melanoma. The microbiome and immune shift, along with the clinical impact of FMT with ⍺PD-1 in non-small cell lung cancer (NSCLC) and in combination with ⍺PD-1+⍺CTLA-4 (dual ICI) in melanoma is unknown. 20 patients (pts) with advanced NSCLC treated with first-line (1L) ⍺PD-1 and 20 with advanced melanoma treated with 1L dual ICI were recruited. FMT from 1 healthy donor (HD) was administered orally to each pt post bowel prep. 1 week later ICI was initiated. A total of 11 different HD were used. The primary endpoint was objective response rate (ORR). The gut microbiome was profiled using shotgun metagenomics. Metabolomic profiling was performed using HPLC. Olink proteomics (96 markers) on plasma and flow cytometry (40 markers) on PBMCs were assessed. FMT was performed in germ-free (GF) mice to recapitulate engraftment. In NSCLC, ORR was 80% (16 PR) with no grade >3 immune-related adverse events (irAE). In melanoma, ORR was 75% (5 CR), with 65% (13 pts) developing grade >3 irAE, including 3 (15%) myocarditis. The irAE occurred earlier than previously reported (median onset of 42 days). Pre-FMT patient microbiome composition was distinct from HD. Post-FMT, the responders (R) and non-responders (NR) clustered separately (p=0.03). Post-FMT, we observed increased polyamines and bile salts in R. Elevation of exhausted T central and T effector memory cells were noted in R. Conversely, proteomics analyses revealed elevated markers of immune exhaustion including CD28 and IL10 in NR. Addressing the link between microbiome and irAE, in melanoma, 6 out of the 13 pts (46%) that developed grade >3 irAE, including 2/3 of the myocarditis received FMT from the same donor (D5). D5 was not associated with irAE in NSCLC treated with ⍺PD-1 alone. Microbiome analysis revealed that D5 clustered separately (p<0.01) from other HD with a high relative abundance of Prevotella copri. We observed a signal for the development of irAE in pts that engrafted P. copri. Pts with grade>3 irAE exhibited higher levels of leaky gut markers such as sST2 post-FMT (p=0.002). In GF mice, oral gavage of baseline stool of R, only when followed by the stool of the respective donor, led to a significant increase in ⍺ diversity and number of species engrafted over time (p<0.01), while those that received baseline stool from NR with or without donor had no change in ⍺ diversity or species engrafted. This study validates the role of FMT to improve ICI activity in NSCLC and melanoma, while differentially modulating irAE according to ICI backbone. We demonstrated that the microbiome shift is distinct among R while engraftment of P. copri was associated with dual ICI irAE. Our results directly inform future microbiome-centered trials. Sreya Duttagupta, Meriem Messaoudene, Rahima Jamal, Catalin Mihalcioiu, Nicolas Marcoux, Sebastian Hunter, Gianmarco Piccinno, Michal Puncochár, Karl Bélanger, Mustapha Tehfe, Normand Blais, Scott Owen, Jacques Raphael, Jade Maillou, Yongjia Hu, Myriam Benlaifaoui, Somayeh Nilli, John Lenehan, Wiam Belkaid, Seema Nair Parvathy, Diogjena Katerina Prifti, Marine Fidelle, Seunghee Kim-schulze, Thomas Marron, Sylvere Durand, Guido Kroemer, Nicola Segata, Lisa Derosa, Laurence Zitvogel, Antoine Desilets, Michael Silverman, Saman MalekiVareki, Bertrand Routy, Arielle Elkrief. Microbiome profiling reveals that fecal microbiota transplantation (FMT) modulates response and toxicity when combined with immunotherapy in patients with lung cancer and melanoma (FMT-LUMINate NCT04951583) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2210.

