Abstract
We report 5-year results of the phase III randomized TRIPLETE study. Eligible patients with RAS/BRAF wild-type metastatic colorectal cancer (mCRC) received first-line modified fluorouracil, leucovorin, oxaliplatin (mFOLFOX)/panitumumab (control group, n = 217) versus modified fluorouracil, leucovorin, oxaliplatin, irinotecan (mFOLFOXIRI)/panitumumab (experimental group, n = 218). We present overall survival (OS) and updated outcomes in the intention-to-treat population. The median follow-up was 60.2 months (IQR, 49.3-70.0). The median OS was 41.1 and 33.3 months for experimental and control groups, respectively (hazard ratio [HR], 0.79 [95% CI, 0.63 to 0.99]; P = .049). OS outcomes favored the experimental group regardless of clinical features. No differences in objective response rate (primary end point; 75%/78%, odds ratio, 0.84 [95% CI, 0.54 to 1.31]; P = .442), early tumor shrinkage rate (P = .954), depth of response (P = .573), no residual tumor resection rate (P = .329), and progression-free survival (HR, 0.95 [95% CI, 0.78 to 1.16]; P = .606) were confirmed. Among patients alive at the time of disease progression, the median postprogression survival was 24.6 and 17.7 months for experimental and control groups, respectively (HR, 0.79 [95% CI, 0.62 to 1.01]; P = .062). Similar proportions of patients in both groups received subsequent lines of therapy (control/experimental: second line 73%/71%, third line 51%/49%, fourth line 31%/32%), as well as nonpalliative locoregional treatments (control/experimental: 16%/16%). Upfront mFOLFOXIRI/panitumumab significantly improves OS compared with mFOLFOX/panitumumab in patients with RAS/BRAF wild-type mCRC.
INTRODUCTION
Although fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab is a potential first-line treatment option,1,2 to date no evidence supports the use of the triplet in combination with an anti-epidermal growth factor receptor (EGFR) antibody (cetuximab or panitumumab). Indeed, for patients with proficient mismatch repair/microsatellite stable, RAS/BRAF wild-type (wt) left-sided tumors, the current upfront standard of care is the combination of fluorouracil, leucovorin, oxaliplatin (FOLFOX) or fluorouracil, leucovorin, and irinotecan with an anti-EGFR antibody.1,2
TRIPLETE is the first phase III randomized study designed to verify whether the upfront exposure to a modified schedule of modified FOLFOXIRI (mFOLFOXIRI) provided higher activity than the modified FOLFOX (mFOLFOX) regimen, both combined with panitumumab, in patients with unresectable RAS/BRAF wt metastatic colorectal cancer (mCRC). At the primary analysis, the primary end point, objective response rate (ORR), was not met,3 and no significant improvements were reported in progression-free survival (PFS), early tumor shrinkage (ETS), depth of response (DoR), and no residual tumor (R0) resection rate, with increased GI adverse events.
Herein, we present overall survival (OS) data and updated results of other end points.
METHODS
Study Design
TRIPLETE (ClinicalTrials.gov identifier: NCT03231722) was a prospective, open-label, investigator-driven randomized phase III study, conducted in 57 Italian centers. The study protocol was approved by the local Ethics Committees at participating sites and adhered to the Declaration of Helsinki and the principles of Good Clinical Practice. Patients provided their written informed consent to study procedures before enrollment at participating sites and adhered to the Declaration of Helsinki and the principles of Good Clinical Practice to study procedures. Details on eligibility criteria and treatment schedules have been previously published3 and can be found in the Appendix (online only). Patients were stratified according to Eastern Cooperative Oncology Group performance status (0-1 v 2), primary tumor location (right v left), and liver-only metastases (yes v no) and randomly assigned (1:1) to mFOLFOX/panitumumab (control group) or mFOLFOXIRI/panitumumab (experimental group).
Statistical Analyses
The primary end point was ORR, analyzed by the intention-to-treat (ITT) principle. The χ2 test for heterogeneity and the odds ratio (OR) with 95% CIs were used to compare the ORR between groups. Random assignment of 432 patients was calculated to provide a power of 90% to detect an ORR of 75% versus 60% in favor of the experimental group with a two-sided χ2 test for heterogeneity at the .05 significance level.
Secondary end points included OS (time from random assignment to death from any cause), PFS, ETS, DoR, R0 resection rate of metastases, and safety.3 For patients undergoing R0 secondary surgery, relapse-free survival (RFS, time from surgical resection to disease relapse or death) and postresection OS (time from surgical resection to death) were reported. Additionally, postprogression survival (PPS; time from first disease progression to death from any cause), systemic therapies, and nonpalliative locoregional interventions after the first disease progression were described in both groups. PPS, RFS, and postresection OS were not part of the initial statistical analysis plan but were assessed retrospectively to interpret OS results.
