Radiation therapy enhances immunotherapy response in microsatellite stable colorectal and pancreatic adenocarcinoma in a phase II trial

Aparna R Parikh, Annamaria Szabolcs, Jill N Allen, Jeffrey W Clark, Jennifer Y Wo, Michael Raabe, Hannah Thel, David Hoyos, Arnav Mehta, Sanya Arshad, David J Lieb, Lorraine C Drapek, Lawrence S Blaszkowsky, Bruce J Giantonio, Colin D Weekes, Andrew X Zhu, Lipika Goyal, Ryan D Nipp, Jon S Dubois, Emily E Van Seventer, Bronwen E Foreman, Lauren E Matlack, Leilana Ly, Jessica A Meurer, Nir Hacohen, David P Ryan, Beow Y Yeap, Ryan B Corcoran, Benjamin D Greenbaum, David T Ting, Theodore S Hong, Aparna R Parikh, Annamaria Szabolcs, Jill N Allen, Jeffrey W Clark, Jennifer Y Wo, Michael Raabe, Hannah Thel, David Hoyos, Arnav Mehta, Sanya Arshad, David J Lieb, Lorraine C Drapek, Lawrence S Blaszkowsky, Bruce J Giantonio, Colin D Weekes, Andrew X Zhu, Lipika Goyal, Ryan D Nipp, Jon S Dubois, Emily E Van Seventer, Bronwen E Foreman, Lauren E Matlack, Leilana Ly, Jessica A Meurer, Nir Hacohen, David P Ryan, Beow Y Yeap, Ryan B Corcoran, Benjamin D Greenbaum, David T Ting, Theodore S Hong

Abstract

Overcoming intrinsic resistance to immune checkpoint blockade for microsatellite stable (MSS) colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) remains challenging. We conducted a single-arm, non-randomized, phase II trial (NCT03104439) combining radiation, ipilimumab and nivolumab to treat patients with metastatic MSS CRC (n = 40) and PDAC (n = 25) with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The primary endpoint was disease control rate (DCR) by intention to treat. DCRs were 25% for CRC (ten of 40; 95% confidence interval (CI), 13-41%) and 20% for PDAC (five of 25; 95% CI, 7-41%). In the per-protocol analysis, defined as receipt of radiation, DCR was 37% (ten of 27; 95% CI, 19-58%) in CRC and 29% (five of 17; 95% CI, 10-56%) in PDAC. Pretreatment biopsies revealed low tumor mutational burden for all samples but higher numbers of natural killer (NK) cells and expression of the HERVK repeat RNA in patients with disease control. This study provides proof of concept of combining radiation with immune checkpoint blockade in immunotherapy-resistant cancers.

Conflict of interest statement

COMPETING INTERESTS STATEMENT

A.R.P is a consultant/advisory board member for Eli Lilly, Natera, Checkmate Pharmaceuticals, Inivata, and Pfizer; holds equity in C2I; serves on the DSMC for Roche; and has research funding from Puretech, PMV Pharmaceuticals, Plexxicon, Takeda, BMS, Novartis, Genentech, Guardant, Array, and Eli Lilly.

J.W.C. is author for McGraw Hill and UpToDate.

A.M. is a consultant/advisory board member for Third Rock Ventures, Asher Biotherapeutics, Abata Therapeutics, Rheos Medicines and Checkmate Pharmaceuticals; and holds equity in Asher Biotherapeutics and Abata Therapeutics, which are not related to this work.

C.D.W. is a consultant/advisory board member for Ipsen, Bristol-Myers Squibb and Eli Lilly; and receives research funding from Dicephera, EMD Serono, Ability Pharmaceuticals, Actuate Therapeutics and Novartis.

A.X.Z is a consultant/advisory board member for AstraZeneca, Bayer, Bristol-Myers Squibb, Eisai, Eli Lilly, Exelixis, Merck, Novartis, and Roche/Genentech; research funding from Bayer, Bristol-Myers Squibb, Eli Lilly, Merck, and Novartis.

