COMETS: COlorectal MEtastatic Two Sequences

Transcription

1 COMETS: COlorectal MEtastatic Two Sequences A Phase III Multicenter Trial Comparing Two Different Sequences of Second/Third Line Therapy (Irinotecan/Cetuximab Followed By FOLFOX-4 vs. FOLFOX-4 Followed by Irinotecan/Cetuximab) in K-RAS WT Metastatic Colorectal Cancer Patients Refractory to FOLFIRI/Bevacizumab Abstract 2006 Cascinu S, Lonardi S, Rosati G, Nasti G, Zaniboni A, Romiti A, Aglietta M, Giordano M, Corsi D, Ferrau F, Labianca R, and Floriani I

2 Background FOLFOX/FOLFIRI are equally effective as first-line treatment but FOLFOX might be more effective in response rate (RR) and progression-free survival (PFS) in second-line 1 The optimal first-line was not clearly defined in RAS wildtype metastatic colorectal cancer (mcrc), and it is still debated even after the FIRE-3 and CALGB/SWOG80405 trials While bevacizumab seems to lose efficacy across treatment lines, cetuximab maintains a comparable activity from the first-line to the third-line 2 FOLFOX is effective in second-line and less in third-line, 3 while cetuximab has a similar activity across all treatment lines 4 1. Tournigand C, et al. J Clin Oncol. 2004;Suppl: Abstract Karapetis CS, et al. N Engl J Med. 2008;359(17): Koopman M, et al. Lancet. 2007;370(9582): Grothey A, et al. J Clin Oncol. 2012;30(15):

3 Hypothesis FOLFIRI and bevacizumab should be used in first-line in order to optimize their efficacy The sequence FOLFOX followed by cetuximab should be more successful than the reverse sequence

4 Study Design Study conducted in 11 centers in Italy PFS Bevacizumab + FOLFIRI (N = 110) PD Randomize 1:1 ARM A ARM B Irinotecan/ Cetuximab FOLFOX FOLFOX Irinotecan/ Cetuximab 101 events were required to achieve a power of 80% of detecting a hazard ratio (HR) of 0.57 in favor of one of the two sequences, translating in an increase of median overall PFS from 4 months to 7 months, with a type I error of 5%, two-sided, using the Mantel-Cox version of the log-rank test. 110 assessable patients were needed to reach the target number of events. Primary endpoint Secondary endpoints PFS Overall survival (OS) from randomization; PFS 2 and 3 line; Overall response rate (ORR) Safety Clinicaltrials.gov: NCT PD, progressive diesase

5 Main Eligibility Criteria Patients 18 years with histologically confirmed diagnosis of KRAS wildtype mcrc Eastern Cooperative Oncology Group (ECOG) PS 0-2 Previously treated with FOLFIRI/bevacizumab and not candidates for primary metastasectomy Progressive disease ( 1 measurable lesion according to RECIST v1 assessed by investigator, documented by CT or MRI), 4 weeks prior to start of study treatment Adequate bone marrow, liver, and renal function Signed informed consent CT, computed tomography; MRI, magnetic resonance imaging; PS, performance status

6 Parameter Patient Demographics Arm A (n = 55) Arm B (n = 55) ECOG PS, % Male/female, % 52/48 65/35 Median age, years (range) 61 (31-75) 62 (32-76) Primary site of disease, % Colon right Colon left Rectum Metastatic sites % Liver Lung Liver + lung 9 7 Others Arm A: Irinotecan/cetuximab followed by FOLFOX Arm B: FOLFOX followed by irinotecan/cetuximab

7 Efficacy Data According to Arm Arm A (n = 55) Arm B (n = 55) Hazard Ratio (95% CI) RR (%) 19/52 (37) 30/53 (57) P =.05 Fisher Exact Test Overall Median PFS, months ( ) P =.37 Median OS, months ( ) P =.26 Arm A: Irinotecan/cetuximab followed by FOLFOX Arm B: FOLFOX followed by irinotecan/cetuximab

8 Overall Median PFS: Primary Endpoint Arm A: Irinotecan/cetuximab followed by FOLFOX Arm B: FOLFOX followed by irinotecan/cetuximab PFS Overall PFS Arm A 9.9 Arm B 11.3 HR 0.83 ( ); P = Number of events Arm A: 49 (90.7%) Arm B: 48 (87.3%) Log-rank: Chi2 = 0.79 df = 1 P = Patients at Risk Time to Event, months Arm A Arm B