Survival curves were calculated using the Kaplan-Meier method and compared with the log-rank test; ORR, PFS, and OS analyses were stratified by the same factors as per random assignment.
Statistical analyses were performed using SAS, version 9.4 (SAS Institute Inc, Cary, NC).
RESULTS
In the ITT population, 435 patients were randomly assigned to control (n = 217) and experimental (n = 218) groups (Fig 1, Table 1).
FIG 1.
CONSORT diagram. The control group indicates FOLFOX plus panitumumab. The experimental group indicates mFOLFOXIRI plus panitumumab. aPatients included in intention-to-treat population. bPatients included in the safety population. cThree patients in the control group and nine patients in the experimental group died on the same day as they had disease progression and were not included in the population for the analysis of PPS. FOLFOX, fluorouracil, leucovorin, oxaliplatin; mFOLFOXIRI, modified fluorouracil, leucovorin, oxaliplatin, irinotecan; PPS, postprogression survival.
TABLE 1.
Baseline Characteristics of Patients in the Intention-to-Treat Population, According to Treatment Group
| Characteristic | Control Group (n = 217) | Experimental Group (n = 218) |
|---|---|---|
| Age, years, median (IQR) | 59 (51-65) | 59 (51-64) |
| Sex, No. (%) | ||
| Male | 138 (64) | 136 (62) |
| Female | 79 (36) | 82 (38) |
| ECOG-PS, No. (%) | ||
| 0 | 174 (80) | 183 (84) |
| 1 | 42 (19) | 34 (15) |
| 2 | 1 (1) | 1 (1) |
| Previous adjuvant therapy, No. (%) | ||
| Yes | 5 (2) | 12 (6) |
| No | 212 (98) | 206 (94) |
| Primary tumor site, No. (%) | ||
| Left colon or rectum | 190 (88) | 192 (88) |
| Right colon | 27 (12) | 26 (12) |
| Resected primary tumor, No. (%) | ||
| Yes | 93 (43) | 111 (51) |
| No | 124 (57) | 107 (49) |
| Time to metastases, No. (%) | ||
| Synchronous | 192 (88) | 188 (86) |
| Metachronous | 25 (12) | 30 (14) |
| No. of metastatic sites, No. (%) | ||
| 1 | 105 (48) | 102 (47) |
| >1 | 112 (52) | 116 (53) |
| Liver-only disease, No. (%) | ||
| Yes | 82 (38) | 86 (39) |
| No | 135 (62) | 132 (61) |
| Mucinous histology, No. (%) | ||
| Yes | 10 (5) | 22 (10) |
| No | 135 (62) | 140 (64) |
| Missing data | 72 (33) | 56 (26) |
| MMR status, No. (%) | ||
| Proficient MMR | 167 (77) | 177 (8) |
| Deficient MMR | 2 (1) | 6 (3) |
| Missing data | 48 (22) | 35 (16) |
NOTE. The control group indicates FOLFOX plus panitumumab. The experimental group indicates mFOLFOXIRI plus panitumumab.
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; FOLFOX, fluorouracil, leucovorin, and oxaliplatin; mFOLFOXIRI, modified FOLFOX, irinotecan; MMR, mismatch repair.
At the data cutoff (December 20, 2024), the median follow-up was 60.2 months (IQR, 49.3-70.0), and 292 (67%, control/experimental: 71%/63%) deaths and 391 (90%, control/experimental: 90%/90%) PFS events were reported.
The median OS was 41.1 and 33.3 months in the experimental and control groups, respectively (hazard ratio [HR], 0.79 [95% CI, 0.63 to 0.99]; P = .049; Fig 2A). Subgroup analyses revealed no significant interaction effect between treatment groups and clinical factors (Fig 2B).
FIG 2.
Kaplan-Meier estimates of OS in the intention-to-treat population, according to treatment groups (A). Forest plot of treatment effect on OS within main clinical and molecular subgroups (B). The control group indicates FOLFOX plus panitumumab. The experimental group indicates mFOLFOXIRI plus panitumumab. ECOG PS, Eastern Cooperative Oncology Group performance status; FOLFOX, fluorouracil, leucovorin, oxaliplatin; HR, hazard ratio; mFOLFOXIRI, modified fluorouracil, leucovorin, oxaliplatin, irinotecan; MMR, mismatch repair; OS, overall survival.
