Public Release: 

More patients with lung cancer could benefit from immunotherapy, study shows

KEYNOTE-010 data further supports broadening pembrolizumab availability for all advanced NSCLC patients with PD-L1 expression over 1 percent

European Society for Medical Oncology

SINGAPORE/LUGANO - More patients with advanced non-small-cell lung cancer (NSCLC) could benefit from pembrolizumab, says Professor Roy Herbst, Chief of Medical Oncology, Yale Cancer Center and Smilow Cancer Hospital at Yale-New Haven, presenting promising results from the pivotal phase 2/3 KEYNOTE-010 trial at the first ESMO Asia Congress in Singapore (1)), in conjunction with a publication in The Lancet (2).

The study shows that two doses of the anti-PD-1 antibody pembrolizumab, the US Food and Drug Administration (FDA)-approved 2 mg/kg dose and an investigational 10 mg/kg dose, each given every 3 weeks, improve median survival in all PD-L1-positive patients compared with the commonly used chemotherapeutic agent docetaxel. The benefit is even greater in the group of patients with PD-L1 staining in ?50% of tumour cells.

Pembrolizumab has demonstrated clinical activity in multiple tumour types, including benefit over standard-of-care therapy in melanoma and lung cancer. By blocking the PD-1/PD-L1 pathway, which has a crucial role in neoplastic growth when activated, the drug has shown its durable antitumour activity and acceptable toxicity in treatment-naive and previously treated advanced NSCLC patients.

The open-label KEYNOTE-010 is the first study to assess the benefits of immunotherapy as second- or later line in patients with refractory lung cancer selected for PD-L1 expression. From August 2013 to April 2015, 1034 patients with advanced NSCLC from 24 countries (EU nations, US and Asia, including Japan, South Korea and Taiwan) were randomised to pembrolizumab (2 mg/kg or 10 mg/kg) or docetaxel. All patients had experienced disease progression after platinum-containing systemic therapy and were stratified by PD-L1 expression level (tumour proportion score, TPS ?50% vs 1-49%).

"The topline results show that both groups of patients receiving pembrolizumab experience a survival benefit compared to docetaxel," Herbst said. "As expected, at the highest biomarker expression, the results were even better with a hazard ratio (HR) of 0.54 and 0.50 at the two doses of pembrolizumab, respectively. Treatment with pembrolizumab was associated with longer overall survival (OS) compared to docetaxel (median 14.9 and 17.3 months with 2 mg/kg and 10 mg/kg of pembrolizumab and 8.2 months with docetaxel).

"We additionally observed a quite clear benefit in patients who expressed >1% PD-L1 positivity in the tumour, with hazard ratios for OS of 0.71 and 0.61 in the pembrolizumab arms (at 2 mg/kg and 10 mg/kg, respectively). These results give further support for broadening the availability of pembrolizumab for all patients with PD-L1 expression over 1%."

In this trial, the safety profile of pembrolizumab was consistent with that from previous NSCLC studies. "Data from KEYNOTE-010 further supports the efficacy, safety and tolerability of pembrolizumab in patients with advanced stage NSCLC," Dr. Ross Soo, Adjunct Principal Investigator, Cancer Science Institute of Singapore, who was not involved in the study, said. "The drug is not yet approved in Asia and in Europe, and this study could help in this direction."

This year, another drug targeting the PD-1/PD-L1 pathway, nivolumab, received approval for the treatment of advanced-stage NSCLC without any required biomarker selection of patients. "The hazard ratio for overall survival favours pembrolizumab as compared with the recently approved second-line treatment options in advanced stage NSCLC such as docetaxel plus ramucirumab or docetaxel plus nintedanib," Soo said. "However, cross-trial comparisons should be interpreted with caution. In the absence of a direct head-to-head comparison, the choice of the specific PD-1 inhibitor relies on different factors such as costs of treatment, scheduling, and availability of biomarker testing."

Future studies are needed to assess whether patients who express PD-L1 in less than 1% of tumour cells would have some benefits from pembrolizumab. "Data from the KEYNOTE-010 study suggests, that pembrolizumab would be given to all patients with PD-L1 expression and this could have an impact on current strategies for lung cancer," Herbst concluded. "I believe we should use the best available weapons first. Now that we have learned which patients are most likely to benefit from the anti-PD-L1 strategy, we could start to move this weapon to the earlier stages. In this direction, I am eager to see the results of ongoing studies testing pembrolizumab in the first-line setting and eventually prevent the recurrence of lung cancer which is still at high rates."

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Notes to Editors

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Information contained in this press release was provided by the abstracts authors and reflects the content of the studies. It does not necessarily express ESMO's point of view.

Reference

(1) Abstract LBA3, "KEYNOTE-010: Phase 2/3 Study of Pembrolizumab (MK-3475) vs Docetaxel for PD-L1-Positive NSCLC After Platinum-Based Therapy", R.S. Herbst, D.-W. Kim, E. Felip, J.L. Perez-Gracia, E.B. Garon, J.-Y. Han, J. Molina, J.-H. Kim, R. Gervais, M.-J. Ahn, M. Majem, M.J. Fidler, G. De Castro Jr., M. Garrido, G.M. Lubiniecki, Y. Shentu, E. Im, P. Baas, will be presented during Presidential Symposium on 20 December at 16:30, HALL 406 Abstract will be available online on 19th December 2015, 23:55 hours (SGT) https://cslide.ctimeetingtech.com/library/esmo/browse/itinerary/5225

(2) Published in The Lancet and available on 19th December 2015, 23:55 (SGT): http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)01281-7/abstract

