e19036 Background: Alopecia is a recognised toxicity of Brentuximab Vedotin (BV), but data on the duration and long-term psychosocial consequences are limited. This study aimed to characterise the patterns of BV-associated alopecia and its impact on patient wellbeing. Methods: Patients diagnosed with Hodgkin’s Lymphoma, aged 16 years or above who received Brentuximab Vedotin along with AVD (Adriamycin, Vinblastine, Dacarbazine) were included. All patients had a minimum follow-up of 12 months post completion of chemotherapy. A structured, patient-completed questionnaire captured responses about patterns of hair loss, and various domains of patient wellbeing. Alopecia was graded using CTCAE criteria. Results: Thirteen patients were included, median age 45(range 16-60); female: male (9:4). Twelve (92%) patients completed six cycles of BV+AVD. All patients (100%) experienced generalised alopecia after starting treatment, with a median onset of 4 weeks. One patient had pre-existing androgenic alopecia. Hair regrowth after stopping chemotherapy was reported as normal in 8/13 (61.5%), while 5/13 (38.5%) had persistent abnormal regrowth at a median follow-up of 27 months (range 12-62 months) after treatment. Among these, one reported grade 2 and four reported grade 1 alopecia. Four patients attempted dermatologic treatments with minimal benefit. Qualitative comments highlighted substantial heterogeneity: some patients embraced hair loss or viewed it as an expected treatment effect, while others reported profound self-consciousness, changes in identity, avoidance of social situations, and persistent difficulty moving beyond the “cancer patient” identity. Eyebrow and eyelash loss were described as particularly distressing. Conclusions: Despite brentuximab vedotin’s wide use and favourable therapeutic profile, this evaluation highlights a crucial and under-recognised toxicity. Nearly 40% of patients reported persistent alopecia more than two years after treatment, with significant psychosocial consequences. The prolonged nature of hair loss underscores the need for further research into the mechanisms underlying BV-associated alopecia, to better guide prevention, counselling, and supportive interventions as this valuable therapy continues to be widely used. Patient-Reported QoL Outcome Percentage Reduced self confidence 29 Reduced willingness for social activities 29 Emotional distress related to alopecia 36 Difficulty accepting changes in appearance 36 Felt adequately supported (family/friends/healthcare staff) 64 Reported insufficient support 21 Financial burden from hair-loss treatments 14

BACKGROUND:Mismatch repair deficiency (MMRd) is a key determinant of tumour biology, however, its prognostic significance in patients with resectable oesophagogastric adenocarcinoma treated with perioperative cytotoxic chemotherapy remains uncertain. METHODS:MMR status was assessed in 1424 patients with oesophagogastric adenocarcinoma enroled in the MRC OE05 and ST03 trials, which investigated perioperative chemotherapy regimens. Associations between MMR status, clinicopathological variables, overall survival (OS), progression-free survival (PFS) and post-progression survival (PPS) were investigated. RESULTS:In total, 78 (5.5%) tumours were MMRd, 80.8% due to MLH1 loss. Patients with MMRd tumours had improved OS compared with patients with MMR proficient (MMRp) tumours (median unreached vs 28.0 months; p = 0.0009; 5-year rates 50.1% vs. 34.3%), and PFS (median 56.7 vs 21.4 months; p = 0.0032). On multivariable analysis, MMRd remained associated with improved OS (HR 0.60, 95% CI 0.42-0.87; p = 0.007) and PFS (HR 0.64, 95% CI 0.45-0.90; p = 0.011). PPS did not differ by MMR status. DISCUSSION:This is the first study to suggest that perioperative cytotoxic chemotherapy does not abrogate the favourable prognostic impact of MMRd prior to disease progression. However, MMR status did not influence survival after progression. Our results challenge clinical concerns that cytotoxic chemotherapy may be detrimental in patients with resectable MMRd oesophagogastric adenocarcinoma.

