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Background: Multiple studies have suggested that gut microbiome may influence immune checkpoint inhibitor (ICI) efficacy, but its association with immune-related adverse events (irAEs) is less well studied. In this prospective cohort study, we assessed whether gut microbiome composition at start, or changes during ICI, are associated with severe irAEs., Methods: Stool samples of cancer patients treated with anti-PD-1 ± anti-CTLA-4 were analyzed using 16S rRNA gene sequencing and metagenomic shotgun sequencing. Differences in alpha and beta diversity between patients with and without severe irAE were assessed, as well as differential relative abundance (RA) of taxa, MetaCyc pathways, and seven prespecified literature-based bacterial groups including pathobionts and Ruminococcaceae., Findings: We analyzed 497 samples of 195 patients before and soon after starting ICI, at severe irAE onset and after starting immunosuppression. Mean RA of the pathobionts group was significantly higher in patients who developed a severe irAE (8.2 %) compared to those who did not (4.8 %; odds ratio 1.40; 95 %CI 1.07-1.87) at baseline, and also early during ICI treatment and at severe irAE onset. A significantly stronger decrease in RA of Ruminococcaceae after starting ICI was observed in patients who developed a severe irAE compared to those who did not. RAs of Ruminococcaceae, the genus Ruminococcus, and the species R. bromii and R. callidus were significantly lower at severe irAE onset compared to other time points., Interpretation: Gut microbiome dysbiosis signaled by higher RA of pathobionts and decrease in RA of Ruminococcaceae may predispose to severe irAEs., Competing Interests: Declaration of Competing Interest FLP is employed at Winclove Probiotics. KPMS reports consulting/advisory relationships with Abbvie, Pierre Fabre, Sairopa. She received honoraria from Bristol Myers Squibb, and research funding from TigaTx, Bristol Myers Squibb, Philips, Pierre Fabre and Genmab. All paid to institution. The other authors declare no conflicts of interest., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Pathologic response following neoadjuvant immune checkpoint blockade (ICB) in stage III melanoma serves as a surrogate marker for long-term outcomes. This may support more personalized, response-directed treatment strategies., Methods: The OpACIN-neo and PRADO trials were phase 2 studies evaluating neoadjuvant treatment with ipilimumab and nivolumab in stage III melanoma. In OpACIN-neo, all patients underwent therapeutic lymph node dissection (TLND) without subsequent adjuvant therapy. In contrast, PRADO explored a response- directed strategy, where patients achieving a major pathologic response (MPR) omitted TLND and adjuvant therapy, while those without a pathologic response (pNR) received TLND and adjuvant therapy. Here, we provide a descriptive post-hoc comparison of 3-year survival outcomes between the non-personalized approach in OpACIN-neo and the response-directed approach in PRADO., Results: For patients who achieved an MPR, the 3-year recurrence-free survival (RFS) was 93 % for those without TLND versus 96 % for those with TLND (log-rank p = 0.47), and distant metastasis-free survival (DMFS) was 98 % compared to 96 % (log-rank p = 0.49), respectively. For patients with pNR, 3-year RFS rates were 64 % for those receiving adjuvant systemic therapy and 35 % for patients without (log-rank p = 0.10). DMFS rates were 70 % versus 52 % (log-rank p = 0.24), respectively., Conclusions: These data suggest that TLND and adjuvant therapy may be safely omitted in most patients achieving an MPR, while adjuvant systemic therapy following TLND appears to improve RFS and DMFS in patients with pNR. Although these results are hypothesis-generating and require further validation, they offer a potential foundation for developing personalized neoadjuvant immunotherapy approaches., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: No author has received financial support for the work on this manuscript. I.L.M.R reports financial interest in Signature Oncology. A.M.M. has served on advisory boards for Bristol Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Novartis, Roche, Pierre Fabre and QBiotics. R.P.M.S. has received honoraria for advisory board participation from MSD, Novartis and Qbiotics and speaking honoraria from BMS and Novartis. W.J.v.H. reports an advisory role for Amgen, BMS, and Sanofi. E.K.A. received honoraria for consultancy/advisory relationships (all paid to the institute) from BMS, Novartis, Merck, Lilly, Immunocore and Pierre Fabre, and received research grants not related to this paper from BMS, Delcath, Pierre-Fabre and Novartis. A.A.M.v.d.V. received compensation for advisory roles and honoraria (all paid to the institute) from BMS, MSD, Merck, Roche, Eisai, Pfizer, Sanofi, Novartis, Pierre Fabre, and Ipsen. K.P.M.S. received compensation for advisory roles and honoraria (all paid to the institute) from BMS, MSD, Novartis, Pierre Fabre, Sairopa and Abbvie and received research funding from Philips, Novartis, TigaTx and BMS. H.E. has served on advisory boards for BMS, Novartis and Pierre Fabre Nordic, and received project funding from SkyLineDx. G.A.P.H. received compensation for consulting and advisory roles (all paid to the institute) from Amgen, Roche, MSD, BMS, Pfizer, Novartis and Pierre Fabre, and received research grants (paid to the institute) from BMS and Seerave. R.A.S. has received fees for professional services from MetaOptima Technology Inc., F. Hoffmann-La Roche, Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, MSD, NeraCare, Amgen, BMS, Myriad Genetics and GlaxoSmithKline. B.A.v.d.W. has served on the advisory board for BMS. A.C.J.v.A. has served on advisory boards and received consultancy honoraria for Amgen, BMS, Neracare, Novartis, MSD Merck, Merck-Pfizer, Pierre Fabre, Provectus, Sanofi, Sirius Medical and 4SC, and received research grants (all paid to the institute) from Amgen and Merck-Pfizer. G.V.L. is consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Boehringer Ingelheim, BMS, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics, Innovent Biologics, MSD, Novartis, Oncosec, PHMR Ltd, Pierre Fabre, Provectus, QBiotics and Regeneron Pharmaceuticals. C.U.B. reports receiving compensation for advisory roles from BMS, MSD, Roche, Novartis, GlaxoSmithKline, AstraZeneca, Pfizer, Eli Lilly, GenMab, Pierre Fabre and Third Rock Ventures and receiving research funding from BMS, MSD, Novartis, 4SC and NanoString. Furthermore, C.U.B. reports to be co-founder of Immagene BV and Signature Oncology. All compensations and funding for C.U.B. were paid to the institute, except for Third Rock Ventures, Immagene and Signature Oncology. The other authors declare no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Immune checkpoint inhibitor (ICI) treatment has proven successful for advanced melanoma, but is associated with potentially severe toxicity and high costs. Accurate biomarkers for response are lacking. The present work is the first to investigate the value of deep learning on CT imaging of metastatic lesions for predicting ICI treatment outcomes in advanced melanoma. Adult patients that were treated