Blood-Based TMB Is Not Predictive of Benefit With Atezolizumab in NSCLC

Rafal Dziadziuszko, MD, PhD

Blood-based tumor mutational burden (TMB) does not predict a benefit of first-line atezolizumab over chemotherapy in patients with non–small cell lung cancer (NSCLC), according to cohort C results of the Blood First Assay Screening Trial (BFAST), which were presented during the 2021 ESMO Congress.¹

Data showed that, in a population selected for high TMB, which was defined as at least 16 mutations/megabase (mut/Mb) using the clinical trial assay (CTA), progression-free survival (PFS), the primary endpoint of cohort C of BFAST, was not significantly improved with atezolizumab, said lead study author Rafal Dziadziuszko, MD, PhD, in a virtual presentation during the meeting.

At a median follow-up of 18.2 months, PFS events occurred in 82% of the atezolizumab arm versus 85% of the chemotherapy arm in the high-TMB cohort (stratified HR, 0.77; 95% CI, 0.59-1.00; P = .053). The median PFS was 4.5 months in the atezolizumab arm vs 4.3 months in the chemotherapy arm.

“Progression rates were initially higher in the atezolizumab vs the chemotherapy arm. The curves crossed around 4 months and then a PFS benefit was observed with atezolizumab after 4 months,” said Dziadziuszko, deputy head and national consultant in radiation oncology, Medical University of Gdansk in Poland.

Overall survival (OS) was not different between the 2 arms in the high-TMB population, with the median OS being 13.3 months with atezolizumab and 10.3 months with chemotherapy (stratified HR, 0.87; 95% CI, 0.64-1.17; P = .035). The OS events were 57% with atezolizumab and 60% with chemotherapy.

TMB, while a promising biomarker for immunotherapy in NSCLC, is largely supported by data from retrospective analyses, with none reported from prospective phase 3 trials.^2,3

“Importantly, up to 30% of patients with NSCLC may have insufficient tissue [at diagnosis] for PD-L1 expression analysis and other biomarker testing⁴,” he said.

BFAST is a global, open-label, multicohort trial investigating the safety and efficacy of targeted therapies or immunotherapy in patients with advanced or metastatic NSCLC, who identified using a blood-based next-generation sequencing assay. Cohort C from BFAST is the first prospective study to evaluate blood-based TMB as a predictive biomarker for immunotherapy.

Eligible patients for BFAST Cohort C had untreated unresectable stage IIIB or IV NSCLC with a blood-based TMB of at least 10 mut/Mb and an absence of an EGFR or ALK genetic alteration. Two TMB cutoffs were used: at least 10 mut/Mb to 15 mut/Mb to define moderately high TMB, and at least 16 mut/Mb to define high TMB. Patients were randomized to atezolizumab given at 1200 mg every 3 weeks until progressive disease or loss of clinical benefit, or platinum-based chemotherapy every 3 weeks for 4 or 6 cycles, with maintenance pemetrexed permitted for patients with nonsquamous NSCLC.

A preplanned bridging study comparing blood-based TMB clinical trial assay and the approved FoundationOne Liquid CDx was conducted to enable the FoundationOne assay data to be used for a companion diagnostic filing in the event that the trial was positive.

In cohort C of the BFAST study, 471 patients were enrolled overall, and 291 in the cohort had blood-based TMB at least 16 mut/Mb. Baseline characteristics were well balanced between the atezolizumab and chemotherapy arms. Brain metastases were present in 14.1% and 19.4%, respectively.

The confirmed objective response rate in the high-TMB population was 25.5% (95% CI, 18.7-33.4) for atezolizumab vs 17.8% (95% CI, 12.0%-25.0%) for chemotherapy.

In the high-TMB cohort, PFS was significantly higher with atezolizumab in patients with nonsquamous histology (5.3 vs 4.2 months; HR, 0.65; 95% CI, 0.48-0.88; P = .007).

Grade 3/4 treatment-related adverse events (TRAEs) occurred in 45.7% of the atezolizumab arm vs 57.5% of the chemotherapy arm. Serious TRAEs of any grade occurred in 44.4% of patients on the atezolizumab vs 37.1% of those on the chemotherapy arm.

An exploratory analysis of PFS and OS in the population with TMB of at least 13.6 mut/Mb by the FoundationOne Liquid CDx found a median PFS of 4.9 months in the atezolizumab arm compared with 4.2 months in the chemotherapy arm (stratified HR, 0.71; 95% CI, 0.52-0.96; P = .028). The median OS was 15.4 months vs 10.6 months, respectively (stratified HR, 0.75; 95% CI, 0.53-1.08; P = .12).

The assays were highly concordant for positive percentage agreement (82.9%), positive predictive value (89.4%), negative percentage agreement (91.5%),, and negative predictive value (86.0%).

References

1. Dziadziuszko R, Peters S, Gadgeel SM, et al. Atezolizumab (atezo) vs platinum-based chemo in blood-based tumour mutational burden-positive (bTMB+) patients (pts) with first line (1L) advanced/metastatic (m)NSCLC: results of the Blood First Assay Screening Trial (BFAST) phase 3 cohort C. Presented at: 2021 ESMO Congress; September 16-21, 2021; virtual. Abstract 1281O3.
2. Carbone DP, Reck M, Paz-Ares L, e al. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med. 2017;376(25):2415-2426. doi:10.1056/NEJMoa1613493
3. Herbst RS, Giaccone G, de Marinis F, et al. Atezolizumab for first-line treatment of PD-L1-selected patients with NSCLC. N Engl J Med. 2020;383(14):1328-1339. doi:10.1056/NEJMoa1917346
4. Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogeneic drivers in lung cancers to select targeted drugs. JAMA. 2014;311(19):1998-2006. doi:10.1001/jama.2014.3741