Introduction: Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer-related mortality. Radiological distinctions between borderline resectable (BR) and locally advanced disease (LA) are increasingly recognised as imperfect when considered without dynamic assessment. Neoadjuvant therapy (NAT) improves outcomes through tumour downstaging and early treatment of occult metastatic disease, but the optimal NAT strategy, particularly in BR disease, remains uncertain. Published data evaluating combined systemic anti-cancer therapies (SACT) with or without chemoradiation (CRT) are limited and heterogeneous. Methods: This is a single-centre retrospective analysis of 44 patients with BR PDAC and a comparator cohort of 121 patients with LA PDAC treated with a total neoadjuvant approach of SACT with or without CRT and surgical resection between June 2017 and September 2022. Results: Median overall survival (OS) did not differ significantly between BR and LA disease (18 vs. 16 months, p = 0.14). Following NAT, 47.7% of BR and 18.1% of LA patients were anatomically suitable for surgical resection. Among unresected BR and LA patients, those treated with CRT in addition to SACT had a median OS of 18 and 21 months respectively. In the resected subgroup, resection margin status was the primary factor associated with survival; with R0 resection conferring a substantial OS advantage over R1, irrespective of initial BR/LA classification as diagnosis (47 vs. 22 months, p < 0.001). Conclusions: Despite anatomical differences at diagnosis, BR and LA PDAC demonstrated comparable survival outcomes when treated with total neoadjuvant strategies in this cohort. These findings challenge traditional radiological staging-based treatment paradigms and confirm that a margin-negative surgical resection offered the greatest opportunity for long-term survival for BR/LA PDAC patients.

BACKGROUND:In oesophageal cancer (OeC) patients, neoadjuvant chemotherapy followed by surgery improves survival. Anti-tumour immune responses are mediated by lymph node (LN) microarchitecture. We investigated whether neoadjuvant chemotherapy and/or presence of tumour changes LN microarchitecture, and whether such changes are associated with survival. METHODS:Microarchitectural features (lymphocytes, germinal centres (GermC), histiocytes) were quantified morphometrically in 433 LNs from 333 OE02 trial patients (165 neoadjuvant chemotherapy+surgery (CS), 168 surgery alone (S)). Features were compared between tumour-negative (LNneg) and tumour-positive LN (LNpos) by treatment group. Associations with clinicopathological variables and overall survival (OS) were evaluated. RESULTS:LNneg GermC density was lower in CS patients than in S patients (median: 1% vs 2%; p = 0.0004). No other microarchitectural features differed by treatment group or LN status (LNneg vs LNpos). Low histiocyte content in LNneg and LNpos was associated with improved OS in S patients only (HR:0.67, 95%CI: 0.46-0.97, p = 0.03). Multivariable analysis confirmed the independent prognostic significance of LNneg histiocytes (HR:0.62, 95%CI: 0.42-0.9, p = 0.01). CONCLUSION:These findings suggest that LN microarchitecture may be a biomarker for treatment-related immune modulation and prognosis in patients with resectable OeC. These findings warrant independent validation and further investigation to determine whether LN microarchitectural features could inform personalised therapeutic strategies.

Tumour infiltrating lymphocytes (TILs) are a key component of the tumour microenvironment. To establish a clinically relevant TILs cut-off for patients with oesophago-gastric (OG) cancer, it is essential to know whether TILs density varies by patient and/or disease characteristics. TILs were quantified as TILs/mm2 (TILs density) by a deep-learning algorithm applied to digitised Haematoxylin/Eosin (H E)-stained biopsies and resection specimens from 4628 patients from nine phase III trials. 4533 patients with TILs density and matched clinicopathological data were included in the final analyses. Associations between TILs density, disease stage, geographical region (UK versus Asia), sex, age, and treatment were analysed. Median TILs density was higher in pre-treatment biopsies from patients with early-stage versus late-stage disease (962 vs 479 TILs/mm2, p < 0.001). Within the same geographical region and disease stage, TILs density was similar across different chemotherapy regimens. In UK-led trials of early-stage disease, post-chemotherapy resections showed higher TILs density than chemotherapy-naïve resections (618 vs 571 TILs/mm2, p = 0.003). TILs density was higher in Asian tumours compared to UK tumours (1419 vs 571 TILs/mm2, p < 0.001). No significant associations were observed with age or sex. This is the largest study to date evaluating TILs density in OG cancer. TILs density varied with stage and geographical region but not by age or sex. These findings may explain enhanced response to immunotherapy observed in published studies of patients with early-stage disease and highlight the need to account for baseline TILs heterogeneity when interpreting TILs as a possible biomarker in future studies.

