563 Background: In the phase 3 KEYNOTE-966 trial (NCT04003636), pembrolizumab (pembro) plus gemcitabine and cisplatin (gem/cis) significantly improved OS (HR, 0.83; 95% CI, 0.72-0.95; P = 0.0034) vs placebo (pbo) plus gem/cis in participants (pts) with advanced biliary tract cancer (BTC), including combined hepatocellular-cholangiocarcinoma (cHCC-CCA). The incidence of adverse events (AEs) and treatment-related AEs were similar between treatment groups. We report data for pts with cHCC-CCA, an understudied population. Methods: Pts aged ≥18 years with untreated unresectable locally advanced or metastatic BTC were randomly assigned 1:1 to pembro 200 mg or pbo every 3 weeks (Q3W) for ≤35 cycles plus gem 1000 mg/m 2 on days 1 and 8 Q3W until progressive disease (PD) and cis 25 mg/m 2 on days 1 and 8 Q3W for ≤8 cycles. Primary end point was OS. Secondary end points included PFS and ORR per RECIST v1.1 by blinded independent central review (BICR), and safety. No formal statistical comparison was made. Results: At data cutoff (Nov 14, 2023), 13 pts with cHCC-CCA were treated (pembro group, n = 8; pbo group, n = 5). Baseline characteristics were generally balanced between treatment groups. Overall, median age of pts was 65.0 years (range, 48-73), 8 (62%) were male, 5 (39%) were enrolled in Asia, and 11 (85%) had metastatic disease. The median duration on study treatment was 9.05 mo (range, 1.54-24.18) in the pembro group vs 6.97 mo (range, 3.52-14.29) in the pbo group. Of the 8 pts in the pembro group, 1 (13%) completed treatment and 7 discontinued, most commonly due to PD (n = 5; 63%). Of the 5 pts in the pbo group, all pts discontinued treatment, most commonly due to PD (n = 3; 60%). The median OS was 13.3 mo (95% CI, 2.9-33.2) in the pembro group vs 13.6 mo (95% CI, 9.5-not reached [NR]) in the pbo group (HR, 0.73; 95% CI, 0.22-2.44). The median PFS was 8.5 mo (95% CI, 2.6-NR) vs 5.6 mo (1.4-NR), respectively (HR, 0.58; 95% CI, 0.15-2.21). The ORR was 25.0% (95% CI, 3.2-65.1) in the pembro group vs 20.0% (95% CI, 0.5-71.6) in the pbo group (difference, 5.0%; 95% CI, -46.1 to 47.9). Treatment-related AEs of any grade occurred in all pts in the pembro group and 4 (80%) in the pbo group. Grade 3-5 treatment-related AEs occurred in 6 (75%) and 4 pts (80%), respectively. Discontinuations of any drug due to treatment-related AEs occurred in 4 pts (50%) in the pembro group and 1 (20%) in the pbo group. Deaths due to treatment-related AEs occurred in 1 pt (13%) in the pembro group (gem-related lower respiratory tract infection); no deaths due to treatment-related AEs were reported in the pbo group. Conclusions: Outcomes in pts with cHCC-CCA were generally consistent with the overall population of the KEYNOTE-966 trial, however, results should be interpreted with caution due to small sample size of the subgroup. Given the paucity of prospective data in this rare population, results suggest pembro plus gem/cis as an active treatment regimen. Clinical trial information: NCT04003636 .

BACKGROUND:Although higher pre-diagnosis physical activity is linked to lower mortality among cancer survivors, it is unclear whether this is due to a reduced likelihood of metastatic cancer at diagnosis. This study evaluated whether adherence to physical activity guidelines before diagnosis is associated with all-cause mortality and metastatic cancer at diagnosis. METHODS:In the prospective Lifelines Cohort Study of 152,915 adults, we identified individuals diagnosed with primary cancer at any site through linkage to the Netherlands Cancer Registry. Adherence to physical activity guidelines was defined as ≥150 minutes of moderate-intensity activity, ≥75 minutes of vigorous-intensity activity, or an equivalent combination per week. Cox and logistic regression estimated adjusted HRs and ORs with 95% confidence intervals (CI) for associations between adherence to physical activity guidelines, all-cause mortality, and metastatic cancer at diagnosis. RESULTS:A total of 5,990 patients with cancer were included: 10.7% reported no physical activity, 19.1% were insufficiently active, and 70.2% were sufficiently active. Patients with cancer adhering to physical activity guidelines had a 16% lower risk of all-cause mortality compared with those who reported no physical activity (HR = 0.84; 95% CI, 0.72-0.98). However, meeting physical activity guidelines was not significantly associated with a reduced likelihood of metastatic cancer at diagnosis (OR = 0.98; 95% CI, 0.79-1.23). CONCLUSIONS:Physical activity at recommended levels before cancer diagnosis is linked to reduced mortality among cancer survivors, independent of metastatic cancer at diagnosis. IMPACT:These findings highlight the beneficial role of physical activity in reducing mortality in patients with cancer.

