Public Release: 

Immuno & targeted therapy provide new options for difficult-to-treat head&neck cancer

Phase I trial reports that pembrolizumab is active in nasopharyngeal cancer. Afatinib is effective as second-line treatment in squamous cell carcinoma of the head and neck in a Phase II study

European Society for Medical Oncology

Singapore/Lugano - Novel strategies are on the way for difficult-to-treat and advanced head and neck cancer, the most heterogeneous group of malignancies which are generally associated with poor survival, and encouraging results have been presented at the first ESMO Asia 2015 Congress in Singapore.

In a Phase I trial (1), the immunotherapy agent pembrolizumab has shown promising antineoplastic activity in patients with heavily pretreated nasopharyngeal cancer, who currently have no effective treatment options. In a large Phase II trial, the targeted agent afatinib was effective in the second-line treatment of recurrent or metastatic squamous cell carcinoma (HNSCC) after failure with platinum-based therapy.

Incidence of some types of head and neck cancer varies substantially between Asia and Europe, to some extent limiting novel options for patients. ESMO spokesperson Dr. Lisa Licitra, chief of the Head and Neck Cancer Medical Oncology Department and head and neck research programme at the Istituto Nazionale Tumori in Milan, Italy, explains this epidemiological difference. "It clearly points out that risk factors for disease development may vary across countries thus potentially affecting the disease biology. To date these biological differences have not been studied and in this sense research may be affected in terms of generalisability of results," she said.

Nasopharyngeal cancer (NPC) is endemic in Asia, with a high incidence in some areas of the continent (26.9 per 100,000 in Southern China), where it is mostly associated with Epstein-Barr virus (EBV) infection. While this type of cancer is rare in Europe and US, in Asian countries it represents a major health issue. KEYNOTE-028 is a non-randomised, multicohort, Phase Ib trial which assessed the safety, tolerability and preliminary efficacy of pembrolizumab in patients with PD-L1 positive advanced solid tumours, including 27 patients with nasopharyngeal cancer. "This study provides the first demonstration of clinical activity of a PD-1 inhibitor in 27 patients with recurrent/metastatic NPC, with an objective response rate of 22.2%," says study author Professor Chiun Hsu, Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan. "We observed a median duration of response of 10.8 months. Pembrolizumab showed a manageable safety profile". Patients were heavily pretreated, including 7 patients who had received at least 5 prior lines of systemic treatment.

"Immunotherapy is a very promising strategy for head and neck cancer and we are awaiting the results of pivotal studies in second-line treatment for recurrent and metastatic patients," Licitra said. "To date we only have promising response rate and PFS data from non-comparative studies. For nasopharyngeal cancer a Phase III study is still to be developed. The development of these drugs in second line might obscure the real impact of these drugs in the disease as patients at advanced stage are highly immunocompromised irrespective of the previous treatment they have received."

Although squamous cell carcinoma of the head and neck is the most common type of cancer in this group, currently it also has a very poor prognosis with no well-defined standard of care after the failure of previous platinum-based therapy. The ErbB family of receptors (including EGFR, HER2, HER3 and HER4) plays an important role in tumourigenesis, and EGFR overexpression (occurring in ~90% of HNSCC cases) is associated with poor prognosis in HNSCC.

The first results from the randomised, open-label, Phase III LUX-Head & Neck 1 trial (2) were presented earlier this year and showed that afatinib, an oral irreversible ErbB family blocker, significantly delayed tumour growth versus chemotherapy in patients following failure of their previous treatment, reducing the risk for disease progression by 20%.

Commenting on the efficacy outcomes in selected pre-specified subgroups and biomarker-defined populations, first author Dr. Makoto Tahara, Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan, says: "The PFS benefit observed with afatinib over methotrexate was generally consistent across most pre-specified patient subgroups analysed, including subgroups based on geographical region (Asia, Europe, or North/Latin America). The ErbB family blocker showed benefit over methotrexate regardless of patient age (?65 or <65 years). More pronounced benefit was observed in patients who have not received prior EGFR-targeted therapy, and those with tumours harbouring certain molecular biomarkers."

The proportion of patients achieving clinical benefit with afatinib over methotrexate was four times greater in patients who did not receive prior EGFR-targeted therapy for recurrent or metastatic disease (37% reduction in risk of progression/death observed) compared with patients who did receive prior therapy (9% reduction in risk observed). Afatinib showed more pronounced antitumour effects in patients with p16-negative disease and dysregulation of ErbB pathway-related biomarkers (EGFR-amplification, HER3-low, PTEN-high expression).

"These data provide important new insights into the efficacy outcomes in selected patient subgroups and may help to identify those who may achieve the most benefit from the targeted therapy," Tahara said. "Three additional Phase III trials are ongoing, LUX-Head & Neck 3, LUX-Head & Neck 2 (global) and LUX-Head & Neck 4 (Asia), to further investigate the potential benefits of afatinib in patients with recurrent HNSCC progressing on/after platinum-based therapy and primary unresected locoregionally advanced HNSCC."