Abstract Background To investigate whether the diffusion kurtosis imaging (DKI) technique can identify tumour response to an anti-angiogenic therapy in a pilot study of patients with RAS-mutant colorectal liver metastases. Methods This prospective imaging study enrolled 20 participants receiving Regorafenib treatment. A target metastasis > 2 cm in each patient was imaged before and at 15 days after treatment on a 1.5T MR scanner using a coronal, free-breathing DKI protocol. Data were motion-corrected and modelled using both the mono-exponential and DKI models. Median values derived from voxel-wise analysis of the whole delineated tumour were reported for three parameters [apparent diffusion coefficient (ADC, 10 − 3 mm 2 /s), apparent kurtosis (K, a.u.) and kurtosis-corrected apparent diffusion (D, 10 − 3 mm 2 /s)] before and after treatment. A 5-patient supplementary cohort was used to assess the repeatability of DKI parameters using the Bland-Altman analysis. Changes in pre- and post-treatment measurements of the three parameters were assessed using Wilcoxon signed-rank tests ( P < 0.05 was considered significant). Diffusion weighted imaging (DWI) and DKI parameter correlations were evaluated with Spearman tests. Functional MR parameters were also compared against Response Evaluation Criteria In Solid Tumours v.1.1 (RECIST) evaluations. Results Significant treatment-induced changes across the cohort were observed for all parameters: K decrease (0.907 vs. 0.786, P < 0.01; 13.3%), D increase (1.256 vs. 1.386 × 10 − 3 mm 2 /s, P < 0.001; 10.4%) and ADC increase (0.910 vs. 1.035 × 10 − 3 mm 2 /s, P < 0.001; 13.7%). For both visits, Spearman correlation tests found a moderate negative correlation between K and D, ( r =-0.70; P < 0.001 and r =-0.58; P < 0.01) and a strong positive correlation ( r = 0.84 and 0.88; P < < 0.001) between ADC and D. The repeatability R was lowest for K (51%), followed by D (12%), and ADC (9.4%). When compared to RECIST v.1.1 evaluations, K identified no clinical responders, whilst D and ADC identified 7/12 and 11/12 responders. Conclusions Both ADC and DKI parameters showed a significant early cohort change to the anti-angiogenic effects of Regorafenib treatment in RAS-mutant colorectal liver metastases. The ADC parameter performed better than the K parameter in identifying patients benefitting from the treatment. Trial registration NCT03010722 clinicaltrials.gov; registration date 6 th January 2015.

Epcoritamab, a CD3xCD20 bispecific antibody, resulted in deep, durable responses with a manageable safety profile in patients with relapsed/refractory large B-cell lymphoma (LBCL) in EPCORE® NHL-1 (NCT03625037). We report results from a 3-year follow-up. Adults with relapsed/refractory LBCL received epcoritamab until progressive disease or unacceptable toxicity. The primary endpoint was overall response rate (ORR). Median age was 64.0 years, 39

To evaluate the feasibility, safety, and technical performance of robot-assisted CT-guided cryoablation for pulmonary metastases. A single-centre IDEAL stage 2a prospective development study of 26 participants (median age 62 years, IQR 47–71; 14 men) who underwent 30 procedures targeting 37 lung metastases using a robotic navigation system. Median tumour diameter was 9.8 mm (IQR 5.1–12.8). All procedures were performed under general anaesthesia with high-frequency jet ventilation. Feasibility, safety, and technical performance (targeting accuracy, manipulations, radiation dose) were recorded. Robotic guidance was successfully completed without conversion in 35/37 tumours (95

