A. Awada

A. Daste

A. Ravaud

B.C. Cho

C. Borel

C. Helwig

E. McClay

J. Gulley

L. Ojalvo

N. Isambert

N. Penel

P.A. Rolfe

S. Salas

English

Open Access Repository

1046O Preliminary results from a phase II trial of tipifarnib in squamous cellcarcinomas (SCCs) with HRAS mutationsA.L. Ho1, N. Chau2, J. Bauman3, K. Bible4, A. Chintakuntlawar4, M.E. Cabanillas5,D.J. Wong6, I. Bra~na Garcia7, M.S. Brose8, V. Boni9, C. Even10, M. Razaq11, V. Mishra12,K. Bracken13, D. Wages13, C. Scholz13, A. Gualberto131Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA,2Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA, 3Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA, 4Medical Oncology, MayoClinic, Rochester, MN, USA, 5Department of Endocrine Neoplasia and HormonalDisorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA,6Medicine, Hematology/Oncology, UCLA - School of Medicine, Los Angeles, CA, USA,7Medical Oncology, Vall d’Hebron University Hospital, Barcelona, Spain, 8MedicalOncology, Abramson Cancer Center at the University of Pennsylvania School ofMedicine, Philadelphia, PA, USA, 9Medical Oncology, START Madrid-CIOCC HM HospitalSanchinarro, Madrid, Spain, 10Department of Head and Neck Surgical & MedicalOncology, Gustave Roussy Institute, Villejuif, France, 11Medical Oncology, StephensonCancer Center, Oklahoma City, OK, USA, 12Diagnostics, Kura Oncology, San Diego, CA,USA, 13Development, Kura Oncology, Cambridge, MA, USABackground: HRAS is a proto-oncogene overexpressed and mutated in head and necksquamous cell carcinomas (HNSCC), bladder, thyroid and salivary gland tumors,among others. Although discovered over 40 years ago, no therapies are yet approvedtargeting mutant HRAS. Tipifarnib is a potent and highly selective inhibitor of farnesyl-transferase, a critical enzyme required for the proper function of HRAS. This Phase 2study (NCT02383927) was conducted to test the hypothesis that inhibition of HRASoncogenic activity could translate to objective responses in solid tumors.Methods: The study was designed to enroll patients (pts) into 2 single-arm studycohorts: Cohort 1 (thyroid cancer) and Cohort 2 (other solid tumors), each one with a2-stage design to determine overall response rate (ORR) as the primary objective. Thisdesign has 80% power to detect a difference between 10% and 30% ORR at one-sidedsignificance level of 0.087. A study cohort was to be considered positive if at least 4responses were observed (N¼ 36, 18 evaluable subjects/cohort). For enrollment, ptsmust have an HRAS mutation, locally advanced/unresectable and/or metastatic, andRECIST v1.1 measurable disease. Tipifarnib was dosed at 900 mg orally twice daily ondays 1-7 and 15-21 of 28-day cycles.Results: As of May 1, 2018, 37 pts have been treated, including 11 pts with HRAS mutatedHNSCC and 2 pts with HRAS mutated SCC. Tipifarnib was generally well tolerated, withfatigue, myelosuppression, nausea and vomiting constituting the most common adverseevents (all grades). 7 HNSCC pts are currently evaluable for efficacy; 5 (71%) achieved aconfirmed partial response with a median duration of response of 14.1 months (95% CI:1.4-17.3 mo), exceeding the pre-specified null hypothesis. Importantly, no HRAS mutatedHNSCC pt experienced an objective response on their last therapy prior to receiving tipifar-nib (including platinum, immunotherapy and cetuximabþ/- chemotherapy regimens).Conclusions: Encouraging activity of tipifarnib was observed in pts with HRAS mutantHNSCCs. The study met its predefined success criteria and has been amended to con-tinue enrolling HRAS mutant HNSCC pts, as well as pts with SCC, other than HNSCC,with HRAS mutations into a new Cohort 3.Clinical trial identification: NCT02383927.Legal entity responsible for the study: Kura Oncology.Funding: Kura Oncology.Disclosure: A.L. Ho, N. Chau, J. Bauman, K. Bible, A. Chintakuntlawar, M.E.Cabanillas, D.J. Wong, I. Bra~na