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Notes to Editors Disclaimer

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 315O_PR, "Antitumor activity and safety of pembrolizumab in patients with PD-L1-positive nasopharyngeal carcinoma: Interim results from a phase 1b study", C. Hsu1, S.-H. Lee2, S. Ejadi3, C. Even4, R. Cohen5, C. Le Tourneau6, J. Mehnert7, A. Algazi8, E. van Brummelen9, S. Saraf10, P. Thanigaimani10, J. Cheng10, A. Hansen11 1Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan, 2Internal Medicine, Seoul National University Hospital, Seoul, Korea, 3Clinical Trials, Virginia G. Piper Cancer Center at Scottsdale Healthcare, Scottsdale, AZ, USA, 4Head and Neck Department, Institut Gustave Roussy, Villejuif, France, 5Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA, 6Dept of Medical Oncology, Institut Curie, Paris, France, 7Medical Oncology, The Cancer Institute of New Jersey, New Brunswick, NJ, USA, 8Medicine (Hematology/Oncology), University of California San Francisco, San Francisco, CA, USA, 9Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, Netherlands, 10,, Merck & Co., Inc., Kenilworth, NJ, USA, 11Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada, will be presented during the Proffered Paper Session on 18 December at 14:30 SGT, Hall 332

(2) Abstract 314O_PR, "Second-line afatinib vs methotrexate (MTX) in patients (pts) with recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC): Subgroup/biomarker analysis of LUX-head and neck 1 (LUX-H&N1)", M. Tahara1, E.E.W. Cohen2, R.I. Haddad3, J. Fayette4, L.F. Licitra5, P.M. Clement6, J.B. Vermorken7, T. Gauler8, D. Cupissol9, J.J. Grau10, J. Guigay11, J.M. del Campo12, K. Okami13, S. Takahashi14, B. Burtness15, X.J. Cong16, N. Gibson17, F. Solca18, E. Ehrnrooth19, J.-P.H. Machiels20

1Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan, 2Department of Medicine, University of California San Diego Moores Cancer Center, La Jolla, CA, USA, 3Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School and, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA, 4Léon Bérard Center and Hospices Civils de Lyon, University of Lyon, Lyon, France, 5Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy, 6Department of Oncology, KU Leuven, Leuven, Belgium, 7Department of Medical Oncology, Antwerp University Hospital, Edegem, Belgium, 8West German Cancer Center, University Hospital Essen, Essen, Germany, 9Medical Oncology, Institut du Cancer de Montpellier Val d'Aurelle, Montpellier, France, 10Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain, 11Gustave Roussy, Villejuif and Centre Antoine Lacassagne, Nice, France, 12Medical Oncology Department, Hospital Universitario Vall D'Hebron, Barcelona, Spain, 13Department of Otolaryngology, Tokai University Hospital, Kanagawa, Japan, 14Department of Medical Oncology, Japanese Foundation for Cancer Research, Tokyo, Japan, 15Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA, 16Statistics, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA, 17Drug Metabolism & Pharmacokinetics, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany, 18Pharmacology and Translational Research, Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria, 19TA Oncology, Boehringer Ingelheim, Danmark A/s, Denmark, 20Institut Roi Albert II, Service d'Oncologie Médicale, Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale (Pole MIRO), Université Catholique de Louvain, Brussels, Belgium, will be presented during the Proffered Paper Session on 18 December at 14:30 SGT, Hall 332

Abstracts will be available online on 17th December 2015, 23:55 hours (SGT) https://cslide.ctimeetingtech.com/library/esmo/browse/itinerary/5225

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ABSTRACTS 314O_PR

Second-line afatinib vs methotrexate (MTX) in patients (pts) with recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC): Subgroup/biomarker analysis of LUX-head and neck 1 (LUX-H&N1)

M. Tahara1, E.E.W. Cohen2, R.I. Haddad3, J. Fayette4, L.F. Licitra5, P.M. Clement6, J.B. Vermorken7, T. Gauler8, D. Cupissol9, J.J. Grau10, J. Guigay11, J.M. del Campo12, K. Okami13, S. Takahashi14, B. Burtness15, X.J. Cong16, N. Gibson17, F. Solca18, E. Ehrnrooth19, J.-P.H. Machiels20

1Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan, 2Department of Medicine, University of California San Diego Moores Cancer Center, La Jolla, CA, USA, 3Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School and, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA, 4Léon Bérard Center and Hospices Civils de Lyon, University of Lyon, Lyon, France, 5Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy, 6Department of Oncology, KU Leuven, Leuven, Belgium, 7Department of Medical Oncology, Antwerp University Hospital, Edegem, Belgium, 8West German Cancer Center, University Hospital Essen, Essen, Germany, 9Medical Oncology, Institut du Cancer de Montpellier Val d'Aurelle, Montpellier, France, 10Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain, 11Gustave Roussy, Villejuif and Centre Antoine Lacassagne, Nice, France, 12Medical Oncology Department, Hospital Universitario Vall D'Hebron, Barcelona, Spain, 13Department of Otolaryngology, Tokai University Hospital, Kanagawa, Japan, 14Department of Medical Oncology, Japanese Foundation for Cancer Research, Tokyo, Japan, 15Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA, 16Statistics, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA, 17Drug Metabolism & Pharmacokinetics, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany, 18Pharmacology and Translational Research, Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria, 19TA Oncology, Boehringer Ingelheim, Danmark A/s, Denmark, 20Institut Roi Albert II, Service d'Oncologie Médicale, Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale (Pole MIRO), Université Catholique de Louvain, Brussels, Belgium

Aim/Background: In the Phase III LUX-H&N1 trial, afatinib, an irreversible ErbB family blocker, significantly improved progression-free survival (PFS) vs MTX (median 2.6 vs 1.7 mos; HR 0.80; p=0.03) in pts with second-line R/M HNSCC (Machiels, Lancet Oncol 2015). Here we report PFS and response rates (RR) in the pre-defined subgroups and biomarker-defined populations.

Methods: R/M HNSCC pts progressing on/after platinum therapy were randomized 2:1 to 40 mg/d oral afatinib (n=322) or 40 mg/m2/wk IV MTX (n=161), stratified by ECOG PS (0/1) and prior use of anti-EGFR monoclonal antibody (mAb) therapy (Yes/No) in the R/M setting. The primary endpoint was PFS by independent review. Optional tumor biomarker assessments, including human papillomavirus status assessed by p16, EGFR amplification, HER3 and PTEN, were conducted in a central laboratory.

Results: Improvements in PFS and RR with afatinib vs MTX in subgroups based on geographical region (Asia, Europe, or North/Latin America) and age (<65 or ?65 yrs) were consistent with the overall study population (Table). Afatinib demonstrated a more pronounced effect in pts not previously treated with anti-EGFR mAb therapy. In the biomarker subgroups, improvements in PFS were observed with afatinib vs MTX in pts with p16-negative, HER3-low, and PTEN-high disease; a trend towards prolonged PFS was observed in pts with EGFR-amplified tumors (Table). Higher RRs with afatinib vs MTX were observed in all biomarker subgroups, with the exception of p16-positive disease.

*Odds ratios are not available for comparisons of subgroups with no responders; †p16 staining was analyzed in tumors from all subsites; ‡ ?50% of cells with ?4 copies, or ?1 cell with ?8 copies CI, confidence interval; HR, hazard ratio; H-score, histology score; NE, not estimable

Conclusions: More pronounced anti-tumor effects were observed with afatinib vs MTX in subgroups of R/M HNSCC pts with p16-negative, EGFR-amplified, HER3-low, and PTEN-high disease. Future prospective studies based on these subgroups and biomarkers are needed to provide a more robust readout of clinical outcomes. Clinical trial identification: ClinicalTrials.gov Identifier: NCT01345682

Disclosure: M. Tahara: MT reports advisory board participation for Merck Sharp & Dohme; honoraria from Merck Serono, Bristol-Myers Squibb, Eisai, Otsuka and Bayer; and research funding from Eisai, Merck Sharp & Dohme, Boehringer Ingelheim and AstraZeneca.

E.E.W. Cohen: EEWC reports advisory board participation for Merck and Pfizer; and honoraria from Eisai and Bayer.

R.I. Haddad: RIH reports advisory board participation for BMS, Merck and Bayer; and corporate-sponsored research from Merck, BMS, Celgene and Boehringer Ingelheim.

L.F. Licitra: Full conflict of interest statement for Lisa F. Licitra has been sent via email to programme@esmo.org.

J.B. Vermorken: JBV reports advisory board participation for Boehringer Ingelheim and being on the steering committee of the LUX H&N trials.

T. Gauler: TG reports stock ownership or options from Bayer AG since 1984; advisory board participation for Boehringer Ingelheim, Merck Serono, Novartis and MSD; honoraria from Novartis, Merck Serono, Boehringer Ingelheim and Roche.

J. Guigay: JG reports advisory board participation from BMS and Merck Serono; and research grants from BMS, Boehringer Ingelheim, Chugai, GSK, MSD, Merck Serono and Sanofi.

K. Okami: KO reports honoraria from Merck Serono and Bristol-Myers Squibb.

S. Takahashi: ST reports corporate-sponsored research from Boehringer Ingelheim.

B. Burtness: BB reports advisory board participation for VentiRX, Medimmune, Amgen, Bayer and Boehringer Ingelheim; corporate-sponsored research for Merck; and expert testimony for Johnson & Johnson.

