Higher Cutoff by FoundationOne CDx for TMB May Determine Atezolizumab Success

April 13, 2021
Audrey Sternberg

In an analysis of a cohort of patients treated with atezolizumab in the myPathway trial, a tumor mutational burden cutoff of 16 mutations per megabase or higher was key for achieving durable responses in various solid tumors.

Patients with advanced solid tumors and a tumor mutational burden (TMB) above 16 mutations per megabase (mut/Mb) who were treated with atezolizumab (Tecentriq) demonstrated durable clinical activity regardless of microsatellite instability (MSI) status, according to an analysis of the multi-basket MyPathway (NCT02091141) study presented at the American Association of Cancer Research Annual Meeting 2021.1

In the efficacy population of patients with high TMB (≥16 mut/Mb), the confirmed objective response rate (ORR) was 38.1% (95% CI, 23.6%-54.4%), comprised of both complete (CR) and partial responses (PRs). The disease control rate (DCR) in this group was 61.9% (95% CI, 45.6%-76.4%).

“Amongst patients with a FoundationOne [CDx] TMB of at least 16 mut/Mb, we observed meaningful clinical activity regardless of MSI status, suggesting that there are genomic mechanisms other than MSI that drive response to atezolizumab in this population,” Claire F. Friedman, MD, of Memorial Sloan Kettering Cancer Center, said during a presentation of the data.

Previous studies have suggested that immune checkpoint inhibitors targeting PD-1 or PD-L1 may result in better response rates in tumors with high TMB. For example, the PD-1 inhibitor pembrolizumab (Keytruda) recently received FDA approval for solid tumors with a TMB of 10 mut/Mb or higher.2 However, the proper threshold for treatment has been disputed, with retrospective studies suggesting that a threshold of 16 mut/Mb may enrich for response in various tumor types.

In the current analysis, the investigators assessed activity and safety of atezolizumab in patients with advanced solid tumors categorized into 2 groups: TMB expression of at least 16 and between 10 and 16 mut/Mb. They received atezolizumab at 1200 mg every 3 weeks until loss of clinical benefit.

Eligible patients on the atezolizumab arm of the MyPathway study (n = 121) were 18 years of age or older and had any advanced solid tumors, TMB of 10 mut/Mb or more by a CLIA assay, and no satisfactory alternative treatment options. Patients could not have prior treatment with a checkpoint inhibitor. The primary end point was investigator-assessed ORR by RECIST 1.1 in patients with high TMB (≥16 mut/Mb) with secondary outcomes of duration of response (DOR), DCR, progression-free survival (PFS), and safety. Outcomes in patients with other TMB expression levels (≥10 and <16 mut/Mb) was an exploratory end point.

In the atezolizumab arm, 56 patients had high TMB expression and 64 had expression of at least 10 but less than 16 mut/Mb. By FoundationOne CDx, which was used to determine the efficacy population (n = 90), those numbers were 42 and 48 patients, respectively.

Patients in the efficacy population with high TMB expression had a median number of prior lines of therapy of 2 (range, 0-13) versus 3 (range, 0-14) in the lower expression group. The majority of patients in the entire cohort were female (45.2% vs 71.4%, respectively), White (88.1% vs 69.4%), and had an ECOG performance status of 1 (73.8% vs 65.3%).

In patients with high TMB, there were 3 complete responses and 13 PRs. Median PFS was 5.7 months (95% CI, 2.7-8.5) and the median overall survival (OS) was 19.8 months (95% CI, 19.8-not evaluable). In the other TMB expression group assessed, the ORR was only 2.1% (95% CI, 0.1%-11.1%), comprised of 1 PR, and the DCR was 22.9% (95% CI, 12.0%-37.3%). Median PFS and OS were 1.8 months (95% CI, 1.4-2.6) and 11.4 (5.3-15.7), respectively. The median DOR was not reached in either group.

In the total cohort with any CLIA testing for TMB, patients with high TMB expression had an ORR of 28.6% (95% CI, 17.3%-42.2%) versus 3.1% (95% CI, 0.4%-10.8%) with expression between 10 or less than 16 mut/Mb. Of note, overall agreement between FoundationOne CDx and other assays was 74.4%, or in 29 of 39 patients assessed.

Response rates increased in step with incremental TMB cutoffs, with a log odds ratio of response for an increase of 1 mutation per megabase resulting in a slop of 0.119 (95% CI, 0.078-0.160).

To investigate the correlation with MSI status, the investigators stratified patients into 3 groups: high TMB and high MSI (n = 11), high TMB and not high MSI (n = 30), and TMB between 10 and less than 16 and not high MSI (n = 45). The ORRs in these groups were 54.5%, 30.0%, and 2.2%, respectively, with corresponding DCRs of 72.7%, 56.7%, and 22.2%. Similarly, patients with high TMB who were also stratified by PD-L1 status by tumor proportion scores of less than 1 (n = 15), between 1 and less than 50 (n = 5), and 50 or greater (n = 6) had ORRs of 33.3%, 40.0%, and 50.0%.

“This suggests that atezolizumab has meaningful activity in patients with tumors characterized by a TMB of at least 16 mut/Mb, regardless of MSI status,” said Friedman. “In subgroups by PD-L1 status, we observed meaningful activity in subgroups, although [they] are numerically increased with higher tumor proportion or combined positive scores.”

In patients with high TMB by FoundationOne CDx, notable responses were seen in 10 patients with colorectal cancer (ORR, 70%) and in 1 patient with biliary tract cancer determined to be MSI not high who had a CR. Other tumor types with response included breast and head and neck cancers that were MSI not high and pancreatic and cervical cancers that were MSI high.

Atezolizumab was generally well tolerated, with a low rate of study drug withdrawal and no dose reductions or deaths related to study drug. Treatment-emergent adverse effects (TEAEs) were noted in 90.9% of patients, with 33.1% considered serious events and 47.9% being grade 3 or higher. Treatment-related TEAEs occurred in 56.2%, with serious events accounting for 6.6% of the population and grade 3 or greater events in 12.4%.


1. Hainsworth J, Friedman CF, Kurzrock R, et al. Efficacy of atezolizumab in the treatment of solid tumors with high tumor mutational burden (TMB): A MyPathway study cohort. Presented at: American Association of Cancer Research Annual Meeting 2021. April 9-14, 2021. Abstract LB012.

2. FDA approves pembrolizumab for adults and children with TMB-H solid tumors. FDA. June 16, 2020. Accessed April 13, 2021. https://bit.ly/3tj2dsI