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імені академіка О.Ф.Возіанова"

PRESS RELEASE

EMBARGOED until 8 October 2016, 8:15 hours (CEST)

Immunotherapy shows promising results in first and second line treatment of metastatic bladder cancer

LUGANO-COPENHAGEN, 8 October, 2016 – Immunotherapy has shown promising results in first and second line treatment of metastatic bladder cancer in two phase II trials presented at the ESMO 2016 Congress in Copenhagen.

Up to half of patients with metastatic bladder cancer are not eligible for survival prolonging first line treatment with cisplatin-based chemotherapy. Survival in these patients is just nine to ten months with currently available alternative chemotherapy.

The phase II KEYNOTE-052 trial¹ evaluated the efficacy and safety of PD-1 blockade with pembrolizumab as first line therapy in cisplatin ineligible patients with metastatic or locally advanced bladder cancer. Today researchers presented the preliminary analysis of the first 100 patients enrolled in the trial. The primary endpoint of objective response rate was 24%. The biomarker cut point to identify patients who are most likely to respond to the drug was determined to be 10% or greater total PD-L1 expression in immune cells or tumour cells. Thirty patients had this level of expression of whom 11 (37%) responded to treatment. The median duration of response has not yet been reached and treatment was well tolerated.

Lead author Dr Arjun Balar, Assistant Professor, NYU Langone Medical Centre, New York, US, said: “Pembrolizumab has substantial activity with a favourable safety profile as first line therapy in cisplatin ineligible patients with metastatic bladder cancer. The biomarker cut point will need to be validated in the larger study population, but seems to identify patients most likely to respond to pembrolizumab well. Immunotherapy is rapidly redefining our treatment approach for patients facing this dreadful disease.”

For several decades, there had been no global standard of care for second line treatment of patients with metastatic bladder cancer who progress despite platinum-based chemotherapy until the recent development of immune checkpoint blockade. In another study presented today, the phase II CheckMate 275 trial² assessed the activity and safety of the PD-1 inhibitor nivolumab in 270 patients with metastatic bladder cancer who have progressed despite first line platinum-based chemotherapy. CheckMate 275 is the largest study of a PD-1 inhibitor in bladder cancer reported to date.

In the 265 patients who could be evaluated for efficacy, the primary endpoint of objective response rate was 19.6%. The median duration of response has not yet been reached, with a median follow-up of seven months. In both patients with tumours expressing higher and lower levels of PD-L1 (including those with less than 1% PD-L1), the objective response rate was above that achieved historically with chemotherapy.

“This data is being submitted to support registration of nivolumab for patients with metastatic urothelial cancer that has progressed despite platinum-based chemotherapy, an indication for which the US Food and Drug Administration has granted breakthrough therapy designation to nivolumab,” said lead author Professor Matthew Galsky, Professor of Medicine, Mount Sinai School of Medicine, New York, US. “Immune checkpoint blockade has become the most promising approach for these patients.”

Commenting on the current management of bladder cancer, Dr Maria De Santis, Associate Clinical Professor for Oncology, Cancer Research Centre, University of Warwick, UK, said: “There are insufficient treatment options for patients ineligible for cisplatin and for those progressing on cisplatin-based chemotherapy.”

She continued: “This year the first immune check point inhibitor, atezolizumab, was approved for patients with bladder cancer and CheckMate 275 provides similar results with nivolumab in the second line setting.”

“KEYNOTE-052 confirms that immunotherapy is also active as first line therapy in cisplatin ineligible patients, with a slightly lower response rate than chemotherapy,” said De Santis. “However, the duration of response with pembrolizumab seems to exceed that of chemotherapy in historical controls. The protocol included a new biomarker definition and cut-off which needs further evaluation.”

She concluded: “Immune check point inhibitors have started to alter the therapeutic landscape for bladder cancer. We expect even more dramatic changes in the coming years with the use of immunotherapy in other clinical stages and as combination therapy.”

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Notes to Editors

References

¹Abstract LBA32_PR - ‘Pembrolizumab (pembro) as first-line therapy for advanced/unresectable or metastatic urothelial cancer: Preliminary results from the phase 2 KEYNOTE-052 study, ‘will be presented by Dr Arjun Balar during the Proffered Paper Session Genitourinary tumours, non-prostate: on Saturday, 8 October, 9:15 to 10:30 (CEST).

