Predictive markers of response and toxicity to tarlatamab in patients with extensive stage small cell lung cancer: a multi-institutional real-world analysis
- 1University of Maryland Greenebaum Comprehensive Cancer Center
Abstract
PurposeTarlatamab, a bispecific T-cell engager, has generated favorable response and survival outcomes in relapsed small cell lung cancer (SCLC). Factors influencing tarlatamab-associated treatment outcomes and toxicity have yet to be established. We performed a multivariate analysis to identify biomarkers associated with cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) and integrated these variables into a novel risk stratification tool to identify patients at high risk of clinically significant toxicity.
Patients and MethodsLogistic and ordinal regression analyses evaluated the predictive value of variables contributing to the presence and severity, respectively, of CRS and ICANS in 115 patients with ES-SCLC receiving tarlatamab. Selected variables were then tuned using 5-fold cross-validation and incorporated into novel elastic net-based prediction models.
ResultsRates of observed CRS, ICANS, and dysgeusia were 46%, 28%, and 47%, respectively. ORR (overall response rate) and DCR (disease control rate) were 44% and 58.2%, while 6-month PFS (progression free survival) and OS (overall survival) rates were 30.4% and 54.9%, respectively. Excluding patients on tarlatamab <30 days, presence of dysgeusia was associated with a lower rate of disease progression (HR 0.44, p=0.00691) and death (HR 0.34, p=0.0145). The presence of, increased size and number of extracranial metastases as well as elevated baseline LDH were significantly associated with increased likelihood of CRS. Increased ECOG performance status, increased volume of brain metastases, development of CRS, and elevated baseline LDH were all associated with increased risk of developing ICANS. Our cross-validated risk model successfully predicted CRS grade [≥]2 and ICANS events with 90.9% and 75% sensitivity, respectively.
ConclusionsThis exploratory analysis identified several predictive biomarkers of toxicity that successfully stratified low and high-risk populations as part of an internally validated novel risk scoring tool.
Statement of Translational RelevanceTarlatamab, a bispecfic T-cell engager (BiTE), is a novel immunotherapeutic agent for the treatment of relapsed extensive-stage small cell lung cancer (ES-SCLC). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are well-documented side effects of tarlatamab, however factors influencing treatment outcomes and toxicity have yet to be fully established. We performed a retrospective multivariate analysis of SCLC patients receiving tarlatamab to assess the association between baseline patient characteristics and the likelihood of developing treatment response and toxicity. Dysgeusia was identified as a predictive indicator of positive response, while CRS and ICANS had no association with favorable treatment outcome. Several clinical variables were found to be associated with CRS and ICANS development and were incorporated into a risk analysis that successfully stratified patients based on likelihood of developing toxicity. This risk stratification algorithm represents a novel tool to help inform patient monitoring needs, treatment planning, and prophylaxis considerations, though further prospective assessment and validation is needed.
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BibTeX
@misc{fenton2026predictive,
title = {{Predictive markers of response and toxicity to tarlatamab in patients with extensive stage small cell lung cancer: a multi-institutional real-world analysis}},
author = {G. Fenton and W. Guo and D. L. Hess and A. L. Zhang and C. Tatsuoka and A. L. Green and M. Sittig and R. Mehra and A. Simms and A. Dowlati and T. K. Owonikoko and M. Hsu and L. Alder and S. Rosner},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.02.26364624},
url = {https://www.medrxiv.org/content/10.64898/2026.10.02.26364624v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Predictive markers of response and toxicity to tarlatamab in patients with extensive stage small cell lung cancer: a multi-institutional real-world analysis
AU - G. Fenton
AU - W. Guo
AU - D. L. Hess
AU - A. L. Zhang
AU - C. Tatsuoka
AU - A. L. Green
AU - M. Sittig
AU - R. Mehra
AU - A. Simms
AU - A. Dowlati
AU - T. K. Owonikoko
AU - M. Hsu
AU - L. Alder
AU - S. Rosner
PY - 2026
DA - 2026/10/02
PB - medRxiv
DO - 10.64898/2026.10.02.26364624
UR - https://www.medrxiv.org/content/10.64898/2026.10.02.26364624v1
AB - PurposeTarlatamab, a bispecific T-cell engager, has generated favorable response and survival outcomes in relapsed small cell lung cancer (SCLC). Factors influencing tarlatamab-associated treatment outcomes and toxicity have yet to be established. We performed a multivariate analysis to identify biomarkers associated with cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) and integrated these variables into a novel risk stratification tool to identify patients at high risk of clinically significant toxicity. Patients and MethodsLogistic and ordinal regression analyses evaluated the predictive value of variables contributing to the presence and severity, respectively, of CRS and ICANS in 115 patients with ES-SCLC receiving tarlatamab. Selected variables were then tuned using 5-fold cross-validation and incorporated into novel elastic net-based prediction models. ResultsRates of observed CRS, ICANS, and dysgeusia were 46%, 28%, and 47%, respectively. ORR (overall response rate) and DCR (disease control rate) were 44% and 58.2%, while 6-month PFS (progression free survival) and OS (overall survival) rates were 30.4% and 54.9%, respectively. Excluding patients on tarlatamab <30 days, presence of dysgeusia was associated with a lower rate of disease progression (HR 0.44, p=0.00691) and death (HR 0.34, p=0.0145). The presence of, increased size and number of extracranial metastases as well as elevated baseline LDH were significantly associated with increased likelihood of CRS. Increased ECOG performance status, increased volume of brain metastases, development of CRS, and elevated baseline LDH were all associated with increased risk of developing ICANS. Our cross-validated risk model successfully predicted CRS grade [≥]2 and ICANS events with 90.9% and 75% sensitivity, respectively. ConclusionsThis exploratory analysis identified several predictive biomarkers of toxicity that successfully stratified low and high-risk populations as part of an internally validated novel risk scoring tool. Statement of Translational RelevanceTarlatamab, a bispecfic T-cell engager (BiTE), is a novel immunotherapeutic agent for the treatment of relapsed extensive-stage small cell lung cancer (ES-SCLC). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are well-documented side effects of tarlatamab, however factors influencing treatment outcomes and toxicity have yet to be fully established. We performed a retrospective multivariate analysis of SCLC patients receiving tarlatamab to assess the association between baseline patient characteristics and the likelihood of developing treatment response and toxicity. Dysgeusia was identified as a predictive indicator of positive response, while CRS and ICANS had no association with favorable treatment outcome. Several clinical variables were found to be associated with CRS and ICANS development and were incorporated into a risk analysis that successfully stratified patients based on likelihood of developing toxicity. This risk stratification algorithm represents a novel tool to help inform patient monitoring needs, treatment planning, and prophylaxis considerations, though further prospective assessment and validation is needed.
ER -