Pembrolizumab: promising response rate in pretreated metastatic gastric cancer

ESMO PRESS RELEASE LUGANO-MADRID, 8 September, 2017 – Pembrolizumab has shown a promising response rate in patients with pretreated metastatic gastric cancer, according to late-breaking results from the KEYNOTE-059 trial presented today at the ESMO 2017 Congress in Madrid. (1)

The expected survival of patients with metastatic gastric cancer is less than one year. Very few new drugs have been approved for this disease in the past decade. The phase II KEYNOTE-059 is one of the largest studies to investigate immunotherapy in recurrent or metastatic gastric cancer.

The study included three cohorts: 1) 259 patients with metastatic gastric cancer who received the programmed death 1 (PD-1) inhibitor pembrolizumab alone, after pretreatment with two or more lines of chemotherapy; 2) 25 patients with newly diagnosed metastatic gastric cancer who received a combination of pembrolizumab and chemotherapy; 3) 31 patients with newly diagnosed metastatic gastric cancer who received pembrolizumab alone.

The primary endpoints were safety (all three cohorts) and objective response rate (cohorts one and three).

After a median follow-up of six months, the investigators found an overall objective response rate of 12% with pembrolizumab alone in the pretreated patients (cohort one). Patients who expressed programmed death-ligand 1 (PD-L1) were more likely to respond than those who did not, with objective response rates of 16% and 6%, respectively. Many of the responses were durable. Grade 3 to 5 treatment-related adverse events occurred in 18% of patients in cohort one and 3% had to discontinue treatment as a result.

Lead author Dr Zev Wainberg, co-director of the Gastrointestinal Oncology Programme, UCLA, Los Angeles, US, said: “The data shows that the tumours were sufficiently shrunk to warrant a response, particularly in those patients who had PD-L1 expression, and the drug was safe. The expected response rate in these heavily pretreated patients was close to zero so the findings are encouraging.”

In patients with newly diagnosed metastatic cancer, both the combination therapy (cohort two) and pembrolizumab alone (cohort three) were safe and showed some promising activity. “These results have set the stage for a larger follow-up study which is already enrolling patients,” said Wainberg.

He concluded: “We hope these results, in combination with evidence from ongoing randomised trials, will support the regulatory approval of pembrolizumab in metastatic gastric cancer.”

Commenting on the results for ESMO, Dr Ian Chau, consultant medical oncologist, Royal Marsden Hospital, London and Surrey, UK, said: “There is currently no standard of care for metastatic gastric cancer treated in the third line or beyond. The KEYNOTE-059 cohort 1 results confirm that the efficacy previously reported for the PD-1 inhibitor nivolumab in patients from East Asia in the ONO-4538 randomised trial can be applied to Western populations.”

“The likelihood is that pembrolizumab will become a standard treatment option in this setting in the near future,” he added.

Chau cautioned that while the toxicity profile of pembrolizumab looked quite favourable in KEYNOTE-059, it could be that patients had not been treated long enough to experience side effects. He said: “Unlike with chemotherapy, toxicities from immunotherapy tend to occur later on. We need to await longer-term results from an ongoing clinical trial in an earlier line of treatment to know the full impact of this drug in metastatic gastric cancer.”

He concluded: “Further research should focus on refining the PD-L1 biomarker and searching for better biomarkers to tell us who benefits from these therapies. We also need more information about quality of life which should be provided by ongoing studies.”

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Notes to Editors

Please make sure to use the official name of the meeting in your reports: ESMO 2017 Congress

References

1 Abstract LBA28_PR ‘KEYNOTE-059 Update: Efficacy and Safety of Pembrolizumab Alone or in Combination With Chemotherapy in Patients With Advanced Gastric or Gastroesophageal (G/GEJ) cancer’ will be presented by Dr Zev Wainberg during Proffered Paper Session ‘Gastrointestinal tumours, non-colorectal’ on Friday, 8 September 2017, 14:00 to 15:30 (CEST) in the Barcelona Auditorium.

