Background

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.

Methods

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.

Results

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 (HR=0.58 [95% CI 0.43 – 0.79]; p=0.0005). Interim analysis of overall survival (OS) also favored atezo in ctDNA+ pts (HR=0.59 [95% CI 0.41 – 0.86]; p=0.0059), 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 (HR=0.52 [95% CI 0.331-0.82]; p=0.004), and TMB-high pts (HR=0.34 [95% CI 0.19-0.6]; p<0.0001]). The rate of ctDNA clearance from C1D1 to C3D1 was higher in atezo (18.2%) vs obs (3.8%) (p=0.0048).

Conclusions

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.

Clinical trial identification

NCT02450331.

Editorial acknowledgement

Medical writing assistance for this abstract was provided by Harbeen Grewal of Anshin BioSolutions Corp. and funded by F. Hoffmann-La Roche, Ltd.

Legal entity responsible for the study

F. Hoffmann-La Roche, Ltd.

Funding

F. Hoffmann-La Roche, Ltd.

Disclosure

T.B. Powles: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): BMS; Advisory/Consultancy, Research grant/Funding (institution): Exelixis; Advisory/Consultancy: Incyte; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Ipsen; Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: MSD; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Seattle Genetics; Advisory/Consultancy, Research grant/Funding (institution): Merck Serono (EMD Serono); Advisory/Consultancy, Research grant/Funding (institution): Astellas; Advisory/Consultancy, Research grant/Funding (institution): Johnson & Johnson; Advisory/Consultancy: Eisai; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche. Z.J. Assaf: Full/Part-time employment: Genentech; Full/Part-time employment, Previous Employment: Natera. N. Davarpanah: Full/Part-time employment: Genentech; Shareholder/Stockholder/Stock options: Roche. M. Hussain: Honoraria (self), Research grant/Funding (self), Research grant/Funding (institution), Honorarium for an educational lecture to Singapore GU Oncology Physicians: AstraZeneca; Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: Bayer; Advisory/Consultancy, Research grant/Funding (self): Genentech; Honoraria (self), Travel/Accommodation/Expenses: Astellas Pharma; Travel/Accommodation/Expenses: Genentech/Roche; Honoraria (self): Physicians' Education Resource; Honoraria (self), Served as a contributing faculty on a written educational chapter: Projects in Knowledge; Honoraria (self): Sanofi/Genzyme; Honoraria (self): Research to Practice; Advisory/Consultancy: Bristol Myers Squibb; Advisory/Consultancy: Daiichi Sankyo; Licensing/Royalties: Systems and Methods For Tissue Imaging; Licensing/Royalties: Method of Treating Cancer; Licensing/Royalties: Dual Inhibition of MET and VEGF for the Treatment of Castration Resistant Prostate Cancer and Osteoblastic Bone Metastases. S. Oudard: Honoraria (self), Advisory/Consultancy: Astellas; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Bayer; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Bristol Myers Squibb; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Eisai; Research grant/Funding (self): Ipsen; Honoraria (self), Advisory/Consultancy: Janssen; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Merck Sharp & Dohme; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Sanofi. J.E. Gschwend: Honoraria (self), Advisory/Consultancy: Amgen; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy: Bayer; Honoraria (self), Advisory/Consultancy: Janssen-Cilag; Honoraria (self), Advisory/Consultancy: Merck; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: Roche; Advisory/Consultancy: Bristol Myers Squibb. P. Albers: Honoraria (self), Advisory/Consultancy: MSD Oncology; Honoraria (self): Sanofi; Advisory/Consultancy: Roche/Genentech. D. Castellano: Advisory/Consultancy, Research grant/Funding (institution): Janssen Oncology; Advisory/Consultancy, Travel/Accommodation/Expenses: Roche/Genentech; Advisory/Consultancy: Astellas