L.G. is a consultant/advisory board member for Alentis, AstraZeneca, Exelixis, and Sirtex, Genetech, Genentech, H3Biomedicine, Incyte, QED Therapeutics, Servier, and Taiho; and has research funding from Adaptimmune, Bayer, Bristol-Myers Squibb, Eisai, Leap Therapeutics, Loxo Oncology, MacroGenics, Merck, Novartis, Nucana, Relay Therapeutics, Genentech, H3Biomedicine, Incyte, QED Therapeutics, Servier, and Taiho.

N.H. is an advisor and equity holder for Related Sciences, holds equity in BioNTech and receives research funding from Bristol-Meyers Squibb.

D.P.R. is a consultant/advisory board member for MPM Capital, Gritstone Oncology, Oncorus, Maverick Therapeutics, 28/7 Therapeutics, Thrive/Exact Sciences; has equity in MPM Capital, Acworth Pharmaceuticals, and Thrive/Exact Sciences; is a legal consultant for Boeringer Ingelheim; and serves as author for Johns Hopkins University Press, UpToDate, McGraw Hill.

R.B.C. is a consultant/advisory board member for Abbvie, Amgen, Array Biopharma/Pfizer, Asana Biosciences, Astex Pharmaceuticals, AstraZeneca, Avidity Biosciences, BMS, C4 Therapeutics, Chugai, Elicio, Erasca, Fog Pharma, Genentech, Guardant Health, Ipsen, Kinnate Biopharma, LOXO, Merrimack, Mirati Therapeutics, Natera, Navire, N-of-one/Qiagen, Novartis, nRichDx, Remix Therapeutics, Revolution Medicines, Roche, Roivant, Shionogi, Shire, Spectrum Pharmaceuticals, Symphogen, Tango Therapeutics, Taiho, Warp Drive Bio, Zikani Therapeutics; holds equity in Avidity Biosciences, C4 Therapeutics, Erasca, Kinnate Biopharma, nRichDx, Remix Therapeutics, and Revolution Medicines; and has research funding from Asana, AstraZeneca, Lilly, Novartis, and Sanofi.

B.D.G. is a consultant or received honoraria for Darwin Health, Merck, PMV Pharma, ROME Therapeutics, Merck, Bristol–Meyers Squibb, and Chugai Pharmaceuticals; is a founder and has equity in ROME Therapeutics; and has research funding from Bristol-Meyers Squibb.

D.T.T. is a consultant/advisory board member for Pfizer, ROME Therapeutics, Merrimack Pharmaceuticals, Ventana Roche, Nanostring Technologies, Inc., Foundation Medicine, Inc., EMD Millipore Sigma, and Third Rock Ventures, which are not related to this work; is a founder and has equity in PanTher Therapeutics, ROME therapeutics, and TellBio, Inc., which are not related to this work; and has research funding from ACD-Biotechne, PureTech Health LLC, and Ribon Therapeutics, which was not used in this work. D.T.T.’s interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies.

T.S.H. is consultant/advisory board member for Merck, EMD Serono, PanTher Therapeutics, Boston Scientific, Novocure, and Synthetic Biologics; and has research funding from Taiho, Astra Zeneca, Bristol Myers Squibb, IntraOp, Puma, and Ipsen.

All other authors have no disclosures.

© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Figures

Extended Data Fig. 1. Tumor Mutational Burden…
Extended Data Fig. 1. Tumor Mutational Burden of all samples between responders and progressive disease.
Mutations per megabase shown with mean (bar) for patients with SD/PR/CR (n = 5) or PD (n = 12). Unpaired 2-tailed t-test p = 0.7738 was not significant.
Extended Data Fig. 2. Expression analysis of…
Extended Data Fig. 2. Expression analysis of paired pre-XRT and post-XRT biopsy samples.
a, Heatmap of cell RNA-seq expression of myCAF and iCAF in pre-XRT and post-XRT biopsies from patients with SD/PR/CR (n = 3) and PD (n = 5). Scale −2 to 2 represents minimum and maximum values within the heatmap. b, Heatmap of cell percentage of immune cells in pre-XRT and post-XRT biopsies from patients with SD/PR/CR (n = 3) and PD (n = 5).
Fig. 1. Consort diagram of enrolled patients.
Fig. 1. Consort diagram of enrolled patients.
Shown are the patients that were enrolled for intention to treat (ITT) and those who received radiation (per-protocol). The n shown represents the number of patients at each stage of the protocol.
Fig. 2. Progression-free and overall survival analysis.
Fig. 2. Progression-free and overall survival analysis.
a, b, Kaplan-Meier curve of progression-free survival (a) and overall survival (b) of patients in ITT cohort. The CRC cohort (n = 40; blue) had a median PFS 2.4 months and median OS of 7.1 months. The PDAC cohort (n = 25; orange) had a median PFS of 2.5 months and median OS of 4.2 months. 95% confidence intervals shown. c, d, Kaplan-Meier curve of progression-free survival (c) and overall survival (d) of patient in per-protocol cohort. The CRC cohort (n = 27; blue) had a median PFS of 2.5 months and median OS of 10.9 months. The PDAC cohort (n = 17; orange) had a median PFS of 2.7 months and median OS of 6.1 months. 95% confidence intervals shown.
Fig. 3. Response to treatment by change…
Fig. 3. Response to treatment by change in measurable disease.
a, Percent (%) change in tumor dimension of comparable lesion(s) at best response for the per-protocol colorectal cancer cohort and duration of treatment for the ITT colorectal cancer cohort. b, Percent (%) change in tumor dimension of comparable lesion(s) at best response for the per-protocol pancreatic cancer cohort and duration of treatment for the ITT pancreatic cancer cohort. Bars color coded for responders (SD – yellow, PR/CR – blue) and non-responders (PD. – red). Non-evaluable (NE - gray) and XRT (radiotherapy) start time (black bar). Of note: patient #44 received radiation but progressed prior to scans. *unequivocal PD due to new metastatic lesions c, Example of response in Patient 57 with 3 lung metastases that responded after radiation treatment of the target lesion in the liver with combined ipilimumab and nivolumab
Fig. 4. Tumor mutational burden and exome…
Fig. 4. Tumor mutational burden and exome mutations in patient biopsies.
a, Tumor mutational burden (TMB) measured in mutations per megabase (MB) in baseline, Pre-XRT, Post-XRT biopsies. In patients with response (left: SD/PR/CR; n = 5) and progressive disease (right: PD; n = 12). b, Curated non-synonymous mutations in whole exome sequencing of colorectal and pancreatic cancer biopsies listing most commonly mutated genes from COSMIC (black), KEGG_PATHWAYS_IN_CANCER (blue), and DNA DAMAGE & REPAIR PATHWAYS (red). Mutation type color coded in legend and responders (SD/PR/CR) in red and non-responders (PD) in gray.
Fig. 5. Coding gene RNA expression and…
Fig. 5. Coding gene RNA expression and immune cell differences in patient biopsies.
a, RNA-seq heatmap of EMT genes found statistically significant (FDR < 0.05) in pretreatment (Pre-Tx) biopsies enriched in patients with response (SD/PR/CR; n = 5) compared to progressive disease (PD; n =7). Scale −2 to 2 represents minimum and maximum values within the heatmap. b, RNA-seq heatmap of myCAF and iCAF genes in Pre-Tx biopsies in patients with SD/PR/CR (n = 5) compared to PD (n =7). Scale −2 to 2 represents minimum and maximum values within the heatmap. c, Immune infiltrate analysis using CIBERSORTx deconvolution in patient biopsies shown as heatmap of cell percentage of immune cells in pre-treatment biopsies from patients with SD/PR/CR (n = 5) and PD (n =7). d, Dot plot of resting NK cell percentage in pre-treatment biopsies between SD/PR/CR (n = 5) and PD (n =7) that was statistically significant * 2-tailed unpaired t-test p = 0.038.
Fig. 6. Repeat RNA expression differences in…
Fig. 6. Repeat RNA expression differences in patient biopsies.
a, Volcano plot of repeat RNAs in comparing Pre-Tx biopsies in patients with SD/PR/CR compared to PD. Y-axis = − log10 (FDR) and x-axis = log2 (Fold change). b, RNA-seq heatmap of repeat RNA genes found statistically significant (FDR < 0.05) in Pre-Tx biopsies enriched in patients with SD/PR/CR (n = 5) compared to PD (n = 7). Scale −2 to 2 represents minimum and maximum values within the heatmap. c, Fold change of significant repeat RNAs in Pre-XRT compared to Post-XRT samples available for analysis for SD/PR/CR (n = 3) and PD (n =5). Higher fold change with increasing red.

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