Abstract Background The introduction of (m)FOLFIRINOX and gemcitabine-nab-paclitaxel has changed the perspective for patients with locally advanced pancreatic cancer (LAPC). Consequently, in experienced centres 23% of patients with LAPC undergo a resection with 5-year overall survival (OS) rates of up to 25%. In the Netherlands, the nationwide resection rate for LAPC remains low at 8%. The PREOPANC-4 program aims for a nationwide implementation of the international multidisciplinary best-practice to improve patient outcome. Methods Nationwide program implementing the international multidisciplinary best-practice for LAPC. In the training phase, multidisciplinary and surgical webinars are given by 4 international experts, leading to a clinical protocol, followed by surgical off-site and on-site proctoring sessions. In the implementation phase, the clinical protocol will be implemented in all centres, including a nationwide expert panel (2022–2024). Healthcare professionals will be trained in shared decision-making. Consecutive patients diagnosed with pathology-proven LAPC (i.e., arterial involvement > 90° and/or portomesenteric venous > 270° involvement or occlusion [DPCG criteria]) are eligible. Primary outcomes are median and 5-year OS from diagnosis, resection rate, in-hospital/30-day mortality and major morbidity (i.e., Clavien-Dindo grade ≥ IIIa), and radical resection (R0) rate. Secondary outcomes include quality of life, functioning, side effects, and patients’ healthcare satisfaction in all included patients. Outcomes will be compared with patients with borderline resectable pancreatic cancer (BRPC) treated with neoadjuvant FOLFIRINOX in the PREOPANC-2 trial (EudraCT: 2017–002036-17) and a historical cohort of patients with LAPC from the PACAP registry (NCT03513705). The existing prospective LAPC Registry and PACAP PROMs (NCT03513705) will be used for data collection. In qualitative interviews, treatment preferences, values, and experiences of LAPC patients, their relatives, and healthcare professionals will be assessed for the development of shared decision-making supportive tools. It is hypothesized that the program will double the nationwide LAPC resection rate to 16% with major morbidity < 50% and mortality ≤ 5%, and OS following resection similar to that observed in patients with BRPC. Discussion The PREOPANC-4 program aims to safely implement the international multidisciplinary best-practice for LAPC leading to benchmark outcomes for both short-term morbidity, mortality, and OS. Trial registration PREOPANC-4 program was registered at ClinicalTrials.gov (NCT05524090) on September 1, 2022.

BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide with a grim prognosis. Current treatment options for advanced HCC are limited, and a large proportion of patients is not amenable to any form of treatment, with best supportive care as the only remaining option. Meanwhile, the use of cannabis-derived products is rising in oncological patients who are seeking symptom relief. Cannabinoids, similar to endogenous endocannabinoids, have shown promise in recent preclinical cancer research due to their ability to interact with various signaling pathways and molecular mechanisms of interest. CASE PRESENTATION: In this report, we present two patients (A aged 82 and B 77, respectively) with advanced HCC with a high tumor burden who demonstrated durable and complete regression after use of cannabis oil (A 10% delta-9-tetrahydrocannabinol (THC) and 5% cannabidiol (CBD), two droplets sublingually three times daily and B 15% THC and 2% CBD, 5 droplets sublingually two times daily) for symptom relief. The observations in this report build on previous (pre)clinical research highlighting the potential anti-tumor qualities of cannabinoids and stress the need for clinical trials investigating the anti-tumor effects of cannabinoids in cancer patients. CONCLUSION: Based on the two cases presented here, we call for further research into the potential beneficial effect of cannabinoids in patients with advanced HCC.

