1530PD - Results of a Randomized, Placebo-Controlled, Phase 2 Study of Tarextumab (TRXT, anti-Notch2/3) in Combination with Etoposide and Platinum (EP) in P...

Date 11 September 2017
Event ESMO 2017 Congress
Session Non-metastatic NSCLC and other thoracic malignancies
Topics Anti-Cancer Agents & Biologic Therapy
Small-Cell Lung Cancer
Lung and other Thoracic Tumours
Presenter Davey Daniel
Citation Annals of Oncology (2017) 28 (suppl_5): v539-v542. 10.1093/annonc/mdx386
Authors D.B. Daniel1, C.M. Rudin2, L. Hart3, D.R. Spigel4, M.J. Edelman5, J. Goldschmidt6, R. Bordoni7, B. Glisson8, T.F. Burns9, A. Dowlati10, G. Dy11, T.J. Beck12, R. Jotte13, S.V. Liu14, A. Kapoun15, L. Faoro16, A.C. Chiang17
  • 1Oncology, Tennessee Oncology, 37404 - Chattanooga/US
  • 2Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, 10065 - New York/US
  • 3Medical Oncology, Florida Cancer Specialists/ Wake Forest University, Fort Myers/US
  • 4Medical Oncology, Sarah Cannon Research Institute/Tennessee Oncology, PLLC, 37203 - Nashville/US
  • 5Hematology/oncology, Fox Chase Cancer center, Philadelphia/US
  • 6Clinical Research, Blue Ridge Cancer Care, Blacksburg/US
  • 7Medicine, Georgia Cancer Specialists and Northside Hospital, Marietta/US
  • 8Thoracic/head And Neck Medical Oncology, MD Anderson Cancer Center, 77030-4095 - Houston/US
  • 9Medicine, University of Pittsburgh, Pittsburgh/US
  • 10Department Of Medicine-hematology And Oncology, University Hospital Cleveland Medical Center, 44106 - Cleveland/US
  • 11Medicine, Roswell Park Cancer Institute, Buffalo/US
  • 12Medical Oncology, Highlands Oncology Group, Fayetteville/US
  • 13Oncology/hematology, Rocky Mountain Cancer Center, Denver/US
  • 14Medicine, Georgetown University, Washington/US
  • 15Translational Medicine, OncoMed Pharmaceuticals, Redwood City/US
  • 16Clinical Development, OncoMed Pharmaceuticals, 94063 - Redwood City/US
  • 17Medical Oncology, Yale University School of Medicine, New Haven/US

Abstract

Background

Notch signaling is implicated in cancer stem cell biology and is an appealing target in the treatment of SCLC. TRXT, a fully human anti-Notch2/3 antibody, has shown preclinical efficacy in SCLC. A randomized phase 1b/2 study was conducted.

Methods

This was a randomized, placebo-controlled, multi-center study. Pts were randomized 1:1 to platinum (cisplatin 75 mg/m2 or carboplatin AUC of 5 mg/ml*min on day 1, investigator’s choice) + etoposide (EP) 100 mg/m2 on days 1-3 + TRXT 15 mg/kg on day 1 or EP + placebo (pbo) every 21 days. Chemotherapy was used for 6 cycles, and TRXT/pbo was continued until disease progression. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), safety, and PFS/OS in 5 biomarker groups.

Results

145 pts were enrolled (137 treated). Demographics and baseline pt characteristics were balanced between arms. PFS was similar between the treatment arms (median 5.5 mo in EP+pbo vs 5.5 mo in EP+TRXT, HR = 0.97, p = 0.94). OS was also similar between the treatment arms (median 10.3 mo in EP+pbo vs 9.3 mo in EP+TRXT, HR = 1.01, p = 0.95). ORR was 70.8% in EP+pbo vs 68.6% in EP+TRXT (p = 0.83). There were no statistically significant differences in OS or PFS according to Notch3, Hes1, Hey2, Hey1, or Hes6 gene expression levels. Adverse events (AE) were more common in EP+TRXT; most commonly increased drug-related AEs included diarrhea (33.8/76.8%), thrombocytopenia (17.6/58.0%), decreased appetite (23.5/37.7%), hypokalemia (7.4/33.3%), and vomiting (13.2/31.9%). Most commonly increased grade 3 or higher AEs in the EP+TRXT arm included thrombocytopenia (10.3/40.6%), anemia (20.6/27.5%), pneumonia (4.4/15.9%), diarrhea (0/18.9%), and hypokalemia (4.4/13%). AEs with fatal outcome were more common in EP+TRXT (4.4/8.7%).

Conclusions

Tarextumab in combination with platinum-based therapy did not improve PFS, OS, ORR in previously untreated SCLC. Biomarker analysis failed to establish a predictive marker for TRXT efficacy. Pts treated with TRXT experienced more toxicity. Clinical development of TRXT has been discontinued.

Clinical trial identification

NCT01859741

Legal entity responsible for the study

OncoMed Pharmaceuticals

Funding

OncoMed Pharmaceuticals

Disclosure

S.V. Liu: Consultant: Ariad, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Genentech, Lilly, Pfizer. A. Kapoun, L. Faoro: Employee and stock holder at OncoMed Pharmaceuticals. All other authors have declared no conflicts of interest.