Garcia, M.S. Brose, V. Boni, C. Even, M. Razaq: Clinicalinvestigator for Study KO-TIP-001. V. Mishra, K. Bracken, C. Scholz: Stock ownershipand employee: Kura Oncology. D. Wages: Consultant: Kura Oncology. A. Gualberto:Chief Medical Officer and stock ownership: Kura Oncology.1048O M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1and TGF-b, in patients (pts) with advanced SCCHN: Results from aphase I cohortB.C. Cho1, A. Daste2, A. Ravaud2, S. Salas3, N. Isambert4, E. McClay5, A. Awada6,C. Borel7, J. Gulley8, L. Ojalvo9, C. Helwig10, P.A. Rolfe11, N. Penel121Medical Oncology, Yonsei Cancer Center Yonsei University, Seoul, Republic of Korea,2Medical Oncology, CHU Bordeaux Hopital St. André, Bordeaux, France, 3MedicalOncology, CEPCM Assistance Publique des Hôpitaux de Marseille, Marseille, France,4Medical Oncology, Centre Georges-François Leclerc (Dijon), Dijon, France, 5MedicalOncology, Institute for Melanoma Research & Education, California Cancer Associatesfor Research & Excellence, Inc, Encinitas, CA, USA, 6Medical Oncology Clinic, InstitutJules Bordet, Université Libre de Bruxelles, Brussels, Belgium, 7Medical Oncology, CentrePaul Strauss Centre de Lutte contre le Cancer, Strasbourg, France, 8GenitourinaryMalignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda,MD, USA, 9Immuno-Oncology, EMD Serono, Billerica, MA, USA, 10Biostatistics, MerckKGaA, Darmstadt, Germany, 11Bioinformatics Immunology and Immuno-Oncology,EMD Serono, Billerica, MA, USA, 12General Oncology Department, Centre OscarLambret, Lille, FranceBackground: The TGF-b pathway promotes tumor immunosuppression, and its inhib-ition may enhance the antitumor activity of PD-(L)1 mAbs. M7824 is an innovativefirst-in-class bifunctional fusion protein composed of an anti–PD-L1 mAb fused withthe extracellular domain of TGF-bRII (a TGF-b “trap”). We report results in pts withStage III/IV2L SCCHN not amenable to local therapy with curative intent that pro-gressed/recurred<6 months since last platinum dose.Methods: In the phase 1 trial NCT02517398, pts with SCCHN received M78241200 mg q2w until confirmed PD, unacceptable toxicity, or trial withdrawal; continua-tion of M7824 beyond PD was permitted if AEs were manageable, PS maintained andno new treatment indicated. Biomarkers include tumor cell PD-L1 level (antibodyclone 73-10) and HPV status (by RNAseq). The primary endpoint is BOR per RECIST;secondary endpoints include safety/tolerability.Results: As of 12 March 2018, 32 pts (75% had2 prior lines of therapy) receivedM7824 for a median duration of 12.1 (range, 2–74) weeks. 5 pts had a confirmed PR byinvestigator read (RECIST v1.1 ORR 15.6%). 2 additional pts developed delayed PRsafter initial increase in index lesions per RECIST (total ORR 21.9%). 6 pts had SD (totalDCR 40.6%). 4/5 pts with PR (DOR 4.1–12.5þmonths) and both pts with PD!PRremain on treatment. The ORR (including pts with PD!PR) in HPVþwas 50% (4/8;HPV- ORR 13.6% [3/22]). PD-L1 expression was not predictive for ORR (20% [5/25pts)] in PD-L11%; 33% [2/6] in PD-L1<1%). 12-month OS rate was 51.2%. 10 pts(31.3%) had grade 3 TRAEs (increased liver enzymes [3 pts], hyperglycemia, maculo-papular rash [2 pts each], anemia, hyperthyroidism, diabetic ketoacidosisþ hypothyr-oidism, keratoacanthomaþ folliculitis, skin SCC [1 pt each]); there were no grade 4TRAEs and no treatment-related discontinuations or deaths.Conclusions: M7824 showed promising early clinical activity and a manageable safetyprofile in pts with refractory/metastatic 2L SCCHN. A total ORR of 21.9% wasobserved (including 2 pts with initial tumor growth), with a possible trend towardhigher activity in HPVþ (ORR 50%) and evidence of clinical activity irrespective ofPD-L1 status.Clinical trial identification: NCT02517398.Editorial acknowledgement: Medical writing support was provided byClinicalThinking and funded by Merck KGaA, Darmstadt, Germany.Legal entity responsible for the study: Merck