ESMO 2016 Press Release: Greater Patient Selection May be Needed for First Line Nivolumab to Improve Progression-free Survival in Advanced Lung Cancer

LUGANO-COPENHAGEN – Greater patient selection may be needed for first line nivolumab to improve progression-free survival over chemotherapy in advanced lung cancer as the CheckMate 026 trial gave negative results in a broad group of patients expressing PD-L1 in their tumour cells. The findings were presented at the ESMO 2016 Congress in Copenhagen.

“Nivolumab represents a standard of care in the second-line treatment of advanced non-small cell lung cancer (NSCLC) as it improved overall survival compared to docetaxel in phase III trials in these patients,” said lead author Dr Mark A. Socinski, Executive Medical Director, Florida Hospital Cancer Institute, US.

“In the first line setting, nivolumab showed a promising response rate in a phase I trial in advanced NSCLC patients with 1% or greater PD-L1 expression in their tumour cells,” he continued.

The phase III CheckMate 026 trial investigated the efficacy of first line treatment with nivolumab compared to platinum-based doublet chemotherapy in patients with advanced NSCLC and PD-L1 positive tumours (defined as present in 1% or more tumour cells). Patients with EGFR activating mutations and ALK translocations, which are sensitive to targeted therapy, were excluded. The primary endpoint was progression-free survival, assessed by an independent radiology review committee in patients with PD-L1 in 5% or more tumour cells.

A total of 541 patients were randomised 1:1 to nivolumab or chemotherapy. Patients who progressed on chemotherapy could crossover to nivolumab as second line treatment.

In the 423 patients with 5% or greater PD-L1 expression, progression-free survival was 4.2 months with nivolumab and 5.9 months with chemotherapy (hazard ratio [HR] 1.15, 95% confidence interval [CI] 0.91–1.45, p=0.25). Overall survival was 14.4 months for nivolumab versus 13.2 months for chemotherapy (HR 1.02, 95% CI 0.80–1.30). Among all treated patients, any and serious treatment-related adverse events were 71% and 18% with nivolumab, and 92% and 51% with chemotherapy, respectively.

“There were no new safety signals with nivolumab and it was less toxic than chemotherapy,” said Socinski.

“There are a number of possible reasons for the disappointing progression-free survival results,” he added. “Regarding overall survival, there was a high rate of crossover to immunotherapy on the chemotherapy arm. Overall survival in the chemotherapy arm was better than historical standards, which could be due to the fact that it had a greater proportion of women and Asian patients. We are conducting further analyses to evaluate these results.”

“Platinum-based chemotherapy is the standard first line treatment because it makes patients live longer and palliates symptoms,” said Socinski. “If we are going to replace it with immunotherapy, we need to be confident that we are identifying the patients who will derive greater benefit.”

Socinski concluded: “Combination immunotherapies may increase the proportion of patients who benefit in the first line. The phase III CheckMate 227 trial is investigating treatment with nivolumab plus ipilimumab in the first line setting relative to standard chemotherapy.”

Commenting on the results, Professor Johan Vansteenkiste, Professor of Medicine, Catholic University Leuven, and Chief Oncology Physician, Unit of Respiratory Oncology, University Hospital  KU Leuven, Belgium, said: “Nivolumab did not improve progression-free survival over chemotherapy in this study. In my view the reason is because the trial included a broad range of patients with a low PD-L1 expression threshold of just 1% or greater. Standard first line treatment with platinum doublet chemotherapy gives a progression-free survival of six months and to beat that may require being more selective on who receives the drug.”

He continued: “More research is needed about how to use the PD-L1 biomarker to select patients for treatment with nivolumab. In addition, phase I studies suggest that combination immunotherapy improves response rate and outcome, but at the expense of increased toxicity, compared to single agent immunotherapy in NSCLC. So, it will be important to investigate this strategy further.”