PURPOSE:CB307 is a trispecific variable heavy-chain antibody fragment against prostate-specific membrane antigen (PSMA), CD137, and human serum albumin. It is designed to mitigate hepatotoxicity by activating T cells only in PSMA-positive tumors and to increase drug half-life through albumin binding. This phase I study investigated the safety and tolerability of CB307 as monotherapy or in combination with pembrolizumab. PATIENTS AND METHODS:Patients who were heavily pretreated with PSMA-positive solid tumors were enrolled in the dose-escalation phase of CB307 monotherapy. The additional safety and efficacy of CB307 were assessed in the CB307 monotherapy expansion cohort and in combination with pembrolizumab. RESULTS:CB307 was administered to 75 patients. CB307 was given once every 7 days as monotherapy (N = 50) or in combination with pembrolizumab (N = 25). Two dose-limiting toxicities (grade 3 transient transaminitis) were observed. A total of three grade 3 transaminitis events (one in the monotherapy cohort and two in the combination cohort) were observed, and none involved bilirubin elevation. Durable RECIST responses were observed in two patients with metastatic castration-resistant prostate cancer enrolled in the 800 mg CB307 monotherapy and in one patient in the combination cohort (overall response rates: 11.1% and 7.1%, respectively). A disease control rate (DCR) of 50% was observed in patients enrolled in the 800 mg CB307 monotherapy cohort and 42.9% in the combination cohort. In a post hoc analysis, the response was numerically better in patients who had not received chemotherapy in the 6 months prior to starting CB307 (ORR = 20%, DCR = 60% vs. ORR = 0%, DCR = 37.5%). CB307 induces cytotoxic cell expansion in tumors and PD-L1 expression. CONCLUSIONS:CB307 was well tolerated as a monotherapy and in combination with pembrolizumab, and tumor responses were observed in patients with metastatic castration-resistant prostate cancer. See related commentary by Nguyen and Luke, p. 3356.

Whole-body CD8+ T-cell PET imaging can detect spatial and temporal localization of CD8+ T cells. To obtain insight into early CD8+ T-cell response to immunotherapy in patients with melanoma, a highly immunogenic tumor, we performed serial PET imaging with the 1-armed CD8 antibody tracer 89ZED88082A. Methods: Immunotherapy-naïve adult patients with stage IV melanoma underwent PET scanning 2 d after receiving 10 mg of 89ZED88082A intravenously at baseline and 6-8 wk after initiation of standard-of-care immunotherapy. Tracer uptake in lesions, normal lymph nodes, and Waldeyer ring was assessed using SUVmax; other healthy tissue uptake was assessed using SUVmean Uptake in tumors and healthy lymph nodes was expressed as the geometric mean SUVmax per patient and in healthy tissue as SUVmean for all patients. Tumor response was evaluated in accordance with iRECIST version 1.1. Tumor tissue was immunohistochemically stained for CD8. Results: Serial imaging was performed for 10 of 11 enrolled patients. The geometric mean tumor SUVmax was 7.2 (95% CI, 5.6-9.4) before treatment and 7.3 (95% CI, 5.7-9.5; P = 0.89) during treatment, with spatial and temporal heterogeneity in tumor uptake. The spleen demonstrated the highest uptake among healthy tissues, and this value remained similar during treatment. After immunotherapy, 2 patients experienced a complete response, 7 a partial response, and 2 progressive disease. Changes in tumor uptake during treatment did occur but did not correlate with tumor response. Nine evaluable pretreatment tumor tissues showed a CD8-inflamed immune phenotype. Conclusion: Lesions demonstrated spatial and temporal heterogeneity in 89ZED88082A uptake within and among patients with melanoma.

