Abstract
Reversion of RAS mutations in metastatic colorectal cancer in the CCTG CO.26 clinical trial.
Author
person
Florence T.H. Wu
University of British Columbia & BC Cancer, Vancouver, BC, Canada
info_outline
Florence T.H. Wu, James T. Topham, Christopher J. O'Callaghan, Harriet Feilotter, Hagen Fritz Kennecke, Kimberly Banks, Daniel John Renouf, Derek J. Jonker, Dongsheng Tu, Eric Xueyu Chen, Jonathan M. Loree
Full text
Authors
person
Florence T.H. Wu
University of British Columbia & BC Cancer, Vancouver, BC, Canada
info_outline
Florence T.H. Wu, James T. Topham, Christopher J. O'Callaghan, Harriet Feilotter, Hagen Fritz Kennecke, Kimberly Banks, Daniel John Renouf, Derek J. Jonker, Dongsheng Tu, Eric Xueyu Chen, Jonathan M. Loree
Organizations
University of British Columbia & BC Cancer, Vancouver, BC, Canada, Pancreas Centre BC, Vancouver, BC, Canada, Canadian Cancer Trials Group, Queen's University, Kingston, ON, Canada, Queen's University, Kingston, ON, Canada, Providence Cancer Institute, Portland, OR, GuardantHealth, Redwood City, CA, BC Cancer Agency, University of British Columbia, Vancouver, BC, Canada, The Ottawa Hospital Cancer Centre, Ottawa, ON, Canada, University Health Network, Toronto, ON, Canada, BCCA, Vancouver Cancer Centre, Vancouver, BC, Canada
Abstract Disclosures
Research Funding
Institutional Funding
The Canadian Clinical Trials Group is funded by the Canadian Cancer Society
Background:
RAS
mutations in metastatic colorectal cancer (mCRC) drive resistance to anti-EGFR antibodies. It is unclear if
RAS
mutations are ever clonally lost, potentially uncovering a new therapeutic option for patients over time.
Methods:
We examined the temporal evolution of
RAS
mutation status among patients enrolled in CO.26 [NCT02870920] – a phase II clinical trial that assessed durvalumab + tremelimumab in patients with heavily pretreated mCRC – using whole exome sequencing (WES) of archival primary tumor tissue and circulating tumor DNA (ctDNA) sequencing of serial plasma samples that were taken at baseline, week 8 and on progression.
Results:
Six out of 95 (6.3%) patients diagnosed with
KRAS
/
NRAS
-mutated mCRC showed ‘neo-
RAS
-wildtype’ reversions at the time of baseline or week-8 ctDNA collection for the CO.26 trial. The majority (4/6) had falling tumor mutation burden (TMB) but stable or rising maximum mutation allele frequency (MAF) when reversions occurred. These were unlikely false negatives from non-secreting cancers as there were continued strong presence of other somatic clonal mutations (e.g.,
TP53
,
ATM
). The majority (4/6) of reversions were transient, with mutations reappearing with progressive disease. ‘Neo-
RAS
-wildtype’ revertors had numerically longer median overall survival (OS) from date of cancer diagnosis to death compared those with persistent
RAS
mutations (7.7 vs. 4.2 yrs, HR = 0.65, 95% CI 0.31 to 1.36, log-rank
P
= 0.26). However, ‘neo-
RAS
-wildtype’ revertors were earlier-stage at diagnosis compared to those with persistent
RAS
mutations (33% vs. 63% had synchronous metastases, χ2
P
= 0.15), and had lower disease burden upon enrollment (50% vs. 68.5% had liver metastases,
P
= 0.17; 33% vs. 75% had > 4 lesions,
P
= 0.03*). Survival from stage IV diagnosis to death did not differ between those with reverted vs. persistent
RAS
mutations (median 3.8 vs. 3.2 yrs, HR = 0.77, 95% CI 0.35 to 1.72,
P
= 0.52). ‘Neo-
RAS
-wildtype’ reversions were not associated with side of primary tumors (
P
= 0.41), archival
BRAF/MEK/ERK
-mutant status (
P
= 0.16, 1.00, 0.09), baseline
HER2
amplifications (
P
= 1.00), or baseline TMB (
P
= 0.21).
Conclusions:
We identified a 6.3% prevalence of ‘neo-
RAS
-wildtype’ reversions in the CO.26 trial, however only 2.1% of patients had persistent loss when serial time points were considered. Further research is needed to understand if ‘neo-
RAS
-wildtype’ revertors may benefit from anti-EGFR therapy. Clinical trial information: NCT02870920.
Clinical status
Clinical
1 clinical trial
11 organizations
2 drugs
2 targets
Clinical trial
A Phase II Randomized Study of Durvalumab and Tremelimumab and Best Supportive Care vs Best Supportive Care Alone in Patients With Advanced Colorectal Adenocarcinoma Refractory to Standard TherapiesStatus: Completed, Estimated PCD: 2018-10-18
Organization
BC Cancer-Vancouver CentreOrganization
Pancreas Centre BCOrganization
Canadian Cancer Trials GroupOrganization
Queen's University, BelfastOrganization
Providence Cancer InstituteOrganization
GuardantHealthOrganization
BC Cancer Agency Vancouver Island CentreOrganization
The Ottawa Hospital Cancer CentreOrganization
University Health NetworkOrganization
BCCAOrganization
Vancouver Cancer CentreDrug
durvalumabTarget
CTLA-4Target
Durvalumab