MIUC carries a substantial risk for death; nearly 50% of patients (pts) develop recurrence within 2 years of cystectomy. IMvigor010, a global Phase III trial, evaluated adjuvant treatment with atezolizumab (atezo) (anti-PD-L1) compared with observation (obs) in MIUC. Circulating tumor DNA (ctDNA) has been shown across multiple indications to be a strong predictor of recurrence. A ctDNA exploratory analysis was included prospectively to evaluate if: 1) atezo provides clinical benefit vs obs in pts with detectable ctDNA (ctDNA+) and 2) ctDNA clearance occurs at a higher rate with atezo vs obs.
Biomarker evaluable pts (BEP) had evaluable tissue whole exome sequencing (WES) and C1D1 plasma (median 11 weeks post-cystectomy) for ctDNA analysis by Natera’s Signatera assay (n=581; 72% of intent to treat population [ITT]). Baseline characteristics were similar between ITT and BEP. Tumor mutational burden (TMB) status and PD-L1 status were determined by WES and Ventana SP142 antibody.
Prevalence of ctDNA+ was 37% (n=214); positivity was associated with nodal status (p<0.001) and to a lesser extent tumor stage (p=0.09) but no other baseline factors. While IMvigor010 did not meet its primary endpoint of disease free survival (DFS) in the ITT, ctDNA+ pts showed substantial DFS benefit with atezo vs obs (stratified HR=0.57 [95% CI 0.41 – 0.79]; p<0.001). Interim analysis of overall survival (OS) also favored atezo in ctDNA+ pts (stratified HR=0.58 [95% CI 0.39 – 0.85]; p=0.005), with median OS 25.8 months with atezo vs 15.8 with obs. No benefit was noted for ctDNA˗ pts. Within the ctDNA+ pts, additional survival benefit was derived for PD-L1-high pts (stratified DFS HR=0.50 [95% CI 0.31-0.80]; p=0.0034), and TMB-high pts (stratified DFS HR=0.32 [95% CI 0.16-0.64]; p<0.001]). The rate of ctDNA clearance from C1D1 to C3D1 was higher in atezo (18.2%) vs obs (3.8%) (p=0.0048).
Post-surgical ctDNA positivity, associated with high risk for recurrence and death, identified MIUC patients likely to benefit from adjuvant atezo. Detection of minimal residual disease in an adjuvant setting will allow personalized treatment selection for patients.
NCT02450331
Medical writing assistance for this abstract was provided by Harbeen Grewal of Anshin BioSolutions Corp. and funded by F. Hoffmann-La Roche, Ltd.
In CheckMate 743 (NCT02899299), a phase 3 randomized trial, NIVO+IPI provided statistically significant and clinically meaningful improvement in overall survival vs standard-of-care chemo in patients (pts) with unresectable MPM. Here, we present PRO results.
Pts ≥18 y with MPM were randomized 1:1 to receive NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W or platinum + pemetrexed chemo Q3W. PROs were exploratory endpoints. Disease-related symptom burden was evaluated using the Lung Cancer Symptom Scale (LCSS)-Meso average symptom burden index (ASBI) and 3-item global index (3-IGI); health-related quality of life (HRQoL) was evaluated using the EQ-5D-3L UI and VAS. PROs were assessed before each dose of chemo or NIVO on day 1 of each cycle for 12 wk, every 6 wk for 12 mo, every 12 wk thereafter, and at specified follow-ups. Analyses included summary of PROs, mixed-effect model repeated measures (MMRM), and time to deterioration.
PRO completion rates were >80% for most on-treatment timepoints across arms for ≥10 pts (up to wk 96 for NIVO+IPI and wk 36 for chemo). Symptoms (LCSS-Meso ASBI mean change from baseline) trended to improve over time with NIVO+IPI and deteriorate with chemo, although the mean changes did not meet clinically important difference thresholds (±10 score change). HRQoL (mean EQ-5D-3L VAS scores) improved over time with NIVO+IPI; pts remaining on treatment over 2 y had scores in line with UK population norms (82.8) with a similar trend for the EQ-5D-3L UI. With both on-treatment and follow-up data, NIVO+IPI significantly delayed deterioration in HRQoL and showed a trend in symptom delay vs chemo (Table).
Overall, pts with unresectable MPM receiving NIVO+IPI vs chemo maintained quality of life and experienced a decreased risk of definitive deterioration in disease-related symptoms and HRQoL.
Table. Time to deterioration with NIVO+IPI vs chemo
| HRa (95% CI) | |
| Time to first deteriorationb | |
| LCSS-Meso ASBI LCSS-Meso 3-IGI EQ-5D-3L VAS EQ-5D-3L UIc | 0.82 (0.63–1.08) 0.80 (0.61–1.04) 0.76 (0.60–0.95) 0.71 (0.57–0.88) |
| Time to definitive deteriorationd | |
| LCSS-Meso ASBI LCSS-Meso 3-IGI EQ-5D-3L VAS EQ-5D-3L UIc | 0.52 (0.36–0.74) 0.61 (0.43–0.86) 0.58 (0.45–0.75) 0.65 (0.50–0.84) |
| Includes on-treatment and f/u assessments. aHR <1 favors NIVO+IPI over chemo bTime from randomization to when change in score first meets/exceeds deterioration threshold cBased on UK norms dIn addition to initial assessment meeting the deterioration threshold, all subsequent assessments must meet/exceed threshold | |
Clinical trial identification: NCT02899299
Release date: 25 May 2016
Writing and editorial assistance were provided by Mhairi Laird, PhD, and Nick Patterson, PhD, of Caudex, and funded by Bristol Myers Squibb.