Multispecific antibodies are engineered antibody derivatives that can bind to two or more distinct epitopes or antigens. Unlike mixtures of monospecific antibodies, the binding properties of multispecific antibodies enable two specific molecules to be physically linked, a characteristic with important applications in cancer therapy. The field of multispecific antibodies is highly dynamic and expanding rapidly; to date, 15 multispecific antibodies have been approved for clinical use, of which 11 were approved for oncological indications, and more than 100 new antibodies are currently in clinical development. Nevertheless, substantial challenges limit the applications of multispecific antibodies in cancer therapy, particularly inefficient targeting of solid tumours and substantial adverse effects. Both PET and single photon emission CT imaging can reveal the biodistribution and complex pharmacology of radiolabelled multispecific antibodies. This Review summarizes the insights obtained from preclinical and clinical molecular imaging studies of multispecific antibodies, focusing on their structural properties, such as molecular weight, shape, target specificity, affinity and avidity. The opportunities associated with use of molecular imaging studies to support the clinical development of multispecific antibody therapies are also highlighted.

Monoclonal antibodies are important cancer medicines. The European Medicines Agency (EMA) approved 48 and the Food and Drug Administration (FDA) 56 anticancer monoclonal antibody-based therapies. Their high prices burden healthcare systems and hamper global drug access. Biosimilars could retain costs and expand the availability of monoclonal antibodies. In Europe, five rituximab biosimilars, six trastuzumab biosimilars, and eight bevacizumab biosimilars are available as anti-cancer drugs. To gain insight into the biosimilar landscape for cancer treatment, we performed a literature search and analysis. In this review, we summarize cancer monoclonal antibodies' properties crucial for the desired pharmacology and point out sources of variability. The analytical assessment of all EMA-approved bevacizumab biosimilars is highlighted to illustrate this variability. The global landscape of investigational and approved biosimilars is mapped, and the challenges for access to cancer biosimilars are identified.

Current immunotherapies have brought major progress in cancer treatments, but not all patients benefit. Therefore, insight into reasons for treatment failure and optimal biomarkers for patient selection are warranted. Current approved biomarkers for cancer immunotherapy do not provide insight into characteristics across tumor lesions in a patient or their heterogeneity. Here, whole-body PET imaging with specific tracers may provide support. Moreover, the biodistribution of cell therapies and complex molecules, such as bispecific antibodies, can be visualized by PET imaging, and repeat PET imaging allows to study the whole-body kinetics of the immune response. In this review, we present the status of using PET imaging-derived biomarkers for patients with cancer receiving immunotherapy. Next, the hopes and scientific challenges ahead to optimize current PET imaging biomarker development and to discover novel PET-derived baseline and dynamic biomarkers to potentially guide us in drug development and more precise patient and therapy selection will be discussed.

Abstract Background Bulk transcriptional profiles of early colorectal cancer (CRC) can fail to detect biological processes associated with disease-free survival (DFS) if the transcriptional patterns are subtle and/or obscured by other processes’ patterns. Consensus-independent component analysis (c-ICA) can dissect such transcriptomes into statistically independent transcriptional components (TCs), capturing both pronounced and subtle biological processes. Methods In this study we (1) integrated transcriptomes (n = 4228) from multiple early CRC studies, (2) performed c-ICA to define the TC landscape within this integrated data set, 3) determined the biological processes captured by these TCs, (4) performed Cox regression to identify DFS-associated TCs, (5) performed random survival forest (RSF) analyses with activity of DFS-associated TCs as classifiers to identify subgroups of patients, and 6) performed a sensitivity analysis to determine the robustness of our results Results We identify 191 TCs, 43 of which are associated with DFS, revealing transcriptional diversity among DFS-associated biological processes. A prominent example is the epithelial-mesenchymal transition (EMT), for which we identify an association with nine independent DFS-associated TCs, each with coordinated upregulation or downregulation of various sets of genes. Conclusions This finding indicates that early CRC may have nine distinct routes to achieve EMT, each requiring a specific peri-operative treatment strategy. Finally, we stratify patients into DFS patient subgroups with distinct transcriptional patterns associated with stage 2 and stage 3 CRC.