² Abstract LBA31_PR - ‘Efficacy and safety of nivolumab monotherapy in patients with metastatic urothelial cancer (mUC) who have received prior treatment: Results from the phase II CheckMate 275 study, ‘will be presented by Professor Matthew Galsky during the Proffered Paper Session Genitourinary tumours, non-prostate: on Saturday, 8 October, 09:15 to 10:30 (CEST).

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This press release contains information provided by the authors of the highlighted abstracts and reflects the content of those abstracts. It does not necessarily reflect the views or opinions of ESMO and ESMO cannot be held responsible for the accuracy of the data. Commentators quoted in the press release are required to comply with the ESMO Declaration of Interests policy and theESMO Code of Conduct .

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Abstract for LBA31_PR

Efficacy and safety of nivolumab monotherapy in patients with metastatic urothelial cancer (mUC) who have received prior treatment: Results from the phase II CheckMate 275 study

M.D. Galsky1, M. Retz2, A.O. Siefker-Radtke3, A. Baron4, A. Necchi5, J. Bedke6, E.R. Plimack7, D. Vaena8, M-O. Grimm9, S. Bracarda10, J. Arranz Arija11, S.K. Pal12, C. Ohyama13, A. Saci14, A. Lambert15, S. Krishnan15, A. Azrilevich14, P. Sharma16
1Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA, 2Department of Urology, Klinikum Rechts der Isar, Munich, Germany, 3Genitourinary Medical Oncolgoy, The M. D. Anderson Cancer Center, Houston, TX, USA, 4Division of Hematology and Oncology, California Pacific Medical Center, San Francisco, CA, USA, 5Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, 6Dept of Urology, Universitätsklinikum Tübingen, Tübingen, Germany, 7Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA, 8Division of Hematology, Oncology, and BMT, University of Iowa, Iowa City, IA, USA, 9Department of Urology, University Hospital of Jena, Jena, Germany, 10Department of Oncology, Ospedale San Donato and U.O.C. of Medical Oncology, Arezzo, Italy, 11Servicio de Oncologia Medica, Hospital General Universitario Gregorio Marañon, Madrid, Spain, 12Medical Oncology and Experimental Therapuetics, City of Hope, Duarte, CA, USA, 13Department of Urology, Hirosaki University, Hirosaki, Japan, 14Research and Development, Bristol-Myers Squibb, Princeton, NJ, USA, 15Biostatistics, Bristol-Myers Squibb, Princeton, NJ, USA, 16Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

Background: Chemotherapy for platinum-resistant advanced mUC yields poor objective response rates (ORR) and overall survival (OS). Nivolumab (NIVO) recently showed promising efficacy and safety in the CheckMate 032 phase I/II study (NCT01928394) in this setting. The current larger study, CheckMate 275 (NCT02387996), investigated efficacy and safety of NIVO in patients (pts) with mUC or surgically unresectable locally advanced UC that progressed after platinum-based chemotherapy.

Methods: In this open-label, single-arm, phase II study, pts received NIVO 3 mg/kg IV every 2 weeks until progression or unacceptable toxicity. The primary endpoint was ORR confirmed by blinded independent review committee (RECIST 1.1). Outcomes were evaluated in all treated pts and by tumor programmed death-1 ligand 1 (PD-L1) expression (≥1% and ≥5%; Dako PD-L1 PharmDx). Biomarkers were analyzed for association between response, UC subtype (by The Cancer Genome Atlas), and immune gene signature expression.

Results: At 7 mo of median follow-up, 24.4% of pts remain on therapy. Confirmed ORR was 19.6% (95% CI 15.0–24.9), and 16.1% (95% CI 10.5–23.1) in pts with low to no PD-L1 expression (Table). Median duration of response was not reached, with responses ongoing in 76.9% of responders. Median progression-free survival was 2.00 mo (95% CI 1.87–2.63); median OS was 8.74 mo (95% CI 6.05–not estimable). Grade 3–4 treatment-related adverse events occurred in 18% of pts (grade 5, 1%), mainly fatigue and diarrhea (2% each). Basal 1 UC subtype had the highest proportion of responders and strongest interferon gamma (IFNγ) gene signature expression. Quality of life was stable over time.

