{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T01:38:47Z","timestamp":1792373927903,"version":"4.4.0"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T00:00:00Z","timestamp":1777852800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Immune checkpoint inhibitors (ICIs) have markedly improved outcomes in metastatic microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) gastrointestinal (GI) malignancies. However, in fragile settings, especially in low- and middle-income countries (LMIC) and areas of conflict, access remains severely limited by prohibitive costs and supply chain disruptions. Starting in late 2019, Lebanon\u2019s economic crisis led to health system collapse, currency devaluation, medication shortages, and ongoing conflict, which necessitated adaptive treatment strategies. Early pharmacodynamic studies suggest lower ICI doses may achieve comparable efficacy; however, real-world evidence from conflict-affected settings where dose reductions occur by necessity rather than design remains absent. This study examines ICI dosing outcomes during Lebanon\u2019s acute crisis period.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted a retrospective analysis of adult patients with metastatic MSI-H\/dMMR GI cancers treated with ICIs at the American University of Beirut Medical Center between 2018 and 2024, encompassing Lebanon\u2019s economic collapse and acute health system fragility. Dose-intensity was calculated as the percentage of actual dose received compared to the recommended dose. Patients were stratified into &amp;lt;75% and \u226575% dose-intensity groups based on actual doses delivered under resource constraints. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall response rate (ORR), clinical benefit rate (CBR), and immune-related adverse events (irAEs). Exploratory endpoint was overall survival (OS).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Twenty-nine patients were included, 19\/29 patients (65.5%) had colorectal cancer. 18\/29 patients (62%) received \u226575% of the recommended dose-intensity, while eleven (38%) received &amp;lt;75%. ORR was 63.6% and 66.7% respectively (p = 0.362), while CBR was 90.9% and 72.2% respectively. No statistically significant difference in PFS or OS was observed. All irAEs (n=4; 14%) occurred in patients receiving \u226575% dose-intensity and included grade 3 diarrhea, grade 3 interstitial nephritis and erythroderma and grade 2 polyarthritis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In LMIC with a conflict-affected health system and experiencing medication shortages and economic collapse, lower dose-intensity ICIs may be feasible for MSI-H\/dMMR GI malignancies, offering a pragmatic approach to maintain treatment continuity when standard dosing is inaccessible. These findings are exploratory, highlighting the need for larger prospective studies and the importance of integrating health system context, resilience, and adaptation into oncology research in fragile settings.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1766420","type":"journal-article","created":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T04:24:33Z","timestamp":1777868673000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Real-world evidence of lower-dose intensity of immune checkpoint inhibitors in MSI-H\/dMMR gastrointestinal cancers from a resource-constrained setting"],"prefix":"10.3389","volume":"16","author":[{"given":"Mohamad","family":"Mourad","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Hematology\/Oncology Division, American University of Beirut Medical Center","place":["Beirut, Lebanon"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noura","family":"Abbas","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Hematology\/Oncology Division, American University of Beirut Medical Center","place":["Beirut, Lebanon"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maya","family":"Charafeddine","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Hematology\/Oncology Division, American University of Beirut Medical Center","place":["Beirut, Lebanon"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Shamseddine","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Hematology\/Oncology Division, American University of Beirut Medical Center","place":["Beirut, Lebanon"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2021.102175","article-title":"Microsatellite instability in gastric cancer: Between lights and shadows","volume":"95","author":"Puliga","year":"2021","journal-title":"Cancer Treat Rev"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa2017699","article-title":"Pembrolizumab in microsatellite-instability-high advanced colorectal cancer","volume":"383","author":"Andr\u00e9","year":"2020","journal-title":"N Engl J Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.humpath.2022.06.009","article-title":"Microsatellite instability in pancreatic and ampullary carcinomas: histology, molecular pathology, and clinical implications","volume":"132","author":"Luchini","year":"2023","journal-title":"Hum Pathol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1111\/cas.16160","article-title":"Microsatellite instability: A 2024 update","volume":"115","author":"Yamamoto","year":"2024","journal-title":"Cancer Sci"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2024.114033","article-title":"A multicenter study evaluating efficacy of immune checkpoint inhibitors in advanced non-colorectal digestive cancers with microsatellite instability","volume":"202","author":"Moreau","year":"2024","journal-title":"Eur J Cancer"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1200\/jco.19.01124","article-title":"Individual patient data meta-analysis of the value of microsatellite instability as a biomarker in gastric cancer","volume":"37","author":"Pietrantonio","year":"2019","journal-title":"J Clin Oncol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1200\/go-24-00409","article-title":"Overcoming financial and access barriers in global cancer care with low-dose immunotherapy: A systematic review","volume":"11","author":"Hoyek","year":"2025","journal-title":"JCO Glob Oncol"},{"key":"B8","unstructured":"Drugs public price list\n          \n          2025"},{"key":"B9","unstructured":""},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.puhe.2024.01.033","article-title":"Prevalence and determinants of non-communicable diseases and risk factors among adults in Lebanon: a multicentric cross-sectional study","volume":"229","author":"El Haidari","year":"2024","journal-title":"Public Health"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.5306\/wjco.v15.i5.644","article-title":"Impact