 

Disclaimer

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 who 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 the ESMO Code of Conduct .

 

About the European Society for Medical Oncology (ESMO)

ESMO is the leading professional organisation for medical oncology. With 16,000 members representing oncology professionals from over 130 countries worldwide, ESMO is the society of reference for oncology education and information. We are committed to supporting our members to develop and advance in a fast-evolving professional environment.

www.esmo.org

 

Abstract LBA28_PR ‘KEYNOTE-059 Update: Efficacy and Safety of Pembrolizumab Alone or in Combination with Chemotherapy in Patients With Advanced Gastric or Gastroesophageal (G/GEJ) cancer’

Z.A. Wainberg1, S. Jalal2, K. Muro3, H.H. Yoon4, M. Garrido5, T. Golan6, T. Doi7, D.V. Catenacci8, R. Geva9, G. Ku10, J. Bleeker11, Y.-J. Bang12, H. Hara13, H.C. Chung14, M. Savage15, J. Wang15, M. Koshiji15, R. Dalal15, C.S. Fuchs16
1Medicine Hematology and Oncology, David Geffen School of Medicine at UCLA, Los Angeles, USA, 2Internal Medicine, Indiana University School of Medicine, Indianapolis, IN, USA, 3Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan, 4Medical Oncology, Mayo Clinic, Rochester, MN, USA, 5Hemato-Oncology, Pontificia Universidad Catolica de Chile, Santiago, Chile, 6Oncology Division, Sheba Medical Center and Sackler School of Medicine, Tel Aviv, Israel, 7Experimental Therapeutics, National Cancer Center Hospital East, Chiba, Japan, 8Medicine, University of Chicago Medicine, Chicago, IL, USA, 9Oncology Division, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel, 10Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA, 11Medical Oncology, Sanford Health, Sioux Falls, SD, USA, 12Internal Medicine, Seoul National University Hospital, Seoul, Korea, Republic of, 13Medical Oncology, Saitama Cancer Center, Saitama, Japan, 14Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea, Republic of, 15Merck Research Laboratory, Merck & Co., Inc., Kenilworth, NJ, USA, 16Cancer Prevention and Control, Yale Cancer Center, New Haven, CT, USA

Background: Prior results from the global, phase 2 KEYNOTE-059 study (NCT02335411) demonstrated manageable safety and promising antitumor activity for pembro alone and pembro + chemo in pts with G/GEJ cancer.

Methods: Pts with recurrent or metastatic G/GEJ adenocarcinoma were enrolled. Pts were enrolled in cohorts 1 and 2 regardless of tumor PD-L1 expression; only pts with PD-L1-positive tumors (combined positive score of ≥1% using the PD-L1 IHC 22C3 pharmDx assay) were enrolled in cohort 3. Cohort 1 pts received pembro alone after ≥2 prior lines of therapy. Cohort 2 pts received pembro + cisplatin (80 mg/m2 day 1) + 5-fluorouracil (800 mg/m2 days 1-5 Q3W) or capecitabine (in Japan only, 1000 mg/m2 twice daily) as first-line. Cohort 3 pts received pembro alone as first-line. In all cohorts, pembro was given at 200 mg Q3W for up to 2 years. Primary end points were safety (all) and ORR by RECIST v1.1 by central review (cohorts 1 and 3); key secondary end points were ORR (cohort 2) and DOR by RECIST v1.1, PFS, and OS.