with ICI for advanced melanoma were retrospectively identified from ten participating centers. A deep learning model (DLM) was trained on volumes of lesions on baseline CT to predict clinical benefit. The DLM was compared to and combined with a model of known clinical predictors (presence of liver and brain metastasis, level of lactate dehydrogenase, performance status and number of affected organs). A total of 730 eligible patients with 2722 lesions were included. The DLM reached an area under the receiver operating characteristic (AUROC) of 0.607 [95%CI 0.565-0.648]. In comparison, a model of clinical predictors reached an AUROC of 0.635 [95%CI 0.59 -0.678]. The combination model reached an AUROC of 0.635 [95% CI 0.595-0.676]. Differences in AUROC were not statistically significant. The output of the DLM was significantly correlated with four of the five input variables of the clinical model. The DLM reached a statistically significant discriminative value, but was unable to improve over known clinical predictors. The present work shows that the assessment over known clinical predictors is an essential step for imaging-based prediction and brings important nuance to the almost exclusively positive findings in this field., Competing Interests: Declarations. Competing interests: AvdE has advisory relationships with Bristol-Myers Squibb, MSD Oncology, Amgen, Roche, Novartis, Sanofi, Pfizer, Ipsen, Merck, Pierre Fabre and has received research study grants not related to this paper from Sanofi, Bristol-Myers Squibb, TEVA, Idera and has received travel expenses MSD Oncology, Roche, Pfizer, Sanofi, Pierre Fabre and has received speaker honoraria from BMS and Novartis. JdG has consultancy/advisory relationships with Bristol Myers Squibb, Pierre Fabre, Servier, MSD, Novartis. PJ has a research collaboration with Philips Healthcare and Vifor Pharma. MBS has consultancy/advisory relationships with Pierre Fabre, MSD and Novartis, none related to current work and paid to institute. EK has consultancy/advisory relationships with Bristol Myers Squibb, Novartis, Merck, Pierre Fabre, Lilly, Bayer, EISAI and Ipsen paid to the institute, and received research grants not related to this paper from Bristol Myers Squibb, Delcath, Novartis and Pierre Fabre. PD has consultancy/advisory relationships with Paige, Pantarei and Samantree paid to the institution and research grants from Pfizer, none related to current work and paid to institute. KS has advisory relationships with Bristol Myers Squibb, Novartis, MSD, Pierre Fabre, AbbVie, Sairopsa and received honoraria from Novartis and MSD and research funding from Bristol Myers Squibb, TigaTx and Philips. TL has received research funding from Philips. GH consultancy/advisory relationships with Amgen, Bristol-Myers Squibb, Roche, MSD, Pfizer, Novartis, Sanofi, Pierre Fabre and has received research grants from Bristol-Myers Squibb, Seerave. All payments to the Institution. HW received honoraria from Merck, Astellas, Roche and travel expenses from Ipsen and Astellas. All remaining authors have declared no conflicts of interest., (© 2024. The Author(s).)

Background: In phase 1-2 trials in patients with resectable, macroscopic stage III melanoma, neoadjuvant immunotherapy was more efficacious than adjuvant immunotherapy., Methods: In this phase 3 trial, we randomly assigned patients with resectable, macroscopic stage III melanoma to two cycles of neoadjuvant ipilimumab plus nivolumab followed by surgery or surgery followed by 12 cycles of adjuvant nivolumab. Only patients in the neoadjuvant group with a partial response or nonresponse received adjuvant treatment. The primary end point was event-free survival., Results: A total of 423 patients underwent randomization. At a median follow-up of 9.9 months, the estimated 12-month event-free survival was 83.7% (99.9% confidence interval [CI], 73.8 to 94.8) in the neoadjuvant group and 57.2% (99.9% CI, 45.1 to 72.7) in the adjuvant group. The difference in restricted mean survival time was 8.00 months (99.9% CI, 4.94 to 11.05; P<0.001; hazard ratio for progression, recurrence, or death, 0.32; 99.9% CI, 0.15 to 0.66). In the neoadjuvant group, 59.0% of patients had a major pathological response, 8.0% had a partial response, 26.4% had a nonresponse (>50% residual viable tumor), and 2.4% had progression; in 4.2%, surgery had not yet been performed or was omitted. The estimated 12-month recurrence-free survival was 95.1% in patients in the neoadjuvant group who had a major pathological response, 76.1% among those with a partial response, and 57.0% among those with a nonresponse. Adverse events of grade 3 or higher that were related to systemic treatment occurred in 29.7% of patients in the neoadjuvant group and in 14.7% in the adjuvant group., Conclusions: Among patients with resectable, macroscopic stage III melanoma, neoadjuvant ipilimumab plus nivolumab followed by surgery and response-driven adjuvant therapy resulted in longer event-free survival than surgery followed by adjuvant nivolumab. (Funded by Bristol Myers Squibb and others; NADINA ClinicalTrials.gov number, NCT04949113.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Adjuvant anti-PD-1 therapy improves relapse free survival in stage III melanoma, but also leads to immune-related adverse events (irAEs). Older patients are of particular interest due to comorbidities and frailty, which may impact their ability to tolerate irAEs and benefit from anti-PD-1 therapy. This study aimed to explore associations between clinical parameters and the occurrence of grade ≥ 3 irAEs and recurrence-free survival (RFS) in older patients with radically resected stage III/IV cutaneous melanoma treated with adjuvant anti-PD-1 therapy., Methods: Patients aged ≥ 65 with resected stage III/IV cutaneous melanoma treated with adjuvant anti-PD-1 therapy between 2018 and 2022 were selected using real-world data from the nationwide Dutch Melanoma Treatment Registry (DMTR). A univariate and multivariable logistic regression was used to compare determinants of grade ≥ 3 irAEs, and univariate and multivariable Cox-proportional hazard models were fitted to identify factors influencing RFS., Results: The study included 885 patients, with 280 aged 75 and older. The incidence of grade ≥ 3 irAEs was 15.5 % in the 65-74 age group and 13.9 % in the ≥ 75 age group. No significant correlation was found between age and grade ≥ 3 irAEs. However, an increasing number of comorbidities was associated with a higher risk of grade ≥ 3 irAEs (multivariable analyses: OR 1.83, 95 % C.I. 0.99-3.40). The 1-year RFS rate of 80.0 % of this study was comparable to those reported in previous registration trials and real-world data. Having ≥ 3 comorbidities was significantly associated with a decrease in RFS (HR: 1.68, 95 % C.I. 1.15-2.44)., Conclusion: Older patients had similar benefit of adjuvant immunotherapy compared to older subgroups in previous trials. However, patients with multiple comorbidities were at increased risk of grade ≥ 3 irAEs and had a lower RFS. This should be considered when deciding upon adjuvant treatment., Competing Interests: Declaration of Competing Interest All remaining authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Retrospective studies suggest that immunosuppressive