{"entity":{"id":"first-line","kind":"term","name":"Lines of therapy","aka":["first-line","second-line","third-line","later-line","later lines","1L","2L","3L","first line","second line","third line","line of therapy","front-line","frontline","previously untreated","prior lines","treatment-naive"],"tldr":"First-line is the first treatment for advanced cancer; second-line is what comes after it fails, and so on.","summary":"Lines of therapy number the successive treatments a patient with advanced cancer receives: first-line is the initial treatment, second-line follows when it fails, and so on, with aliases such as 1L, 2L, front-line and treatment-naive. Drugs are usually approved first in later lines, where control arms are weak, and then move earlier, and each shift to an earlier line reshapes the entire sequence, as happened with ADCs in TNBC in 2026. The concept is central to Project FrontRunner and to the bottlenecks on too many combinations to test, fragmented care and incentives that reward me-too drugs. It also frames the DESTINY-Breast06, FLAURA, MARIPOSA, KEYNOTE-189, HARMONi-2 and NAPOLI-3 papers and ideas on pathology-triggered trial referral and reflex genomic profiling at diagnosis.","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/Therapy#Lines_of_therapy","links":[{"label":"NCI Dictionary of Cancer Terms: first-line therapy","url":"https://www.cancer.gov/publications/dictionaries/cancer-terms/def/first-line-therapy"}],"tags":[],"related":[],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"category":"Clinical"},"route":"/terms/first-line/","neighbours":{"bottleneck":[{"id":"b-care-fragmentation","kind":"bottleneck","name":"Fragmented care and guideline gaps","route":"/bottlenecks/b-care-fragmentation/"},{"id":"b-incentive-misalignment","kind":"bottleneck","name":"Incentives reward me-too drugs and marginal gains","route":"/bottlenecks/b-incentive-misalignment/"},{"id":"b-combination-space","kind":"bottleneck","name":"Too many combinations to test","route":"/bottlenecks/b-combination-space/"}],"idea":[{"id":"idea-acc-reflex-genomic-profiling-at-diagnosis","kind":"idea","name":"Pathologists order genomic profiling automatically at diagnosis of advanced cancer","route":"/ideas/idea-acc-reflex-genomic-profiling-at-diagnosis/"},{"id":"idea-tr1-pathology-triggered-referral","kind":"idea","name":"The pathology lab triggers a trial referral the day a rare cancer is diagnosed","route":"/ideas/idea-tr1-pathology-triggered-referral/"}],"term":[{"id":"cross-resistance","kind":"term","name":"Cross-resistance","route":"/terms/cross-resistance/"},{"id":"maintenance-therapy","kind":"term","name":"Maintenance therapy","route":"/terms/maintenance-therapy/"},{"id":"progression","kind":"term","name":"Progression","route":"/terms/progression/"},{"id":"progressive-disease","kind":"term","name":"Progressive disease and radiographic progression","route":"/terms/progressive-disease/"},{"id":"project-frontrunner","kind":"term","name":"Project FrontRunner","route":"/terms/project-frontrunner/"},{"id":"refractory","kind":"term","name":"Refractory","route":"/terms/refractory/"},{"id":"relapsed-refractory","kind":"term","name":"Relapsed / refractory (R/R)","route":"/terms/relapsed-refractory/"},{"id":"salvage-therapy","kind":"term","name":"Salvage therapy","route":"/terms/salvage-therapy/"}],"paper":[{"id":"paper-breakwater-nejm-2025","kind":"paper","name":"BREAKWATER: encorafenib plus cetuximab with chemotherapy as first treatment for BRAF V600E-mutated colorectal cancer","route":"/key-papers/paper-breakwater-nejm-2025/"},{"id":"paper-checkmate-649-lancet-2021","kind":"paper","name":"CheckMate 649: nivolumab plus chemotherapy as