Results: At data cutoff (Apr 21, 2017), median (range) follow-up was 6 (1-25), 14 (2-24), and 18 (2-21) months for cohorts 1 (259 pts), 2 (25 pts) and 3 (31 pts), respectively. Confirmed ORR (95% CI) was 12% (8-17) overall, 16% (11-23) in PD-L1-positive, and 6% (3-13) in PD-L1-negative tumors in cohort 1. Confirmed ORR was 60% (39-79) overall, 73% (45-92) in PD-L1-positive, and 38% (9-76) in PD-L1-negative tumors in cohort 2. In cohort 3, confirmed ORR (95% CI) was 26% (12-45). Median PFS (95% CI) was 2 (2-2), 7 (6-11), and 3 (2-6) months in cohorts 1, 2, and 3, respectively. Median OS (95% CI) in months was 6 (4-7), 14 (9-not estimable), and not reached (9-21) in cohorts 1, 2, and 3, respectively. In cohorts 1, 2 and 3, grade 3-5 treatment-related adverse event (TRAE) incidence was 46 (18%), 19 (76%), and 7 (23%), respectively. In cohort 1, TRAEs led to discontinuation in 7 pts (3%) and death in 2 pts (1%); in cohort 2, TRAEs led to discontinuation in 3 pts (12%); in cohort 3, TRAEs led to death in 1 pt (3%).

Conclusions: These updated results show manageable safety and promising antitumor activity for pembro alone and pembro + chemo in pts with advanced G/GEJ cancer.

Clinical trial identification: NCT02335411

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

Funding: Merck & Co, Inc., Kenilworth, NJ, USA

Disclosure:

Z.A. Wainberg: Consultant for Genetech, Array, Sirtex, Novartis, and Five Prime Therapeutics
S. Jalal: Research funding: AstraZeneca
K. Muro: Research funding: Shionogi & Co, MSD K.K., Daiichi Sankyo, Kyowa Hakko Kirin,. Gilead Sciences Honoraria: Chugai Pharmaceutical, Takeda Pharmaceutical, Eli Lilly Japan K.K., Merck Serono, Taiho, Yakult Honsha
T. Doi: Advisory board: Lilly, Chugai Pharma, Kyowa Hakko, Kirin, Novartis, MSD, Daiichi Sankyo, Amgen Research funding: Taiho, Novartis, Merck Serono, Astellas, MSD, Janssen Pharma, Behringer Ingelheim, Takeda, Pfizer, Lilly, Sumitomo Group, Chugai Pharma, Bayer, Kyowa Hakko, Kirin, Daiichi Sankyo, Celegene
D.V. Catenacci: Advisory board: Merck, BMS, Lilly, Genentech Honoraria: Merck, BMS, Lilly, Genentech Travel expenses, including accommodations: Merck, BMS, Lilly, Genentech
R. Geva: Advisory board: Bayer, MSD, Novartis Honoraria: BMS, Lilly, Medison, Roche, Novartis, Janssen Travel expenses: Roche, BMS
G. Ku: Advisory board member: Merck Research funding: Merck (to institution) Travel expenses: Merck
J. Bleeker: Travel expenses: Merck & Co., Inc. Consultant fee: BMS
Y.-J. Bang: Advisory board: AstraZeneca, Novartis, Roche, Genentech, MSD, Pfizer, Bayer, BMS, Eli Lilly, Merck Serano, FivePrime, Merrimack, Taiho, Ono, ADC Therapeutics, GreenCross, Samyang Biopharm Research funding: AstraZeneca, Novartis, Genentech/Roche, MSD, Merck Serano, Bayer, GSK, BMS, Pfizer, Eli Lilly, Boeringer-Ingelheim, MacroGenics, , Boston Biomedical, FivePrime, CKD, Ono, Otsuka, Taiho, Takeda, BeiGene, Hanmi, Green Cross, Curis
H. Hara: Research funding to institution: AstraZenaca, Chugai Pharma, Merck Serono, MSD, Ono Pharmaceutical, Taiho Pharmaceutical, Takeda, Boehringer Ingelheim, Dainippon Sumitomo Pharma, Daiichi Sankyo, Lilly Honoraria: Chugai Pharma, Taiho Pharmaceuticals, Merck Serono, Yakult Honsha, Lilly
M. Savage, J. Wang, M. Koshiji, R. Dalal: Employment: Merck & Co., Inc.
C.S. Fuchs: Advisory board: Eli Lilly, Entrinsic Health, Genentech, Merck, Gilead, Sanofi, Dicerna, Five Prime Therapeutics, Merrimack, Bayer, Agios, Taiho
All other authors have declared no conflicts of interest.

