A F C Okines1, D Gonzalez de Castro1, D Cunningham2, I Chau1, R E Langley3, L C Thompson3, S P Stenning3, C Saffery1, Y Barbachano1, F Coxon4, G Middleton5, D Ferry6, T Crosby7, S Madhusudan8, J Wadsley9, J Waters10, M Hall11, D Swinson12, A Robinson13, D Smith14, J S Reis-Filho15, T S Waddell1, L Puckey1, S Hulkki Wilson1, Z Eltahir1, M Band1, A Wotherspoon1. 1. The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom. 2. The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom. Electronic address: david.cunningham@rmh.nhs.uk. 3. Medical Research Council Clinical Trials Unit, London, United Kingdom. 4. Northern Centre for Cancer Care, Newcastle, United Kingdom. 5. Royal Surrey County Hospital, Guildford, United Kingdom. 6. Russells Hall Hospital, Dudley, United Kingdom. 7. Velindre Cancer Centre, Cardiff, United Kingdom. 8. Nottingham University Hospitals, United Kingdom. 9. Weston Park Hospital, Sheffield, United Kingdom. 10. Kent Oncology Centre, Maidstone, United Kingdom. 11. Heatherwood and Wexham Park Hospital, United Kingdom. 12. St. James' Hospital, Leeds, United Kingdom. 13. Conquest Hospital, United Kingdom. 14. Clatterbridge Centre for Oncology, Wirral, United Kingdom. 15. The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
Abstract
BACKGROUND: REAL3 (Randomised ECF for Advanced or Locally advanced oesophagogastric cancer 3) was a phase II/III trial designed to evaluate the addition of panitumumab (P) to epirubicin, oxaliplatin and capecitabine (EOC) in untreated advanced oesophagogastric adenocarcinoma, or undifferentiated carcinoma. MAGIC (MRC Adjuvant Gastric Infusional Chemotherapy) was a phase III study which demonstrated that peri-operative epirubicin, cisplatin and infused 5-fluorouracil (ECF) improved survival in early oesophagogastric adenocarcinoma. PATIENTS AND METHODS: Analysis of response rate (RR; the primary end-point of phase II) and biomarkers in the first 200 patients randomised to EOC or modified dose (m) EOC+P in REAL3 was pre-planned to determine if molecular selection for the on-going study was indicated. KRAS, BRAF and PIK3CA mutations and PTEN expression were assessed in pre-treatment biopsies and results correlated with response to mEOC+P. Association between these biomarkers and overall survival (OS) was assessed in MAGIC patients to determine any prognostic effect. RESULTS: RR was 52% to mEOC+P, 48% to EOC. Results from 175 assessable biopsies: mutations in KRAS (5.7%), BRAF (0%), PIK3CA (2.5%) and loss of PTEN expression (15.0%). None of the biomarkers evaluated predicted resistance to mEOC+P. In MAGIC, mutations in KRAS, BRAF and PIK3CA and loss of PTEN (phosphatase and tensin homolog) were found in 6.3%, 1.0%, 5.0% and 10.9%, respectively, and were not associated with survival. CONCLUSIONS: The RR of 52% in REAL3 with mEOC+P met pre-defined criteria to continue accrual to phase III. The frequency of the mutations was too low to exclude any prognostic or predictive effect.
BACKGROUND: REAL3 (Randomised ECF for Advanced or Locally advanced oesophagogastric cancer 3) was a phase II/III trial designed to evaluate the addition of panitumumab (P) to epirubicin, oxaliplatin and capecitabine (EOC) in untreated advanced oesophagogastric adenocarcinoma, or undifferentiated carcinoma. MAGIC (MRC Adjuvant Gastric Infusional Chemotherapy) was a phase III study which demonstrated that peri-operative epirubicin, cisplatin and infused 5-fluorouracil (ECF) improved survival in early oesophagogastric adenocarcinoma. PATIENTS AND METHODS: Analysis of response rate (RR; the primary end-point of phase II) and biomarkers in the first 200 patients randomised to EOC or modified dose (m) EOC+P in REAL3 was pre-planned to determine if molecular selection for the on-going study was indicated. KRAS, BRAF and PIK3CA mutations and PTEN expression were assessed in pre-treatment biopsies and results correlated with response to mEOC+P. Association between these biomarkers and overall survival (OS) was assessed in MAGIC patients to determine any prognostic effect. RESULTS: RR was 52% to mEOC+P, 48% to EOC. Results from 175 assessable biopsies: mutations in KRAS (5.7%), BRAF (0%), PIK3CA (2.5%) and loss of PTEN expression (15.0%). None of the biomarkers evaluated predicted resistance to mEOC+P. In MAGIC, mutations in KRAS, BRAF and PIK3CA and loss of PTEN (phosphatase and tensin homolog) were found in 6.3%, 1.0%, 5.0% and 10.9%, respectively, and were not associated with survival. CONCLUSIONS: The RR of 52% in REAL3 with mEOC+P met pre-defined criteria to continue accrual to phase III. The frequency of the mutations was too low to exclude any prognostic or predictive effect.
Authors: Siraj M Ali; Eric M Sanford; Samuel J Klempner; Douglas A Rubinson; Kai Wang; Norma A Palma; Juliann Chmielecki; Roman Yelensky; Gary A Palmer; Deborah Morosini; Doron Lipson; Daniel V Catenacci; Fadi Braiteh; Rachel Erlich; Philip J Stephens; Jeffrey S Ross; Sai-Hong Ignatius Ou; Vincent A Miller Journal: Oncologist Date: 2015-04-16