Durable responders in advanced NSCLC with elevated TMB and treated with 1L immune checkpoint inhibitor: a real-world outcomes analysis
Background For patients with advanced non-small cell lung carcinoma (NSCLC), immune checkpoint inhibitor (ICPI) and chemotherapy (chemo) ICPI represent two distinct first-line standard-of-care regimens without clear and established biomarkers to inform the optimal choice for individual patients. Her...
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BMJ Publishing Group
2023-01-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/1/e005801.full |
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| author | David P Carbone David Spigel Jeffrey S Ross Karthikeyan Murugesan Gerald Li Richard S P Huang Ryon P Graf Geoffrey R Oxnard Alexa Schrock Liangliang Zhang Khaled Tolba Jacob Sands |
| author_facet | David P Carbone David Spigel Jeffrey S Ross Karthikeyan Murugesan Gerald Li Richard S P Huang Ryon P Graf Geoffrey R Oxnard Alexa Schrock Liangliang Zhang Khaled Tolba Jacob Sands |
| author_sort | David P Carbone |
| collection | DOAJ |
| description | Background For patients with advanced non-small cell lung carcinoma (NSCLC), immune checkpoint inhibitor (ICPI) and chemotherapy (chemo) ICPI represent two distinct first-line standard-of-care regimens without clear and established biomarkers to inform the optimal choice for individual patients. Here, we examined the complementary roles of tumor mutational burden (TMB) and programmed death ligand-1 (PD-L1) immunohistochemistry (IHC) to inform first-line therapy using a large real-world (rw) data set.Materials and methods The study included patients with NSCLC from an rw de-identified clinico-genomic database. All patients underwent genomic testing using Foundation Medicine’s tissue comprehensive genomic profiling assay and PD-L1 IHC assay scored for tumor cell staining (TS).Results Of 2165 patients included in the analysis, 150 exhibited durable benefit from first-line ICPI regimens (these patients were enriched for PD-L1 TS ≥50, non-squamous histology, and TMB ≥20 mutations/megabase (muts/Mb)). Comparing low TMB (<10 muts/Mb), high TMB (10–19 muts/Mb), and very high TMB (≥20 muts/Mb) receiving ICPI alone, we observed a stepwise increase in median rwPFS (real world-progression free survival) (6.5, 7.5, 17.2 months) and rwOS (real world-overall survival) (10.1, 11.8, 26.9 months) as TMB increased. In the low PD-L1 (TS <50%) cohort, TMB <20 muts/Mb showed a more favorable rwPFS (HR: 0.56 (95% CI: 0.40 to 0.79)) and rwOS (HR 0.74 (95% CI: 0.58 to 0.96)) on chemoICPI when compared with ICPI alone while the point estimate in rwPFS favored monoICPI in the TMB ≥20 muts/Mb cohort, the CI is wide and does not reach statistical significance (HR: 1.68 (95% CI: 0.52 to 5.48)).Conclusion This study provides evidence that higher TMB cut-offs, such as 20 muts/Mb, can identify patients with prolonged benefit from ICPI. TMB ≥20 muts/Mb is a potential biomarker that may identify patients in whom an ICPI without chemo could be considered, even in the setting of lower PD-L1 levels. Prospective validation of these findings could increase access to chemo-sparing regimens for the first-line treatment of advanced NSCLC. |
| format | Article |
| id | doaj-art-93d396e4896a4daf9ffa2a8edbac359e |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2023-01-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-93d396e4896a4daf9ffa2a8edbac359e2025-01-29T12:05:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-01-0111110.1136/jitc-2022-005801Durable responders in advanced NSCLC with elevated TMB and treated with 1L immune checkpoint inhibitor: a real-world outcomes analysisDavid P Carbone0David Spigel1Jeffrey S Ross2Karthikeyan Murugesan3Gerald Li4Richard S P Huang5Ryon P Graf6Geoffrey R Oxnard7Alexa Schrock8Liangliang Zhang9Khaled Tolba10Jacob Sands11The Ohio State University and the Pelotonia Institute for Immune Oncology, Columbus, Ohio, USAchief scientific officerDepartment of Pathology and Diagnostic Medicine, Medical Team, Foundation Medicine Inc, Cambridge, Massachusetts, USA3Foundation