BACKGROUND:Immunotherapy in the presence of COVID-19 infections raises concerns because of potential overlapping clinical complications and immune system enhancement. Further investigation is warranted to establish its safety and to improve clinical decisions. METHODS:We conducted a retrospective cohort study using linked health administrative data from Ontario, Canada to assess 30-day mortality in patients with solid tumors who were treated with immunotherapy within 120 days before testing positive for COVID-19. A stepwise multivariable logistic regression model was used to identify clinical factors associated with 30-day mortality. RESULTS:Between January 2020 and April 2023, 281 patients tested positive for COVID-19 and were included in our study. The mean age was 68 (Standard Deviation: 10.3), 45% (127/281) were females and 58% (163/281) had lung cancer. 59% of patients (167/281) were treated with single agent immunotherapy, and almost 80% received at least one dose of COVID-19 vaccine. The 30-day mortality was 22% (63/281) and < 5% of patients were admitted to ICU or required ventilation. Factors associated with higher mortality were older age (Odds Ratio (OR) 1.60, 95% confidence interval (CI) 1.07-2.39), prior radiation therapy (OR 2.38, 95%CI 1.08-5.28), lower hemoglobin (< 10 g/dl) (OR 4.08, 95%CI 1.89-8.82) and higher leucocytes count (> 11,000/mm3) (OR 3.63, 95%CI 1.55-8.52). CONCLUSIONS:Immunotherapy does not seem to increase the risk of 30-day mortality in patients with COVID-19 infections compared to published outcomes of patients with cancer and COVID-19. Mortality was associated with certain clinical characteristics that need to be carefully examined when prescribing immunotherapy during future comparable pandemics.

LBA1005 Background: Standard first line therapy in ER+/ HER2 negative endocrine sensitive metastatic breast cancer (MBC) is a CDK4/6 inhibitor plus AI. Upon progression the majority of patients will receive further endocrine based therapy. Alterations in PI3K/AKT pathway genes are a known mechanism of endocrine resistance – either de novo or acquired. The MA.40 trial evaluated the efficacy and safety of the AKT inhibitor ipatasertib versus placebo plus fulvestrant in the metastatic breast cancer (MBC) setting immediately post progression on 1 st line CDK4/6 inhibitor and AI. Methods: This phase III, randomized, double-blind trial enrolled pre/peri/postmenopausal women and men with ER+/HER-2 negative MBC. Patients were randomly assigned 1:1 to receive ipatasertib plus fulvestrant versus (vs) placebo plus fulvestrant. Stratification factors included: AKT pathway altered ( PIK3CA , AKT1 , and/or PTEN genomic alteration(s)) vs wild-type/unknown and endocrine resistance (primary vs secondary). Primary objective: To compare investigator assessed PFS (RECIST 1.1) between treatment arms in the ITT population. Pre-specified secondary analysis: PFS in the AKT pathway altered cohort using a hierarchical procedure. The FoundationOne Liquid cfDNA NGS assay was utilized to assess genomic alterations in the AKT pathway for stratification. Results: 250 participants (females 247/males 3) were enrolled from Canada, Australia and New Zealand between January 2021 and May 2024. Baseline characteristics between arms were balanced. 44.4% of the study population had AKT pathway alteration(s) per cfDNA assay. Median follow-up 15.2 months(mo); proportion remaining on protocol treatment at time of analysis 21.0% ipatasertib vs 11.3% placebo arm. Median PFS ITT ipatasertib vs placebo arms were: 5.32 mo (95% CI: 3.58 to 5.62 mo) vs 1.94 mo (95% CI: 1.84 to 3.22 ) [HR 0.61, 95% CI: 0.46 to 0.81; p= 0.0007] and in the AKT pathway altered cohort: 5.45 mo (95% CI: 3.55 to 11.01 ) vs 1.91 mo (95% CI: 1.77 to 3.48) [HR = 0.47, 95% CI: 0.31 to 0.72; p= 0.0005]. Grade 3 or higher adverse events (AE) ipatasertib vs placebo arms (%):37.1 vs 27.4. Grade 3 or higher non haematological treatment related AE > 1% ipatasertib vs placebo arms: diarrhea (16% vs 0%); fatigue (3% vs 0%); vomiting (2% vs 0), rash (2% vs 0%). Treatment discontinuation due to AEs ipatasertib vs placebo arms: 6.5% vs 0.8%. Conclusions: Ipatasertib plus fulvestrant significantly prolongs PFS compared to placebo/fulvestrant in patients with hormone receptor–positive MBC post progression on 1 st line CDK 4/6 inhibitor and AI. Follow-up and additional analyses continue. Supported by Hoffmann-La Roche Ltd, CCS grant #707213. Clinical trial information: NCT04650581 .

