ESMO 2016 Press Release: Pembrolizumab New Option for First Line Treatment of Patients with Advanced Lung Cancer and High PD-L1 Expression

LUGANO-COPENHAGEN – Pembrolizumab is set to become a new option for first line treatment of patients with advanced lung cancer and high PD-L1 expression, according to the results of the phase III KEYNOTE-024 trial presented at the ESMO 2016 Congress in Copenhagen and published in the New England Journal of Medicine.

”Pembrolizumab is a PD-1 antibody approved for second line treatment of patients with advanced non-small-cell lung cancer (NSCLC) and PD-L1 expression in their tumour cells,” said lead author Professor Martin Reck, chief oncology physician, Department of Thoracic Oncology, Lung Clinic Grosshansdorf, Germany. “KEYNOTE-024 is the first phase III trial of pembrolizumab as first line treatment in patients with high PD-L1 expression, who represent 27–30% of those with advanced NSCLC.”

KEYNOTE-024 investigated the efficacy of pembrolizumab compared to standard of care with platinum-based chemotherapy in untreated patients with advanced NSCLC and high PD-L1 expression (defined as expression in at least 50% of tumour cells). Patients with EGFR activating mutations and ALK translocations were excluded from recruitment. “There is a substantial need to find better options than chemotherapy for these patients,” said Reck.

The trial included 305 patients from 16 countries who were randomised 1:1 to pembrolizumab or chemotherapy. Patients in the chemotherapy arm who progressed were eligible to crossover to pembrolizumab as second line treatment – this occurred in 44% of these patients.

The investigators found that pembrolizumab significantly improved the primary endpoint of progression-free survival by approximately four months compared to chemotherapy (10.3 months versus 6.0 months, hazard ratio [HR] 0.50). The secondary endpoint of overall survival was also significantly prolonged, and 80% of patients on pembrolizumab were alive at six months compared to 72% on chemotherapy (HR=0.60).

“The significant improvement in overall survival with pembrolizumab was remarkable given that more than 40% of patients crossed over from the control arm to pembrolizumab after progression of the disease,” said Reck.

Pembrolizumab was associated with a higher overall response rate compared to chemotherapy (45% versus 28%), a longer duration of response, and lower incidences of all and serious (3/4) adverse events.

“This data will completely change the management of patients with advanced NSCLC,” said Reck. “All endpoints of efficacy and tolerability favoured treatment with pembrolizumab, suggesting it should become one standard of care for first line treatment of patients with advanced NSCLC and high PD-L1 expression. This is primarily an opportunity for patients without oncogenic alterations. More information is needed for those with alterations.”

He concluded: “This is a landmark trial for the 30% of patients with advanced NSCLC who are high expressers of PD-L1. The new treatment algorithm should include upfront testing for PD-L1 expression to identify patients who will benefit from first line treatment with pembrolizumab.”

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: “This study may change current practice for the treatment of patients with advanced NSCLC. It is the first time a therapy has improved progression-free survival over the current standard first line treatment with platinum-based doublet chemotherapy.”

“The reason KEYNOTE-024 met its primary endpoint, in contrast with other studies, is probably because the trial only included patients who had PD-L1 expression of at least 50% and were therefore optimal candidates for treatment with pembrolizumab,” he added.

“A study is needed to confirm these findings in patients with high PD-L1 expression,” continued Vansteenkiste. “Additional research should be done to find out whether patients with lower levels of PD-L1 expression also benefit more from pembrolizumab than chemotherapy.”

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Notes to Editors

References

Abstract LBA8_PR ‘KEYNOTE-024: Pembrolizumab (pembro) vs platinum-based chemotherapy (chemo) as first-line therapy for advanced NSCLC with a PD-L1 tumour proportion score (TPS) >50%‘ will be presented by Professor Martin Reck during the Presidential Symposium 2 on Sunday, 9 October 2016, 16:25 to 18:20 (CEST) in Room Copenhagen.

Reck M, Rodríguez-Abreu D, Robinson A, et al. Pembrolizumab or Chemotherapy in PD-L1–Positive Non–Small-Cell Lung Cancer. N Engl J Med. DOI: 10.1056/NEJMoa1606774

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Abstract for LBA8_PR

KEYNOTE-024: Pembrolizumab (pembro) vs platinum-based chemotherapy (chemo) as first-line therapy for advanced NSCLC with a PD-L1 tumor proportion score (TPS) ≥50%

M. Reck1, D. Rodríguez-Abreu2, A.G. Robinson3, R. Hui4, T. Csoszi5, A. Fülöp6, M. Gottfried7, N. Peled8, A. Tafreshi9, S. Cuffe10, M. O'Brien11, S. Rao12, K. Hotta13, M. Leiby14, G.M. Lubiniecki15, Y. Shentu16, R. Rangwala15, J.R. Brahmer17