treatment of immune-related adverse events (irAEs) impairs survival in patients with melanoma who received immune checkpoint inhibitors. Here, we study this association across tumor types using data from six international phase II/III registrational trials., Methods: A post hoc analysis was performed on individual patient data from the anti-programmed cell death-1 (anti-PD-1) + anti-cytotoxic T lymphocyte-associated protein-4 (anti-CTLA-4) treatment arms of six clinical trials (CheckMate-067, -142, -214, -648, -743, and -9LA). Among patients who received systemic immunosuppression for treatment-related adverse events (trAEs), associations of peak and cumulative corticosteroid dose, and use of second-line immunosuppression with overall survival (OS) and progression-free survival (PFS) were assessed using multilevel Cox regression with adjustment for age and sex., Results: Of the 1,959 patients who received anti-PD-1 + anti-CTLA-4 therapy, 834 patients who were treated with immunosuppression for trAEs were included. Eight hundred and thirty-two patients (100%) received corticosteroids and 81 patients (10%) received second-line immunosuppressants. High corticosteroid peak dose was associated with worse PFS: adjusted hazard ratio (HR adj ), 1.15 (95% CI, 1.02 to 1.29) for 1 versus 0.5 mg/kg prednisolone and HR adj , 1.43 (95% CI, 1.05 to 1.96) for 2 versus 0.5 mg/kg. Similar effects were observed for OS: HR adj , 1.21 (95% CI, 1.06 to 1.39) and HR adj , 1.66 (95% CI, 1.17 to 2.37) for 1 and 2 versus 0.5 mg/kg, respectively. Cumulative corticosteroid dose was not associated with survival. HR adj of use of second-line immunosuppression was 1.23 (95% CI, 0.90 to 1.68) for PFS and 1.25 (95% CI, 0.88 to 1.77) for OS., Conclusion: Higher corticosteroid peak dose for trAEs is associated with worse survival across tumor types, while cumulative dose is not. Too few patients received second-line immunosuppressants to confirm or reject an association with survival. These data argue for a reconsideration of irAE management approaches, starting with lower corticosteroid dose whenever feasible.

Background: The intestinal microbiota plays a significant role in maintaining systemic and intestinal homeostasis, but can also influence diseases such as inflammatory bowel disease (IBD) and cancer. Certain bacterial species within the intestinal tract can chronically activate the immune system, leading to low-grade intestinal inflammation. As a result, plasma cells produce high levels of secretory antigen-specific immunoglobulin A (IgA), which coats the immunostimulatory bacteria. This IgA immune response against intestinal bacteria may be associated with the maintenance of homeostasis and health, as well as disease. Unraveling this dichotomy and identifying the immunostimulatory bacteria is crucial for understanding the relationship between the intestinal microbiota and the immune system, and their role in health and disease. IgA-SEQ technology has successfully identified immunostimulatory, IgA-coated bacteria from fecal material. However, the original technology is time-consuming and has limited downstream applications. In this study, we aimed to develop a next-generation, high-throughput, magnet-based sorting approach (ng-IgA-SEQ) to overcome the limitations of the original IgA-SEQ protocol., Results: We show, in various settings of complexity ranging from simple bacterial mixtures to human fecal samples, that our magnetic 96-well plate-based ng-IgA-SEQ protocol is highly efficient at sorting and identifying IgA-coated bacteria in a high-throughput and time efficient manner. Furthermore, we performed a comparative analysis between different IgA-SEQ protocols, highlighting that the original FACS-based IgA-SEQ approach overlooks certain nuances of IgA-coated bacteria, due to the low yield of sorted bacteria. Additionally, magnetic-based ng-IgA-SEQ allows for novel downstream applications. Firstly, as a proof-of-concept, we performed metagenomic shotgun sequencing on 10 human fecal samples to identify IgA-coated bacterial strains and associated pathways and CAZymes. Secondly, we successfully isolated and cultured IgA-coated bacteria by performing the isolation protocol under anaerobic conditions., Conclusions: Our magnetic 96-well plate-based high-throughput next-generation IgA-SEQ technology efficiently identifies a great number of IgA-coated bacteria from fecal samples. This paves the way for analyzing large cohorts as well as novel downstream applications, including shotgun metagenomic sequencing, culturomics, and various functional assays. These downstream applications are essential to unravel the role of immunostimulatory bacteria in health and disease. Video Abstract., (© 2024. The Author(s).)

Introduction: The Utrecht Symptom Diary (USD) is a validated Dutch patient-reported outcome measurement (PROM) tool - based on the Edmonton Symptom Assessment System - to assess and monitor symptoms in cancer patients. The USD contains 11 items concerning frequently occurring symptoms in cancer patients (pain, sleeping problems, dry mouth, dysphagia, lack of appetite, abnormal stool, nausea, shortness of breath, fatigue, anxiety and depressed mood) and an item on overall well-being. For the outpatient USD 11 items concerning frequently occurring signs and symptoms in patients receiving chemotherapy and/or targeted therapy were added to the USD: taste alteration, oral pain, weight loss, diarrhoea, hair changes, skin problems, nail problems, eye problems, tingling, concentration problems and problems with sexuality. This current study aimed to evaluate the 11 added items on this treatment specific outpatient USD in cancer patients receiving intravenous chemotherapy and/or targeted therapy., Methods: Observational longitudinal retrospective cohort study including all adult outpatients with cancer receiving intravenous chemotherapy and/or targeted therapy in an academic hospital in the Netherlands who completed at least one outpatient USD as part of routine care (2012-2021). Relevance, comprehensiveness as well as criterion and construct validity were assessed., Results: 1733 patients who completed ≥ 1 outpatient USD during intravenous chemotherapy and/or targeted therapy were included for analysis. Relevance as well as comprehensiveness of the items on the outpatient USD in this patient population was shown. Criterion validation was demonstrated for all added items of the outpatient USD - except for the item on oral pain. An additional analysis showed that mouth problems were detected with both outpatient USD items oral pain and dry mouth. Construct validity was demonstrated for the items hair changes and skin and nail problems. Construct validity on eye problems was not tested due to the low number of paired outpatient USDs., Conclusions: The treatment specific outpatient USD is a validated PROM in outpatients with cancer receiving intravenous chemotherapy and/or targeted therapy. Considering its validity in this broad group of patients, we think the treatment-specific outpatient USD is widely applicable. In addition to providing tailored supportive symptom care, the USD-data can be used to increase knowledge about symptom burden in daily practice in this population., (© 2024. The Author(s).)