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.

Small-cell lung cancer (SCLC) remains a disease with poor prognosis, particularly in extensive-stage SCLC (ES-SCLC). Current standard-of-care treatment includes chemotherapy with platinum agents and etoposide plus immunotherapy with atezolizumab or durvalumab, which has achieved a mean overall survival of 12-13 months in clinical trials. However, long-term survival in ES-SCLC, even with the addition of immunotherapy, continues to be rare. We present the case of a middle-aged male patient diagnosed with ES-SCLC who was treated with four cycles of induction chemotherapy (carboplatin and etoposide) and atezolizumab, starting maintenance atezolizumab every 21 days thereafter, and thoracic radiotherapy. After 9 months, he experienced mild disease progression and was rechallenged with six cycles of carboplatin and etoposide with continued atezolizumab. Subsequent imaging showed near-complete disease resolution which has been sustained since. He has continued on maintenance atezolizumab since diagnosis and has achieved 60 months overall survival and 44 months progression-free survival. Throughout treatment, he has maintained a high functional capacity and only experienced one immune-related adverse event. Our patient is representative of a small subset who are capable of achieving durable responses to immunotherapy and his case highlights the need for further research to elucidate the clinical and biological factors driving this response.

e20077 Background: Neoadjuvant (NA) nivolumab-chemotherapy (nivo-chemo) has shown an improved survival and pathological complete response (pCR) rate, vs chemo alone, in early-stage, resectable non-small cell lung cancer (NSCLC). Nevertheless, there is a paucity of real-world data. Methods: We performed a real-world, retrospective analysis of outcomes and toxicities in patients with resectable NSCLC (stage IB-IIIA; EGFR/ALK alterations excluded) treated with three cycles of NA nivo-chemo followed by surgery at a single, tertiary-level Canadian cancer centre from September 2022 to September 2023. Results: Fifteen patients were treated with NA nivo-chemo. The median age was 70 years (range, 58 to 78) and 66% were males. 20% (n-3) and 40% (n-6) had N1 and N2 nodes, respectively. All patients completed three cycles of NA nivo-chemo. Objective response rate was 73% (n-11); including 1 complete response. Progression was noted in two patients (the CT predated initiation of treatment by more than 8 weeks in these patients). The median time to surgery was 10.6 weeks (range, 6-17.5). 80% patients (n-12) had a surgery (1 pneumonectomy, 11 lobectomies); and of these, 83% (n-10) are on surveillance while two patients had an event (death or progression). All (n-11) had R0 resection except one. 33% patients (n-5) had a pCR, including two with stage IIIA disease (PDL1 TPS < 1% in three patients, PDL1 TPS ≥ 50% in two patients). 60% patients were started at a reduced chemo dose in cycle 1. 25% patients required further dose reduction. Grade 3 or 4 toxicities were seen in 25% patients (n-4) (neutropenia (n-2), febrile neutropenia (n-1) and pneumonitis (n-1)). Surgical complications were seen in 33% patients (n-5), including death in one patient due to postoperative intrathoracic bleed. Conclusions: NA nivo-chemo in resectable NSCLC is safe and associated with improved pCR rate. A few patients may progress on NA treatment or have a grade 3-5 toxicity precluding curative surgery. Hence, individualized informed decisions should be made. There is an unmet need of biomarkers/models that can predict pCR/toxicity for better patient selection. [Table: see text]