ORR was 75% and 78% in the experimental and control groups, respectively (OR, 0.84 [95% CI, 0.54 to 1.31]; P = .442). No difference was confirmed after adjustment for stratification factors (OR, 0.80 [95% CI, 0.51 to 1.26]; P = .339). Updated results of other secondary end points did not differ from those previously reported (Appendix Fig A1 and Tables A1 and A2). Additionally, among patients undergoing secondary R0 surgery, nonstatistically significant differences in RFS (HR, 0.82 [95% CI, 0.55 to 1.23]; P = .339) and postresection OS (HR, 0.64 [95% CI, 0.37 to 1.11]; P = .112) were evident (Appendix Figs A2A and A2B).
Among 365 patients alive at the time of first disease progression, the median PPS was 24.6 and 17.7 months for experimental (n = 180) and control (n = 185) groups, respectively (HR, 0.79 [95% CI, 0.62 to 1.01]; P = .062; Appendix Fig A3). Similar proportions of patients in both groups received subsequent lines of therapy (control/experimental: second line 73%/71%, third line 51%/49%, fourth line 31%/32%; Fig 3) and nonpalliative locoregional treatments (control/experimental: 16%/16%).
FIG 3.
Treatments received after disease progression to first-line therapy. Funnel plot in the control group (A) and experimental group (B). Percentages on the left are calculated as the number of patients receiving second, third, and fourth line of therapy relative to the total of enrolled subjects in each treatment group. Percentages on the right are calculated as the number of patients receiving second, third, and fourth line of therapy relative to the total of subjects alive at the time of first, second, and third disease progression, respectively, in each treatment group. Sankey plot depicting the percentage of patients receiving different systemic treatments across subsequent lines of therapy in the control group (C) and experimental group (D). EGFR, epidermal growth factor receptor; FOLFOX, fluorouracil, leucovorin, oxaliplatin; FTP/TPI, trifluridine/tipiracil; mFOLFOXIRI, modified fluorouracil, leucovorin, oxaliplatin, irinotecan; PD, progression disease; VEGF, vascular endothelial growth factor.
Notably, among patients receiving systemic treatments after disease progression, those in the control group received more frequently irinotecan (91% v 79%, P = .007) and antiangiogenics (80% v 63%, P = .001), and less frequently oxaliplatin (35% v 47%, P = .039). No differences were found between treatment groups in terms of exposure to regorafenib (25% v 30%, P = .448), trifluridine/tipiracil (40% v 43%, P = .647), and anti-EGFR retreatment (48% v 53%, P = .367). Although a higher proportion of patients in the experimental group received an anti-EGFR–based treatment after the first disease progression (20% v 31%, P = .031), no difference was reported in terms of anti-EGFR retreatment after at least one anti-EGFR–free intervening therapy (27% v 33%, P = .262). Details regarding the chemotherapy treatments received in association with anti-EGFR are provided in Appendix Tables A3 and A4.
DISCUSSION
At an extended follow-up of 5 years, the phase III TRIPLETE study provides evidence of an OS benefit, one of the secondary end points of the study, from upfront mFOLFOXIRI/panitumumab compared with mFOLFOX/panitumumab for patients with unresectable RAS and BRAF wt mCRC. The OS improvement is both statistically significant and clinically relevant, showing an 18% reduction in the risk of death, along with an absolute gain of 7.8 months in median OS duration, which reaches 41.1 months in the experimental group. A consistent OS benefit with mFOLFOXIRI/panitumumab was shown across all investigated subgroups, thus not helping to identify ideal candidates for this treatment.
These OS results are clearly unexpected, based on the absence of any significant difference in terms of ORR, DoR, ETS, PFS, and R0 resection rate. Apparently, this was not driven by a better clinical outcome of patients undergoing radical resection in the experimental rather than in the control group based on the lack of difference in RFS and postresection OS. Conversely, the PPS benefit reported in the experimental group led us to deeply investigate potential differences in the quantity and quality of systemic and locoregional treatments received after progression, but modest differences between arms do not provide a reasonable explanation for the observed OS difference.