first treatment for advanced gastric, gastro-oesophageal junction and oesophageal adenocarcinoma","route":"/key-papers/paper-checkmate-649-lancet-2021/"},{"id":"paper-clear-nejm-2021","kind":"paper","name":"CLEAR: lenvatinib plus pembrolizumab versus sunitinib as first treatment for advanced kidney cancer","route":"/key-papers/paper-clear-nejm-2021/"},{"id":"paper-destiny-breast06-nejm-2024","kind":"paper","name":"DESTINY-Breast06: trastuzumab deruxtecan before any chemotherapy in hormone-receptor-positive, HER2-low or ultralow breast cancer","route":"/key-papers/paper-destiny-breast06-nejm-2024/"},{"id":"paper-ev-302-nejm-2024","kind":"paper","name":"EV-302: enfortumab vedotin plus pembrolizumab replaces chemotherapy as first treatment for advanced bladder cancer","route":"/key-papers/paper-ev-302-nejm-2024/"},{"id":"paper-flaura-nejm-2018","kind":"paper","name":"FLAURA: osimertinib as first treatment for EGFR-mutated lung cancer","route":"/key-papers/paper-flaura-nejm-2018/"},{"id":"paper-flaura2-long-term-safety-lung-cancer-2026","kind":"paper","name":"FLAURA2: long-term safety of first-line osimertinib plus platinum-pemetrexed in EGFR-mutated advanced lung cancer","route":"/key-papers/paper-flaura2-long-term-safety-lung-cancer-2026/"},{"id":"paper-harmoni-2-lancet-2025","kind":"paper","name":"HARMONi-2: ivonescimab, a PD-1 x VEGF bispecific, beats pembrolizumab head-to-head in PD-L1-positive lung cancer","route":"/key-papers/paper-harmoni-2-lancet-2025/"},{"id":"paper-imbrave150-nejm-2020","kind":"paper","name":"IMbrave150: atezolizumab plus bevacizumab replaces sorafenib as first treatment for advanced liver cancer","route":"/key-papers/paper-imbrave150-nejm-2020/"},{"id":"paper-keynote-048-lancet-2019","kind":"paper","name":"KEYNOTE-048: pembrolizumab, alone or with chemotherapy, as first treatment for recurrent or metastatic head and neck cancer","route":"/key-papers/paper-keynote-048-lancet-2019/"},{"id":"paper-keynote-177-nejm-2020","kind":"paper","name":"KEYNOTE-177: pembrolizumab instead of chemotherapy as first treatment for mismatch-repair-deficient metastatic colorectal cancer","route":"/key-papers/paper-keynote-177-nejm-2020/"},{"id":"paper-keynote-189-nejm-2018","kind":"paper","name":"KEYNOTE-189: pembrolizumab plus chemotherapy as first treatment for non-squamous lung cancer without a driver mutation","route":"/key-papers/paper-keynote-189-nejm-2018/"},{"id":"paper-mariposa-nejm-2024","kind":"paper","name":"MARIPOSA: amivantamab plus lazertinib versus osimertinib as first treatment for EGFR-mutated lung cancer","route":"/key-papers/paper-mariposa-nejm-2024/"},{"id":"paper-napoli-3-lancet-2023","kind":"paper","name":"NAPOLI-3: NALIRIFOX versus gemcitabine plus nab-paclitaxel as first treatment for metastatic pancreatic cancer","route":"/key-papers/paper-napoli-3-lancet-2023/"},{"id":"paper-netter-2-lancet-2024","kind":"paper","name":"NETTER-2: lutetium-177 dotatate as first treatment for higher-grade gastroenteropancreatic neuroendocrine tumours","route":"/key-papers/paper-netter-2-lancet-2024/"},{"id":"paper-relativity-047-nejm-2022","kind":"paper","name":"RELATIVITY-047: relatlimab plus nivolumab, the first LAG-3 checkpoint combination, in untreated advanced melanoma","route":"/key-papers/paper-relativity-047-nejm-2022/"},{"id":"paper-ruby-nejm-2023","kind":"paper","name":"RUBY: dostarlimab with chemotherapy for advanced or recurrent endometrial cancer","route":"/key-papers/paper-ruby-nejm-2023/"},{"id":"paper-spotlight-lancet-2023","kind":"paper","name":"SPOTLIGHT: zolbetuximab, the first Claudin 18.2 antibody, added to chemotherapy in gastric cancer","route":"/key-papers/paper-spotlight-lancet-2023/"}]}}