1Thoracic Oncology, Lung Clinic Grosshansdorf, Airway Research Center North (ARCN), member of the German Center for Lung Research (DZL), Grosshansdorf, Germany, 2Medical Oncology, Hospital Universitario Insular de Gran Canaria, Las Palmas De Gran Canaria, Spain, 3Oncology, Cancer Centre of Southeastern Ontario at Kingston General Hospital and Queens University, Kingston, ON, Canada, 4Medical Oncology, Westmead Hospital and University of Sydney, Sydney, Australia, 5Onkologiai Kozpont, Hetenyi G Korhaz, Szolnok, Hungary, 6Oncology, National Koranyi Institute of Pulmonology, Budapest, Hungary, 7Oncology, Meir Medical Center, Kfar Saba, Israel, 8Thoracic Cancer Unit, Davidoff Cancer Center, Petach Tiqwa, Israel, 9Medical Oncology, Southern Medical Day Care Centre, Wollongong, Australia, 10Medical Oncology, St James's Hospital, Dublin, Ireland, 11Medical Oncology, Royal Marsden Hospital NHS Foundation Trust, London, UK, 12Oncology, MedStar Franklin Square Medical Center, Baltimore, MD, USA, 13Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan, 14Global Scientific and Medical Publications, Merck & Co., Inc., Kenilworth, NJ, USA, 15Oncology Clinical Development, Merck & Co., Inc., Kenilworth, NJ, USA, 16Biostatistics and Research Decision Statistics, Merck & Co., Inc., Kenilworth, NJ, USA, 17Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA

Background: Platinum-based doublet chemo is the standard first-line therapy for advanced NSCLC without a treatable oncogenic aberration. Pembro (anti–PD-1) is approved in the US and EU for previously treated, PD-L1–expressing advanced NSCLC. KEYNOTE-024 (NCT02142738) is an open-label, phase 3 study of pembro vs platinum-doublet chemo as first-line therapy for advanced NSCLC of PD-L1 TPS ≥50% without treatable EGFR mutations or ALK translocations.

Methods: Patients (pts) were randomized to 35 cycles of pembro 200 mg Q3W or 4-6 cycles of investigator’s choice of carboplatin or cisplatin + pemetrexed, carboplatin or cisplatin + gemcitabine, or carboplatin + paclitaxel, with optional pemetrexed maintenance for nonsquamous NSCLC. Pts in the chemo arm could crossover to pembro upon PD. Response was assessed every 9 wk (RECIST v1.1, central imaging vendor). Primary end point was PFS. Secondary end points were OS, ORR, and safety. Differences in PFS and OS were assessed in the ITT population using the stratified log-rank test. At the prespecified second interim analysis (data cutoff, May 9, 2016), the study had 97% power to detect a HR of 0.55 for PFS at a 1-sided α = 2.0%.

Results: From Sep 19, 2014, to Oct 29, 2015, 305 pts from 16 countries were randomized: 154 to pembro, 151 to chemo. After a median follow-up of 11.2 mo, 48% of pts remained on pembro, 10% remained on chemo, and 44% crossed over from chemo to pembro upon PD. With 189 events, pembro significantly prolonged PFS over chemo (HR 0.50, 95% CI 0.37-0.68, P < 0.001; median 10.3 mo vs 6.0 mo). With 108 deaths, pembro also significantly prolonged OS (HR 0.60, 95% CI 0.41-0.89, P = 0.005; 6-mo OS 80% vs 72%). Pembro was also associated with higher ORR (45% vs 28%), longer response duration (median NR vs 6.3 mo), and lower incidence of any-grade (73% vs 90%) and grade 3-5 (27% vs 53%) treatment-related AEs.

Conclusions: Pembro demonstrated superior PFS and OS over platinum-based chemo in pts with advanced NSCLC of PD-L1 TPS ≥50%. Along with the lower rate of treatment-related AEs, these data suggest pembro may be the new standard of care for first-line therapy of PD-L1–expressing advanced NSCLC without treatable oncogenic aberrations.

Clinical trial identification: ClinicalTrials.gov number NCT02142738, originally posted May 16, 2014; EudraCT number 2014-000323-25, originally issued 27-Mar-2014

Legal entity responsible for the study: Merck & Co., Inc.

Funding: Merck & Co., Inc.

Disclosure:

M. Reck: Served as Advisory board member for Roche, Lilly, BMS, MSD, AstraZeneca, Pfizer, Boehringer-Ingelheim, and Celgene. Also, served on Speakers’ bureau for Roche, Lilly, BMS, MSD, AstraZeneca, Pfizer, Boehringer-Ingelheim, and Celgene.
D. Rodríguez-Abreu: Advisory board member, speakers' bureau, and travel expenses: BMS, MSD, Boehringer, Roche.
A.G. Robinson: Speakers' bureau: Merck, Pfizer, Roche, Novartis.
R. Hui: Advisory board member: MSD, AstraZeneca, Pfizer, Novartis.
N. Peled: Speakers' bureau and travel expenses: MSD.
A. Tafreshi: Advisory board member: Merck, Ipsen.
M. O'Brien: Advisory board member: MSD, Bristol-Myers Squibb, Abbive, Boehringer Ingelheim, Pierre Fabre; Travel expenses: Bristol-Myers Squibb.
K. Hotta: Speakers' bureau: Chugai, Lilly, AstraZeneca, Daiichi-Sankyo Pharmaceutical, Boehringer-Ingelheim, Nihon Kayaku, Taiho Pharmaceutical, and Sanofi-Aventis; Research funding: Merck, Chgai, Lilly.
M. Leiby, G.M. Lubiniecki, Y. Shentu, R. Rangwala: Employment and stock options: Merck & Co., Inc.
J.R. Brahmer: Advisory board: Bristol-Myers Squibb, MedImmune/AstraZeneca, Merck; Advisory board: Bristol-Myers Squibb (uncompensated), Celgene, Lilly, MedImmume/AstraZeneca.
All other authors have declared no conflicts of interest.

Keywords: first-line chemotherapy, NSCLC, PD-L1, pembrolizumab