Pharma; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy: Novartis; Advisory/Consultancy: Ipsen; Advisory/Consultancy, Travel/Accommodation/Expenses: Bristol Myers Squibb; Advisory/Consultancy: MSD Oncology; Advisory/Consultancy: Bayer; Advisory/Consultancy: Lilly; Advisory/Consultancy: Sanofi; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Boehringer Ingelheim; Travel/Accommodation/Expenses: AstraZeneca Spain. H. Nishiyama: Advisory/Consultancy: Bayer; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Chugai Pharma; Advisory/Consultancy: Janssen; Advisory/Consultancy, Speaker Bureau/Expert testimony: MSD; Advisory/Consultancy, Speaker Bureau/Expert testimony: Astellas Pharma; Advisory/Consultancy, Speaker Bureau/Expert testimony: AstraZeneca; Advisory/Consultancy: Bristol Myers Squibb; Research grant/Funding (institution): Ono Pharmaceutical. S. Daneshmand: Honoraria (self), Advisory/Consultancy: Ferring; Honoraria (self): MDxHealth; Honoraria (self): Olympus; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: Photocure; Honoraria (self), Advisory/Consultancy: QED Therapeutics; Honoraria (self): Spectrum Pharmaceuticals; Honoraria (self): Pacific Edge; Advisory/Consultancy: Taris. P. Grivas: Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy, Research grant/Funding (institution), Non-remunerated activity/ies, Participation in educational program: Bristol Myers Squibb; Advisory/Consultancy, Research grant/Funding (institution): Clovis Oncology; Advisory/Consultancy: Driver; Advisory/Consultancy: EMD Serono; Advisory/Consultancy: Exelixis; Advisory/Consultancy: Foundation Medicine; Advisory/Consultancy, Research grant/Funding (institution): GlaxoSmithKline; Advisory/Consultancy, Research grant/Funding (institution): Genentech/Roche; Advisory/Consultancy: Genzyme; Advisory/Consultancy: Heron Therapeutics; Advisory/Consultancy: Janssen; Advisory/Consultancy, Research grant/Funding (institution): Merck; Mirati Therapeutics; Pfizer; QED Therapeutics; Research grant/Funding (institution): Immunomedics; Research grant/Funding (institution): Kure It Cancer Research; Research grant/Funding (institution): Debiopharm; Advisory/Consultancy: Seattle Genetics; Research grant/Funding (institution): Oncogenex; Research grant/Funding (institution): Bavarian Nordic. S. Sharma: Full/Part-time employment: Natera. H. Sethi: Full/Part-time employment: Natera. A. Aleshin: Full/Part-time employment: Natera. J. Zhang: Full/Part-time employment: Hoffmann-La Roche Ltd. V. Degaonkar: Full/Part-time employment: Genentech; Shareholder/Stockholder/Stock options: Roche. C. Bais: Full/Part-time employment: Genentech. C.A. Carter: Full/Part-time employment: Genentech. J. Bellmunt: Advisory/Consultancy: Astellas Pharma; Advisory/Consultancy: AstraZeneca/MedImmune; Advisory/Consultancy: Bristol Myers Squibb; Advisory/Consultancy: Genentech; Advisory/Consultancy: Merck; Advisory/Consultancy: Novartis; Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy: Pierre Fabre; Research grant/Funding (institution): Millennium; Research grant/Funding (institution): Sanofi; Travel/Accommodation/Expenses: MSD Oncology; Honoraria (self): UpToDate; Shareholder/Stockholder/Stock options: Rainier; Research grant/Funding (institution): Pfizer/EMD Serono; Travel/Accommodation/Expenses: Ipsen. S. Mariathasan: Full/Part-time employment: Genentech.

Background

In CheckMate LBA1 (NCT02899299), a phase III 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.

Methods

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.

Results

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).

Conclusions

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: LBA1

Time to deterioration with NIVO+IPI vs chemo

Clinical trial identification

NCT02899299; Release date: 25 May 2016.

Editorial acknowledgement

Writing and editorial assistance were provided by Mhairi Laird, PhD, and Nick Patterson, PhD, of Caudex, and funded by Bristol Myers Squibb.

Legal entity responsible for the study

Bristol Myers Squibb.

Funding

Bristol Myers Squibb.

