PET-derived parameters for response assessment in neoadjuvant atezolizumab: A secondary analysis of PRINCEPS phase II trial

ABSTRACT

Background: Immune Checkpoint Blockade (ICB) is moving from metastatic to curative setting in different diseases including NSCLC. While for metastatic disease radiological endpoints are currently the standard surrogate marker of benefit from ICBs, based on RECIST or PERCIST criteria, in neoadjuvant setting they often underestimate the response and then pathological response (PR) criteria were developed to evaluate Major PR (MPR), defined as ≤10% viable tumor cells after neoadjuvant treatment, and PR, defined as less than 50% residual tumor cells. Anyway, a non-invasive approach to determine the response to treatment is still an unmet need. Methods: PRINCEPS was a phase 2 clinical trial including limited-stage (IB-IIIA) NSCLC patients who received one administration of atezolizumab before surgery. 18-F FDG PET was performed within 28 days and after 15-22 days from atezolizumab. Surgery was performed at day 22-29 from atezolizumab. PET derived parameters including MTV and TLG was extracted by experienced nuclear physicians. Results: 30 patients were enrolled, all received A and underwent surgical resection after a median of 23 days. MPR was identified in 4, pPR in 8 tumors. Paired PET were available for 28 pts. Mean time from A to PET was 18 days (IQR 3.5). Total TLG and MTV reduction was not correlated with percentage of pPR (p=0.117 and p=0.843, respectively). Reduction of MTV (Pearson correlation 0.509, p=0.006) and TLG (Pearson correlation 0.562, p=0.002) in the primary tumor were strongly correlated with pPR, while no correlation was observed between percentage of pPR and variation in tumor diameters by RECIST criteria (-0.24, p=0.2) nor metabolic response (-0.12, p=0.55). The appearance of metabolically active hilar and mediastinal, non-pathological lymph nodes (LN) was noted in 12/28 patients, and specifically in. 2 out of 4 MPR and 5 out of 8 pPR. A trend toward an higher pPR was observed with LN appearance (mean 52% reduction in pts with LN appearance vs 29% without, p 0.061), probably reflecting immune activation. LN appearance was associated with hyperplasia and histiocytosis in resected, non-metastatic LNs. Conclusions: PET is able to early detect tumor response in localized NSCLC patients treated with ICBs in neoadjuvant setting. Clinical trial identification NCT02994576. Legal entity responsible for the study Institut Gustave Roussy. Funding: Roche. Disclosure N. Chaput-Gras Financial Interests, Personal, Advisory Board, Strong-Iopredi Scientific Advisory Board AstraZeneca;Financial Interests, Institutional, Invited Speaker, Educational Session On Immune Cell Death Servier;Financial Interests, Institutional, Expert Testimony, Expertise On Immune Cell Death Biomarkers Servier;Financial Interests, Personal, Invited Speaker Cytune Pharma;Financial Interests, Institutional, Research Grant, Research grant to identify immune biomarkers associated to clinical response in patients treated with agonistic mAbs GSK;Financial Interests, Institutional, Research Grant, Preclinical studies in mice GSK;Financial Interests, Institutional, Research Grant, Immune profiling of Head & Neck tumors Sanofi. D. Planchard Financial Interests, Personal, Advisory Board AstraZeneca, BMS, Merck, Novartis, Pfizer, Roche, Samsung, Celgene, AbbVie, Daiichi Sankyo, Janssen;Financial Interests, Personal, Invited Speaker AstraZeneca, Novartis, Pfizer, priME Oncology, Peer CME, Samsung, AbbVie, Janssen;Non-Financial Interests, Principal Investigator, Institutional financial interests AstraZeneca, BMS, Merck, Novartis, Pfizer, Roche, Daiichi Sankyo, Sanofi-Aventis, Pierre Fabre;Non-Financial Interests, Principal Investigator AbbVie, Sanofi, Janssen. L. Mezquita Financial Interests, Personal, Advisory Board Takeda, AstraZeneca, Roche;Financial Interests, Personal, Invited Speaker Roche, BMS, AstraZeneca, Takeda;Financial Interests, Personal, Research Grant, SEOM Beca Retorno 2019 BI;Financial Interests, Personal, Research Grant, ESMO TR Research Fellowship 2019 BMS;Financial Interests, Institutional, Resea ch Grant, COVID research Grant Amgen;Financial Interests, Institutional, Invited Speaker Inivata, Stilla. J. Remon Masip Financial Interests, Personal, Invited Speaker Roche, Pfizer, MSD, Boehringer-Ingelheim;Financial Interests, Personal, Advisory Board AstraZeneca, BMS, Janssen, Takeda, Sanofi;Financial Interests, Personal, Expert Testimony Ose Immunotherapeutics;Non-Financial Interests, Principal Investigator, PI of PECATI trial in Thymic malignancies endorsed by a grant by MSD MSD;Non-Financial Interests, Other, Co-PI of APPLE trial (EORTC-1525) AstraZeneca. F. Barlesi Financial Interests, Personal, Advisory Board AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Novartis, Merck, Mirati, MSD, Pierre Fabre, Pfizer, Sanofi Aventis, Seattle Genetics, Takeda;Non-Financial Interests, Principal Investigator AstraZeneca, BMS, Merck, Pierre Fabre, F. Hoffmann-La Roche Ltd. B. Besse Financial Interests, Institutional, Funding: 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi-Sankyo, Eli Lilly, GSK, Janssen, Onxeo, OSE Immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals;Financial Interests, Institutional, Research Grant Chugai Pharmaceutical, Eisai, Genzyme Corporation, Inivata, Ipsen, Turning Point Therapeutics. All other authors have declared no conflicts of interest.