Conclusions: In this large study in advanced/unresectable UC, NIVO had clinically meaningful efficacy and a manageable safety profile. Efficacy benefit of NIVO was seen across all PD-L1 subgroups.

Clinical trial identification: NCT02387996

Legal entity responsible for the study: Matthew D. Galsky

Funding: Funding for this study was provided by Bristol-Myers Squibb

Keywords: objective response rate, overall survival (OS), urothelial cancer, nivolumab

Abstract for LBA32_PR

Pembrolizumab (pembro) as first-line therapy for advanced/unresectable or metastatic urothelial cancer: Preliminary results from the phase 2 KEYNOTE-052 study

A. Balar1, J. Bellmunt2, P.H. O'Donnell3, D. Castellano4, P. Grivas5, J. Vuky6, T. Powles7, E.R. Plimack8, N.M. Hahn9, R. de Wit10, L. Pang11, M.J. Savage12, R. Perini13, S. Keefe14, D. Bajorin15
1Medical Oncology, Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY, USA, 2Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA, 3Dept. of Medicine, The University of Chicago Medical Centre, Chicago, IL, USA, 4Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain, 5Hematology/Oncology, Cleveland Clinic, Cleveland, OH, USA, 6Hematology and Oncology, Oregon Health Sciences University, Portland, OR, USA, 7Genitourinary Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK, 8Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA, 9Oncology and Urology, Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA, 10Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands, 11BARDS Late Development Statistics, Merck & Co., Inc., Kenilworth, NJ, USA, 12Companion Diagnostics, Merck & Co., Inc., Kenilworth, NJ, USA, 13Medical Oncology, Merck & Co., Inc., Kenilworth, NJ, USA, 14Clinical Research & Development, Merck & Co., Inc., Kenilworth, NJ, USA, 15Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

Background: KEYNOTE-052 (NCT02335424), an open-label, multicenter, phase 2 study, evaluated the efficacy and safety of pembro in first-line cisplatin-ineligible pts with u/m UC.

Methods: 374 pts have been enrolled. Eligibility included pathologically confirmed and measurable u/m UC, age ≥18 y, no chemotherapy for u/m disease, ECOG PS 0-2, and cisplatin ineligibility (ECOG PS 2, creatinine clearance <60 mL/min, ≥ grade 2 neuropathy or hearing loss, NYHA class III CHF). Pts received pembro 200 mg Q3W until progressive disease, unacceptable toxicity, or 24 mo of treatment. Primary end point was RECIST v1.1 confirmed objective response rate (ORR) by independent review in all pts and in PD-L1–positive pts by combined positive score (CPS) (tumor and immune cell PD-L1 expression). Secondary objective was to determine the CPS-high biomarker cutpoint. Interim analysis was planned to evaluate ORR for the first 100 pts and to determine the CPS-high cutpoint.

Results: Median age was 75 years (13% ≥85). 13% received perioperative chemotherapy. 87% had visceral disease. 46% were ECOG 2/3. 45% were cisplatin ineligible because of renal insufficiency only. 11% were cisplatin ineligible because of ECOG 2 performance status and renal insufficiency. The CPS-high cutpoint was determined to be ≥10% PD-L1 expression. As of 6/1/16, data cutoff (median 8 mo follow-up), ORR was as follows:

Median duration of response (DOR) has not been reached (range, 1.4+ - 9.8+ mo). DOR rate ≥6 months was 83% (Kaplan-Meier estimate). 67% of pts experienced a drug-related adverse event (DRAE), most commonly fatigue (14%). 16% experienced a grade 3/4 DRAE. 5% discontinued therapy because of a DRAE.

Conclusions: Pembro 200 mg Q3W demonstrates substantial antitumor activity and has a manageable toxicity profile in cisplatin-ineligible pts with u/m UC. CPS high cutpoint was determined to be ≥10% PD-L1 expression. CR rate of 6% for all pts and 13.3% for pts CPS ≥10% is encouraging.

Clinical trial identification: NCT02335424

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

Funding: Merck & Co., Inc.

Keywords: pembrolizumab, urothelial cancer, PD-1, cisplatin-ineligible