Скачать презентацию Clinical outcome according to tumor HER 2 status Скачать презентацию Clinical outcome according to tumor HER 2 status

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Clinical outcome according to tumor HER 2 status and EGFR expression in advanced gastric Clinical outcome according to tumor HER 2 status and EGFR expression in advanced gastric cancer patients from the EXPAND study F. Lordick, * Y-K. Kang, P. Salman, S. C. Oh, G. Bodoky, G. P. Kurteva, C. D. Volovat, V. Moiseyenko, A. Sawaki, J. O. Park, V. A. Gorbunova, H. Goette, H. Melezinkova, C. Stroh, M. Moehler *University Cancer Center Leipzig, Germany (presenting author)

Introduction • In the EXPAND study, the addition of cetuximab (EGFR-antibody) to first-line chemotherapy Introduction • In the EXPAND study, the addition of cetuximab (EGFR-antibody) to first-line chemotherapy did not improve clinical outcome in patients with advanced gastric or GEJ cancer 1 • High EGFR expression was associated with a survival benefit in advanced NSCLC patients treated with first-line chemotherapy + cetuximab 2 • Tumor EGFR expression levels have not been investigated in gastric cancer patients in this treatment setting 1. Lordick F, et al. Lancet Oncol 2013; 14: 490 -9 2. Pirker R, et al. Lancet Oncol 2012; 13: 33 -42

Introduction (2) • HER 2 is a tyrosine kinase receptor in the same family Introduction (2) • HER 2 is a tyrosine kinase receptor in the same family as EGFR, patients with HER 2 +ve advanced gastric cancer showed significantly improved OS when treated with trastuzumab (HER 2 antibody) added to first-line chemotherapy 1 • HER 2 +ve status has been associated with poor prognosis in some studies of advanced gastric cancer patients, 2 whilst in other studies no prognostic or predictive value was reported 3 1. Bang Y-J, et al. Lancet Oncol 2010; 376: 687 -97 2. Gravalos C, et al. Ann Oncol 2008; 19: 1523 -29 3. Van Cutsem E, et al. J Clin Oncol 2012; 30: 2119 -27

Objectives • To assess treatment outcome according to tumor HER 2 status (a pre-defined Objectives • To assess treatment outcome according to tumor HER 2 status (a pre-defined subgroup) and EGFR expression in EXPAND study patients

Methods • The EXPAND study was a multinational, open-label randomized phase III study in Methods • The EXPAND study was a multinational, open-label randomized phase III study in locally advanced unresectable or metastatic gastric or GEJ cancer patients 1 • Patients were randomly assigned to 3 -week cycles of twice daily (days 1– 14) capecitabine 1000 mg/m 2 and iv cisplatin 80 mg/m 2 (day 1) chemotherapy plus weekly cetuximab (day 1) 400 mg/m 2 initial infusion followed by 250 mg/m 2/week thereafter, or chemotherapy alone • The primary endpoint was PFS assessed blind by an independent review committee (IRC) • Secondary endpoints included OS and best overall response (IRC) 1. Lordick F, et al. Lancet Oncol 2013; 14: 490 -9

Methods (2) • Tumor HER 2 status was determined according to a scoring system Methods (2) • Tumor HER 2 status was determined according to a scoring system for gastric cancer, 1 primarily by IHC (Dako Hercep. Test) HER 2 +ve tumors were IHC 3+ or IHC 2+ and fluorescence in situ hybridization (FISH) +ve • EGFR expression was assessed by IHC (Dako EGFR pharm. Dx). A continuous scoring system (scale of 0– 300) was used to determine the level of EGFR expression 2 • Biomarker status was correlated with clinical outcome (exploratory analysis) • Statistical analysis was performed with SAS version 9. 1. 3 or later and R version 2. 14. 1 1. Lordick F, et al. Lancet Oncol 2013; 14: 490 -9 2. Pirker R, et al. Lancet Oncol 2012; 13: 33 -42

