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Can combined immune checkpoint inhibition improve overall survival (OS) in patients with advanced refractory colorectal cancer (CRC)?
In this randomized phase 2 study with 180 patients randomized in a 2:1 ratio to tremelimumab and durvalumab plus best supportive care or best supportive care alone, the median OS was 6.6 months for durvalumab and tremelimumab and 4.1 months for best supportive care; correlative analysis revealed that patients with plasma tumor mutation burden (TMB) of 28 or more variants per megabase had the greatest OS benefit.
Combined immune checkpoint inhibition may prolong OS in patients with advanced refractory CRC.
Single-agent immune checkpoint inhibition has not shown activities in advanced refractory colorectal cancer (CRC), other than in those patients who are microsatellite-instability high (MSI-H).
To evaluate whether combining programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) inhibition improved patient survival in metastatic refractory CRC.
Design, Setting, and Participants
A randomized phase 2 study was conducted in 27 cancer centers across Canada between August 2016 and June 2017, and data were analyzed on October 18, 2018. Eligible patients had histologically confirmed adenocarcinoma of the colon or rectum; received all available standard systemic therapies (fluoropyrimidines, oxaliplatin, irinotecan, and bevacizumab if appropriate; cetuximab or panitumumab if RAS wild-type tumors; regorafenib if available); were aged 18 years or older; had adequate organ function; had Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease.
We randomly assigned patients to receive either 75 mg of tremelimumab every 28 days for the first 4 cycles plus 1500 mg durvalumab every 28 days, or best supportive care alone (BSC) in a 2:1 ratio.
Main Outcomes and Measures
The primary end point was overall survival (OS) and a 2-sided P<.10 was considered statistically significant. Circulating cell-free DNA from baseline plasma was used to determine microsatellite instability (MSI) and tumor mutation burden (TMB).
Of 180 patients enrolled (121 men [67.2%] and 59 women [32.8%]; median [range] age, 65 [36-87] years), 179 were treated. With a median follow-up of 15.2 months, the median OS was 6.6 months for durvalumab and tremelimumab and 4.1 months for BSC (hazard ratio [HR], 0.72; 90% CI, 0.54-0.97; P = .07). Progression-free survival was 1.8 months and 1.9 months respectively (HR, 1.01; 90% CI, 0.76-1.34). Grade 3 or 4 adverse events were significantly more frequent with immunotherapy (75 [64%] patients in the treatment group had at least 1 grade 3 or higher adverse event vs 12 [20%] in the BSC group). Circulating cell-free DNA analysis was successful in 168 of 169 patients with available samples. In patients who were microsatellite stable (MSS), OS was significantly improved with durvalumab and tremelimumab (HR, 0.66; 90% CI, 0.49-0.89; P = .02). Patients who were MSS with plasma TMB of 28 variants per megabase or more (21% of MSS patients) had the greatest OS benefit (HR, 0.34; 90% CI, 0.18-0.63; P = .004).
Conclusions and Relevance
This phase 2 study suggests that combined immune checkpoint inhibition with durvalumab plus tremelimumab may be associated with prolonged OS in patients with advanced refractory CRC. Elevated plasma TMB may select patients most likely to benefit from durvalumab and tremelimumab. Further confirmation studies are warranted.
ClinicalTrials.gov Identifier: NCT02870920
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Corresponding Author: Eric X. Chen, MD, PhD, Princess Margaret Cancer Center, 700 University Ave, Rm 7-824, Toronto, ON M5G 1X6 Canada (firstname.lastname@example.org).
Accepted for Publication: March 2, 2020.
Published Online: May 7, 2020. doi:10.1001/jamaoncol.2020.0910
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Chen EX et al. JAMA Oncology.
Author Contributions: Drs Chen and O’Callaghan had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Chen, Jonker, Loree, Ahmad, Kavan, Tu, O'Callaghan.
Acquisition, analysis, or interpretation of data: Chen, Jonker, Loree, Kennecke, Berry, Couture, Goffin, Kavan, Harb, Colwell, Samimi, Samson, Abbas, Aucoin, Aubin, Koski, Wei, Magoski, Tu, O'Callaghan.
Drafting of the manuscript: Chen, Jonker, Loree, Ahmad, Kavan, Abbas.
Critical revision of the manuscript for important intellectual content: Chen, Jonker, Loree, Kennecke, Berry, Couture, Goffin, Kavan, Harb, Colwell, Samimi, Samson, Aucoin, Aubin, Koski, Wei, Magoski, Tu, O'Callaghan.
Statistical analysis: Loree, Tu, O'Callaghan.
Obtained funding: Jonker, Aucoin, O'Callaghan.
Administrative, technical, or material support: Chen, Jonker, Loree, Kennecke, Couture, Goffin, Samimi, Aucoin, Aubin, Wei, Magoski, O'Callaghan.
Supervision: Jonker, Ahmad, Kavan, Samimi, Abbas, Aubin, Koski, O'Callaghan.
Conflict of Interest Disclosures: Dr Chen participated in clinical trials sponsored by Merck, BMS, Boston Biomedical, AZ, and received research support (drugs only) from AZ. Dr Chen received honoraria from Eisai and Taiho. Dr Loree received research support from Ipsen and honoraria from Ipsen, Amgen, Bayer, Novartis, and Taiho. Dr Samson received honorarium from Taiho. Dr Goffin received honoraria from Merck and Amgen and nonfinancial support from AZ. Dr Samimi received honoraria from Amgen, Celgene, Ipsen, Apobiologix, Eisai, Taiho, and Roche. Dr Aubin received honoraria from Taiho, Shire, Amgen, BMS, and Celgene, and participated in clinical trials sponsored by Merck and BMS. Dr Aucoin received honoraria from AZ, Roche, BMS, Amgen, Takeda, Pfizer, Taiho, Celgene. Dr Wei received honoraria from Shire and Celgene, and nonfinancial support from Bayer. All other authors declared no competing interests.
Data Sharing Statement: See Supplement 3.
Funding/Support: AstraZeneca provided durvalumab and tremelimumab and contributed partial funding for this study. The Canadian Cancer Trials Group (CCTG) is funded by the Canadian Cancer Society.
Role of the Funder/Sponsor: AstraZeneca was consulted on design of the study, and reviewed a draft of the manuscript. It played no role in conduct of the study; collection, management, analysis, and interpretation of the data; preparation, or approval of the manuscript; and decision to submit the manuscript for publication.
Meeting Presentation: Presented at ASCO GI Symposium, January 19, 2019, San Francisco, California; and at ASCO Annual Meeting, June 3, 2019, Chicago, Illinois.
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