KGaA, Darmstadt, Germany.Funding: Merck KGaA, Darmstadt, Germany.Disclosure: N. Isambert: Travel, accommodations, expenses: Roche, MedImmune,AstraZeneca, Novartis, Celgene, Pharmara. E. McClay: Honoraria: Genentech, Bristol-Myers Squibb; Speakers bureau: Genentech, Bristol-Myers Squibb, Merck. C. Borel:Honoraria: Merck, Bristol-Myers Squibb, AstraZeneca, Amgen; Consultancy: Bristol-Myers Squibb, AstraZeneca; Travel, accommodations, expenses: Merck. L. Ojalvo:Employment: EMD Serono. C. Helwig: Employment: Merck KGaA; Equity ownership:Merck KGaA. P.A. Rolfe: Employment: EMD Serono. All other authors have declaredno conflicts of interest.1047PD Pembrolizumab for recurrent head and neck squamous cellcarcinoma (HNSCC): Post hoc analyses of treatment options fromthe phase III KEYNOTE-040 trialC. Le Tourneau1, E.E.W. Cohen2, K.J. Harrington3, J. Dinis4, L. Licitra5, M.-J. Ahn6,A. Soria7, J-P. Machiels8, N. Mach9, R. Mehra10, B. Burtness11, P. Zhang12, J. Cheng12,R. Swaby12, D. Soulières131Drug Development and Innovation, Institut Curie, INSERM U900 Research Unit, andVersailles-Saint-Quentin-en-Yvelines University, Paris, France, 2Moores Cancer Center,UC San Diego Health, La Jolla, CA, USA, 3Targeted Therapy, The Institute of CancerResearch/The Royal Marsden NHS Foundation Trust, National Institute of HealthResearch Biomedical Research Centre, London, UK, 4Medical Oncology, InstitutoPortuguês de Oncologia do Porto Francisco Gentil, Porto, Portugal, 5Oncology,Fondazione IRCCS Istituto Nazionale dei Tumori and University of Milan, Milan, Italy,6Hematology & Oncology, Samsung Medical Center, Seoul, Republic of Korea, 7MedicalOncology, Hospital Universitario Ramon y Cajal, Madrid, Spain, 8Oncology, CliniquesUniversitaires Saint-Luc and Université Catholique de Louvain, Brussels, Belgium,9Hôpitaux Universitaires de Genève, Geneva, Switzerland, 10Medical Oncology, FoxChase Cancer Center, Philadelphia, PA, Johns Hopkins Sidney Kimmel ComprehensiveCancer Center, Baltimore, MD, USA, 11Medicine, Yale University School of Medicine andYale Cancer Center, New Haven, CT, USA, 12Medical Oncology, Merck & Co, Inc,Kenilworth, NJ, USA, 13Department of Medicine - Department of Hemato-Oncology,Centre Hospitalier de l’Université de Montréal, Montréal, QC, CanadaBackground: In the phase 3, randomized, open-label KEYNOTE-040 study(NCT02252042), pembrolizumab (pembro), compared with standard of care (SOC),prolonged survival in patients (pts) with recurrent and/or metastatic HNSCC that pro-gressed during or after platinum-based therapy. Post hoc analyses were conducted toevaluate pembro vs SOC by (1) each of 3 SOC choices, (2) prior cetuximab, and (3) sec-ond PFS (PFS2; time from randomization to disease progression after initiation of newanticancer therapy).Methods: Eligible pts (N¼ 495) randomly assigned (1:1) to receive pembro(200 mg every 3 weeks) or investigator choice of methotrexate (40 mg/m2 weekly),docetaxel (75 mg/m2 every 3 weeks), or cetuximab (400 mg/m2 loading dosethen 250 mg/m2 weekly). Primary end point: OS; PFS and ORR were secondaryend points.Results: Outcomes for pembro vs each SOC choice are in the table. Regardless of priorcetuximab exposure, survival benefit with pembro was observed. There was a trendtoward improved PFS and ORR in those with no prior cetuximab. In pts (N¼ 210)Annals of Oncology abstractsVolume 29 | Supplement 8 | October 2018 doi:10.1093/annonc/mdy287 | viii373Downloaded from https://academic.oup.com/annonc/article-abstract/29/suppl_8/mdy287.004/5140740 by guest on 04 December 2018

m7824 msb0011359c a bifunctional fusion protein targeting pd l1 and tgf β in patients pts with advanced scchn results from a phase i cohort

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m7824 msb0011359c a bifunctional fusion protein targeting pd l1 and tgf β in patients pts with advanced scchn results from a phase i cohort

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