We therefore hypothesize that patients in the experimental group may present with a lower disease burden at the time of disease progression. Of note, this hypothesis was suggested also to explain the OS difference reported with anti-EGFR–based regimens in head-to-head trials against bevacizumab-based treatments, where no PFS differences were shown, but ORR and/or DoR advantages in favor of the anti-EGFR arms were observed.4,5
It should be noticed that those trials used RECIST 1.0, allowing to identify up to 10 target lesions (up to five per organ), whereas according to RECIST 1.1 used in TRIPLETE only up to five target lesions (up to two per organ) can be measured.6,7 Therefore, the overall assessment of the tumor burden dynamics might have been more accurate in previous trials. The lack of a Blinded Independent Central Review, which could have provided a more unbiased evaluation of treatment activity, is a limitation of our study and is planned for future analyses,8,9 as well as the analysis of plasma samples to assess the modulation of tumor fraction from baseline to disease progression in both arms. Unfortunately, relevant prognostic parameters at the time of disease progression as identified by Bachet et al10 were not collected in this trial, thus hampering the opportunity to rule out unbalances between arms.
Other clinical trials recently investigated the upfront use of the triplet plus an anti-EGFR agent with relevant activity results.11-14 The phase II PANIRINOX study14 recently demonstrated a statistically nonsignificant 9-month OS benefit with FOLFIRINOX versus FOLFOX in the nonliver-limited cohort, with no difference in activity parameters. Of note, the OS difference was not evident in the liver-limited stratum, with less mature data available.
Furthermore, the toxicity price of the triplet plus an anti-EGFR cannot be neglected. Higher occurrence of grade 3 or 4 adverse events and, especially, diarrhea (control/experimental 8%/25%) was confirmed in TRIPLETE, even if a modified schedule of FOLFOXIRI with reduced doses of irinotecan and fluorouracil was adopted. Other trials reported heterogeneous safety results with different treatment schedules.11,12,14 To minimize the risk of clinically relevant diarrhea, screening for UGT1A1 polymorphisms might be considered.
To this purpose, the lack of patient-reported outcomes to assess patients' quality of life is a clear limitation of this study.
In conclusion, mFOLFOXIRI plus panitumumab warrants reconsideration as an efficacious regimen for fit patients with RAS/BRAF wt left-sided mCRC. Future efforts should focus on mitigating treatment toxicity and providing a better estimation of the overall benefit by pooling together available data.
APPENDIX
FIG A1.
Kaplan-Meier estimates of PFS in the intention-to-treat population, according to treatment groups. The control group indicates FOLFOX plus panitumumab. The experimental group indicates mFOLFOXIRI plus panitumumab. FOLFOX, fluorouracil, leucovorin, oxaliplatin; HR, hazard ratio; mFOLFOXIRI, modified fluorouracil, leucovorin, oxaliplatin, irinotecan; PFS, progression-free survival.
FIG A2.
Kaplan-Meier estimates of RFS (A) and postresection OS (B) in patients who underwent secondary R0 surgery, according to treatment groups. The control group indicates FOLFOX plus panitumumab. The experimental group indicates mFOLFOXIRI plus panitumumab. FOLFOX, fluorouracil, leucovorin, oxaliplatin; HR, hazard ratio; mFOLFOXIRI, modified fluorouracil, leucovorin, oxaliplatin, irinotecan; NE, not estimable; OS, overall survival; R0, no residual tumor; RFS, relapse-free survival.
FIG A3.
Kaplan-Meier estimates of PPS in the intention-to-treat population, according to treatment groups. The control group indicates FOLFOX plus panitumumab. The experimental group indicates mFOLFOXIRI plus panitumumab. FOLFOX, fluorouracil, leucovorin, oxaliplatin; HR, hazard ratio; mFOLFOXIRI, modified fluorouracil, leucovorin, oxaliplatin, irinotecan; PPS, postprogression survival.
TABLE A1.
Efficacy Results in the Intention-to-Treat Population, According to Treatment Group
| End Point | Control Group (n = 217) | Experimental Group (n = 218) | OR or HR (95% CI)a | P |
|---|---|---|---|---|
| ORR | ||||
| No. (%) | 170 (78) | 164 (75) | 0.84 (0.54 to 1.31) | .442 |
| 95% CI | 72 to 84 | 69 to 81 | 0.80b (0.51 to 1.26) | .339b |
| Disease control rate | .597 | |||
| No. (%) | 202 (93) | 200 (92) | 0.83 (0.41 to 1.68) | |
| 95% CI | 89 to 96 | 87 to 95 | ||
| ETS | .954 | |||
| No. (%) | 129 (59) | 129 (59) | 0.99 (0.67 to 1.45) | |
| 95% CI | 53 to 66 | 52 to 66 | ||
| Deepness of response | .573 | |||
| Median | 46% | 49% | — | |
| IQR | 31 to 62 | 32 to 62 | ||
| R0 resection rate | .329 | |||
| No. (%) | 69 (32) | 60 (28) | 0.82 (0.54 to 1.23) | |
| 95% CI | 26 to 39 | 22 to 34 | ||
| PFS | ||||
| Events, No. (%) | 195 (90) | 196 (90) | 0.95 (0.78 to 1.16) | .606 |
| Months—median (95% CI) | 12.4 (11.0 to 14.3) | 12.7 (11.2 to 15.2) | 0.95b (0.78 to 1.16) | .606b |
NOTE. The control group indicates FOLFOX plus panitumumab. The experimental group indicates mFOLFOXIRI plus panitumumab.