Previous studies demonstrated limited efficacy of immune checkpoint inhibitors in unresectable acral melanoma (AM); it remains unclear how this translates to the adjuvant setting. This study investigates clinical outcomes of acral compared to cutaneous melanoma (CM) patients treated with adjuvant anti-PD-1 after complete resection. All stages III-IV AM and CM patients receiving adjuvant anti-PD-1 after complete resection between 2018 and 2022 were included from the prospective nationwide Dutch Melanoma Treatment Registry. We analyzed recurrence-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS). A multivariable Cox regression analysis of RFS was performed to adjust for potential confounders. We included 1958 (86 AM and 1872 CM) patients. At baseline, AM patients more frequently had KIT mutations, higher disease stages, and Eastern Cooperative Oncology Group Performance Status, and fewer BRAF and NRAS mutations. Median RFS was 14.8 months (95% confidence interval [CI]: 11.5-29.3) in AM and 37.4 months (95% CI: 34.6 to not reached) in CM (p = .002). After correcting for potential confounders, AM remained associated with a higher risk of recurrence (HR adj 1.53; 95% CI: 1.07-2.17; p = .019). Two-year DMFS tended to be worse for AM than for CM: 64.5% versus 79.7% (p = .050). Two-year OS was significantly lower in AM (71.5% vs. 84.3%; p = .027). The results of this study suggest a poorer outcome of adjuvant-treated AM compared to CM. Studies assessing the added value of adjuvant treatment in AM are needed. Future research should investigate alternative treatment strategies to improve outcomes of high-risk AM., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Introduction: The presence of tumor-infiltrating lymphocytes (TILs) in melanoma has been linked to survival. Their predictive capability for immune checkpoint inhibition (ICI) response remains uncertain. Therefore, we investigated the association between treatment response and TILs in the largest cohort to date and analyzed if this association was independent of known clinical predictors., Methods: In this multicenter cohort study, patients who received first-line anti-PD1 ± anti-CTLA4 for advanced melanoma were identified. TILs were scored on hematoxylin and eosin (H&E) slides of primary melanoma and pre-treatment metastases using the validated TILs-WG, Clark and MIA score. The primary outcome was objective response rate (ORR), with progression free survival and overall survival being secondary outcomes. Univariable and multivariable logistic regression and Cox proportional hazard were performed, adjusting for known clinical predictors., Results: Metastatic melanoma specimens were available for 650 patients and primary specimens for 565 patients. No association was found in primary melanoma specimens. In metastatic specimens, a 10-point increase in the TILs-WG score was associated with a higher probability of response (aOR 1.17, 95 % CI 1.07-1.28), increased PFS (HR 0.93, 95 % CI 0.87-0.996), and OS (HR 0.94, 95 % CI 0.89-0.99). When categorized, patients in the highest tertile TILs-WG score (15-100 %) compared to the lowest tertile (0 %) had a longer median PFS (13.1 vs. 7.3 months, p = 0.04) and OS (49.4 vs. 19.5 months, p = 0.003). Similar results were noted using the MIA and Clark scores., Conclusion: In advanced melanoma patients, TIL patterns on H&E slides of pre-treatment metastases, regardless of measurement method, are independently associated with ICI response. TILs are easily scored on readily available H&Es, facilitating the use of this biomarker in clinical practice., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Karijn P.M. Suijkerbuijk reports financial support was provided by Netherlands Organisation for Health Research and Development. Karijn P.M. Suijkerbuijk reports financial support was provided by Hanarth Fund Foundation. Karijn P.M. Suijkerbuijk reports financial support was provided by Philips. Dr. de Groot reports a relationship with Bristol Myers Squibb Co that includes: consulting or advisory. Dr. De Groot has advisory board relationships with BMS. Dr. Aarts has advisory board / consultancy honoraria from Amgen, Bristol Myers Squibb, Novartis, MSD-Merck, Merck-Pfizer, Pierre Fabre, Sanofi, Astellas, Bayer and received research grants from Merck-Pfizer and all were paid to the institution and not related to current work. Dr. Hospers has consultancy/advisory relationships with Amgen, Bristol Myers Squibb, Roche, MSD, Pfizer, Novartis, Sanofi and Pierre Fabre and has received research grants from Bristol Myers Squibb and Seerave and all were paid to the institution. Dr. Kapiteijn has consultancy/advisory relationships with Bristol Myers Squibb, Novartis, Merck, Pierre Fabre, Lilly and Bayer not related to current work and paid to institute, and received research grants not related to this paper from Bristol Myers Squibb, Delcath and Pierre-Fabre. Dr. Piersma had advisory board relationships with BMS, Novartis and Pierre Fabre, honoraria were paid to institution. Dr. Suijkerbuijk has consulting/advisory relationships with Bristol-Myers Squibb, Merck Sharp and Dome, Abbvie, Pierre Fabre Novartis, Sairopa, received honoraria from Novartis, Roche, Merck Sharp and Dome and received research funding from TigaTx, Bristol Myers Squibb and Philips and all were paid to institution and not related to the study. Dr. Schrader received honoraria/research funding from Kyowa Kirin paid to the institution and not related to the study. The remaining authors of this manuscript have no conflicts of interest to disclose. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Recent studies indicate an association between immunosuppression for immune-related adverse events (irAEs) and impaired survival in patients who received immune checkpoint inhibitors. Whether this is related to corticosteroids or second-line immunosuppressants is unknown. In the largest cohort thus far, we assessed the association of immunosuppressant type and dose with survival in melanoma patients with irAEs., Methods: Patients with advanced melanoma who received immunosuppressants for irAEs induced by first-line anti-PD-1 ± anti-CTLA-4 were included from 18 hospitals worldwide. Associations of cumulative and peak dose corticosteroids and use of second-line immunosuppression with survival from start of immunosuppression were assessed using multivariable Cox proportional hazard regression., Results: Among 606 patients, 404 had anti-PD-1 + anti-CTLA-4-related irAEs and 202 had anti-PD-1-related irAEs. 