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
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 3565. 2. Karapetis CS, et al. N Engl J Med. 2008;359(17):1757-1765. 3. Koopman M, et al. Lancet. 2007;370(9582):135-142. 4. Grothey A, et al. J Clin Oncol. 2012;30(15):1735-1737.
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
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: NCT01030042 PD, progressive diesase
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
Parameter Patient Demographics Arm A (n = 55) Arm B (n = 55) ECOG PS, % 0 79 79 1 21 21 Male/female, % 52/48 65/35 Median age, years (range) 61 (31-75) 62 (32-76) Primary site of disease, % Colon right 26 30 Colon left 38 34 Rectum 36 36 Metastatic sites % Liver 54 53 Lung 19 20 Liver + lung 9 7 Others 18 20 Arm A: Irinotecan/cetuximab followed by FOLFOX Arm B: FOLFOX followed by irinotecan/cetuximab
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 9.9 11.3 0.83 (0.56-1.24) P =.37 Median OS, months 12.3 18.6 0.79 (0.52-1.19) P =.26 Arm A: Irinotecan/cetuximab followed by FOLFOX Arm B: FOLFOX followed by irinotecan/cetuximab
Overall Median PFS: Primary Endpoint 1.0.09 Arm A: Irinotecan/cetuximab followed by FOLFOX Arm B: FOLFOX followed by irinotecan/cetuximab.08.07 PFS.06.05 Overall PFS Arm A 9.9 Arm B 11.3 HR 0.83 (0.56-1.24); P =.37.04.03.02.01 Number of events Arm A: 49 (90.7%) Arm B: 48 (87.3%) Log-rank: Chi2 = 0.79 df = 1 P =.373 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Patients at Risk Time to Event, months Arm A 54 49 42 34 31 24 16 14 13 12 11 8 6 5 4 4 Arm B 55 54 46 41 35 30 22 20 13 12 10 9 7 7 4 2
Median PFS According to Line of Treatment 1.0.09 PFS II Line Arm A: Irinotecan/cetuximab followed by FOLFOX Arm B: FOLFOX followed by irinotecan/cetuximab 1.0.09 PFS III Line Arm A: Irinotecan/cetuximab followed by FOLFOX Arm B: FOLFOX followed by irinotecan/cetuximab.08.08.07.07 PFS (Line II).06.05.04.03.02 Number of events Arm A: 51 (94.4%) Arm B: 51 (92.7%) PFS (Line III).06.05.04.03.02 Number of events Arm A: 30 (100.0%) Arm B: 51 (94.4%).01 Log-rank: Chi2 = 0.87 df = 1 P =.352.01 Log-rank: Chi2 = 0.13 df = 1 P =.724 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Time to Event, Months Patients at Risk A 54 50 42 35 29 27 21 15 11 10 9 7 6 B 55 52 50 40 34 30 26 19 15 11 8 7 6 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Time to Event, Months Patients at Risk A 30 28 24 18 14 10 9 6 5 4 3 3 2 B 36 33 31 22 19 17 9 7 6 3 3 3 3
1.0.09 Overall Median Survival Arm A: Irinotecan/cetuximab followed by FOLFOX Arm B: FOLFOX followed by irinotecan/cetuximab.08.07.06 OS.05.04.03.02 Number of events Arm A: 46 (85.2%) Arm B: 43 (78.2%) Log-rank: Chi2 = 1.30 df = 1 P =.255.01 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Time to Event, months Patients at Risk A 54 49 42 36 35 33 25 19 17 16 15 13 12 10 8 5 B 55 53 48 43 40 37 33 31 28 25 19 18 11 11 8 5
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%).001 0 0 - Anemia 3 (5.8%) 0.28 1 (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%).001 0 7 (19%).008 Neurologic toxicity 1 (0.02%) 3 (5.4%).001 2 (6.7%) 0.03
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
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
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-S61. 2. Norguet E, et al. Dig Liver Dis. 2011;43(11): 917-919. 3. Ciardiello F, et al. Clin Cancer Res. 2004;10(2):784-793. 4. Modest DP, et al. J Clin Oncol. 2015 August 10. [Epub ahead of print].