Results: HER 2 analysis • Baseline characteristics in the EXPAND ITT (n=904) and HER Results: HER 2 analysis • Baseline characteristics in the EXPAND ITT (n=904) and HER 2 evaluable populations (n=679) were similar, no differences were noted between the treatment arms • Imbalances in baseline characteristics in patients with HER 2 +ve vs HER 2 –ve tumors were found for sex, tumor location, histology, and peritoneal involvement (Table 1)

Table 1. Baseline characteristics Characteristics, n (%) Sex Male Female Age, years ≥ 65 Table 1. Baseline characteristics Characteristics, n (%) Sex Male Female Age, years ≥ 65 <65 Ethnic group White Asian Other ECOG PS* 0 1 Tumor location* Gastric GEJ Histological type* Intestinal Diffuse Mixed Unknown Peritoneal mets ITT n=904 HER 2 +ve n=144 HER 2 –ve n=535 673 (74) 231 (26) 116 (81) 28 (19) 384 (72) 151 (28) 280 (31) 624 (69) 43 (30) 101 (70) 166 (31) 369 (69) 490 (54) 339 (38) 75 (8) 81 (56) 56 (39) 7 (5) 319 (60) 174 (33) 42 (8) 465 (51) 438 (48) 87 (61) 56 (39) 284 (53) 251 (47) 747 (83) 144 (16) 102 (73) 38 (27) 448 (85) 80 (15) 311 (34) 170 (19) 50 (6) 373 (41) 229 (25) 60 (42) 15 (10) 12 (8) 56 (39) 22 (15) 187 (35) 107 (20) 31 (6) 208 (39) 137 (26) *Missing data: ECOG PS, 1 HER 2 +ve, tumor location, 4 HER 2 +ve and 7 HER 2 –ve, histological type, 1 HER 2 +ve and 2 HER 2 –ve.

Table 2. HER 2 status and treatment outcome Median OS, mo 95 % CI Table 2. HER 2 status and treatment outcome Median OS, mo 95 % CI Hazard ratio 95 % CI Median PFS, mo 95% CI Hazard ratio 95% CI ORR, % 95 % CI Odds ratio 95% CI HER 2 +ve CT CT + cetuximab n=72 14. 0 13. 3 11. 3– 17. 1 10. 9– 15. 5 1. 04 0. 71– 1. 53 6. 9 5. 6 5. 5– 8. 2 4. 3– 6. 0 1. 33 0. 88– 2. 01 37. 5 51. 4 26. 4– 49. 7 39. 3– 63. 3 1. 76 0. 91– 3. 42 HER 2 –ve CT CT + cetuximab n=254 n=281 9. 7 9. 2 8. 6– 11. 0 8. 1– 10. 5 0. 98 0. 82– 1. 19 5. 5 4. 6 4. 2– 5. 7 4. 2– 5. 6 0. 99 0. 80– 1. 23 26. 4 27. 0 21. 1– 32. 3 21. 9– 32. 6 1. 03 0. 71– 1. 52 CT, chemotherapy • HER 2 status did not seem to be predictive of cetuximab benefit • In both treatment arms, patients with HER 2 +ve vs HER 2 –ve tumors had a longer median OS and a better ORR

Figure 1. OS according to HER 2 status and treatment Cet, cetuximab; CT, chemotherapy Figure 1. OS according to HER 2 status and treatment Cet, cetuximab; CT, chemotherapy

Multivariable selection models • A final multivariable selection model of OS included: Asian/ Non. Multivariable selection models • A final multivariable selection model of OS included: Asian/ Non. Asian, peritoneal involvement, previous esophagectomy/ gastrectomy, number of metastatic sites, baseline alkaline phosphatise levels, histological subclassification, ECOG PS, HER 2 status and treatment group • Patients with HER 2 –ve (vs HER 2 +ve) tumors had a greater risk of death (adjusted HR 1. 55, 95% CI 1. 24– 1. 94) • In a similar model, patients with HER 2 –ve (vs HER 2 +ve) tumors had reduced odds of response (adjusted odds ratio 0. 48, 95% CI 0. 32– 0. 72)