425 patients (70 %) received corticosteroids only; 181 patients (30 %) additionally received second-line immunosuppressants. Median PFS and OS from starting immunosuppression were 4.5 (95 %CI 3.4-8.1) and 31 (95 %CI 15-not reached) months in patients who received second-line immunosuppressants, and 11 (95 %CI 9.4-14) and 55 (95 %CI 41-not reached) months in patients who did not. High corticosteroid peak dose was associated with worse PFS and OS (HR adj 1.14; 95 %CI 1.01-1.29; HR adj 1.29; 95 %CI 1.12-1.49 for 80vs40mg), while cumulative dose was not. Second-line immunosuppression was associated with worse PFS (HR adj 1.32; 95 %CI 1.02-1.72) and OS (HR adj 1.34; 95 %CI 0.99-1.82) compared with corticosteroids alone., Conclusions: High corticosteroid peak dose and second-line immunosuppressants to treat irAEs are both associated with impaired survival. While immunosuppression is indispensable for treatment of severe irAEs, clinicians should weigh possible detrimental effects on survival against potential disadvantages of undertreatment., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: GAPH reports consultancy/advisory relationships with Amgen, Bristol-Myers Squibb, Roche, Merck Sharp and Dome, Pfizer, Novartis, Sanofi, Pierre Fabre and has received research funding from Bristol-Myers Squibb and Seerave. All paid to institution. MJBA reports consultancy/advisory relationships with Amgen, Bristol Myers Squibb, Novartis, Merck Sharp and Dome, Merck-Pfizer, Pierre Fabre, Sanofi, Astellas and Bayer, and received research funding from Merck-Pfizer. All paid to institution. KC reports consultancy fees from Eli Lilly AbbVie and Pfizer. ATJM has received fees from AbbVie, Actelion, CSL Behring, Experf, Novartis, and Shire and declares speaking fees from AstraZeneca, Sanofi-Aventis and Bristol-Myers Squibb. CUB reports consulting/advisory relationships with AstraZeneca, Bristol-Myers Squibb, GenMab, GSK, Lilly, Merck Sharp and Dome, Novartis, Pfizer, Pierre Fabre, Roche and Third Rock Ventures, and received research funding from 4SC, Bristol-Myers Squibb, NanoString and Novartis. All paid to institution. His is co-founder of and owns shares in Immagene BV and Signature Oncology, and is inventor on several related patents (including submitted): WO 2021/177822 A1, N2027907 and P091040NL2. SA reports consulting/advisory relationships with Merck Sharp and Dome, Sanofi, Roche, Bristol-Myers Squibb, Pfizer, Ipsen and Galapagos. All paid to institution. DP reports consultancy/advisory relationships with Pierre Fabre and Novartis. Partly paid to intstitution. EK reports consultancy/advisory relationships with Bristol Myers Squibb, Novartis, Pierre Fabre, Immunocore and Lilly, and received research grants not related to this paper from Bristol Myers Squibb, Delcath, Novartis and Pierre-Fabre. Not related to current work and paid to institute. ML reports consultancy/advisory relationships with Bristol-Myers Squibb and Janssen-Cilag B.V. All paid to institution. AMMvdV reports consultancy/advisory relationships with Bristol-Myers Squibb, Merck Sharp and Dome, Sanofi, Pfizer, Novartis, Roche, Eisai, Merck, Pierre Fabre and Ipsen. All paid to institution. JBAGH reports consultancy/advisory relationships with Achillus Tx, AstraZenica, BioNTech, Bristol-Myers Squibb, CureVac, GlaxoSmithKline, Imcyse, Iovance Bio, Instil Bio, Ipsen, Merck, Merck Sharp and Dome, Molecular Partners, Neogene TX, Novartis, Pfizer, PokeAcell, Roche, Sanofi, Scenic, T-Knife and TRV, and received research funding from Amgen, Bristol-Myers Squibb, BioNTech, Merck Sharp and Dome, Novartis and Sastra Cell Therapy. All paid to institution. KPMS reports consulting/advisory relationships with Bristol-Myers Squibb, Merck Sharp and Dome, Abbvie, Pierre Fabre, Novartis, Sairopa. She received honoraria from Novartis and Merck Sharp and Dome, and research funding from TigaTx, Bristol Myers Squibb, Philips and Genmab. All paid to institution. All remaining authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Importance: Long-term survival data from clinical trials show that survival curves of patients with advanced melanoma treated with immune checkpoint inhibitors (ICIs) gradually reach a plateau, suggesting that patients have a chance of achieving long-term survival., Objective: To investigate long-term survival in patients with advanced melanoma treated with ICIs outside clinical trials., Design, Setting, and Participants: Cohort study using prospectively collected data from the nationwide Dutch Melanoma Treatment Registry, including patients in the Netherlands with advanced melanoma treated with first-line ICIs from 2012 to 2019. Data were analyzed from January to September 2023., Exposures: Patients were treated with first-line ipilimumab-nivolumab, antibodies that target programmed cell death (anti-PD-1), or ipilimumab., Main Outcomes and Measures: Progression-free survival (PFS) and melanoma-specific survival were analyzed, and a Cox proportional hazards model was used to investigate factors associated with PFS after reaching partial response (PR) or complete response (CR)., Results: A total of 2490 patients treated with first-line ICIs were included (median [IQR] age, 65.0 [55.3-73.0] years; 1561 male patients [62.7%]). Most patients had an Eastern Cooperative Oncology Group Performance Status of 1 or lower (2202 patients [88.5%]) and normal lactate dehydrogenase levels (1715 patients [68.9%]). PFS for all patients was 23.4% (95% CI, 21.7%-25.2%) after 3 years and 19.7% (95% CI, 18.0%-21.4%) after 5 years. Overall survival for all patients was 44.0% (95% CI, 42.1%-46.1%) after 3 years and 35.9% (95% CI, 33.9%-38.0%) after 5 years. Patients with metastases in 3 or more organ sites had a significantly higher hazard of progression after reaching PR or CR (adjusted hazard ratio, 1.37; 95% CI, 1.11-1.69)., Conclusions and Relevance: This cohort study of patients with advanced melanoma treated with ICIs in clinical practice showed that their survival reached a plateau, comparable with patients participating in clinical trials. These findings can be used in daily clinical practice to guide long-term surveillance strategies and inform both physicians and patients regarding long-term treatment outcomes.

Objective: Immune checkpoint inhibitors (ICIs) are revolutionary in oncology but may cause immune-related (IR) side effects, such as hypophysitis. Treatment with anti-PD-(L)1, anti-CTLA-4 or anti-CLTA-4/PD-1 may induce hypophysitis, but little is known about the differences in clinical presentation or need for different treatment. We analyzed the differences of anti-PD-(L)1, anti-CTLA-4 and anti-CTLA-4/PD-1 induced hypophysitis., Methods: retrospective analysis of 67 patients (27 anti-PD-(L)1, 6 anti-CLTA-4 and 34 anti-CTLA-4/PD-1 induced hypophysitis)., Results: The median time between starting ICIs and IR-hypophysitis was longer after anti-PD(L)-1) therapy (22 weeks versus 11 and 14 weeks after anti-CTLA-4 and anti-CTLA-4/PD-1 therapy, respectively). The majority of patients (>90%), presented with atypical complaints such as fatigue, nausea, and muscle complaints. Headache, TSH or LH/FSH deficiency were more common in anti-CTLA-4 and anti-CLTA-4/PD-1 versus anti-PD-(L)1 induced hypophysitis (83% and 58% versus 8%, 67% and 41% versus 11%, and 83% and 48% versus 7%, respectively). Pituitary abnormalities on MRI (hypophysitis or secondary empty sella syndrome) were only seen in patients receiving anti-CTLA-4 or anti-CTLA-4/PD-1 therapy. Recovery from TSH, LH/FSH and ACTH deficiency was described in 92%, 70% and 0% of patients after a mean period of 14 and 104 days, respectively, and did not differ between patients who did or did not receive high-dose steroids., Conclusion: The clinical presentation of IR-hypophysitis varies depending on the type of ICIs. MRI abnormalities were only seen in anti-CTLA-4 or anti-CTLA-4/PD-1 induced hypophysitis. Endocrine recovery is seen for LH/FSH and TSH deficiency but not for ACTH deficiency, irrespective of the corticosteroid dose., Competing Interests: KS has consulting/advisory relationships with Bristol-Myers Squibb, Merck Sharp and Dome, Abbvie, Pierre Fabre Novartis, Sairopa, received honoraria from Novartis, Roche, Merck Sharp and Dome and received research funding from TigaTx, Bristol Myers Squibb and Philips. HS has received research funding from Pfizer Quality Improvement Grant and travel plus accommodation costs for an international meeting from Rhythm Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 van der Leij, Suijkerbuijk, van den Broek, Valk, Dankbaar and van Santen.)

