Tissue and plasma tumor mutation burden (TMB) as predictive biomarkers in the CO.26 trial of durvalumab + tremelimumab (D+T) versus best supportive care (BSC) in metastatic colorectal cancer (mCRC).

Abstract

61 Background: Pembrolizumab was recently granted tissue agnostic FDA accelerated approval for metastatic cancers with TMB≥10 mut/Mb. However, limited data supports immunotherapy in microsatellite stable (MSS) mCRC with TMB≥10 mut/Mb. We assessed tissue TMB and contrasted it to plasma derived TMB in the CO.26 trial. Methods: CO.26 was a phase 2 trial (2-sided ⍺ = 0.1 and 80% power) that randomized 180 patients (pts) 2:1 to D+T or BSC in refractory mCRC. Pre-treatment plasma was sequenced with the GuardantOMNI assay and archival tissue underwent exome sequencing with TMB assessed per the TMB harmonization project. MSI-H cases were excluded. For plasma TMB, we used a previously published cut point (≥28). Results: Overall survival (OS) but not progression free survival (PFS) was improved with D+T in the entire population. Of 180 pts, 163 were evaluable for plasma and 110 for tissue TMB. Median time between archival tissue and plasma collection was 3.1 yrs (IQR 1.9-5.1). Median tissue TMB was 6.6 muts/Mb (IQR 4.1-12.0), while median plasma TMB was 16.3 muts/Mb (IQR 9.4-25.9). Tissue and plasma TMB (r = -0.039, P = 0.69) were not correlated. Tissue TMB≥10 was not prognostic in the BSC arm (HR 1.01, 90%CI 0.52-1.92, P = 0.99) and OS was not improved in pts with tissue TMB≥10 (32/110 pts) following D+T vs BSC. A test of interaction suggested this threshold was not predictive (P = 0.85). Using a minimum P-value approach, no threshold supported high tissue TMB as predictive in MSS mCRC. In fact, the optimal cut point suggested low tissue TMB ( < 4.1 muts/Mb) had the greatest benefit from D+T (P-interaction = 0.048) and pts with TMB ≥4.1 mut/Mb (HR 0.50, 90%CI 0.26-0.96, P = 0.083) trended to better OS in the BSC arm. In contrast, 35/163 pts (21%) were identified in a high plasma TMB group associated with worse OS (HR 2.56, 90%CI 1.45-4.54, P = 0.007) in the BSC arm but improved OS following D+T compared to BSC with P-interaction = 0.082. Only 1 response was noted following D+T in a pt with tissue TMB = 16 mut/Mb and plasma TMB = 13 mut/Mb. Conclusions: Archival tissue TMB≥10 mut/Mb does not appear predictive of D+T benefit in MSS mCRC. Plasma derived TMB may better reflect evolutionary changes following intervening therapy than archival tissue. Clinical trial information: NCT02870920. [Table: see text]

Validity and utility of blood tumor mutational burden is dependent on circulating tumor DNA shed

“…This study compared frequencies of bTMB and TMB ≥ 10 mut/Mb across 25 different solid tumor types. In contrast to previous reports [12,13], we did not observe overall higher prevalence of bTMB-high, even at the low threshold of bTMB ≥ 10. Rather, the frequency of bTMB-high tended to be comparable or lower than the frequency of TMB-high in most cancer types.…”

Assessment of Capecitabine and Bevacizumab With or Without Atezolizumab for the Treatment of Refractory Metastatic Colorectal Cancer

“…Future studies could focus on dual inhibition of the VEGF and PD-1/PD-L1 axes in patients with MSS/pMMR mCRC who do not have a history of liver metastasis. Tumor mutational burden has emerged as a biomarker of response to anti–PD-1/PD-L1 therapy, but there may be differences in archival tissue vs plasma tumor mutational burden . Comprehensive immune profiling being conducted in collaboration with National Cancer Institute–funded Cancer Immune Monitoring and Analysis Center laboratories may provide biological insight into differences between those who respond and do not respond to treatment.…”

Tumor Biomarker Testing for Metastatic Colorectal Cancer: a Canadian Consensus Practice Guideline

“… 125 However, in this same trial, the use of tissue TMB as a biomarker did not identify a group of patients with improved outcome following durvalumab and tremelimumab, and a cut point of 10 mutations/Mb did not result in improved outcomes (HR 0.54, 90% CI: 0.27–1.08, p = 0.14). 126 This suggests that optimization and validation of different TMB thresholds for different tumor types may be needed.…”