Abbreviations: ETS, early tumor shrinkage; FOLFOX, fluorouracil, leucovorin, and oxaliplatin; HR, hazard ratio; mFOLFOXIRI, modified FOLFOX, irinotecan; OR, odds ratio; ORR, objective response rate; PFS, progression-free survival; R0, no residual tumor.
The ratios listed are ORs, except for the PFS, for which the HR is shown.
Adjusted for stratification factors.
TABLE A2.
All-Cause Adverse Events, Occurring During First-Line Therapy in the Safety Population, According to the Treatment Group
| Adverse Event | Control Group (n =213), No. (%) | Experimental Group (n = 218), No. (%) | ||
|---|---|---|---|---|
| Grade 1 and 2 | Grade 3 and 4 | Grade 1 and 2 | Grade 3 and 4 | |
| Any event | 85 (40) | 123 (58) | 55 (25) | 156 (72) |
| Nausea | 72 (34) | 4 (2) | 103 (47) | 11 (5) |
| Vomiting | 26 (12) | 2 (1) | 49 (22) | 5 (2) |
| Diarrhea | 72 (34) | 16 (8) | 105 (48) | 54 (25) |
| Stomatitis | 84 (39) | 15 (7) | 82 (38) | 15 (7) |
| Neutropenia | 44 (21) | 43 (20) | 62 (28) | 72 (33) |
| Febrile neutropenia | — | 7 (3) | — | 12 (5) |
| Thrombocytopenia | 65 (31) | 2(1) | 62 (28) | 3 (1) |
| Anemia | 57 (27) | 5(2) | 88 (40) | 6 (3) |
| Neurotoxicity | 99 (46) | 8 (4) | 98 (45) | 5 (2) |
| Alopecia | 3 (1) | — | 4 (2) | — |
| Asthenia | 93 (44) | 4 (2) | 109 (50) | 18 (8) |
| Anorexia | 25 (12) | 0 (0) | 36 (17) | 5 (2) |
| Hand and foot syndrome | 39 (18) | 5 (2) | 29 (13) | 0 (0) |
| Fever | 28 (12) | 1 (1) | 42 (19) | 1 (1) |
| Acneiform rash | 128 (60) | 62 (29) | 131 (60) | 44 (20) |
| Hypomagnesemia | 42 (20) | 3 (1) | 61 (28) | 3 (1) |
| Hypokalemia | 38 (18) | 8 (4) | 52 (24) | 16 (7) |
| Hypocalcemia | 19 (9) | 1 (1) | 19 (9) | 1 (1) |
| Infusion-related reaction | 16 (7) | 4 (2) | 18 (8) | 2 (1) |
NOTE. The table lists all grade 1 and 2 and grade 3 and 4 events that occurred in any treatment group. The control group indicates FOLFOX plus panitumumab. The experimental group indicates mFOLFOXIRI plus panitumumab.
Abbreviations: FOLFOX, fluorouracil, leucovorin, and oxaliplatin; mFOLFOXIRI, modified fluorouracil, leucovorin, and oxaliplatin, irinotecan.
TABLE A3.
Chemotherapy Regimens Administered with Anti-EGFR Reintroduction After First Disease Progression
| Treatment | Control Group (n = 32), No. (%) | Experimental Group (n = 48), No. (%) |
|---|---|---|
| mFOLFOXIRI + panitumumab | 0 (0) | 8 (17) |
| FOLFOX + panitumumab | 24 (75) | 17 (35) |
| FOLFIRI + panitumumab | 5 (16) | 15 (31) |
| Irinotecan + panitumumab | 0 (0) | 1 (2) |
| 5-FU/LV + panitumumab | 2 (6) | 6 (13) |
| Panitumumab | 0 (0) | 1 (2) |
| Cetuximab | 1 (3) | 0 (0) |
Abbreviations: 5-FU/LV, fluorouracil, leucovorin; EGFR, epidermal growth factor receptor; FOLFIRI, fluorouracil, leucovorin, and irinotecan; FOLFOX, fluorouracil, leucovorin, and oxaliplatin; mFOLFOXIRI, modified fluorouracil, leucovorin, and oxaliplatin, irinotecan.