Introduction : The difference in incidence and severity of anti-PD-1 therapy-related adverse events (irAEs) between adjuvant and advanced treated melanoma patients remains unclear, as no head-to-head studies have compared these groups. Methods : This multi-center cohort study analyzed melanoma patients treated with anti-PD-1 in adjuvant or advanced settings between 2015 and 2021. Comorbidities and ECOG performance status were assessed before treatment, and grade III-IV irAEs were monitored during treatment. Univariate and multivariate regression analyses were conducted to identify factors associated with irAE development. Results : A total of 1465 advanced melanoma patients and 908 resected melanoma patients received anti-PD-1 therapy. Adjuvant-treated patients were younger, with a median age of 63 years compared to 69 years in the advanced group ( p < 0.01), and had a better ECOG performance status ( p < 0.01). Comorbidities were seen more frequently in advanced melanoma patients than in those receiving adjuvant treatment, 76% versus 68% ( p < 0.01). Grade III-IV irAEs occurred in 214 (15%) advanced treated patients and in 119 (13%) adjuvant-treated patients. Multivariate analysis showed an increased risk of severe irAE development with the presence of any comorbidity (adjusted OR 1.22, 95% CI 1.02-1.44) and ECOG status greater than 1 (adjusted OR 2.00, 95% CI 1.20-3.32). Adjuvant therapy was not associated with an increased risk of irAE development compared to advanced treatment (adjusted OR 0.95, 95% CI 0.74-1.21) after correcting for comorbidities and ECOG performance score. Anti-PD-1 therapy was halted due to toxicity (any grade irAE) more often in the adjuvant setting than in the advanced setting, 20% versus 15% ( p < 0.01). Conclusions : Higher ECOG performance status and presence of any comorbidity were independently associated with an increased risk of Grade III-IV irAE in adjuvant and advanced treated melanoma patients. Patients treated in the adjuvant setting did not have an increased risk of developing severe irAEs compared to advanced melanoma patients. These findings are of clinical significance in consulting patients for adjuvant anti-PD-1 treatment.

PD-1 blockade therapy has revolutionized melanoma treatment, but still not all patients benefit and pre-treatment identification of those patients is difficult. Increased expression of inflammatory markers such as interleukin (IL)-6 in blood of patients correlates with poor treatment response. We set out to study the effect of inflammatory cytokines on PD-1 blockade in vitro. For this, we studied the effect of IL-6 and type I interferon (IFN) in vitro on human T cells in a mixed leukocyte reaction (MLR) in the absence or presence of PD-1 blockade. While IL-6 reduced IFN-γ secretion by T cells in both the presence and absence of PD-1 blockade, IFN-α specifically reduced the IFN-γ secretion only in the presence of PD-1 blockade. IFN-α reduced T cell proliferation independent of PD-1 blockade and reduced the percentage of cells producing IFN-γ only in the presence of PD-1 blockade. Next we determined the type I IFN score in a cohort of 22 melanoma patients treated with nivolumab. In this cohort, we did not find a correlation between clinical response and type I IFN score, nor between clinical response and IFN-γ secretion in vitro in a MLR in the presence of PD-1 blockade. We conclude that IFN-α reduces the effectiveness of PD-1 blockade in vitro, but that in this cohort, type I IFN score in vivo, nor IFN-γ secretion in vitro in a MLR in the presence of PD-1 blockade correlated to decreased therapy responses in patients., (© 2024. The Author(s).)

Background: The predictive value of tumor-infiltrating lymphocytes (TILs) in immune-related adverse event (irAE) development remains unknown, although an association between tumor immunogenicity and irAEs has been suggested. We investigated the association between TIL abundance in pretreatment primary and metastasis specimens and the subsequent development of severe irAEs., Patients and Methods: We retrospectively identified patients with advanced cutaneous melanoma who received first-line anti-programmed cell death protein 1 (PD-1) with or without anti-cytotoxic T-lymphocyte associated protein 4 (anti-CTLA-4) from 10 hospitals in the Netherlands. TILs were scored on representative hematoxylin and eosin (H&E) stains of the primary melanoma and pretreatment melanoma metastasis as 'absent', 'nonbrisk', or 'brisk'. A univariable logistic regression analysis was carried out to assess the association between the TIL scores and the development of severe irAEs. Fine and Gray subdistribution hazard models were used to estimate the cumulative incidence of severe irAEs., Results: Of the 1346 eligible patients, 536 patients had primary melanoma specimens available, and 613 patients had metastasis specimens available. Severe irAEs occurred in 15% of anti-PD-1-treated patients and 49% of anti-PD-1 + anti-CTLA-4-treated patients. The presence of TILs was not associated with the occurrence of grade ≥3 irAEs in primary melanoma specimens ( P  = 0.70) nor pretreatment metastasis specimens ( P  = 0.91). In the univariable analysis, patients with brisk TILs did not have a higher chance of developing severe irAEs compared with patients with absent TILs, for both primary specimen (odds ratio 1.15, 95% confidence interval 0.60-2.18) and metastasis specimen (odds ratio 0.77, 95% confidence interval 0.37-1.59). There was also no significant difference in the lifetime risk or timing of the development of severe irAEs in patients with TILs present compared with patients with TILs absent., Conclusion: There was no association between the TIL scores on H&E-stained slides from the primary melanoma or pretreatment metastasis and the development of grade 3 or higher irAEs. Additionally, no correlation was found between the presence of TILs and the timing of irAEs., (© 2024 The Authors.)