Background: In 2-5% of patients with colorectal cancer (CRC), human epidermal growth factor 2 (HER2) is amplified or overexpressed. Despite prior evidence that anti-HER2 therapy confers clinical benefit (CB) in onethird of these patients, it is not approved for this indication in Europe. In the Drug Rediscovery Protocol (DRUP), patients are treated with off -label drugs based on their molecular profile. Here, we present the results of the cohort 'trastuzumab/pertuzumab for treatment -refractory patients with RAS/BRAF-wild-type HER2amplified metastatic CRC (HER2+mCRC)'. Methods: Patients with progressive treatment -refractory RAS/BRAF-wild-type HER2+mCRC with measurable disease were included for trastuzumab plus pertuzumab treatment. Primary endpoints of DRUP are CB (defined as confirmed objective response (OR) or stable disease (SD) >= 16 weeks) and safety. Patients were enrolled using a Simon -like 2 -stage model, with 8 patients in stage 1 and 24 patients in stage 2 if at least 1/8 patients had CB. To identify biomarkers for response, whole genome sequencing (WGS) was performed on pre-treatment biopsies. Results: CB was observed in 11/24 evaluable patients (46%) with HER2+mCRC, seven patients achieved an OR (29%). Median duration of response was 8.4 months. Patients had undergone a median of 3 prior treatment lines. Median progression -free survival and overall survival were 4.3 months (95% CI 1.9-10.3) and 8.2 months (95% CI 7.2-14.7), respectively. No unexpected toxicities were observed. WGS provided potential explanations for resistance in 3/10 patients without CB, for whom WGS was available. Conclusions: The results of this study confirm a clinically significant benefit of trastuzumab plus pertuzumab treatment in patients with HER2+mCRC.

Importance Implementation of new cancer treatment strategies as recommended by evidence-based guidelines is often slow and suboptimal. Objective To improve the implementation of guideline-based best practices in the Netherlands in pancreatic cancer care and assess the impact on survival. Design, setting, and participants This multicenter, stepped-wedge cluster randomized trial compared enhanced implementation of best practices with usual care in consecutive patients with all stages of pancreatic cancer. It took place from May 22, 2018 through July 9, 2020. Data were analyzed from April 1, 2022, through February 1, 2023. It included all patients in the Netherlands with pathologically or clinically diagnosed pancreatic ductal adenocarcinoma. This study reports 1-year follow-up (or shorter in case of deceased patients). Intervention The 5 best practices included optimal use of perioperative chemotherapy, palliative chemotherapy, pancreatic enzyme replacement therapy (PERT), referral to a dietician, and use of metal stents in patients with biliary obstruction. A 6-week implementation period was completed, in a randomized order, in all 17 Dutch networks for pancreatic cancer care. Main Outcomes and Measures The primary outcome was 1-year survival. Secondary outcomes included adherence to best practices and quality of life (European Organisation for Research and Treatment of Cancer [EORTC] global health score). Results Overall, 5887 patients with pancreatic cancer (median age, 72.0 [IQR, 64.0-79.0] years; 50% female) were enrolled, 2641 before and 2939 after implementation of best practices (307 during wash-in period). One-year survival was 24% vs 23% (hazard ratio, 0.98, 95% CI, 0.88-1.08). There was no difference in the use of neoadjuvant chemotherapy (11% vs 11%), adjuvant chemotherapy (48% vs 51%), and referral to a dietician (59% vs 63%), while the use of palliative chemotherapy (24% vs 30%; odds ratio [OR], 1.38; 95% CI, 1.10-1.74), PERT (34% vs 45%; OR, 1.64; 95% CI, 1.28-2.11), and metal biliary stents increased (74% vs 83%; OR, 1.78; 95% CI, 1.13-2.80). The EORTC global health score did not improve (area under the curve, 43.9 vs 42.8; median difference, −1.09, 95% CI, −3.05 to 0.94). Conclusions and Relevance In this randomized clinical trial, implementation of 5 best practices in pancreatic cancer care did not improve 1-year survival and quality of life. The finding that most patients received no tumor-directed treatment paired with the poor survival highlights the need for more personalized treatment options. Trial Registration ClinicalTrials.gov Identifier: NCT03513705