7053 Background: Second primary malignancies (SPMs) are the leading cause of long-term treatment-related mortality in Hodgkin Lymphoma (HL). Although substantial improvements have been made to treatments over recent decades, few studies have demonstrated reduced SPM risk, particularly following modern treatments, and how risks should inform screening. Methods: We assembled a national cohort of 7,428 women treated for HL aged <36 across England & Wales 1954-2010, with 99% complete follow-up until 2018. We analyzed SPM incidence from national cancer registry linkage. Treatment data were collated from >250 treatment centers. Standardized incidence ratios (SIRs) and Absolute Excess Risks (AERs) for SPMs were calculated, and multivariable analyses (Hazard Ratios, HR) were undertaken to assess the impact of changes in treatment and assess changing incidence trends over time. Results: Twelve hundred women (16%) developed 1,467 SPMs with mean follow-up of 22 years (range 0-62 years). Overall SIR to develop any SPM was 3.3 (95% CI 3.1-3.5), with breast cancer contributing the greatest excess risk (AER 30.8 95% CI 27.7-34.1). Radiotherapy use halved from 1954-1980 to 2000-2010 (98% to 47%) and mean dose dropped from 48Gy to 33Gy. Conversely chemotherapy use doubled from 55% to 97%, with anthracyclines used in 94% and classic alkylators in 31% of treatments in the most recent period compared with 6% and 48% respectively pre-1980. Radiotherapy conferred the greatest treatment-specific risk factor for SPMs, (SIR 3.5 95% 3.3-3.7), with a strong dose-response relationship trend (HR 1.01/Gy p<0.001), and highest relative risks seen in those treated with radiotherapy aged <15years (SIR 7.4 (95% CI 5.7-9.1). There was a 25% reduction in SPM risk from the earliest treatment period (<1990) to most recent (2000-2010) and 34% reduction in solid SPM risk (Table). The decrease in risk for SPMs became smaller and non-significant after adjusting for reduced radiotherapy use and dose (HR 0.89, p trend 0.11). There was no attenuation after adjustment for chemotherapy. Despite declining risks, risks remained significantly elevated beyond 40 years after treatment. Conclusions: Modern HL treatments are associated with a substantial reduction in SPM risks, which appears to be largely attributable to decreased radiotherapy use and dose. However large persistent excess risks, particularly for breast and lung cancers, underscore the need for targeted screening in high-risk survivors treated in more recent eras. Risk of SPMs by treatment era. SPMs & treatments Treated <1990HR (ref) Treated 1990-1999HR (95% CI) Treated 2000-2010HR (95% CI) p trend All SPMs Any treatment 1.0 0.77 (0.65-0.90 0.75 (0.57-0.99) 0.001 Adjusted for radiotherapy & dose 1.0 0.83 (0.69-1.00) 0.90 (0.63-1.28) 0.11 Solid SPMs Any treatment 1.0 0.71 (0.60-0.85) 0.66 (0.48-0.90) <0.001 Adjusted for radiotherapy & dose 1.0 0.79 (0.65-0.96) 0.81 (0.55-1.20) 0.03

Adjuvant chemotherapy for colorectal cancer (CRC) with oxaliplatin and fluoropyrimidine was traditionally given for 6 months but is associated with cumulative peripheral neuropathy. The SCOT study (ISRCTN59757862) was an international, randomized, phase III, noninferiority trial investigating treatment reduction from 6 to 3 months. It originally reported noninferior disease-free survival with reduced toxicity and improved quality of life for 3 months of treatment in 6,088 patients. Here, we report overall survival (OS) with 38 months of additional follow-up. Patients with high-risk stage II and stage III CRC were assigned (1:1) to receive 3 or 6 months of either capecitabine and oxaliplatin (CAPOX) or infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX; bolus and infused fluorouracil with oxaliplatin) that were selected before random assignment. With a median of 113 months follow-up and 1,255 OS events, 5-year OS for 3 versus 6 months of treatment was 82.4% in both groups (hazard ratio, 0.96; 95% CI, 0.8 to 1.07), proving noninferiority of 3 months of treatment. Noninferiority of 3 months of treatment for OS was also shown in 1,087 patients with rectal cancer. The duration effect is regimen-dependent with noninferiority shown for CAPOX but not for FOLFOX. In summary, SCOT has shown noninferiority for OS with 3 months of adjuvant chemotherapy treatment, which should be recommended for most patients.

