LUGANO-COPENHAGEN – The first phase III study of PD-L1 inhibitor atezolizumab in previously-treated non-small-cell lung cancer has seen significant improvements in survival compared to standard chemotherapy, researchers reported today at the ESMO 2016 Congress in Copenhagen.
PD-L1 inhibitors are of a class of cancer immunotherapies called checkpoint inhibitors, and work by inhibiting one of the mechanisms of resistance developed by cancer cells in order to evade the immune system.
“The goal of this treatment is to allow the immune system to control and possibly eliminate cancer calls, so atezolizumab might be useful in a very large setting of different cancers,” said investigator Dr. Fabrice Barlesi, head of Multidisciplinary Oncology and Therapeutic Innovations Deparment at Aix-Marseille University and the Assistance Publique Hôpitaux de Marseille, France.
The OAK study enrolled 1225 patients with previously treated non-small-cell lung cancer and, after stratifying them according to PD-L1 status, number of prior chemotherapy regimens and histology, randomised them to intravenous atezolizumab (1200mg every 3 weeks) or docetaxel (75 mg/m2 every 3 weeks).
In the preliminary analysis of data from 850 patients, researchers saw a 27% improvement in overall survival in the patients receiving azetolizumab compared to those treated with docetaxel (p=0.0003), regardless of their PD-L1 expression levels and including patients with PD-L1 expression of less than 1%.
When patients were stratified according to their level of PD-L1 expression, the overall survival was 59% greater among patients in the highest tertile of PD-L1 expression who were treated with azetolizumab, compared to the same group treated with docetaxel (P < 0.0001).
However even in patients with no PD-L1 expression, there was still a significant 25% improvement in overall survival with atezolizumab compared to those treated with docetaxel. The improvements in overall survival were similar in patients with squamous and non-squamous histology.
“This is the first phase III study of atezolizumab, a PD-L1 inhibitor, and it confirms the efficacy seen in the POPLAR phase II study, along with the results of PD-1 inhibitors” said Barlesi.
“Azetizolumab offers a new second-line therapeutic strategy for patients with non-small-cell lung cancer, regardless of the PD-L1 status of the tumor.”
Commenting on the study, Professor Martin Reck, from the Department of Thoracic Oncology at Lung Clinic Grosshansdorf, Germany, said: “This is a very important piece of information on the role of PD-L1/PD-1 antibodies in treatment of non-small-cell lung cancer, and confirms the overall survival benefits shown in the POPLAR and CHECKMATE trials.”
“Interestingly, the study also showed an improvement in overall survival, even in patients with no PD-L1 expression, which means we have a problem with using PD-L1 negativity as an exclusion factor for treatment,” Reck explained.
“My suggestion would be that PD-L1 is perhaps one imperfect surrogate marker to describe the activity; it’s a good enrichment factor but we need additional markers for the characterization of patients who might not benefit from this treatment or who might really benefit.”
Notes to Editors
Abstract LBA44_PR – “Primary analysis from OAK, a randomized phase III study comparing atezolizumab with docetaxel in 2L/3L NSCLC” will be presented by Dr Fabrice Barlesi during the Presidential Symposium 2 on Sunday 9 October, 16:25 to 18:20 (CEST)
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Abstract for LBA44_PR
Primary analysis from OAK, a randomized phase III study comparing atezolizumab with docetaxel in 2L/3L NSCLC
F. Barlesi1, K. Park2, F. Ciardiello3, J. von Pawel4, S. Gadgeel5, T. Hida6, D. Kowalski7, M.C. Dols8, D. Cortinovis9, J. Leach10, J. Polikoff11, D. Gandara12, C.H. Barrios13, D.S. Chen14, P. He15, M. Kowanetz16, M. Ballinger17, D. Waterkamp14, A. Sandler14, A. Rittmeyer18
1Assistance Publique Hôpitaux de Marseille, Aix Marseille University, Marseille, France, 2Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul, Republic of Korea, 3Medical Oncology, AOU Seconda Università degli Studi di Napoli (AOU-SUN), Naples, Italy, 4Oncology, Asklepios-Fachklinikum, Gauting, Germany, 5Wayne State University, Karmanos Cancer Institute, Detroit, MI, USA, 6Aichi Cancer Center Hospital, Nagoya, Japan, Aichi Cancer Center Hospital, Nagoya, Japan, Nagoya, Japan, 7Department of Lung Cancer and Chest Tumours, The Maria Sklodowska-Curie Institute of Oncology, Warsaw, Poland, 8Medical Oncology Section, Hospital Universitario Málaga General Carlos Haya, Malaga, Spain, 9Dept. of Medical Oncology, Azienda Ospedaliera San Gerardo Hospital, Monza, Italy, 10Medical Oncology, Metro-Minnesota Community Oncology Research Consortium, Minneapolis, MN, USA, 11Oncology, Southern California Permanente Medical Group, San Diego, CA, USA, 12Internal Medicine, University of California Davis Cancer Center, Sacramento, CA, USA, 13Department of Medicine, Pontifical Catholic University of Rio Grande do Sul School of Medicine, Porto Alegre, Brazil, 14Product Development Oncology, Genentech, Inc., South San Francisco, CA, USA, 15Biostatistics, Genentech, Inc., South San Francisco, USA, 16Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA, USA, 17Product Development, Oncology, Genentech, Inc., South San Francisco, CA, USA, 18Oncology, Lungenfachklinik Immenhausen, Immenhausen, Germany
Background: Atezolizumab (atezo) inhibits the binding of PD-L1 to its receptors PD-1 and B7.1, thereby restoring tumor-specific T-cell immunity, while leaving the PD-L2/PD-1 interaction intact. Atezo demonstrated survival benefit vs docetaxel (doc) in the Ph2 trial POPLAR. Here we present the primary analysis from the Ph3 OAK study evaluating atezo vs doc in previously treated NSCLC.