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Notes to Editors

References

Abstract LBA7_PR ‘CheckMate 026: A Phase 3 Trial of Nivolumab vs Investigator's Choice (IC) of Platinum-Based Doublet Chemotherapy (PT-DC) as First-Line Therapy for Stage IV/Recurrent Programmed Death Ligand 1 (PD-L1) − Positive NSCLC’ will be presented by Dr Mark Socinski during the Presidential Symposium 2 on Sunday, 9 October, 2016 16:25 to 18:20 (CEST) in Room Copenhagen.

Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 20159;373(2):123–135. doi: 10.1056/NEJMoa1504627. Epub 2015 May 31.

Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373(17):1627–1639. doi: 10.1056/NEJMoa1507643. Epub 2015 Sep 27.

Gettinger S, Rizvi NA, Chow LQ, et al. Nivolumab monotherapy for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol. 2016;34(25):2980–2987. doi: 10.1200/JCO.2016.66.9929. Epub 2016 Jun 27.

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Abstract for LBA7_PR

CheckMate 026: A Phase 3 Trial of Nivolumab vs Investigator's Choice (IC) of Platinum-Based Doublet Chemotherapy (PT-DC) as First-Line Therapy for Stage IV/Recurrent Programmed Death Ligand 1 (PD-L1) − Positive NSCLC

M. Socinski1, B. Creelan2, L. Horn3, M. Reck4, L. Paz-Ares5, M. Steins6, E. Felip7, M. van den Heuvel8, T.E. Ciuleanu9, F. Badin10, N. Ready11, T.J.N. Hiltermann12, S. Nair13, R. Juergens14, S. Peters15, E. Minenza16, W.J. Geese17, P. Bhagavatheeswaran18, A. Chen19, D.P. Carbone20

1Medical Oncology, UPMC Cancer Center, Pittsburgh, PA, USA, 2Thoracic Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA, 3Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA, 4Thoracic Oncology, LungenClinic Grosshansdorf, Airway Research Center North (ARCN), Grosshansdorf, Germany, 5Medical Oncology, Hospital Universitario Doce de Octubre & CNIO, Madrid, Spain, 6Oncology, Thoraxklinik-Heidelberg gGmbH, Heidelberg, Germany, 7Oncologia Médica, Hospital Universitari Vall d’Hebron, Barcelona, Spain, 8Thoracic Oncology, Antoni Van Leeuwenhoek Ziekenhuis, Amsterdam, Netherlands, 9Medical Oncology, Prof. Dr. Ion Chiricuta Institute of Oncology and UMF Iuliu Hatieganu, Cluj-Napoca, Romania, 10Oncology, Baptist Health Lexington, Lexington, KY, USA, 11Oncology, Duke University Medical Center, Durham, NC, USA, 12Pulmology Oncology, University of Groningen and University Medical Center Groningen, Groningen, Netherlands, 13Hematology-Medical Oncology, Lehigh Valley Health Network, Allentown, PA, USA, 14Oncology, Juravinski Cancer Centre, Hamilton, ON, Canada, 15Oncology, University of Lausanne, Lausanne, Switzerland, 16Oncology, Ospedale S. Maria Nuova, Terni, Italy, 17Oncology, Bristol-Myers Squibb, Princeton, NJ, USA, 18Global Biometric Sciences, Bristol-Myers Squibb, Princeton, NJ, USA, 19Global Clinical Research Oncology, Bristol-Myers Squibb, Princeton, NJ, USA, 20Department of Medical Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH, USA

Background: Nivolumab improves OS compared with docetaxel in previously treated NSCLC. In a phase 1 study (CheckMate 012), nivolumab showed promising activity and manageable safety as monotherapy and in combination with ipilimumab in treatment naive advanced NSCLC. CheckMate 026 (NCT02041533), an open-label, randomized phase 3 study, evaluated the efficacy of nivolumab vs IC PT-DC as first-line therapy in stage IV/recurrent PD-L1−positive NSCLC.