Keywords: pembrolizumab, gastric cancer, PD-L1, immunotherapy

 

New data confirms superiority of docetaxel based triplet therapy in gastric cancer

ESMO PRESS RELEASE LUGANO-MADRID, 8 September, 2017 – The superiority of docetaxel based triplet therapy over standard care in patients with resectable oesophago-gastric cancer has been confirmed in late-breaking results from the FLOT4 trial presented at the ESMO 2017 Congress in Madrid. (1)

Survival in resectable oesophago-gastric cancer is poor. Five-year overall survival is around 25% with surgery, and is increased to 36% by adding a perioperative regimen of epirubicin, cisplatin, and infused fluorouracil (ECF). (2) Phase II studies have shown encouraging pathological response rates with perioperative docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT).

The phase III FLOT4 trial randomised 716 patients with resectable gastric or gastroesophageal junction adenocarcinoma to perioperative FLOT or ECF. As previously reported, FLOT was superior to ECF for all efficacy endpoints including curative resection rates, progression-free survival and overall survival.

Today researchers reveal the results of multivariate, subgroup and sensitivity analyses for the first time. The relative effect of FLOT was observed in all subgroups, including the elderly and signet cell tumours, and was particularly pronounced in Siewert type 1 oesophageal tumours (hazard ratio [HR], 0.60), Barrett tumours (HR, 0.62), small tumours (HR, 0.66) and nodal negative tumours (HR, 0.64).

Lead author Professor Salah-Eddin Al-Batran, director, Institute of Clinical Cancer Research, UCT-University Cancer Centre, Krankenhaus Nordwest, Frankfurt, Germany, said: “These new analyses confirm the superiority of FLOT, which is the new standard of care in the perioperative treatment of patients with resectable gastric or gastroesophageal junction adenocarcinoma.”

He concluded: “Some oncologists believe that patients with small tumours and those with signet cell cancer should not be treated preoperatively. The results of the FLOT4 trial contradict this and show that these patients do benefit.”

Commenting for ESMO, Professor Michel Ducreux, head, Gastrointestinal Oncology Unit, Gustave Roussy, Villejuif, France, said: “The triplet regimen used in the FLOT4 trial was developed to improve the results of ECF. It decreased toxicity by replacing epirubicin with low-dose docetaxel, and using oxaliplatin instead of cisplatin. FLOT is also more convenient to use, with one 24-hour infusion every two weeks rather than continuous infusion of fluorouracil in the ECF protocol.”

“The results show that FLOT is clearly the new standard of care,” continued Ducreux. “The new analysis presented at the ESMO 2017 Congress shows that the advantage of the FLOT regimen was seen across all subgroups, including those with a very poor prognosis such as the elderly and patients with signet cell tumours.”

He concluded: “FLOT will be the best backbone of chemotherapy that we can use in this setting. A step forward would be to try to improve the results by adding targeted therapies or immune checkpoint inhibitors. It would also be interesting to know if the FLOT regimen shows different levels of effectiveness in the four molecular biological subgroups of gastric cancer.”

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Notes to Editors

Please make sure to use the official name of the meeting in your reports: ESMO 2017 Congress

References

1 Abstract LBA27_PR ‘Docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) for resectable esophagogastric cancer: updated results from multicenter, randomized phase 3 FLOT4-AIO trial (German Gastric Group at AIO)‘ will be presented by Professor Salah-Eddin Al-Batran during Proffered Paper Session ‘Gastrointestinal tumours, non-colorectal’ on Friday, 8 September 2017, 14:00 to 15:30 (CEST) in the Barcelona Auditorium.