Methods: Previously treated NSCLC patients (pts) were stratified by PD-L1 status, prior chemotherapy regimens (1 vs 2) and histology, and randomized 1:1 to atezo (1200 mg IV q3w) or doc (75 mg/m2 IV q3w). The co-primary endpoints were OS in the ITT and PD-L1–expression subgroup TC1/2/3 or IC1/2/3 (PD-L1 expression on ≥ 1% TC or IC). Secondary endpoints included PFS, ORR, DoR and safety.
Results: The primary efficacy analysis was conducted in the first 850 of 1225 total enrolled pts. Pts had a median age of 64 y, 61% were male, 25% had 2 prior lines of therapies, 26% had squamous histology, 67% were previous smokers and 37% were PS 0. Superior OS was seen with atezo vs doc in ITT (HR 0.73; P = .0003) and TC1/2/3 or IC1/2/3 pts (HR 0.74; P = .0102). Survival was improved regardless of PD-L1 expression levels, including in pts with no PD-L1 expression (TC0 and IC0). There was pronounced benefit in pts with high PD-L1 expression (TC3 or IC3). OS benefit was similar in pts with squamous or nonsquamous histology. In ITT pts, PFS HR was 0.95 (2.8 vs 4.0 mo), ORR 13.6% vs 13.4%, and DoR 16.3 vs 6.2 mo for atezo vs doc. Gr 3-4 treatment-related AEs occurred in 15% of atezo pts and 43% of doc pts. There were no deaths related to atezo and 1 related to doc. No new safety signal was observed.
Conclusions: This first Ph3 trial of a PD-L1-directed drug in NSCLC demonstrates that atezo treatment results in a statistically significant and clinically relevant improvement in OS vs doc in 2L/3L NSCLC, regardless of PD-L1 expression and histology. Atezo was well tolerated with a favorable safety profile vs doc.
Clinical trial identification: NCT02008227
Legal entity responsible for the study: F. Hoffmann-La Roche Ltd
Funding: F. Hoffmann-La Roche Ltd
K. Park: Consultant: Astellas, Astra-Zeneca, Aveo, Boehringer Ingelheim, Clovis, Eli Lilly, Hanmi, KHK Novartis, Ono, Roche Research funding: Astra-Zeneca.
F. Ciardiello: Advisory boards: Merck Serono, AstraZeneca, Lilly, Roche, Bayer.
J. von Pawel: Consultant/Advisory (compensated) role for Paischi, Pfizer, Vertex, Cloves.
S. Gadgeel: Served on Advisory Boards and was compensated by the following pharmaceutical companies- Roche/Genentech, Pfizer, BMS, Ariad, Boehringer-Ingelheim, Astra-Zeneca. Speaker's Bureau- Astra-Zeneca.
T. Hida: Corporate-sponsored research: Chugai Pharmaceutical.
D. Gandara: Grant and consultant: Genentech, BMS, MERCK and EMD Serrano.
C.H. Barrios: Research/Consulting: Pfizer, Novartis, Amgen, AstraZeneca, BI, GSK, Roche, Lilly, Sanofi, Taiho, Mylan, Merrimack, Merck, Abbvie, Astellas, Biomarin, BMS, Daiichi Sankyo, Abraxis, ABS, Asana, Medivation, Exelixis, ImClone, LEO, Millennium, Eisai, Bioepis.
D.S. Chen: Genentech employee, Genentech Roche stock.
P. He: Genentech employee, Roche and Amgen stocks.
M. Kowanetz: Employee of Genentech + Genentech stock.
M. Ballinger: Genentech employee; Stocks: Roche, Exelixis, Sunesis.
D. Waterkamp: Genentech employee, Roche stock.
A. Sandler: Genentech employee, Compensated Consultant role for Genentech/Roche, Genentech/Roche stock, Honoraria recipient from Genentech/Roche, Genentech research funding paid to institution, Provided compensated expert testimony for Genentech/Roche.
A. Rittmeyer: Consulting or advisory role for Roche, Lilly, BMS, Boehing. Grants: Roche, Lilly, BMS, AstraZeneca, MSD, Boehringer Ingelheim, Pfizer.
All other authors have declared no conflicts of interest.
Keywords: atezolizumab, NSCLC, cancer immunotherapy