Methods: Patients with histologically confirmed and previously untreated stage IV or recurrent NSCLC, ECOG PS 0−1, and PD-L1 positivity were randomized 1:1 to receive nivolumab 3 mg/kg IV Q2W or IC PT-DC (histology-based) Q3W (up to 6 cycles) until disease progression or unacceptable toxicity. Patients with EGFR/ALK mutations sensitive to targeted therapy were excluded. Patients on IC PT-DC could crossover to nivolumab upon progression. The primary objective was comparison of PFS (per RECIST 1.1) as assessed by an independent radiology review committee in patients with ≥5% PD‑L1 tumor expression at randomization.

Results: A total of 541 patients were randomized to treatment. In patients with ≥5% PD-L1 expression (n = 423), nivolumab did not improve PFS (HR, 1.15; 95% CI 0.91 to 1.45; P=0.25). Median PFS was 4.2 mo and 5.9 mo with nivolumab and IC PT-DC, respectively. Among all treated patients, any grade and grade 3/4 treatment-related adverse events were 71% and 18% with nivolumab, as compared to 92% and 51% with IC PT-DC, respectively. Secondary endpoints including PFS in all randomized patients, OS, and ORR will be presented.

Conclusions: Nivolumab did not show superior PFS compared to IC PT-DC as first-line therapy in stage IV/recurrent NSCLC patients with ≥5% PD-L1 tumor expression. The safety profile of nivolumab was favorable to IC PT-DC and consistent with previous studies. Nivolumab plus ipilimumab and nivolumab plus chemotherapy are being evaluated in a phase 3 trial in previously untreated NSCLC (CheckMate 227).

Clinical trial identification: NCT02041533

Legal entity responsible for the study: Bristol-Myers Squibb

Funding: Bristol-Myers Squibb

Disclosure:

B. Creelan: Honoraria and research funding from Boehringer-Ingelheim. Received Speakers’ Bureau payment and Travel, Accommodations, and Expenses from Bristol-Myers Squibb and AstraZeneca
L. Horn: Consulting/Advisory Role with Genetech and Merck (compensated) & BMS, BI, Xcovery and Bayer (compensated). Research funding from AstraZeneca. Relationship with Biodesix.
M. Reck: Consulting and Speakers' Bureau: Roche, Eli Lilly, Bristol Myers Squibb, MSD, AstraZeneca, Pfizer, Boehringer-Ingelheim, Celgene.
M. Steins: The author reports Honoraria and Consulting or Advisory Role for BMS.
E. Felip: The author reports honoraria and consulting/advisory role with Boeheringer Ingelheim, MSD, Eli Lilly, Roche, Pfizer, Novartis, BMS, Celgene. The author reports Speakers Bureau for BMS, Novartis, Roche.
T.E. Ciuleanu: The author reports advisory board work for Amgen, Astellas, AZ, BMS, Janssen, Lilly, Merck, Merck Sharp and Dohme.
N. Ready: The author reports honoraria from BMS, Celgene, Heat Biologics and travel/accommodations/expenses from AZ.
S. Nair: Received Research Funding from Bristol-Myers Squibb, Celldex—site PI for trials.
R. Juergens: The author reports: Research Funding from AZ/MedImmune, BMS, Merck Sharp & Dohme, Novartis; Honoraria from Bayer, BMS, BI, BetaPharma, AZ, AZ/MedImmune, Roche Canada; Consulting /Advisory role for AZ, BI, BMS, Lilly, Novartis, Pfizer and Merck Sharp&Dohme.
S. Peters: The author reports a consulting or advisory role with Roche, MSD, Lilly, Merck, Serono, Pfizer, AZ, Amgen, Celgene, BI, BMS.
W.J. Geese: The author reports employment from BMS, stock or other ownership from BMS, and travel/accommodations/expenses from BMS.
P. Bhagavatheeswaran, A. Chen: The author reports Employment and Stock or Other Ownership from BMS.
D.P. Carbone: Writing Assistance provided by StemScientific, consulting for Genentech, Bristol Myers Squibb, Boehringer Ingelheim, Novartis, Pfizer, and Clovis (in the past but within the last 36 months). Grants from Bristol-Myers Squibb.
All other authors have declared no conflicts of interest.

Keyword: nivolumab, metastatic NSCLC, first-line, PD-L1