2 Cunningham D, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355:11–20.

 

Disclaimer

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 who 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 the ESMO Code of Conduct .

 

About the European Society for Medical Oncology (ESMO)

ESMO is the leading professional organisation for medical oncology. With 16,000 members representing oncology professionals from over 130 countries worldwide, ESMO is the society of reference for oncology education and information. We are committed to supporting our members to develop and advance in a fast-evolving professional environment.

www.esmo.org

 

Abstract LBA27_PR ‘Docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) for resectable esophagogastric cancer: updated results from multicenter, randomized phase 3 FLOT4-AIO trial (German Gastric Group at AIO)’

S-E. Al-Batran1, C. Pauligk1, N. Homann2, H. Schmalenberg3, H.-G. Kopp4, G.M. Haag5, K. Luley6, G. Folprecht7, S. Probst8, P. Thuss-Patience9, J. Trojan10, M. Koenigsmann11, U. Lindig12, M. Pohl13, S. Kasper14, M. Möhler15, T. Goetze1, M. Schuler16, E. Jaeger17, R.D. Hofheinz18 
1Institute of Clinical Cancer Research (IKF), UCT-University Cancer Center, Krankenhaus Nordwest, Frankfurt, Germany, 2Department of Internal Medicine II, Klinikum Wolfsburg, Wolfsburg, Germany, 3IV. Medizinische Klinik, Städtisches Krankenhaus Dresden, Dresden, Germany, 4Medical Center II, Universitätsklinikum Tübingen Medizinische Universitätsklinik, Tübingen, Germany, 5Department of Medical Oncology, Nationales Zentrum für Tumorerkrankungen (NCT), Heidelberg, Germany, 6Med. Klinik I, University SH.-Lübeck, Lübeck, Germany, 7University Cancer Center, Medical Dept. I  , University Hospital Carl Gustav Carus, Dresden  , Dresden, Germany, 8Klinik für Hämatologie und Onkologie, Klinikum Bielefeld, Bielefeld, Germany, 9Department of Hematology, Oncology, and Tumor Immunology, Charité University Medicine Berlin, Campus Virchow-Klinikum, Berlin, Germany, 10Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany, 11MediProjekt, Onkologisches Ambulanzzentrum OAZ, Hannover, Germany, 12Klinik für Innere Medizin II, University Hospital Jena, Friedrich-Schiller-University, Jena, Germany, 13Medical Clinic, Ruhr University Bochum Medizinische Universitätsklinik, Bochum, Germany, 14Westdeutsches Tumorzentrum, University Hospital Essen, Essen, Germany, 15I. Med. Klinik und Poliklinik, Johannes Gutenberg University, Mainz, Germany, 16Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany, 17Department of Medical Oncology, Krankenhaus Nordwest, Frankfurt, Germany, 18III. Medizinische Klinik, Universitätsklinikum Mannheim, Mannheim, Germany

Background: FLOT4 is the first study to show improvement of outcome over another well-established bimodality therapy in patients with esophagogastric cancer. To consolidate initial results, we performed multivariate, subgroup and sensitivity analyses.

Methods: In the FLOT4, pts with resectable gastric or GEJ adenocarcinoma of stage ≥cT2 and/or cN+ (n=716) were randomized to either 3 pre-operative and 3 post-operative 3-week cycles of ECF/ECX (epirubicin 50 mg/m2 i.v., cisplatin 60 mg/m² i.v., both on day 1, and 5-FU 200 mg/m² as continuous i.v. infusion or capecitabine 1250 mg/m2 orally on days 1 to 21) or 4 pre-operative and 4 post-operative 2-week cycles of FLOT (docetaxel 50 mg/m2 i.v., oxaliplatin 85 mg/m² i.v., leucovorin 200 mg/m² i.v., and 5-FU 2600 mg/m² as 24-hour i.v, infusion, all on day 1). The primary endpoint was overall survival.

