Effect of Pembrolizumab After Stereotactic Body Radiotherapy vs Pembrolizumab Alone on Tumor Response in Patients With Advanced Non–Small Cell Lung Cancer: Results of the PEMBRO-RT Phase 2 Randomized Clinical Trial
Willemijn S. M. E. Theelen,Heike Peulen,Ferry Lalezari,Vincent van der Noort,Jeltje F. de Vries,Joachim G.J.V. Aerts,Daphne W. Dumoulin,Idris Bahce,Anna-Larissa N. Niemeijer,Adrianus J. de Langen,Kim Monkhorst,Paul Baas +11 more
TLDR
Stereotactic body radiotherapy on a single tumor site preceding pembrolizumab treatment enhances tumor response in patients with metastatic NSCLC was well tolerated and a doubling of ORR was observed, but results did not meet the study's prespecified end point criteria for meaningful clinical benefit.Abstract:
Importance: Many patients with advanced non-small cell lung cancer (NSCLC) receiving immunotherapy show primary resistance. High-dose radiotherapy can lead to increased tumor antigen release, improved antigen presentation, and T-cell infiltration. This radiotherapy may enhance the effects of checkpoint inhibition. Objective: To assess whether stereotactic body radiotherapy on a single tumor site preceding pembrolizumab treatment enhances tumor response in patients with metastatic NSCLC. Design, Setting, and Participants: Multicenter, randomized phase 2 study (PEMBRO-RT) of 92 patients with advanced NSCLC enrolled between July 1, 2015, and March 31, 2018, regardless of programmed death-ligand 1 (PD-L1) status. Data analysis was of the intention-to-treat population. Interventions: Pembrolizumab (200 mg/kg every 3 weeks) either alone (control arm) or after radiotherapy (3 doses of 8 Gy) (experimental arm) to a single tumor site until confirmed radiographic progression, unacceptable toxic effects, investigator decision, patient withdrawal of consent, or a maximum of 24 months. Main Outcomes and Measures: Improvement in overall response rate (ORR) at 12 weeks from 20% in the control arm to 50% in the experimental arm with P <.10. Results: Of the 92 patients enrolled, 76 were randomized to the control arm (n = 40) or the experimental arm (n = 36). Of those, the median age was 62 years (range, 35-78 years), and 44 (58%) were men. The ORR at 12 weeks was 18% in the control arm vs 36% in the experimental arm (P =.07). Median progression-free survival was 1.9 months (95% CI, 1.7-6.9 months) vs 6.6 months (95% CI, 4.0-14.6 months) (hazard ratio, 0.71; 95% CI, 0.42-1.18; P =.19), and median overall survival was 7.6 months (95% CI, 6.0-13.9 months) vs 15.9 months (95% CI, 7.1 months to not reached) (hazard ratio, 0.66; 95% CI, 0.37-1.18; P =.16). Subgroup analyses showed the largest benefit from the addition of radiotherapy in patients with PD-L1-negative tumors. No increase in treatment-related toxic effects was observed in the experimental arm. Conclusions and Relevance: Stereotactic body radiotherapy prior to pembrolizumab was well tolerated. Although a doubling of ORR was observed, the results did not meet the study's prespecified end point criteria for meaningful clinical benefit. Positive results were largely influenced by the PD-L1-negative subgroup, which had significantly improved progression-free survival and overall survival. These results suggest that a larger trial is necessary to determine whether radiotherapy may activate noninflamed NSCLC toward a more inflamed tumor microenvironment. Trial Registration: ClinicalTrials.gov identifier: NCT02492568.read more
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Ferroptosis, necroptosis, and pyroptosis in anticancer immunity
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Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination.
Jiali Yu,Michael D. Green,Michael D. Green,Shasha Li,Yilun Sun,Sara Journey,Jae Eun Choi,Syed Monem Rizvi,Angel Qin,Jessica Waninger,Xueting Lang,Zoey Chopra,Issam El Naqa,Jiajia Zhou,Yingjie Bian,Long Jiang,Alangoya Tezel,Jeremy Skvarce,Rohan K. Achar,Merna Sitto,B.S. Rosen,Fengyun Su,Sathiya Pandi Narayanan,Xuhong Cao,Shuang Wei,Wojciech Szeliga,Linda Vatan,Charles S. Mayo,Meredith A. Morgan,C.A. Schonewolf,Kyle C. Cuneo,Ilona Kryczek,Vincent T. Ma,Christopher D. Lao,Theodore S. Lawrence,Nithya Ramnath,Nithya Ramnath,Fei Wen,Arul M. Chinnaiyan,Marcin Cieslik,Ajjai Alva,Weiping Zou +41 more
TL;DR: In this paper, liver metastases siphon activated CD8+ T cells from systemic circulation, resulting in a systemic immune desert in preclinical models, and the combination of liver-directed radiotherapy and immunotherapy could promote systemic antitumor immunity.
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Pembrolizumab with or without radiotherapy for metastatic non-small-cell lung cancer: a pooled analysis of two randomised trials.
Willemijn S. M. E. Theelen,Dawei Chen,Vivek Verma,Brian P. Hobbs,Heike Peulen,Joachim G.J.V. Aerts,Idris Bahce,Anna Larissa N. Niemeijer,Joe Y. Chang,Patricia M. de Groot,Quynh Nhu Nguyen,Nathan Comeaux,George R. Simon,Ferdinandos Skoulidis,Steven H. Lin,Kewen He,Roshal R. Patel,John V. Heymach,Paul Baas,James W. Welsh +19 more
TL;DR: A pooled analysis was done to infer whether radiotherapy improves responses to immunotherapy in patients with metastatic non-small-cell lung cancer, and best out-of-field (abscopal) response rate (ARR), best abscopal disease control rate (ACR), ARR at 12 weeks, progression-free survival, and overall survival.
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Randomized Phase II Trial of Nivolumab With Stereotactic Body Radiotherapy Versus Nivolumab Alone in Metastatic Head and Neck Squamous Cell Carcinoma.
Sean McBride,Eric J. Sherman,Eric J. Sherman,C. Jillian Tsai,Shrujal S. Baxi,Jahan Aghalar,Juliana Eng,Wanqing Iris Zhi,Daniel C. McFarland,Loren S. Michel,Robert J. Young,Robert A. Lefkowitz,D. Spielsinger,Zhigang Zhang,Jessica Flynn,Lara Dunn,Lara Dunn,Alan L. Ho,Alan L. Ho,Nadeem Riaz,David G. Pfister,David G. Pfister,Nancy Y. Lee +22 more
TL;DR: No improvement in response was found and no evidence of an abscopal effect with the addition of SBRT to nivolumab in unselected patients with metastatic HNSCC.
References
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TL;DR: Pembrolizumab had an acceptable side-effect profile and showed antitumor activity in patients with advanced non-small-cell lung cancer and PD-L1 expression in at least 50% of tumor cells correlated with improved efficacy of pembrolIZumab.
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