9 Median PFS According to Line of Treatment PFS II Line Arm A: Irinotecan/cetuximab followed by FOLFOX Arm B: FOLFOX followed by irinotecan/cetuximab PFS III Line Arm A: Irinotecan/cetuximab followed by FOLFOX Arm B: FOLFOX followed by irinotecan/cetuximab PFS (Line II) Number of events Arm A: 51 (94.4%) Arm B: 51 (92.7%) PFS (Line III) Number of events Arm A: 30 (100.0%) Arm B: 51 (94.4%).01 Log-rank: Chi2 = 0.87 df = 1 P = Log-rank: Chi2 = 0.13 df = 1 P = Time to Event, Months Patients at Risk A B Time to Event, Months Patients at Risk A B

10 Overall Median Survival Arm A: Irinotecan/cetuximab followed by FOLFOX Arm B: FOLFOX followed by irinotecan/cetuximab OS Number of events Arm A: 46 (85.2%) Arm B: 43 (78.2%) Log-rank: Chi2 = 1.30 df = 1 P = Time to Event, months Patients at Risk A B

11 Grade 3/4 Adverse Events According to Regimens Cetuximab/ Irinotecan 2 Line 3 Line Cetuximab/ FOLFOX FOLFOX Irinotecan (n = 54) (n = 55) P (n = 30) (n = 36) P Neutropenia 7 (13.5%) 3 (5.5%).46 1 (3.3%) 3 (8.3%).53 Febrile neutropenia 0 2 (3.6%).37 2 (6.7%) 0.12 Thrombocytopenia 0 2 (3.6%) Anemia 3 (5.8%) (3.3%) 0.06 Diarrhea 6 (11.5%) 3 (5.5%).09 1 (3.3%) 6 (16.7%).02 Nausea/vomiting 1 (1.9%) 1 (1.8%).6 1 (3.3%) 2 (5.6%).3 Asthenia 3 (5.8%) 6 (10.9%).6 6 (20%) 2 (5.6%).6 Allergic reaction 0 2 (3.6%).26 1 (3.3%) 1 (2.8%).5 Mucositis 0 2 (3.6%).26 1 (3.3%) 1 (2.8%).5 Skin toxicity 15 (28%) 1 (0.2%) (19%).008 Neurologic toxicity 1 (0.02%) 3 (5.4%) (6.7%) 0.03

12 Toxicities Grade 3/4 Adverse Events According to Arm Arm A (n = 54) Arm B (n = 55) Neutropenia 8 (15%) 6 (11%) Febrile neutropenia 2 (4%) 2 (4%) Thrombocytopenia 0 2 (4%) Anemia 4 (8%) 0 Diarrhea 7 (13%) 9 (16%) Nausea/vomiting 2 (4%) 3 (5%) Asthenia 9 (16%) 8 (15%) Allergic reaction 3 (5%) 2 (4%) Mucositis 1 (0.1%) 3 (5%) Skin toxicity 15 (27%) 8 (15%) Neurologic toxicity 3 (5%) 3 (5%) Arm A: Cetuximab/irinotecan followed by FOLFOX Arm B: FOLFOX followed by Cetuximab/irinotecan

13 Summary of COMET Results The study did not meet its primary endpoint Arm A (Cetuximab/FOLFOX) vs ARM B (FOLFOX/Cetuximab) PFS: 9.9 months vs 11.3 months, HR = 0.83, P =.37 BUT ORR: 37% vs 57% P =.05 OS: 12.3 months vs 18.6 months, HR = 0.79, P =.26 Toxicity profile is independent of sequences

14 Conclusions In KRAS-wildtype patients, cetuximab seems to be less effective immediately after bevacizumab Our findings support preclinical and clinical data suggesting that EGFR inhibition is not active after VEGF blockade 1-3 These results are in accordance with data from the FIRE-3 trial in terms of drug sequences 4 The sequence of biological agents seems to be relevant to optimize the management of patients Based on our results, we can speculate that in RAS-wildtype patients cetuximab should be not given after bevacizumab 1. Ellis LM. Clin Colorectal Cancer. 2004;4 Suppl 2:S55-S Norguet E, et al. Dig Liver Dis. 2011;43(11): Ciardiello F, et al. Clin Cancer Res. 2004;10(2): Modest DP, et al. J Clin Oncol August 10. [Epub ahead of print].