The phase III VELOUR trial demonstrated improved outcomes with aflibercept plus FOLFIRI in patients with metastatic colorectal cancer previously treated with oxaliplatin-based regimens. We retrospectively evaluated the prognostic and predictive impact of RAS/BRAF mutations, intrinsic consensus molecular subtype (iCMS), and tumour sidedness in 439 profiled patients. Targeted sequencing identified RAS mutations in 57.5

BACKGROUND:PLATFORM is an adaptive phase II trial assessing maintenance therapies in advanced oesophagogastric adenocarcinoma (OGA). We evaluated maintenance capecitabine in patients with disease control after first-line chemotherapy. METHODS:HER2-negative patients with advanced OGA who had response or stable disease after 18 weeks of first-line chemotherapy were randomised (1:1) to surveillance or capecitabine. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS) and safety. RESULTS:Between May 2015 and May 2024, 266 patients were randomised (129 surveillance, 137 capecitabine). Median follow up was 70.7 months. Capecitabine significantly improved PFS (HR 0.69; 95% CI 0.54-0.89; p = 0.002), with median PFS of 5.0 vs 2.8 months. One-year PFS rates were 19.9% vs 6.8%; and two-year rates 8.1% vs 4.3%. No OS difference was observed (median OS: 10.5 vs 10.0 months; HR 0.87; 95% CI 0.67-1.12; p = 0.143). One and two-year OS rates were similar (1-year: 44.1% vs 45.7%; 2-year: 18.8% vs 16.8%). Grade ≥3 adverse events were more frequent with capecitabine (46% vs 29%), with 21% experiencing grade 3 treatment related events. DISCUSSION:Maintenance capecitabine significantly prolonged PFS compared to surveillance, meeting the primary endpoint and supporting its use to extend disease control in advanced OGA.

Introduction: Increasingly, identification of BRAF mutation in colorectal cancer is used to guide management and predict cancer behaviour. There is, however, still significant diversity within this cohort of patients, both in terms of clinical phenotype and treatment outcomes. This may be explained, at least in part, by differences between classes of BRAF mutations and the presence of concomitant mutations. Methods: We present a retrospective cohort study of sequential patients diagnosed with BRAF-mutated (V600 and non-V600) colorectal cancer between 2014 and 2022. Information regarding presentation, treatment outcomes and molecular subtype was identified using the electronic medical record. Results: This study included 406 patients with BRAF-mutated colorectal cancer, 253 (228 V600BRAF) of whom had localised disease and 153 (137 V600BRAF) with metastatic disease at the time of diagnosis. In patients with localised disease at diagnosis, the V600BRAF mutation was associated with older median age (73 vs. 63 years, p = 0.04) and a higher prevalence of right-sided primary (73% vs. 40%, p < 0.01), mismatch repair deficiency (56% vs. 8%, p < 0.01), and faster time to disease relapse (p = 0.006). In the metastatic setting, non-V600BRAF mutation was associated with a higher prevalence of KRAS mutation (27% vs. 1%, p < 0.01), NRAS mutation (14% vs. 3%, p = 0.04) and PIK3CA mutation (33% vs. 8%, p = 0.02). Mismatch repair deficiency was more common in patients with V600BRAF mutations than in those with non-V600BRAF mutations (20% vs. 0%, p = 0.01). The median survival of patients with the V600BRAF mutation was 14 months, and 34 months in those with non-V600BRAF mutations. Concomitant RNF43 mutation in metastatic disease, was associated with a significantly higher incidence of disease control from combined BRAF and EGFR inhibition, when compared to those without an RNF43 mutation (100% vs. 54%, p = 0.02). Conclusions: Presentation and outcomes of BRAF-mutated colorectal cancer are heterogenous. The type of BRAF mutation, and the presence of concomitant RNF43 mutation, may explain some of the differences in cancer behaviour. Routine reporting of RNF43 mutations would assist clinicians to give more personalised treatment recommendations.

