Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2020 Dec 15;26(24):6437-6444.
doi: 10.1158/1078-0432.CCR-20-1790. Epub 2020 Oct 7.

Improved Survival Associated with Local Tumor Response Following Multisite Radiotherapy and Pembrolizumab: Secondary Analysis of a Phase I Trial

Jason J Luke #  1 , Benjamin E Onderdonk #  2 , Sandeep R Bhave  3 , Theodore Karrison  2 , Jeffrey M Lemons  4 , Paul Chang  2 , Yuanyuan Zha  2 , Tim Carll  2 , Thomas Krausz  2 , Lei Huang  2 , Carlos Martinez  2 , Linda A Janisch  2 , Robyn D Hseu  2 , John W Moroney  2 , Jyoti D Patel  5 , Nikolai N Khodarev  2 , Joseph K Salama  6 , Patrick A Ott  7 , Gini F Fleming  2 , Thomas F Gajewski  2 , Ralph R Weichselbaum  2 , Sean P Pitroda #  2 , Steven J Chmura #  8
Affiliations
Clinical Trial

Improved Survival Associated with Local Tumor Response Following Multisite Radiotherapy and Pembrolizumab: Secondary Analysis of a Phase I Trial

Jason J Luke et al. Clin Cancer Res. .

Abstract

Purpose: Multisite stereotactic body radiotherapy followed by pembrolizumab (SBRT+P) has demonstrated safety in advanced solid tumors (ASTs). However, no studies have examined the relationships between irradiated tumor response, SBRT-induced tumor gene expression, and overall survival (OS).

Patients and methods: Patients with AST received SBRT (30-50 Gy in 3-5 fractions) to two to four metastases followed by pembrolizumab (200 mg i.v. every 3 weeks). SBRT was prescribed to a maximum tumor volume of 65 mL. Small metastases received the complete prescribed coverage (complete-Rx), while larger metastases received partial coverage (partial-Rx). Treated metastasis control (TMC) was defined as a lack of progression for an irradiated metastasis. Landmark analysis was used to assess the relationship between TMC and OS. Thirty-five biopsies were obtained from 24 patients: 19 pre-SBRT and 16 post-SBRT (11 matched) prior to pembrolizumab and were analyzed via RNA microarray.

Results: Sixty-eight patients (139 metastases) were enrolled with a median follow-up of 10.4 months. One-year TMC was 89.5% with no difference between complete-Rx or partial-Rx. On multivariable analysis, TMC was independently associated with a reduced risk for death (HR, 0.36; 95% confidence interval, 0.17-0.75; P = 0.006). SBRT increased expression of innate and adaptive immune genes and concomitantly decreased expression of cell cycle and DNA repair genes in the irradiated tumors. Elevated post-SBRT expression of DNASE1 correlated with increased expression of cytolytic T-cell genes and irradiated tumor response.

Conclusions: In the context of SBRT+P, TMC independently correlates with OS. SBRT impacts intratumoral immune gene expression associated with TMC. Randomized trials are needed to validate these findings.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest:

JJL declares Data and Safety Monitoring Board: TTC Oncology, Scientific Advisory Board: 7 Hills, Actym, Alphamab Oncology, Array, BeneVir, Mavu, Tempest, Consultancy: Aduro, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Castle, CheckMate, Compugen, EMD Serono, IDEAYA, Immunocore, Janssen, Jounce, Leap, Merck, Mersana, NewLink, Novartis, RefleXion, Spring Bank, Syndax, Tempest, Vividion, WntRx, Research Support: (clinical trials unless noted) AbbVie, Array (Scientific Research Agreement; SRA), Boston Biomedical, Bristol-Myers Squibb, Celldex, CheckMate (SRA), Compugen, Corvus, EMD Serono, Evelo (SRA), Delcath, Five Prime, FLX Bio, Genentech, Immunocore, Incyte, Leap, MedImmune, Macrogenics, Novartis, Pharmacyclics, Palleon (SRA), Merck, Tesaro, Xencor, Travel: Array, AstraZeneca, Bayer, BeneVir, Bristol-Myers Squibb, Castle, CheckMate, EMD Serono, IDEAYA, Immunocore, Janssen, Jounce, Merck, Mersana, NewLink, Novartis, RefleXion, Patents: (both provisional) Serial #15/612,657 (Cancer Immunotherapy), PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic,Prognostic and Therapeutic Uses Thereof).

PAO declares Research funding paid to the institution: Bristol Myers Squibb, Merck, AstraZeneca, Celldex, CytomX, Neon Therapeutics, ARMO Biosciences; Consultancy: Bristol Myers Squibb, Merck, Genentech, Pfizer, Novartis, CytomX, Celldex, Neon Therapeutics.