Purpose: The introduction of immunotherapy and targeted therapy has drastically improved the life expectancy of patients with advanced cancer. Despite improved survival, obtaining long-term response can be highly distressing and comes with uncertainties that affect several life domains. The aim of this study is to gain a deeper understanding of long-term responders' lived experiences with obtaining long-term response to immunotherapy or targeted therapy., Methods: We conducted an exploratory qualitative study using thematic data analysis. Semi-structured in-depth interviews were conducted with 17 patients with advanced melanoma or lung cancer who had a confirmed response to or long-term stable disease while on immunotherapy or targeted therapy., Results: Long-term responders are living in a twilight zone, where they neither feel like a patient, nor feel healthy. This impacts their self-image, interactions with their social environment, and feelings of uncertainty. Due to their uncertain life perspective, long-term responders are going back and forth between hope and despair, while they are longing for their 'old' life, several barriers, such as protective behavior of the social environment, force them to adjust to a life with cancer., Conclusion: Long-term responders are facing many challenges, such as searching for a renewed identity, dealing with ongoing uncertainty, and having to adapt to a new normal. This emphasizes the importance of providing this new patient group with tailored information and support., Implications for Cancer Survivors: Healthcare professionals can support patients by normalizing their feelings and providing space for varying emotions. Using patient-tailored scan frequencies could help temper fear of progression., (© 2022. The Author(s).)

We evaluated the prognostic value of hypoalbuminemia in context of various biomarkers at baseline, including clinical, genomic, transcriptomic, and blood-based markers, in patients with metastatic melanoma treated with anti-PD-1 monotherapy or anti-PD-1/anti-CTLA-4 combination therapy (n = 178). An independent validation cohort (n = 79) was used to validate the performance of hypoalbuminemia compared to serum LDH (lactate dehydrogenase) levels. Pre-treatment hypoalbuminemia emerged as the strongest predictor of poor outcome for both OS (HR = 4.01, 95% CI 2.10-7.67, Cox P = 2.63e-05) and PFS (HR = 3.72, 95% CI 2.06-6.73, Cox P = 1.38e-05) in univariate analysis. In multivariate analysis, the association of hypoalbuminemia with PFS was independent of serum LDH, IFN-γ signature expression, TMB, age, ECOG PS, treatment line, treatment type (combination or monotherapy), brain and liver metastasis (HR = 2.76, 95% CI 1.24-6.13, Cox P = 0.0131). Our validation cohort confirmed the prognostic power of hypoalbuminemia for OS (HR = 1.98, 95% CI 1.16-3.38; Cox P = 0.0127) and was complementary to serum LDH in analyses for both OS (LDH-adjusted HR = 2.12, 95% CI 1.2-3.72, Cox P = 0.00925) and PFS (LDH-adjusted HR = 1.91, 95% CI 1.08-3.38, Cox P = 0.0261). In conclusion, pretreatment hypoalbuminemia was a powerful predictor of outcome in ICI in melanoma and showed remarkable complementarity to previously established biomarkers, including high LDH., (© 2024. The Author(s).)

Predicting who will benefit from treatment with immune checkpoint inhibition (ICI) in patients with advanced melanoma is challenging. We developed a multivariable prediction model for response to ICI, using routinely available clinical data including primary melanoma characteristics. We used a population-based cohort of 3525 patients with advanced cutaneous melanoma treated with anti-PD-1-based therapy. Our prediction model for predicting response within 6 months after ICI initiation was internally validated with bootstrap resampling. Performance evaluation included calibration, discrimination and internal-external cross-validation. Included patients received anti-PD-1 monotherapy (n = 2366) or ipilimumab plus nivolumab (n = 1159) in any treatment line. The model included serum lactate dehydrogenase, World Health Organization performance score, type and line of ICI, disease stage and time to first distant recurrence-all at start of ICI-, and location and type of primary melanoma, the presence of satellites and/or in-transit metastases at primary diagnosis and sex. The over-optimism adjusted area under the receiver operating characteristic was 0.66 (95% CI: 0.64-0.66). The range of predicted response probabilities was 7%-81%. Based on these probabilities, patients were categorized into quartiles. Compared to the lowest response quartile, patients in the highest quartile had a significantly longer median progression-free survival (20.0 vs 2.8 months; P < .001) and median overall survival (62.0 vs 8.0 months; P < .001). Our prediction model, based on routinely available clinical variables and primary melanoma characteristics, predicts response to ICI in patients with advanced melanoma and discriminates well between treated patients with a very good and very poor prognosis., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Effectivity of BRAF(/MEK) inhibitor rechallenge has been described in prior studies. However, structured data are largely lacking., Methods: Data from all advanced melanoma patients treated with BRAFi(/MEKi) rechallenge were retrieved from the Dutch Melanoma Treatment Registry. The authors analyzed objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) for both first treatment and rechallenge. They performed a multivariable logistic regression and a multivariable Cox proportional hazards model to assess factors associated with response and survival., Results: The authors included 468 patients in the largest cohort to date who underwent at least two treatment episodes of BRAFi(/MEKi). Following rechallenge, ORR was 43%, median PFS was 4.6 months (95% confidence interval [CI], 4.1-5.2), and median OS was 8.2 months (95% CI, 7.2-9.4). Median PFS after rechallenge for patients who discontinued first BRAFi(/MEKi) treatment due to progression was 3.1 months (95% CI, 2.7-4.0) versus 5.2 months (95% CI, 4.5-5.9) for patients who discontinued treatment for other reasons. Discontinuing first treatment due to progression and lactate dehydrogenase (LDH) levels greater than two times the upper limit of normal were associated with lower odds of response and worse PFS and OS. Symptomatic brain metastases were associated with worse survival, whereas a longer treatment interval between first treatment and rechallenge was associated with better survival. Responding to the first BRAFi(/MEKi) treatment was not associated with response or survival., Conclusions: This study confirms that patients benefit from rechallenge. Elevated LDH levels, symptomatic brain metastases, and discontinuing first BRAFi(/MEKi) treatment due to progression are associated with less benefit from rechallenge. A prolonged treatment interval is associated with more benefit from rechallenge., (© 2024 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: A substantial proportion of patients with macroscopic stage III melanoma do not benefit sufficiently from adjuvant anti-PD-1 therapy, as they either recur despite therapy or would never have recurred. To better inform adjuvant treatment selection, we have performed translational analyses to identify prognostic and predictive biomarkers., Patients and Methods: Two cohorts of patients with macroscopic stage III melanoma from an ongoing biobank study were included. Clinical data were compared between an observation cohort (cohort 1) and an adjuvant intention cohort (cohort 2). RNA sequencing for translational analyses was performed and treatment subgroups (cohort 1A and cohort 2A) were compared for possible biomarkers, using a cut-off based on the treatment-naïve