of the economic crisis and drug shortage on Lebanese cancer patients' care","volume":"15","author":"Eid","year":"2024","journal-title":"World J Clin Oncol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1063","DOI":"10.1016\/s1470-2045(21)00396-x","article-title":"Lebanon faces critical shortage of drugs","volume":"22","author":"Das","year":"2021","journal-title":"Lancet Oncol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/s1470-2045(24)00522-9","article-title":"Integrating cancer into crisis: a global vision for action from WHO and partners","volume":"26","author":"Casolino","year":"2025","journal-title":"Lancet Oncol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"170","DOI":"10.2471\/blt.21.285627","article-title":"The quality-of-care agenda in fragile, conflict-affected and vulnerable settings","volume":"99","author":"Neilson","year":"2021","journal-title":"Bull World Health Organ"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.ccr-14-2607","article-title":"Phase I study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in patients with advanced solid tumors","volume":"21","author":"Patnaik","year":"2015","journal-title":"Clin Cancer Res"},{"key":"B16","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1186\/s40425-016-0177-2","article-title":"Nivolumab dose selection: challenges, opportunities, and lessons learned for cancer immunotherapy","volume":"4","author":"Agrawal","year":"2016","journal-title":"J Immunother Cancer"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(15)01281-7","article-title":"Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial","volume":"387","author":"Herbst","year":"2016","journal-title":"Lancet"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(18)32409-7","article-title":"Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial","volume":"393","author":"Mok","year":"2019","journal-title":"Lancet"},{"key":"B19","unstructured":"FDA expands pembrolizumab indication for first-line treatment of NSCLC (TPS \u22651%)\n          \n          2019"},{"key":"B20","first-page":"96","article-title":"Keytruda (pembrolizumab): First PD-1 inhibitor approved for previously treated unresectable or metastatic melanoma","volume":"8","author":"Raedler","year":"2015","journal-title":"Am Health Drug Benefits"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1503093","article-title":"Pembrolizumab versus ipilimumab in advanced melanoma","volume":"372","author":"Robert","year":"2015","journal-title":"N Engl J Med"},{"key":"B22","unstructured":"KEYTRUDA (pembrolizumab) [prescribing information]\n          \n          2025"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1200\/go.24.00122","article-title":"Low-dose anti-PD(L)1 for the treatment of solid Malignancies","volume":"10","author":"Souza","year":"2024","journal-title":"JCO Glob Oncol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1200\/go.24.00141","article-title":"Performance of low-dose immunotherapy and standard-dose immunotherapy in microsatellite instability-high metastatic colorectal cancer: Real-world data (CLouD-High Study)","volume":"10","author":"Trikha","year":"2024","journal-title":"JCO Glob Oncol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"2509","DOI":"10.1200\/jco.2025.43.16_suppl.2509","article-title":"Phase III randomized study comparing ultra-low dose immunotherapy to standard cytotoxic chemotherapy for solid tumors in second line and beyond setting (DELII: Development of Low dose Immunotherapy in India)","volume":"43","author":"Noronha","year":"2025","journal-title":"J Clin Oncol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1083836","article-title":"The state of cancer research in fragile and conflict-affected settings in the Middle East and North Africa region: A bibliometric analysis","volume":"13","author":"Sater","year":"2023","journal-title":"Front Oncol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1186\/s13031-023-00560-7","article-title":"Health systems resilience in fragile and conflict-affected settings: a systematic scoping review","volume":"18","author":"Truppa","year":"2024","journal-title":"Conflict Health"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djaf152","article-title":"The association between new cancer therapy innovations and financial toxicity","volume":"117","author":"Khor","year":"2025","journal-title":"JNCI: J Natl Cancer Institute"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-024-04697-x","article-title":"Pharmacokinetics and clinical outcomes of low-dose nivolumab relative to conventional dose in patients with advanced cancer","volume":"94","author":"Gandhi","year":"2024","journal-title":"Cancer Chemother Pharmacol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1177\/10732748251399259","article-title":"Extent and mitigation of financial toxicity of immune checkpoint inhibitors for the treatment of advanced hepatocellular carcinoma","volume":"32","author":"Omar","year":"2025","journal-title":"Cancer Control"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1111\/jdv.20672","article-title":"Survival after cessation of immunotherapies in melanoma: A systematic review and meta-analysis","volume":"39","author":"Mayer","year":"2025","journal-title":"J Eur Acad Dermatol Venereol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12113486","article-title":"Circulating tumour DNA in advanced melanoma patients ceasing PD1 inhibition in the absence of disease progression","volume":"12","author":"Warburton","year":"2020","journal-title":"Cancers (Basel)"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1280730","article-title":"Detectable ctDNA at the time of treatment cessation of ipilimumab and nivolumab for toxicity predicts disease progression in advanced melanoma patients","volume":"13","author":"Warburton","year":"2023","journal-title":"Front Oncol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1665716","article-title":"Safety of immune checkpoint inhibitors for cancer treatment: real-world retrospective data analysis from Qatar (SAFE-ICI-Q study)","volume":"16","author":"Omar","year":"2025","journal-title":"Front Immunol"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1766420\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T04:24:35Z","timestamp":1777868675000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1766420\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,4]]},"references-count":34,"alternative-id":["10.3389\/fonc.2026.1766420"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2026.1766420","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,4]]},"article-number":"1766420"}}