TABLE A4.
Chemotherapy Regimens Administered with Anti-EGFR Rechallenge After at Least One Anti-EGFR–Free Intervening Therapy
| Treatment | Control Group (n = 52), No. (%) | Experimental Group (n = 41), No. (%) |
|---|---|---|
| FOLFOX + panitumumab | 4 (8) | 2 (5) |
| FOLFIRI + cetuximab | 0 (0) | 3 (7) |
| Irinotecan + cetuximab | 8 (15) | 5 (13) |
| Irinotecan + panitumumab | 1 (2) | 0 (0) |
| Capecitabine + cetuximab | 1 (2) | 0 (0) |
| 5-FU/LV + panitumumab | 1 (2) | 0 (0) |
| Panitumumab | 30 (58) | 23 (56) |
| Cetuximab | 0 (0) | 3 (7) |
| Cetuximab + other | 5 (9) | 3 (7) |
| Panitumumab + other | 2 (4) | 2 (5) |
Abbreviations: 5-FU/LV, fluorouracil, leucovorin; EGFR, epidermal growth factor receptor; FOLFIRI, fluorouracil, leucovorin, and irinotecan; FOLFOX, fluorouracil, leucovorin, and oxaliplatin; mFOLFOXIRI, modified fluorouracil, leucovorin, and oxaliplatin, irinotecan.
Daniele Rossini
Speakers' Bureau: Amgen, Pierre Fabre, Bayer, Takeda, MSD
Carlotta Antoniotti
Honoraria: Merck
Travel, Accommodations, Expenses: Merck
Sara Lonardi
Consulting or Advisory Role: Amgen, Merck Serono, Lilly, Servier, AstraZeneca, Incyte, Daiichi Sankyo, Bristol Myers Squibb, MSD, Astellas Pharma, Bayer, GlaxoSmithKline, Takeda, Rottapharm Biotech, BeiGene, Nimbus Therapeutics, Fosun Pharma
Speakers' Bureau: Roche, Lilly, Bristol Myers Squibb, Servier, Merck Serono, Pierre Fabre, GlaxoSmithKline, Amgen, MSD Oncology, Incyte
Research Funding: Amgen, Merck Serono, Bayer (Inst), Roche (Inst), Lilly (Inst), AstraZeneca (Inst), Bristol Myers Squibb (Inst)
Filippo Pietrantonio
Honoraria: Servier, Bayer, MSD Oncology, Amgen, Pierre Fabre, Bristol Myers Squibb, Merck Serono, Astellas Pharma, Takeda, Ipsen, Johnson and Johnson, Rottapharm Biotech, Seagen, AstraZeneca, Daiichi-Sankyo, BeiGene, Incyte
Consulting or Advisory Role: Amgen, Servier, MSD Oncology, Bayer, Merck Serono, Takeda, GlaxoSmithKline, Rottapharm Biotech, Johnson and Johnson/Janssen, Pfizer, Astellas Pharma, BMS, BeiGene, Agenus, Gilead Sciences, Daiichi-Sankyo, Incyte, Jazz Pharmaceuticals, Pierre Fabre, AstraZeneca, Revolution Medicines
Research Funding: Bristol Myers Squibb (Inst), AstraZeneca (Inst), Incyte (Inst), Agenus (Inst), Lilly (Inst), Amgen (Inst), Rottapharm Biotech (Inst), GlaxoSmithKline (Inst), Johnson and Johnson/Janssen (Inst)
Travel, Accommodations, Expenses: Pierre Fabre, Merck Serono, Takeda Science Foundation, Amgen, Astellas Pharma, Johnson and Johnson/Janssen
Lorenzo Antonuzzo
Honoraria: Amgen, Roche, AstraZeneca, Novartis
Consulting or Advisory Role: Merck Serono, MSD Oncology
Giovanni Randon
Honoraria: Accademia Nazionale Di Medicina (ACCMED)
Daniele Lavacchi
Consulting or Advisory Role: Amgen
Travel, Accommodations, Expenses: Pfizer
Carmelo Pozzo
Consulting or Advisory Role: Amgen, Servier, Lilly
Francesca Bergamo
Consulting or Advisory Role: Advanced Accelerator Applications/Novartis, Teysuno, Takeda
Speakers' Bureau: Lilly, MSD Oncology, Bayer, BMS, AstraZeneca, Pierre Fabre
Travel, Accommodations, Expenses: Advanced Accelerator Applications/Novartis
Emiliano Tamburini
Consulting or Advisory Role: Servier, Amgen, AstraZeneca, Astellas Pharma
Beatrice Borelli
Honoraria: Terumo
Consulting or Advisory Role: Terumo
Travel, Accommodations, Expenses: Servier, Merck Serono
Marco Maria Germani
Company: Merck
Vincenzo Formica
Honoraria: Amgen, Servier, MSD, Pierre Fabre, Merck Serono
Giuseppe Aprile