Links between patient subgroups and HER 2 status • Although not included in the Links between patient subgroups and HER 2 status • Although not included in the multivariable model, gender and tumor location demonstrated a prognostic OS effect in univariable analysis (data not shown) • Exploratory regression-tree analysis (investigating links between patient subgroups and HER 2 status), identified GEJ site as the main factor associated with HER 2 status: – In GEJ tumors (n=118), 68% were HER 2 –ve – In gastric cancer subgroups, 79% of male patients (n=389) and 88% (n=161) of female patients were HER 2 –ve • Therefore, patient HER 2 status and outcome (OS) may be linked via associations with prognostic baseline factors (tumor location, gender)

Results: EGFR analysis • EGFR tumor expression was evaluable in 774/904 patients; 376 in Results: EGFR analysis • EGFR tumor expression was evaluable in 774/904 patients; 376 in the CT arm and 398 in the CT + cetuximab arm • The EGFR IHC score was low (median 0, range 0– 300, 75 th percentile 40)

Figure 2. EGFR IHC score and clinical outcome* *Reprinted from Lordick et al 1 Figure 2. EGFR IHC score and clinical outcome* *Reprinted from Lordick et al 1 with permission from Elsevier (see acknowledgments). Triangles and circles are median times plotted against the midpoint EGFR IHC score in overlapping sliding windows of patient subpopulations each containing 20% of the data (15% in the first and last windows). Windows change in 5% steps (0%-15%, 0%-20%, 5%-25% etc, and final 80%-100%, 85%-100%) Cet, cetuximab; CT, chemotherapy 1. Lordick F, et al. Lancet Oncol 2013; 14: 490 -9

Results: EGFR analysis continued • In patient subgroups defined by a series of cut-off Results: EGFR analysis continued • In patient subgroups defined by a series of cut-off points from an IHC score of 10 upwards (rising incrementally by 10), there was a tendency for improved PFS, and OS when adding cetuximab to CT in patients with high tumor EGFR IHC scores (Figures 3 & 4) • Findings were similar for tumor response (data not shown) • However, this association was based on a very low number of patients. For example, for EGFR IHC scores 200, there were only 8 patients in CT + cetuximab group (Figure 2) • No clear association between EGFR IHC score and patient prognosis was evident (Figure 2)

Figure 3. PFS: Hazard ratios in subgroups by EGFR IHC score Cet, cetuximab; CT, Figure 3. PFS: Hazard ratios in subgroups by EGFR IHC score Cet, cetuximab; CT, chemotherapy

Figure 4. OS: Hazard ratios in subgroups by EGFR IHC score Cet, cetuximab; CT, Figure 4. OS: Hazard ratios in subgroups by EGFR IHC score Cet, cetuximab; CT, chemotherapy

Conclusions • In EXPAND study patients, those with HER 2 +ve vs HER 2 Conclusions • In EXPAND study patients, those with HER 2 +ve vs HER 2 –ve tumors were associated with better outcome irrespective of the treatment • The prognostic value of HER 2 status in this setting remains controversial and may be dependent on patient baseline and tumor prognostic factors • Tumor EGFR expression was generally low • Adding cetuximab to chemotherapy failed to improve outcome overall, but may benefit a very small proportion of patients with high EGFR tumor expression

Acknowledgments • The trial was sponsored by Merck KGa. A, Darmstadt, Germany • The Acknowledgments • The trial was sponsored by Merck KGa. A, Darmstadt, Germany • The authors would like to thank patients, the investigators, co-investigators and the study teams at each of the participating centers and at Merck KGa. A, Darmstadt, Germany • Medical writing assistance was provided by Paul Hoban, Cancer Communications and Consultancy Ltd, Knutsford, UK and funded by Merck KGa. A, Darmstadt, Germany • Figure 2 was reprinted from Lancet Oncol 2013; 14: 490 -9 Florian Lordick Yoon-Koo Kang, Hyun-Cheol Chung, Pamela Salman, Sang Cheul Oh, György Bodoky, Galina Kurteva, Constantin Volovat, Vladimir M. Moiseyenko, Vera Gorbunova, Joon Oh Park, Akira Sawaki, Heiko Goette, Helena Melezínková, Marcus Moehler, Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomized open-label phase 3 trial (2013) with permission from Elsevier http: //www. sciencedirect. com/science/journal/aip/14702045