Medicine, Inc., Cambridge, MA, USAFoundation Medicine Inc, Cambridge, Massachusetts, USAFoundation Medicine Inc, Cambridge, Massachusetts, USADepartment of Clinical Development, Medical Team, Foundation Medicine Inc, San Diego, California, USAFoundation Medicine, Inc, Cambridge, Massachusetts, USAFoundation Medicine Inc, Cambridge, Massachusetts, USAFoundation Medicine Inc, Cambridge, Massachusetts, USAFoundation Medicine Inc, Cambridge, Massachusetts, USA1Dana-Farber Cancer Institute, Boston, MA, USABackground For patients with advanced non-small cell lung carcinoma (NSCLC), immune checkpoint inhibitor (ICPI) and chemotherapy (chemo) ICPI represent two distinct first-line standard-of-care regimens without clear and established biomarkers to inform the optimal choice for individual patients. Here, we examined the complementary roles of tumor mutational burden (TMB) and programmed death ligand-1 (PD-L1) immunohistochemistry (IHC) to inform first-line therapy using a large real-world (rw) data set.Materials and methods The study included patients with NSCLC from an rw de-identified clinico-genomic database. All patients underwent genomic testing using Foundation Medicine’s tissue comprehensive genomic profiling assay and PD-L1 IHC assay scored for tumor cell staining (TS).Results Of 2165 patients included in the analysis, 150 exhibited durable benefit from first-line ICPI regimens (these patients were enriched for PD-L1 TS ≥50, non-squamous histology, and TMB ≥20 mutations/megabase (muts/Mb)). Comparing low TMB (<10 muts/Mb), high TMB (10–19 muts/Mb), and very high TMB (≥20 muts/Mb) receiving ICPI alone, we observed a stepwise increase in median rwPFS (real world-progression free survival) (6.5, 7.5, 17.2 months) and rwOS (real world-overall survival) (10.1, 11.8, 26.9 months) as TMB increased. In the low PD-L1 (TS <50%) cohort, TMB <20 muts/Mb showed a more favorable rwPFS (HR: 0.56 (95% CI: 0.40 to 0.79)) and rwOS (HR 0.74 (95% CI: 0.58 to 0.96)) on chemoICPI when compared with ICPI alone while the point estimate in rwPFS favored monoICPI in the TMB ≥20 muts/Mb cohort, the CI is wide and does not reach statistical significance (HR: 1.68 (95% CI: 0.52 to 5.48)).Conclusion This study provides evidence that higher TMB cut-offs, such as 20 muts/Mb, can identify patients with prolonged benefit from ICPI. TMB ≥20 muts/Mb is a potential biomarker that may identify patients in whom an ICPI without chemo could be considered, even in the setting of lower PD-L1 levels. Prospective validation of these findings could increase access to chemo-sparing regimens for the first-line treatment of advanced NSCLC.https://jitc.bmj.com/content/11/1/e005801.full |
| spellingShingle | David P Carbone David Spigel Jeffrey S Ross Karthikeyan Murugesan Gerald Li Richard S P Huang Ryon P Graf Geoffrey R Oxnard Alexa Schrock Liangliang Zhang Khaled Tolba Jacob Sands Durable responders in advanced NSCLC with elevated TMB and treated with 1L immune checkpoint inhibitor: a real-world outcomes analysis Journal for ImmunoTherapy of Cancer |
| title | Durable responders in advanced NSCLC with elevated TMB and treated with 1L immune checkpoint inhibitor: a real-world outcomes analysis |
| title_full | Durable responders in advanced NSCLC with elevated TMB and treated with 1L immune checkpoint inhibitor: a real-world outcomes analysis |
| title_fullStr | Durable responders in advanced NSCLC with elevated TMB and treated with 1L immune checkpoint inhibitor: a real-world outcomes analysis |
| title_full_unstemmed | Durable responders in advanced NSCLC with elevated TMB and treated with 1L immune checkpoint inhibitor: a real-world outcomes analysis |
| title_short | Durable responders in advanced NSCLC with elevated TMB and treated with 1L immune checkpoint inhibitor: a real-world outcomes analysis |
| title_sort | durable responders in advanced nsclc with elevated tmb and treated with 1l immune checkpoint inhibitor a real world outcomes analysis |
| url | https://jitc.bmj.com/content/11/1/e005801.full |
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