PLATFORM is an adaptive phase II study assessing maintenance therapies in advanced esophagogastric adenocarcinoma (OGA). We evaluated the role of capecitabine plus a vascular endothelial growth factor receptor 2 inhibitor ramucirumab (cape-ram) in these patients. Human epidermal growth factor receptor 2 (HER2)-negative patients with advanced OGA with stable or responding disease after 18 weeks of induction platinum-based chemotherapy were randomly assigned 1:1 to surveillance or cape-ram. The primary end point was progression-free survival (PFS), and key secondary end points were overall survival (OS) and safety. Recruitment to the cape-ram arm closed prematurely because of industry support withdrawal. A one-sided log-rank test with a 2.5% significance level was considered significant. Between April 2019 and November 2022, 25 surveillance and 22 cape-ram patients were contemporaneously randomly assigned. Median follow-up was 24.4 months. Compared with surveillance, cape-ram significantly prolonged PFS (hazard ratio [HR], 0.33 [95% CI, 0.17 to 0.63], P < .001; median PFS: 2.5 months with surveillance versus 5.5 months with cape-ram; 6-month PFS rate: 4% [95% CI, 0.3% to 17.0%] v 42.9% [95% CI, 21.9% to 62.3%], respectively) and OS (HR, 0.51 [95% CI, 0.26 to 1.00], P = .023; median OS: 7.1 months with surveillance v 14.4 months with cape-ram; median OS from start of induction chemotherapy was 12.1 months v 19.5 months, respectively). Of 10 cape-ram patients with measurable disease, 1 had an incremental partial response. Grade ≥3 adverse events (AEs) were seen in 32% surveillance and 57% cape-ram patients. Six cape-ram patients had grade 3 treatment-related AEs, and no new safety signals were identified. Maintenance cape-ram after induction chemotherapy for patients with HER2-negative OGA significantly improved survival compared with surveillance. To our knowledge, this is the first randomized maintenance study demonstrating survival benefit and provides support for maintenance treatment.