INTRODUCTION:The aim of this systematic review and meta-analysis was to review evidence and pool outcomes to assess the effectiveness of stereotactic ablative radiotherapy (SABR) in patients treated for oligoprogressive metastases. METHODS AND MATERIALS:A search was conducted January 2010 to January 2023 in five bibliographic databases for studies of patients with oligoprogressive disease treated with SABR to all lesions. Clinical outcomes included PFS (progression-free survival), OS (overall survival) and CST (change in systemic therapy). Descriptive statistics were used to summarize the data. Binary random effects model was used for pooled analyses. RESULTS:12,366 titles/abstracts screened, of which 25 met eligibility criteria and were included the review. All studies were published after 2017 with approximately 80% of the publications in 2021 and 2022. The primary tumour was prostate (n=8, 32%), kidney (n=6, 24%), colorectal (n=4, 16%) followed by breast (n=3, 12%), lung (n=2, 8%) and mixed (n=3, 12%). At 1 year, the pooled PFS was 44% (95% confidence interval [CI]: 34-53%, I2=91%); 53% (95% CI: 45-60%, I2=46%) in prostate, 49% (95% CI: 33-65%, I2=88%) in kidney, 62% (95% CI: 11-113%, I2=96%) in lung, 13% (95% CI: 3-24%, I2=39%) in breast and 30% (95% CI: 19-41%, I2=59%) in mixed. DISCUSSION:There has been a surge in publications describing the use of SABR in oligoprogressive tumours. Published studies are mostly retrospective reported in prostate and kidney cancers, with limited evidence in other sites. Universal guidelines are recommended to ensure consistency in reporting and comparability of future studies.

Purpose/Objective(s) Recent efforts aimed to add ICI to chemotherapy in the neoadjuvant and adjuvant setting (Neo/Adj) to improve outcomes of patients with resectable NSCLC. The objective of this systematic review and meta-analysis is to evaluate the efficacy and safety of such strategy and identify subgroups of patients who may derive the most benefit. Materials/Methods Randomized control trials comparing Neo/Adj ICI plus chemotherapy vs chemotherapy alone in resectable NSCLC (pre-Sep 2022) were retrieved from PubMed, Embase, Cochrane Library and updated based on recent conferences. Primary outcomes were pathological complete response (pCR), event-free, disease-free, and progression-free survival (EFS, DFS, PFS). Secondary outcomes were major pathologic response (MPR), overall survival (OS), and safety. Subgroup analyses of EFS/ DFS/ PFS included histology, smoking status, and PDL-1 status. Pooled hazard ratios (HR), odds ratios (OR) and risk ratios (RR) were meta-analyzed using the generic variance, Peto and Mantel-Haenszel methods as appropriate. Random effect models were used to compute pooled estimates. Results 3926 patients across five neoadjuvant and two adjuvant trials were included. Neoadjuvant ICI improved pCR fivefold compared to chemotherapy alone (OR 5.35; 95% CI, 4.02 - 7.13). Both neo- and adjuvant use of ICI decreased recurrence risk by 34% (HR 0.66; 95% CI, 0.54 - 0.81). Two-year OS improved with adding either neo- or adjuvant ICI (RR 0.73; 95% CI, 0.58 - 0.92) with a trend towards better median OS (HR 0.76; 95% CI, 0.57 - 1.02). Neoadjuvant ICI improved MPR fourfold vs. chemotherapy (OR = 3.91; 95%, CI 2.90 - 5.28). In subgroup analyses, those with non-squamous NSCLC, ever smokers, and tumors with PD-L1>=1% seem to derive a greater benefit from ICI. Neo/Adj ICI increased immune-related adverse effects risk threefold (RR = 3.36; 95% CI, 2.11 - 5.36), with an increase in grade 3 treatment-related toxicity (RR = 1.28; 95% CI, 0.93 - 1.78). Conclusion Based on preliminary data, adding Neo/Adj ICI improves recurrence rate in resectable NSCLC with a trend towards improved OS. Safety signals were consistent with historical data. Further subgroup evaluations may help to identify suitable population for either approach.