Consulting or Advisory Role: Amgen, Astellas Pharma, Bristol Myers Squibb/Sanofi, Lilly, Novartis, Servier, MSD Oncology
Alberto Zaniboni
Consulting or Advisory Role: Amgen, Servier, Bayer, Merck Serono, Merck
Speakers' Bureau: Servier, Astellas Pharma (Inst)
Gianluca Masi
Consulting or Advisory Role: AstraZeneca, Eisai, MSD Oncology, Roche, Terumo
Research Funding: Terumo (Inst)
Patents, Royalties, Other Intellectual Property: Terumo (Inst)
Luca Boni
Consulting or Advisory Role: Pfizer
Patents, Royalties, Other Intellectual Property: International Patent no. PCT/EP2012/065661
Chiara Cremolini
Honoraria: Roche, Amgen, Bayer, Servier, MSD, Merck, Pierre Fabre, GlaxoSmithKline, Takeda
Consulting or Advisory Role: Roche, Bayer, Amgen, MSD, Pierre Fabre, Nordic Bioscience, Rottapharm Biotech, Bicara Therapeutics, Takeda, Revolution Medicines
Speakers' Bureau: Servier, Merck, Pierre Fabre, MSD
Research Funding: Merck, Bayer, Roche, Servier
No other potential conflicts of interest were reported.
DISCLAIMER
The corresponding author had full access to all study data and had the final responsibility for the decision to submit for publication. Amgen had no role in the design and conduct of the trial; collection, management, analysis, and interpretation of the data; or the decision to submit the manuscript for publication.
PRIOR PRESENTATION
Presented in part at the 2022 ASCO Annual Meeting, Chicago, IL, June 3-7, 2022 and also at the 2025 ASCO Annual Meeting, Chicago, IL, May 30-June 4, 2025.
SUPPORT
Supported by the GONO Foundation. Amgen provided panitumumab in the experimental arm and partial financial support for study conduction. The research leading to these results received funding from the European Union—NextGenerationEU through the Italian Ministry of University and Research under PNRR—M4C2-I1.3 Project PE_00000019 “HEAL ITALIA” to Chiara Cremolini, Veronica Conca and Marco Maria Germani CUP: I53C22001440006.
CLINICAL TRIAL INFORMATION
Protocols
Data Sharing Statement
DATA SHARING STATEMENT
A data sharing statement provided by the authors is available with this article at DOI https://doi.org/10.1200/JCO-25-01337.
AUTHOR CONTRIBUTIONS
Conception and design: Daniele Rossini, Carlotta Antoniotti, Roberto Moretto, Gianluca Masi, Luca Boni, Chiara Cremolini, Veronica Conca
Administrative support: Giovanni Randon, Emiliano Tamburini, Federica Marmorino, Martina Carullo
Provision of study materials or patients: Carlotta Antoniotti, Filippo Pietrantonio, Giovanni Randon, Carmelo Pozzo, Francesca Bergamo, Alessandro Passardi, Roberta Fazio, Angela Buonadonna, Gianluca Masi
Collection and assembly of data: All authors
Data analysis and interpretation: Veronica Conca, Daniele Rossini, Carlotta Antoniotti, Roberto Moretto, Federica Marmorino, Beatrice Borelli, Marco Maria Germani, Roberto Bordonaro, Giuseppe Aprile, Alberto Zaniboni, Gianluca Masi, Luca Boni, Chiara Cremolini
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Upfront Modified FOLFOXIRI Plus Panitumumab for RAS/BRAF Wild-Type Metastatic Colorectal Cancer: Final Results of the Phase III TRIPLETE Study
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
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Daniele Rossini
Speakers' Bureau: Amgen, Pierre Fabre, Bayer, Takeda, MSD
Carlotta Antoniotti
Honoraria: Merck
Travel, Accommodations, Expenses: Merck
Sara Lonardi