BACKGROUND:In the phase 3 CodeBreaK 300 study, sotorasib (KRASG12C inhibitor) plus panitumumab (EGFR inhibitor) significantly prolonged progression-free survival versus investigator's choice of trifluridine-tipiracil or regorafenib (standard of care) in patients with KRASG12C-mutated chemorefractory metastatic colorectal cancer. This analysis evaluated patient-reported outcomes (PROs) as secondary and exploratory endpoints. METHODS:In this open-label, randomised clinical trial, adult (aged ≥18 years) patients from 67 centres in 13 countries in Asia, Australia, Europe, and North America with KRASG12C-mutated chemorefractory metastatic colorectal cancer (as assessed by central molecular testing of tumour biopsy specimens) who were KRASG12C inhibitor-naive, had progressed to recurrence after previous therapy with fluoropyrimidine, oxaliplatin, and irinotecan, with measurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1, and with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2, were enrolled. Patients were randomly assigned 1:1:1 using interactive response technology to receive sotorasib 960 mg (daily, orally)-panitumumab (6 mg/kg every 2 weeks, intravenous infusion), sotorasib 240 mg (daily, orally)-panitumumab (6 mg/kg every 2 weeks, intravenous infusion), or investigator's choice of trifluridine-tipiracil (35 mg/m2 [up to 80 mg per dose] on days 1-5 and 8-12 twice a day, orally) or regorafenib (160 mg daily for the first 21 days, orally). Randomisation was stratified by by previous anti-angiogenic therapy, time from initial diagnosis of metastatic disease to randomisation, and ECOG performance status. The primary endpoint was progression-free survival (reported previously). PROs included fatigue at its worst according to the Brief Fatigue Inventory, pain at its worst according to the Brief Pain Inventory (where lower score is better), and Global Health Status-Quality of Life (GHS-QoL) and physical function subscales of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (where higher score is better) assessed via validated PRO questionnaires, administered at baseline, day 1 of each 4-week cycle until disease progression, and safety follow-up. Analyses were conducted in a modified intention-to-treat population. Least squares mean changes from baseline to week 9 were estimated using a mixed effects model for repeated measures. Time to deterioration (TTD), change in overall status, and patient-reported tolerability were also evaluated as prespecified exploratory outcomes. TTD was summarised using a stratified Cox proportional hazards model and Kaplan-Meier curve. Change in overall status and patient-reported tolerability were also summarised descriptively over time. The study is registered with ClinicalTrials.gov, NCT05198934, and prespecified analyses are completed. FINDINGS:Between April 19, 2022, and March 14, 2023, 160 patients were enrolled and randomly assigned to receive sotorasib 960 mg-panitumumab (n=53), sotorasib 240 mg-panitumumab (n=53), and investigator's choice (n=54). Median duration of treatment was 6·0 months (IQR 3·7-7·0), 4·6 months (3·3-6·2), and 2·2 months (1·8-4·2) in these groups, respectively. 81 (51%) patients in the study were female; 109 (68%) patients were White, 40 (25%) were Asian, one (1%) was Black, and ten (6%) were of another race or not reported; 12 (8%) were Hispanic or Latino and three (2%) were of unknown ethnicity. Compliance rates for PRO assessments at week 9 were high (approximately 80%) and similar across treatment groups. Least squares mean changes in PROs at week 9 favoured the two sotorasib groups. Differences in changes from baseline for sotorasib 960 mg-panitumumab and sotorasib 240 mg-panitumumab (both vs investigator's choice), respectively were: -0·89 (95% CI -1·80 to 0·01) and -0·58 (-1·47 to 0·30) for fatigue at its worst, -1·45 (-2·32 to -0·58) and -1·14 (-2·00 to -0·28) for pain at its worst, 9·43 (2·31 to 16·56) and 6·49 (-0·43 to 13·41) for GHS-QoL, and 5·38 (-0·01 to 10·78) and 6·34 (1·07 to 11·62) for physical function. INTERPRETATION:Along with improved clinical outcomes, these analyses suggest that sotorasib plus panitumumab could represent a valuable new treatment in patients with KRASG12C-mutated chemorefractory metastatic colorectal cancer. FUNDING:Amgen.

To evaluate the feasibility, safety, and efficacy of image-guided percutaneous cryoablation for the treatment of soft-tissue metastatic tumours in patients with oligoprogressive disease. Consecutive patients undergoing percutaneous cryoablation between March 2017 and December 2024 were identified from a prospectively maintained database. Patient demographics, disease characteristics, procedural details, and outcomes were recorded. The Kaplan–Meier method was used to calculate local tumour progression-free survival (LTPFS), progression-free survival (PFS), and overall survival (OS). Technical success, technique efficacy, complications, and oncologic outcomes were analysed. The primary endpoints were technical success, major complications, LTPFS, and PFS. The secondary endpoint was OS. Fifty-two metastatic tumours (median size: 20 mm [interquartile range, 12–36 mm]) were treated across 46 sessions in 38 patients. The technical success rate (defined as complete tumour coverage by the ablation zone with a 5-mm margin) was 100