SJC declares Consultancy Reflexion, Abviee, Spouse (Astellas)

Figures

Figure 1:
Figure 1:. Treated Metastasis Control was independent of PD-L1 status, tumor size, and tumor histology
Kaplan-Meier estimates of (A) Overall Treated Metastasis Control (TMC) (n=139). (B) TMC by PD-L1 Status (n=105). (C) TMC by treated metastasis quartile volume prior to stereotactic body radiation therapy. In B and C, P-values were determined using shared-frailty Cox and then fit to a flexible parametric model to generate figures. Values along the x-axis are the number of metastases at risk among 68 evaluable patients. NSCLC = non-small cell lung cancer, cholangio = cholangiocarcinoma.
Figure 1:
Figure 1:. Treated Metastasis Control was independent of PD-L1 status, tumor size, and tumor histology
Kaplan-Meier estimates of (A) Overall Treated Metastasis Control (TMC) (n=139). (B) TMC by PD-L1 Status (n=105). (C) TMC by treated metastasis quartile volume prior to stereotactic body radiation therapy. In B and C, P-values were determined using shared-frailty Cox and then fit to a flexible parametric model to generate figures. Values along the x-axis are the number of metastases at risk among 68 evaluable patients. NSCLC = non-small cell lung cancer, cholangio = cholangiocarcinoma.
Figure 1:
Figure 1:. Treated Metastasis Control was independent of PD-L1 status, tumor size, and tumor histology
Kaplan-Meier estimates of (A) Overall Treated Metastasis Control (TMC) (n=139). (B) TMC by PD-L1 Status (n=105). (C) TMC by treated metastasis quartile volume prior to stereotactic body radiation therapy. In B and C, P-values were determined using shared-frailty Cox and then fit to a flexible parametric model to generate figures. Values along the x-axis are the number of metastases at risk among 68 evaluable patients. NSCLC = non-small cell lung cancer, cholangio = cholangiocarcinoma.
Figure 2:
Figure 2:. Treatment outcomes stratified by prescription radiotherapy dose volume
Treated Metastasis Control (TMC) by prescription stereotactic body radiation therapy dose covering the entire metastasis (cRx) compared to partial metastasis coverage (pRx) (n=139). P-values were determined using shared-frailty Cox Regression and then fit to a flexible parametric model. Values along the x-axis are the number of metastases at risk among 68 evaluable patients.
Figure 3:
Figure 3:. Kaplan-Meier overall survival stratified by SBRT response
Overall survival stratified by irradiated tumor response (responders, mixed responders, and non-responders) from those that survived to the 2-month landmark time (n=67). HR 0.44; 95% CI 0.23–0.85; p=0.015. SBRT, stereotactic body radiation therapy; HR = hazard ratio; mo = month.
Figure 4:
Figure 4:. Gene expression analysis of irradiated tumors following SBRT and association with irradiated tumor response
(A) Enriched canonical pathways and predicted upstream activators following SBRT. P-values were determined using Fisher’s exact tests. (B) Association of irradiated tumor response with post-SBRT gene expression. Pearson correlation coefficients plotted against statistical significance of correlation for all protein-coding genes. (C) Change in intratumoral cytolytic gene expression (PRF1 + GZMA expression) in relation to change in DNASE1 (upper panel) or TREX1 (lower panel) expression after SBRT. Δ>0 indicates increased expression, while Δ<0 indicates decreased expression. Tumors were dichotomized as low or high expressors based on the median expression value of DNASE1 and TREX1. P-values were determined using Mann-Whitney U tests. (D) Change in irradiated tumor size ([(post-treatment largest diameter / pre-treatment largest diameter) −1] * 100%) after SBRT + pembrolizumab as a function of post-SBRT DNASE1 and TREX1 expressions in matched tumor specimens. Tumors were dichotomized as low or high expressors based on the median expression value of DNASE1 and TREX1. P-values were determined using Mann-Whitney U tests. PD, progressive disease; SD, stable disease; CR/PR, complete response/partial response based on RECIST criteria.
See this image and copyright information in PMC

References

    1. Trujillo JA, Sweis RF, Bao R, Luke JJ. T Cell-Inflamed versus Non-T Cell-Inflamed Tumors: A Conceptual Framework for Cancer Immunotherapy Drug Development and Combination Therapy Selection. Cancer Immunol Res. 2018;6(9):990–1000. doi:10.1158/2326-6066.CIR-18-0277 - DOI - PMC - PubMed
    1. Ayers M, Lunceford J, Nebozhyn M, et al. IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest. 2017;127(8):2930–2940. doi:10.1172/JCI91190 - DOI - PMC - PubMed
    1. Deng L, Liang H, Xu M, et al. STING-Dependent Cytosolic DNA Sensing Promotes Radiation-Induced Type I Interferon-Dependent Antitumor Immunity in Immunogenic Tumors. Immunity. 2014;41(5):843–852. doi:10.1016/j.immuni.2014.10.019 - DOI - PMC - PubMed
    1. Liang H, Deng L, Hou Y, et al. Host STING-dependent MDSC mobilization drives extrinsic radiation resistance. Nat Commun. 2017;8(1):1736. doi:10.1038/s41467-017-01566-5 - DOI - PMC - PubMed
    1. Luke JJ, Lemons JM, Karrison TG, et al. Safety and Clinical Activity of Pembrolizumab and Multisite Stereotactic Body Radiotherapy in Patients With Advanced Solid Tumors. J Clin Oncol Off J Am Soc Clin Oncol. 2018;36(16):1611–1618. doi:10.1200/JCO.2017.76.2229 - DOI - PMC - PubMed

Publication types

Substances