X.J. Cong: XJC reports employment by Boehringer Ingelheim Pharmaceuticals, Inc.

N. Gibson: NG reports employment by Boehringer-Ingelheim Pharma GmbH & Co. KG.

F. Solca: FS reports employment by Boehringer Ingelheim RCV.

E. Ehrnrooth: EE reports employment by Boehringer Ingelheim.

J.-P.H. Machiels: J-PHM reports advisory board participation for Boehringer Ingelheim (without compensation). A

ll other authors have declared no conflicts of interest.

Keywords: afatinib, methotrexate, HNSCC, Phase III

315O_PR

Antitumor activity and safety of pembrolizumab in patients with PD-L1-positive nasopharyngeal carcinoma: Interim results from a phase 1b study

C. Hsu1, S.-H. Lee2, S. Ejadi3, C. Even4, R. Cohen5, C. Le Tourneau6, J. Mehnert7, A. Algazi8, E. van Brummelen9, S. Saraf10, P. Thanigaimani10, J. Cheng10, A. Hansen11

1Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan, 2Internal Medicine, Seoul National University Hospital, Seoul, Korea, 3Clinical Trials, Virginia G. Piper Cancer Center at Scottsdale Healthcare, Scottsdale, AZ, USA, 4Head and Neck Department, Institut Gustave Roussy, Villejuif, France, 5Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA, 6Dept of Medical Oncology, Institut Curie, Paris, France, 7Medical Oncology, The Cancer Institute of New Jersey, New Brunswick, NJ, USA, 8Medicine (Hematology/Oncology), University of California San Francisco, San Francisco, CA, USA, 9Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, Netherlands, 10,, Merck & Co., Inc., Kenilworth, NJ, USA, 11Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada

Aim/Background: Nasopharyngeal carcinoma (NPC) exhibits high expression of PD-1, and expression of PD-1/PD-L1 correlated with poor outcome. Pembrolizumab is a potent, highly selective, humanized monoclonal antibody against PD-1 designed to block interaction with PD-L1 and PD-L2 and enhance antitumor immune response. We present results on safety and antitumor activity of pembrolizumab in patients (pts) with PD-L1+ advanced NPC.

Methods: KEYNOTE-028 (NCT02054806) is a nonrandomized, multicohort, phase 1b trial of pembrolizumab in pts with PD-L1+ advanced solid tumors. Key eligibility criteria for the NPC cohort included advanced (unresectable and/or metastatic) solid tumor, failure of prior therapy, and PD-L1 expression in ?1% of cells in tumor nests or PD-L1+ bands in stroma as determined by a prototype immunohistochemical assay at a central laboratory. Pembrolizumab 10 mg/kg was given every 2 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Primary end points were safety, tolerability, and preliminary efficacy. Response was assessed per RECIST v1.1 by investigators every 8 weeks for the first 6 months and every 12 weeks thereafter.

Results: 27 pts were treated with pembrolizumab. Median (range) age was 52.0 (18-68) years; 63% were Asian. 92.5% received prior therapies for recurrent/metastatic disease (33.3% received ?5 therapies). 7 pts experienced partial response and 14 had stable disease. Best overall (confirmed and unconfirmed) response rate was 25.9% (95% CI, 11.1-46.3). Most common adverse events (AEs) (?20%) were fatigue (37.0%), pruritus (29.6%), nausea (25.9%), pyrexia (25.9%), and myalgia (22.2%). Drug-related AEs occurred in 74.1% of pts; most common (?10%) were pruritus (25.9%), fatigue (18.5%), hypothyroidism (18.5%), rash (11.1%), maculopapular rash (11.1%), pneumonitis (11.1%), herpes zoster infection (11.1%), and hepatitis (11.1%); grade ?3 drug-related AEs occurred in 8/27 (29.6%) pts. 5 pts remain on pembrolizumab treatment.

Conclusions: Pembrolizumab was well tolerated with significant antitumor activity in pts with NPC. This preliminary signal will be further investigated.

Clinical trial identification: ClinicalTrials.gov: NCT02054806

Disclosure: J. Mehnert: Advisory board member for Amgen. Received research funding from Amgen, Novartis, Merck & Co., Inc., and sanofi-aventis.

A. Algazi: Received research funding from Merck & Co., Inc.

S. Saraf: Employee of Merck & Co., Inc.

P. Thanigaimani: Employee of Merck & Co., Inc. Owns stock in Gilead Sciences.

J. Cheng: Employee of and owns stock in Merck & Co., Inc.

All other authors have declared no conflicts of interest.

Keywords: PD-1, nasopharyngeal carcinoma, pembrolizumab

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