Background Neutralization of interferon (IFN)-γ abrogates the efficacy of anti-programmed death-ligand 1 (PD-(L)1) checkpoint inhibitors. Most epithelial cells do not constitutively express major histocompatibility complex (MHC) class II but can be induced to do so by IFN-γ. Inducible tumor-specific MHC class II (tsMHC-II) underlies responsiveness to anti-PD-(L)1. Retrospective studies show that tsMHC-II positivity associates with improved outcomes in patients treated with anti-PD-(L)1. The ANICCA-Class II single-arm Bayesian phase II trial prospectively explored whether positive tsMHC-II status could be a useful selection marker for anti-programmed cell death protein-1 (PD-1) in proficient mismatch repair colorectal cancer (pMMR CRC). In parallel, we retrospectively evaluated the potential predictive power of immunoscore-immune checkpoint (IS-IC) for outcome with single-agent immune checkpoint blockade.Methods Patients with histologically confirmed locally advanced/metastatic pMMR CRC with >1% MHC class II expression, Eastern Cooperative Oncology Group performance status 0–2, aged ≥18 years were eligible. Participants received 480 mg nivolumab every 28 days for up to 24 cycles. The primary outcome was durable clinical benefit (DCB) defined as participants remaining progression-free at their third trial-specific scan since treatment start (ie, at approximately 27 weeks). Secondary outcomes included progression-free survival time (PFS) and overall survival time (OS).Results 35 participants were treated: 65.7% of participants’ cancers were tsMHC-II ≥5%. 3/35 patients achieved DCB (8.6%), estimating the true DCB rate (R) of 11% (95% credible interval 3% to 22%) with 0.002 probability that the true DCBR was >30%, below the required 0.5 to warrant further research. The higher tsMHC-II cut-point ≥5% was not more useful in predicting duration of disease stabilization. All three participants who achieved DCB had no evidence of liver metastases (LM); DCBR 23.1% in those without versus 0% in those with LM. PFS and OS were significantly greater in those without LM. There was no evidence that IS-IC high predicted for prolonged time on treatment or improved tumor growth inhibition.Conclusions In pMMR CRC, tsMHC-II positivity fails to identify a subset of patients with metastatic pMMR CRC obtaining potentially meaningful benefit from single-agent anti-PD-1. Although numbers are limited, there is no clear evidence that IS-IC is predictive of outcome with single-agent anti-PD-1. The poor outcome in those with LM underscores the need for therapies that overcome the systemic immunosuppression driven by LM.

391 Background: Although perioperative FLOT therapy is a standard for locally advanced oesophagogastric adenocarcinoma (LA-OGA), completing all cycles, especially in the adjuvant chemotherapy (ACT) phase, is often challenging. This study examined the survival impact of treatment delivery in LA-OGA patients receiving FLOT therapy. Methods: 423 patients who underwent radical resection at The Royal Marsden Hospital from 2017 to 2023 were screened. Major inclusion criteria included patients with LA-OGA (cT2≤ and Nany or Tany and N+), treated with FLOT (at least one cycle of neoadjuvant chemotherapy) and radical resection, with an ECOG performance status of 0–2. Patients were divided into therapy incomplete (Tx Incomp, less than eight cycles of FLOT) and therapy (Tx comp) groups. We performed univariate and multivariate analyses, as well as propensity score matching (PSM) analysis, to evaluate whether treatment delivery was associated with recurrence-free survival (RFS) and overall survival (OS). Kaplan-Meier curves and restricted mean survival times (RMST) up to 36 months were used to evaluate the survival time. The primary endpoint was the 3-year RFS and OS rate. Results: Of the screened patients, 210 met the inclusion criteria, with 79 (38%) in the Tx Incomp and 131 (62%) in the Tx comp group, and 50 (24%) patients did not receive ACT. The median follow-up time was 26.5 months. The 3-year RFS and OS rates in the Tx Incomp and Tx comp groups after PSM were 54% vs 59% (p=0.14) (RMST difference: 4.04 months, p=0.09) and 58% vs 78% (p=0.04) (RMST difference: 6.15 months, p<0.001), respectively. Multivariable analysis showed a significant impact of Tx comp on OS (HR 0.53, 95% CI: 0.32-0.88). In the subgroup of ypN-positive patients, a significant difference of RMST in OS rate was observed between those who started ACT and those who did not start ACT (RMST difference: 7.89 months, p=0.01), whereas no significant difference was found in the ypN-negative group (RMST difference: 0.65 months, p=0.75). Conclusions: This study suggests that completing FLOT therapy is associated with better OS. The impact of ACT might differ according to ypN stage.