Disclosure

A. Scherpereel: Advisory/Consultancy: AstraZeneca, Bristol Myers Squibb, MSD, Roche; Speaker Bureau/Expert testimony: AstraZeneca, Bristol Myers Squibb, MSD. S. Antonia: Advisory/Consultancy: Bristol Myers Squibb, Celsius, Merck, Samyang Biopharma, AstraZeneca, MedImmune, CBMG, Memgen, Rapt, Venn, Achilles Therapeutics, GSK, Amgen. F. Grossi: Advisory/Consultancy: Bristol Myers Squibb, MSD, Eli Lilly, Roche, AstraZeneca, Takeda, Bayer; Speaker Bureau/Expert testimony: Bristol Myers Squibb, MSD, Roche, Astra Zeneca, Eli Lilly, Amgen, Boehringer, Pfizer, Pierre Fabre; Research grant/Funding (self): Bristol Myers Squibb. D. Kowalski: Advisory/Consultancy: MSD, Merck, Bristol Myers Squibb, Roche, Pfizer, Boehringer-Ingelheim, AstraZeneca, Takeda, Amgen. G. Zalcman: Honoraria (self): AstraZeneca, Bristol Myers Squibb; Advisory/Consultancy: Bristol Myers Squibb, AstraZeneca, MSD; Research grant/Funding (self): Roche. A.K. Nowak: Advisory/Consultancy: Bayer Pharmaceuticals, Pharmabcine, Trizell, Roche Pharmaceuticals, Boehringer Ingelheim, Merck Sharp Dohme, Douglas Pharmaceuticals, Atara Biotherapeutics; Research grant/Funding (self): AstraZeneca, Douglas Pharmaceuticals; Travel/Accommodation/Expenses: Boehringer Ingelheim, AstraZeneca. N. Fujimoto: Honoraria (self): ONO Pharmaceutical, Bristol Myers Squib, Daiichi Sankyo. S. Peters: Honoraria (self): AbbVie, Amgen, AstraZeneca, Bayer, Biocartis, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffman- La Roche, Foundation Medicine, Illumina, Janssen, Merck Sharp and Dohme, Merck Serono, Merrimack, Novarti; Advisory/Consultancy: AbbVie, Amgen, AstraZeneca, Bayer, Biocartis, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffman- La Roche, Foundation Medicine, Illumina, Janssen, Merck Sharp and Dohme, Merck Serono, Merrimack, Novarti; Advisory/Consultancy: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, F. Hoffman-La Roche, Merck Sharp and Dohme, Novartis, Pfizer, Sanofi, Takeda; Research grant/Funding (self): Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, F. Hoffman-La Roche, Illumina, Merck Sharp and Dohme, Merck Serono, Novartis, Pfizer. A.S. Tsao: Advisory/Consultancy: Bristol Myers Squibb, Eli Lilly, Genentech, Roche, Novartis, Ariad, EMD Serono, Merck, Seattle Genetics, AstraZeneca, Boehringer Ingelheim, Sellas Life Science; Research grant/Funding (self): Eli Lilly, Millennium, Polaris, Genentech, Merck, Boehringer- Ingelheim, BMS, Ariad, Epizyme, Seattle Genetics; Licensing/Royalties: UptoDate, Wiley. A.S. Mansfield: Advisory/Consultancy: AbbVie, AstraZeneca, Bristol Myers Squibb, Genentech/Roche; Research grant/Funding (self): Novartis, Verily; Non-remunerated activity/ies, Director: Mesothelioma Applied Research Foundation. S. Popat: Advisory/Consultancy: Bristol Myers Squibb, Roche, Takeda, AstraZeneca, Chugai, Novartis, Pfizer, MSD, EMD Serono, Guardant Health, AbbVie, Boehringer Ingelheim, Tesaro, Incyte, Paradox; Full/Part-time employment: Elsevier. X. Sun: Full/Part-time employment: Adelphi Values. B. Padilla: Full/Part-time employment: Adelphi Values. P. Aanur: Full/Part-time employment: Bristol Myers Squibb. M.J. Daumont: Shareholder/Stockholder/Stock options: Bristol Myers Squibb; Full/Part-time employment: Bristol Myers Squibb. B. Bennett: Full/Part-time employment: Bristol Myers Squibb. M. McKenna: Advisory/Consultancy: Bristol Myers Squibb. P. Baas: Advisory/Consultancy: MSD, AstraZeneca, Takeda, Bristol Myers Squibb; Research grant/Funding (self): Bristol Myers Squibb.