Consulting or Advisory Role: Amgen, Merck Serono, Lilly, Servier, AstraZeneca, Incyte, Daiichi Sankyo, Bristol Myers Squibb, MSD, Astellas Pharma, Bayer, GlaxoSmithKline, Takeda, Rottapharm Biotech, BeiGene, Nimbus Therapeutics, Fosun Pharma
Speakers' Bureau: Roche, Lilly, Bristol Myers Squibb, Servier, Merck Serono, Pierre Fabre, GlaxoSmithKline, Amgen, MSD Oncology, Incyte
Research Funding: Amgen, Merck Serono, Bayer (Inst), Roche (Inst), Lilly (Inst), AstraZeneca (Inst), Bristol Myers Squibb (Inst)
Filippo Pietrantonio
Honoraria: Servier, Bayer, MSD Oncology, Amgen, Pierre Fabre, Bristol Myers Squibb, Merck Serono, Astellas Pharma, Takeda, Ipsen, Johnson and Johnson, Rottapharm Biotech, Seagen, AstraZeneca, Daiichi-Sankyo, BeiGene, Incyte
Consulting or Advisory Role: Amgen, Servier, MSD Oncology, Bayer, Merck Serono, Takeda, GlaxoSmithKline, Rottapharm Biotech, Johnson and Johnson/Janssen, Pfizer, Astellas Pharma, BMS, BeiGene, Agenus, Gilead Sciences, Daiichi-Sankyo, Incyte, Jazz Pharmaceuticals, Pierre Fabre, AstraZeneca, Revolution Medicines
Research Funding: Bristol Myers Squibb (Inst), AstraZeneca (Inst), Incyte (Inst), Agenus (Inst), Lilly (Inst), Amgen (Inst), Rottapharm Biotech (Inst), GlaxoSmithKline (Inst), Johnson and Johnson/Janssen (Inst)
Travel, Accommodations, Expenses: Pierre Fabre, Merck Serono, Takeda Science Foundation, Amgen, Astellas Pharma, Johnson and Johnson/Janssen
Lorenzo Antonuzzo
Honoraria: Amgen, Roche, AstraZeneca, Novartis
Consulting or Advisory Role: Merck Serono, MSD Oncology
Giovanni Randon
Honoraria: Accademia Nazionale Di Medicina (ACCMED)
Daniele Lavacchi
Consulting or Advisory Role: Amgen
Travel, Accommodations, Expenses: Pfizer
Carmelo Pozzo
Consulting or Advisory Role: Amgen, Servier, Lilly
Francesca Bergamo
Consulting or Advisory Role: Advanced Accelerator Applications/Novartis, Teysuno, Takeda
Speakers' Bureau: Lilly, MSD Oncology, Bayer, BMS, AstraZeneca, Pierre Fabre
Travel, Accommodations, Expenses: Advanced Accelerator Applications/Novartis
Emiliano Tamburini
Consulting or Advisory Role: Servier, Amgen, AstraZeneca, Astellas Pharma
Beatrice Borelli
Honoraria: Terumo
Consulting or Advisory Role: Terumo
Travel, Accommodations, Expenses: Servier, Merck Serono
Marco Maria Germani
Company: Merck
Vincenzo Formica
Honoraria: Amgen, Servier, MSD, Pierre Fabre, Merck Serono
Giuseppe Aprile
Consulting or Advisory Role: Amgen, Astellas Pharma, Bristol Myers Squibb/Sanofi, Lilly, Novartis, Servier, MSD Oncology
Alberto Zaniboni
Consulting or Advisory Role: Amgen, Servier, Bayer, Merck Serono, Merck
Speakers' Bureau: Servier, Astellas Pharma (Inst)
Gianluca Masi
Consulting or Advisory Role: AstraZeneca, Eisai, MSD Oncology, Roche, Terumo
Research Funding: Terumo (Inst)
Patents, Royalties, Other Intellectual Property: Terumo (Inst)
Luca Boni
Consulting or Advisory Role: Pfizer
Patents, Royalties, Other Intellectual Property: International Patent no. PCT/EP2012/065661
Chiara Cremolini
Honoraria: Roche, Amgen, Bayer, Servier, MSD, Merck, Pierre Fabre, GlaxoSmithKline, Takeda
Consulting or Advisory Role: Roche, Bayer, Amgen, MSD, Pierre Fabre, Nordic Bioscience, Rottapharm Biotech, Bicara Therapeutics, Takeda, Revolution Medicines
Speakers' Bureau: Servier, Merck, Pierre Fabre, MSD
Research Funding: Merck, Bayer, Roche, Servier
No other potential conflicts of interest were reported.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
A data sharing statement provided by the authors is available with this article at DOI https://doi.org/10.1200/JCO-25-01337.