e15030 Background: Programmed death-ligand 1 (PD-L1) is a predictive biomarker for immunotherapy in the treatment of non-small cell lung cancer (NSCLC). Assessing PD-L1 expression from the tumor specimen can be challenging because of tissue accessibility, heterogeneity, and dynamic changes in PD-L1 expression that may impact the status of PD-L1 during disease evolution and treatment. Hence, assessing PD-L1 status from archival tumor might not reflect its actual state on the tumor and having a real-time assessment of its expression with the use of non-invasive techniques such circulating tumor cells (CTCs) is useful. Methods: We conducted a single centre prospective study to detect CTCs in the blood of patients with stage III-IV NSCLC treated with immunotherapy using the standard CellSearch technology for CTC enumeration and the Epic Sciences technology for CTCs enumeration and assessment of PD-L1 protein expression on CTCs. CTCs were detected at baseline before treatment initiation and after 2 cycles of treatment. Study endpoints included CTCs detection and concordance between the 2 technologies, PD-L1 expression assessment on CTCs with the Epic Sciences technology, and concordance with tissue-based expression. Comparisons were made using Pearson correlation coefficient (PCC) and intraclass correlation coefficient (ICC) for count data and percentage of perfect agreement. Results: Between 2019 and 2022, 48 patients treated with immunotherapy were enrolled in the study. The mean ± standard deviation (SD) age was 66.8 ± 10.3 years, 63% were females, 42% received combination chemotherapy and immunotherapy, and 44% had adenocarcinoma histology. The tissue PD-L1 expression was high (≥50%), intermediate (1-49%), and low (<1%) in 36%, 31% and 33% of patients respectively. The mean ± SD baseline CTCs count per 7.5ml was 1.97 ± 4 with CellSearch and 1.38 ± 2.72 per ml with Epic Sciences. After 2 treatment cycles, 22% and 41% of patients had an increase in their CTCs count with CellSearch and Epic Sciences, respectively and 30% and 29% had a decrease in their CTCs. The PCC and ICC for baseline CTCs detected by CellSearch and Epic Sciences were 0.72 and 0.61, respectively and for CTCs detected after 2 cycles of treatment by the 2 technologies were -0.16 and 0.45 respectively. One patient had PD-L1 expression on their CTCs with the Epic Sciences technology and there was no association between the PD-L1 expression on CTCs and on matched tissue samples. Conclusions: This study showed a moderate to strong correlation between the 2 technologies for baseline CTCs detection and moderate to poor correlation for CTCs detection after 2 cycles of therapy. No association was found between CTCs and tissue PD-L1 expression. Future work needs to further investigate the role of PD-L1 expression on CTCs.

Immune-checkpoint inhibitors (ICIs) have an established role in the treatment of locally advanced and metastatic non-small cell lung cancer (NSCLC). ICIs have now entered the paradigm of early-stage NSCLC. The recent evidence shows that the addition of ICI to neoadjuvant chemotherapy improves the pathological complete response (pCR) rate and survival rate in early-stage resectable NSCLC and is now a standard of care option in this setting. In this regard, stage III NSCLC merits special consideration, as it is heterogenous and requires a multidisciplinary approach to management. As the neoadjuvant approach is being adopted widely, new challenges have emerged and the boundaries for resectability are being re-examined. Consequently, it is ever more important to carefully individualize the treatment strategy for each patient with resectable stage III NSCLC. In this review, we discuss the recent literature in this field with particular focus on evolving definitions of resectability, T4 disease, N2 disease (single and multi-station), and nodal downstaging. We also highlight the controversy around adjuvant treatment in this setting and discuss the selection of patients for adjuvant treatment, options of salvage, and next line treatment in cases of progression on/after neoadjuvant treatment or after R2 resection. We will conclude with a brief discussion of predictive biomarkers, predictive models, ongoing studies, and directions for future research in this space.