patients. In addition, two validation cohorts (Melanoma Institute Australia (MIA) and University Medical Centre Utrecht (UMCU)) were obtained., Results: After a median follow-up of 26 months of the 98 patients in our discovery set, median recurrence-free survival (RFS) was significantly longer for the adjuvant intention cohort (cohort 2, n=49) versus the observation cohort (cohort 1, n=49). Median overall survival was not reached for either cohort, nor significantly different. In observation cohort 1A (n=24), RFS was significantly longer for patients with high interferon-gamma (IFNγ) score (p=0.002); for adjuvant patients of cohort 2A (n=24), a similar trend was observed (p=0.086). Patients with high B cell score had a longer RFS in cohort 1A, but no difference was seen in cohort 2A. The B cell score based on RNA correlated with CD20 + cells in tumor area but was not independent from the IFNγ score. In the MIA validation cohort (n=44), longer RFS was observed for patients with high IFNγ score compared with low IFNγ score (p=0.046), no difference in RFS was observed according to the B cell score. In both the observation (n=11) and the adjuvant (n=11) UMCU validation cohorts, no difference in RFS was seen for IFNγ and B cell., Conclusions: IFNγ has shown to be a prognostic marker in both patients who were and were not treated with adjuvant therapy. B cell score was prognostic but did not improve accuracy over IFNγ. Our study confirmed RFS benefit of adjuvant anti-PD-1 for patients with macroscopic stage III melanoma., Competing Interests: Competing interests: PD reported financial interest in Signature Oncology and will receive some possible revenues if the IFN-γ signature is being developed as a clinical companion diagnostic. AMM is a consultant advisor for BMS, MSD, Novartis, Roche, Pierre-Fabre, and QBiotics. RAS has received fees for professional services from MetaOptima Technology Inc., F. Hoffmann-La Roche Ltd, Evaxion, Provectus Biopharmaceuticals Australia, QBiotics, Novartis, Merck Sharp & Dohme, NeraCare, AMGEN Inc., Bristol-Myers Squibb, Myriad Genetics, GlaxoSmithKline. KPMS is consult advisor for Bristol-Myers Squibb, Merck Sharp and Dome, Abbvie, Pierre Fabre, Novartis, and Sairopa; has received honoraria from Novartis, Roche, Merck Sharp, and Dome; and has received research funding from TigaTx, Bristol Myers Squibb, and Philips; all paid to the institute. GVL is a consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, OncoSec, PHMR Ltd, Pierre Fabre, Provectus, QBiotics, and Regeneron. ACJvA has received advisory board and consultancy honoraria from Amgen, Bristol-Myers Squibb, Novartis, MSD-Merck, Merck-Pfizer, Pierre Fabre, Provectus, Sanofi, and 4SC, all paid to the institute; and research grants received from Amgen, Bristol-Myers Squibb, Merck-Pfizer, and Novartis, all paid to the institute. CB received compensation (all paid to the institute except TRV) for advisory roles for Bristol-Myers Squibb, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre, and Third Rock Ventures; received research funding (all paid to the institute) from Bristol-Myers Squibb, Novartis, and NanoString, and declares stockownership in Immagene BV, where he is cofounder. All remaining authors have declared no conflicts of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Although animal experiments suggest beneficial effects of physical activity (PA) on antitumor immunity, little is known about the effects of PA on immune checkpoint inhibitor (ICI) toxicity and effectiveness in humans. We assessed the association of PA with immune-related adverse events (irAE) and survival in patients undergoing ICI., Methods: Patients receiving ICI who completed the Dutch short questionnaire to assess health enhancing physical activity (SQUASH) questionnaire at the start of treatment as part of the prospective UNICIT study in an academic hospital were included. PA was quantified by calculating total metabolic equivalent task hours per week (total PA) and hours per week of moderate- to vigorous-intensity PA during sport and leisure time (MVPA-SL). Associations of PA with severe irAE occurrence within 1 year and overall survival (OS) were evaluated using logistic regression and Cox proportional hazard regression, respectively, with adjustment for probable confounders., Results: In total, 251 patients were included, with a median follow-up of 20 months. Moderate and high levels of total PA were associated with lower odds of severe irAE occurrence compared to low levels of total PA (adjusted OR: 0.34 [95% CI = 0.12 to 0.90] and 0.19 [95% CI = 0.05 to 0.55], respectively). Moderate and high levels of total PA were also associated with prolonged survival (adjusted HR: 0.58 [95% CI = 0.32 to 1.04] and 0.48 [95% CI = 0.27 to 0.89], respectively). Similar associations were observed in patients who performed more MVPA-SL., Conclusions: Higher physical activity levels at the start of ICI treatment are associated with lower risk of severe irAEs and probably prolonged survival. Randomized controlled trials are needed to investigate whether patients indeed benefit from increasing PA levels after diagnosis., (© The Author(s) 2023. Published by Oxford University Press.)

With immune checkpoint inhibitors (ICIs) becoming the mainstay of treatment for many cancers, managing their immune-related adverse events (irAEs) has become an important part of oncological care. This Review covers the clinical presentation of irAEs and crucial aspects of reversibility, fatality and long-term sequelae, with special attention to irAEs in specific patient populations, such as those with autoimmune diseases. In addition, the genetic basis of irAEs, along with cellular and humoral responses to ICI therapy, are discussed. Detrimental effects of empirically used high-dose steroids and second-line immunosuppression, including impaired ICI effectiveness, call for more tailored irAE-treatment strategies. We discuss open therapeutic challenges and propose potential avenues to accelerate personalized management strategies and optimize outcomes., (© 2024. Springer Nature America, Inc.)

Purpose: Despite improved survival for people with advanced cancer due to new medical treatments, a growing group of long-term responders (LTRs) has to learn to live with uncertainties that affect several life domains. At the core of their experience, they neither feel like a patient nor feel healthy. Despite growing awareness of LTRs' experiences, learning more about how they cope with their long-term response can provide insight into how to best support them. Our study aimed to gain a deeper understanding what LTRs experience as helpful in navigating life with a long-term response., Methods: We conducted an exploratory qualitative study using thematic data analysis. Semi-structured in-depth interviews were conducted with 17 participants with advanced melanoma or lung cancer with confirmed response or long-term stable disease while on immuno- or targeted therapy., Results: LTRs reported several strategies to navigate life with a long-term response, for example, by involving the social environment, seeing uncertainty as an opportunity, and being present in the moment. This helped them to reclaim a sense of control, alter their perspective, and reshape their lives according to their values., Conclusion: Using different coping strategies enables LTRs to acknowledge both their sick and healthy side. Striking a healthy balance between being oriented on feeling sick or feeling healthy can help LTRs and their close others to navigate life with a long-term response. Healthcare professionals can provide support by recognizing whether LTRs are oriented at feeling sick or healthy, and by actively involving close others during medical appointments., (© 2024. The Author(s).)