Importance:Implementation of new cancer treatment strategies as recommended by evidence-based guidelines is often slow and suboptimal. Objective:To improve the implementation of guideline-based best practices in the Netherlands in pancreatic cancer care and assess the impact on survival. Design, setting, and participants:This multicenter, stepped-wedge cluster randomized trial compared enhanced implementation of best practices with usual care in consecutive patients with all stages of pancreatic cancer. It took place from May 22, 2018 through July 9, 2020. Data were analyzed from April 1, 2022, through February 1, 2023. It included all patients in the Netherlands with pathologically or clinically diagnosed pancreatic ductal adenocarcinoma. This study reports 1-year follow-up (or shorter in case of deceased patients). Intervention:The 5 best practices included optimal use of perioperative chemotherapy, palliative chemotherapy, pancreatic enzyme replacement therapy (PERT), referral to a dietician, and use of metal stents in patients with biliary obstruction. A 6-week implementation period was completed, in a randomized order, in all 17 Dutch networks for pancreatic cancer care. Main Outcomes and Measures:The primary outcome was 1-year survival. Secondary outcomes included adherence to best practices and quality of life (European Organisation for Research and Treatment of Cancer [EORTC] global health score). Results:Overall, 5887 patients with pancreatic cancer (median age, 72.0 [IQR, 64.0-79.0] years; 50% female) were enrolled, 2641 before and 2939 after implementation of best practices (307 during wash-in period). One-year survival was 24% vs 23% (hazard ratio, 0.98, 95% CI, 0.88-1.08). There was no difference in the use of neoadjuvant chemotherapy (11% vs 11%), adjuvant chemotherapy (48% vs 51%), and referral to a dietician (59% vs 63%), while the use of palliative chemotherapy (24% vs 30%; odds ratio [OR], 1.38; 95% CI, 1.10-1.74), PERT (34% vs 45%; OR, 1.64; 95% CI, 1.28-2.11), and metal biliary stents increased (74% vs 83%; OR, 1.78; 95% CI, 1.13-2.80). The EORTC global health score did not improve (area under the curve, 43.9 vs 42.8; median difference, -1.09, 95% CI, -3.05 to 0.94). Conclusions and Relevance:In this randomized clinical trial, implementation of 5 best practices in pancreatic cancer care did not improve 1-year survival and quality of life. The finding that most patients received no tumor-directed treatment paired with the poor survival highlights the need for more personalized treatment options. Trial Registration:ClinicalTrials.gov Identifier: NCT03513705.

Flow chart of patients with BRCA1/2 alterations submitted to the study team between September 2016 and December 2019, and reasons for drop-out, rejection or screen failure. Abbreviations: VUS = Variant of Unknown Significance, LOH = Loss of Heterozygosity.

Background Surgical resection followed by adjuvant mFOLFIRINOX (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) is currently the standard of care for patients with resectable pancreatic cancer. The main concern regarding adjuvant chemotherapy is that only half of patients actually receive adjuvant treatment. Neoadjuvant chemotherapy, on the other hand, guarantees early systemic treatment and may increase chemotherapy use and thereby improve overall survival. Furthermore, it may prevent futile surgery in patients with rapidly progressive disease. However, some argue that neoadjuvant therapy delays surgery, which could lead to progression towards unresectable disease and thus offset the potential benefits. Comparison of perioperative (i.e., neoadjuvant and adjuvant) with (only) adjuvant administration of mFOLFIRINOX in a randomized controlled trial (RCT) is needed to determine the optimal approach. Methods This multicenter, phase 3, RCT will include 378 patients with resectable pancreatic ductal adenocarcinoma with a WHO performance status of 0 or 1. Patients are recruited from 20 Dutch centers and three centers in Norway and Sweden. Resectable pancreatic cancer is defined as no arterial contact and ≤ 90 degrees venous contact. Patients in the intervention arm are scheduled for 8 cycles of neoadjuvant mFOLFIRINOX followed by surgery and 4 cycles of adjuvant mFOLFIRINOX (2-week cycle of oxaliplatin 85 mg/m 2 , leucovorin 400 mg/m 2 , irinotecan 150 mg/m 2 at day 1, followed by 46 h continuous infusion of 5-fluorouracil 2400 g/m 2 ). Patients in the comparator arm start with surgery followed by 12 cycles of adjuvant mFOLFIRINOX. The primary outcome is overall survival by intention-to-treat. Secondary outcomes include progression-free survival, resection rate, quality of life, adverse events, and surgical complications. To detect a hazard ratio of 0.70 with 80% power, 252 events are needed. The number of events is expected to be reached after the inclusion of 378 patients in 36 months, with analysis planned 18 months after the last patient has been randomized. Discussion The multicenter PREOPANC-3 trial compares perioperative mFOLFIRINOX with adjuvant mFOLFIRINOX in patients with resectable pancreatic cancer. Trial registration Clinical Trials: NCT04927780. Registered June 16, 2021.