Results: Compared to ECF, FLOT was associated with less progressive disease cases during/after preoperative therapy (1% vs. 5%; p<0.001), more R0-resections (84% vs. 77%; p=0.011), higher number of pT0/pT1 tumors (25% vs. 15%; p=0.001), longer progression-free (30 vs. 18 months; HR 0.75; p=0.001) and overall survival (50 vs. 35 months; HR0.77; p=0.012). The relative effect from FLOT was observed in all subgroups, including elderly and signet cell tumors, and was numerically pronounced in Siewert type 1 esophageal tumors (HR 0.60), Barrett tumors (HR 0.62), small tumors T1/2 (HR 0.66) or nodal negative tumors (HR 0.64). In multivariate analyses, parameters associated with favorable survival were FLOT therapy (HR 0.75, p=0.006); stomach as the primary (HR 0.74; p=0.005), and nodal negativity (HR 0.72, p=0.022). ECOG PS of 0 showed a trend (HR 0.82; p=0.078). Age and Lauren’s type of histology had no impact on survival. Post-hoc analyses of relapse-free survival (PFS excluding pts without R0-resection) still favored FLOT (HR 0.8; p=0.049). 87% of relapses were systemic or both systemic and locoregional. The most frequent sites of relapse were peritoneal (31%) followed by lymphatic (26%), and liver (19%). Further Analysis will be presented at the meeting.

Conclusions: Updated analysis confirmed the superiority of FLOT. Pts derived benefit from FLOT even if they were old (>=70), had small tumors, a nodal negative status, or a signet cell component. The presence of one of these factors should no longer be a reason for not considering perioperative therapy in daily practice.

Clinical trial identification: FLOT4: NCT01216644

Legal entity responsible for the study: Krankenhaus Nordwest GmbH

Funding: Deutsche Krebshilfe, Sanofi

Disclosure:

S-E. Al-Batran: Advisory role: Merck, Roche, Celgene, Lilly, Nordic Pharma Speaker: Roche, Celgene, Lilly , Nordic Pharma Research grants: Merck, Roche, Celgene, Vifor, Medac, Hospira, Lilly 
N. Homann: Consulting or Advisory Role: Sanofi, Roche, Amgen, Cellgene, Lilly 
H. Schmalenberg: Consulting or Advisory Role: Lilly, Baxalter; Research Funding: Sanofi; Travel, Accomodations, expenses: Merck 
G.M. Haag: Consulting or Advisory Role: Sanofi, Roche, Taiho, Lilly, Pfizer, Nordic; Research Funding: Taiho, Nordic; Travel, Accomodations, expenses: Amgen, Ipsen, Celgene 
K. Luley: Travel, accomodations, expenses: Ipsen, Novartis, Sanofi
P. Thuss-Patience: Consulting or Advisory Role: Roche, Lilly, BMS, MSD, Nordic, Pfizer; Research Funding: Novartis; Travel, Accomodations, expenses: Roche, Merck, Teva 
M. Koenigsmann: Honoraria: Novartis, Celgene; Consulting or Advisory Role: Novartis, Celgene; Travel, Accomodations, expenses: Novartis 
M. Pohl: Research Funding: Amgen, Baxalta, Celgene, Lilly 
T. Goetze: Honoraria: MSD, Celgene Advisory board: BMS, Baxalta- Shire 
M. Schuler: Honoraria: AstraZeneca, Alexion, Boehringer Ingelheim, Celgene, Lilly, MSD, Novartis, Roche; Consulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Celgene, Lilly, Novartis, Roche; Research Funding: Boehringer Ingelheim, BMS, Novartis 
All other authors have declared no conflicts of interest.

Keywords: FLOT, neoadjuvant chemotherapy, gastric cancer, perioperative chemotherapy