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ABSTRACT LBA 3_PR

KEYNOTE-010: Phase 2/3 Study of Pembrolizumab (MK-3475) vs Docetaxel for PD-L1-Positive NSCLC After Platinum-Based Therapy
R.S. Herbst1, D.-W. Kim2, E. Felip3, J.L. Perez-Gracia4, E.B. Garon5, J.-Y. Han6, J. Molina7, J.-H. Kim8, R. Gervais9, M.-J. Ahn10, M. Majem11, M.J. Fidler12, G. De Castro Jr.13, M. Garrido14, G.M. Lubiniecki15, Y. Shentu16, E. Im15, P. Baas17 1Medical Oncology, Yale University School of Medicine Medical Oncology, New Haven, CT, US, 2Internal Medicine, Seoul National University Hospital, Seoul, KP, 3Department of Oncology, Vall d' Hebron University Hospital, Barcelona, ES, 4Oncology, Clinica Universitaria de Navarra, Pamplona, ES, 5Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, US, 6Center for Lung Cancer, National Cancer Center, Goyang, KR, 7Oncology, Mayo Clinic, Rochester, MN, US, 8Medical Oncology, Cha Bundang Medical Center, Cha University, Seongnam-si, Gyeonggi-do, KP, 9Medicine, Centre Francois Baclesse, Caen, FR, 10Medicine, Samsung Medical Center, Seoul, KP, 11Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, ES, 12Division of Hematology, Oncology, and Cell Therapy, Rush University Medical Center, Chicago, IL, US, 13Oncologia Clínica, ICESP - Instituto do Câncer do Estado de São Paulo, Sao Paulo, BR, 14Medical Oncology, Pontificia Universidad Catolica de Chile-Cancer centre, Santiago, CL, 15Clinical Oncology, Merck & Co., Inc., Kenilworth, NJ, US, 16BARDS, Merck & Co., Inc., Kenilworth, NJ, US, 17Thoracic Oncology, The Netherlands Cancer Institute, Amsterdam, NL

Aim: Pembrolizumab (pembro) has shown efficacy in NSCLC, with improved outcomes in pts with greater tumor PDL1 expression. KEYNOTE-010 (NCT01905657) compared the efficacy and safety of 2 pembro doses with those of docetaxel for PD-L1+ advanced NSCLC that progressed after ?2 platinum-doublet chemotherapy cycles, with an appropriate tyrosine kinase inhibitor also required for pts with EGFR sensitizing mutations or ALK translocations.

Methods: Pts were stratified by ECOG PS (0 vs 1), region (East Asia vs non-East Asia), and PD-L1 expression level (tumor proportion score [TPS] ?50% vs 1%-49%) and randomized 1:1:1 to pembro 2 or 10 mg/kg Q3W or docetaxel 75 mg/m2 Q3W. Treatment was continued up to 24 mo or until progression or intolerable toxicity. Response was assessed every 9 wk. Primary end points were OS and PFS (RECIST v1.1, central review) in the TPS ?50% stratum and total population (ie, TPS ?1%). ORR was a secondary end point. At final analysis, the study had ?80% power to detect a 0.70 HR for OS in the total population (1-sided α = 0.825%).

Results: From Aug 2013 to Apr 2015, 1034 pts from 24 countries were randomized: 345 to pembro 2 mg/kg, 346 to pembro 10 mg/kg, and 343 to docetaxel. Pembro significantly improved OS over docetaxel for TPS ?50% and ?1% (Table). Pembro significantly improved PFS for TPS ?50% and numerically improved PFS for TPS ?1% (Table). ORR was significantly higher with pembro for TPS ?50% (30.2% at 2 mg/kg vs 29.1% at 10 mg/kg vs 7.9% with docetaxel, P < 0.0001 for both doses) and ?1% (18.0% vs 18.5% vs 9.3%, P < 0.0005 for both doses). Pembro was associated with fewer grade 3-5 drug-related AEs (12.7% at 2 mg/kg vs 16.0% at 10 mg/kg vs 35.3% with docetaxel). Drugrelated deaths occurred in 0.9%, 0.9%, and 1.6% of patients.

Conclusions: Pembro 2 and 10 mg/kg Q3W significantly prolonged OS compared with docetaxel and showed a favorable benefit-to-risk profile in PD-L1+ advanced NSCLC after progression on platinum-based therapy.

Clinical trial identification: ClinicalTrials.gov identifier: NCT01905657; EudraCT number 2012-004391-19.

Keyword: docetaxel, immunotherapy, PD-L1, pembrolizumab

Disclosure: R. S. Herbst: advisory board member for Merck. E. Felip: advisory board member for Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Novartis, Pfizer, and Roche. J.L. Perez-Gracia: corporatesponsored research from Merck. E.B. Garon: relationships with AstraZeneca, Bristol-Myers Squibb, Genentech, Merck, Pfizer, and Novartis. R. Gervais: advisory board member for Bristol-Myers Squibb, Clovis, Merck, and Pfizer. M.-J. Ahn: advisory board member for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, and Eli-Lilly. G. De Castro Jr.: corporate-sponsored research from AstraZeneca, Bristol-Myers Squibb, Genentech, Merck Sharp & Dohme, Merck Serono, Pfizer, and Roche. G.M. Lubiniecki, Y. Shentu, E. Im: employee of and holds stock in Merck & Co., Inc. P. Baas: Advisory board member for Adaro, AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, and Pfizer. Corporatesponsored research from Bristol-Myers Squibb and Merck Sha

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