CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC).

Sobre  este estudio presentado en ASCO 2014 se podrían efectuar algunas reflexiones: en sus comienzos fueron reclutados más de 3.000 pacientes no seleccionados de cáncer colorrectal metastático. Con el desarrollo de nuevas investigaciones, se observó que el Cetuximab solo era útil en los paciente con el KRas de tipo salvaje en los codones 12 y 13, por lo cual se redujeron los pacientes a los que tenían estas características. ¿Esto no produce alteraciones en la randomización? Posteriores investigaciones sobre el RAS demostraron que en algunas mutaciones el Cetuximab podría llegar a ser perjudicial.

Yo pienso también que el esquema  de quimioterapia (FOLFOX o FOLFIRI, debería haber sido randomizado y no a elección del investigador, ya que finalmente no se pudo llegar  conclusiones de cual es mejor)

También llama la atención que en otros estudios tanto de bevacizumab o cetuximab con otros comparadores la supervivencia media fue de aproximadamente 25 meses. En este llegó a 30. Es incompleto porque como lo mencionan lo autores faltan datos de respuesta, análisis de subgrupos, etc. No debería decirse que se obtuvo una nueva marca en supervivencia, sino que eso es solamente lo que se observó en este trabajo

Author(s): 

Alan P. Venook, Donna Niedzwiecki, Heinz-Josef Lenz, Federico Innocenti, Michelle R. Mahoney, Bert H. O'Neil, James Edward Shaw, Blase N. Polite, Howard S. Hochster, James Norman Atkins, Richard M. Goldberg, Robert J. Mayer, Richard L. Schilsky, Monica M. Bertagnolli, Charles David Blanke, Cancer and Leukemia Group B (Alliance), SWOG, and ECOG; University of California, San Francisco, San Francisco, CA; Duke University, Durham, NC; USC Norris Comprehensive Cancer Center, Los Angeles, CA; The University of North Carolina at Chapel Hill, Chapel Hill, NC; Mayo Clinic, Rochester, MN; Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN; Virginia Commonwealth University, Richmond, VA; Pritzker School of Medicine, The University of Chicago, Chicago, IL; Department of Medical Oncology, Yale University School of Medicine, New Haven, CT; Southeast Cancer Control Consortium, CCOP, Goldsboro, NC; The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH; Dana-Farber Cancer Institute, Boston, MA; American Society of Clinical Oncology, Alexandria, VA; Brigham and Women's Hospital, Boston, MA; SWOG and Oregon Health & Science University, Portland, OR

Background: Irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6), combined with bevacizumab (BV) or cetuximab (CET), are first-line treatments for metastatic adenocarcinoma of the colon or rectum (MCRC). The optimal antibody combination is unknown. Methods: Patients (pts) with KRAS wild-type (wt)(codons 12 and 13) MCRC and performance status 0-1 received FOLFIRI or mFOLFOX6 (MD/pt choice at enrollment) and randomized to either CET 400 mg/m² X 1, then 250 mg/m² qw or BV 5 mg/kg q2w. The original study included unselected MCRC pts receiving FOLFIRI or mFOLFOX6 and randomized to CET, BV, or both. After 1,420 pts accrued the study amended as follows: only pts with KRAS wt tumors (codon 12 and 13) were included and the combination CET + BV arm was deleted. Rx continued until progression, death, unacceptable toxicity, curative surgery; treatment holidays of 4 wks permitted. Subsequent Rx not mandated. Accrual goal was 1,142 pts. One° endpoint was overall survival (OS). Results: Between November 2005 and March 2012, 3,058 unselected pts enrolled, 2,334 KRAS wt pts randomized; final N =1137 (333 pre-amend eligible retrospectiveKRAS test, 804 post-amend), median f/u = 24 mos; Median age – 59 y; 61% male. Chemo/BV – 559; chemo/CET – 578. FOLFIRI = 26.6%, mFOLFOX6 = 73.4%. OS analysis planned at 849 events; efficacy futility boundary crossed at 10^th interim analysis on 1/29/14. OS - chemo/BV v. chemo/CET = 29.04 (25.66 - 31.21) v. 29.93 (27.56 - 31.21) mos; HR = 0.92 (0.78, 1.09) (p value = 0.34). PFS (by investigator): chemo/BV v. chemo/CET: 10.84 (9.86 - 11.4) v. 10.45 (9.66 - 11.33) mos. There were 94 pts free of disease following surgery, median f/u 40 mos (range 8.0 - 86.0). Outcomes similar by gender. On-study toxicity and deaths as expected. Analyses underway: Expanded RAS, FOLFOX v. FOLFIRI, subsequent therapies, long-term survivors, correlates. Conclusions: Chemo/CET and chemo/BV equivalent in OS in pts KRAS wt (codons 12 + 13) MCRC; either is appropriate in first line. Overall OS of 29 + mos and 8% long-term survivors confirms progress in MCRC. The preference for FOLFOX limits chemotherapy comparison. Expanded RAS and other molecular and clinical analyses may identify subsets

of pts who get more or less benefit from specific regimens. Clinical trial information: NCT00265850.

 Bevacizumab or cetuximab, in combination with either FOLFOX or FOLFIRI chemotherapy regimens, yielded similarly effective overall survival outcomes in patients with metastatic colorectal cancer (CRC) and no KRAS mutations, according to results from a large phase III trial presented during the Plenary Session on Sunday. The trial established a new benchmark in median overall survival (OS) in this setting, at approximately29 months.

“For patients, what this tells us is that either FOLFIRI or FOLFOX with either bevacizumab or cetuximab are perfectly reasonable options,” said Alan P. Venook, MD, of the University of California, San Francisco, during a press conference on Sunday morning.

The CALGB/SWOG 80405 study, which began in 2004 when the two study drugs had been recently approved for this indication (bevacizumab in the first line, cetuximab in the second or third line), included 1,137 patients who were previously untreated. When the trial began, patients were unselected for KRAS status, and a combination bevacizumab/cetuximab arm was included. This design was later amended to focus on patients without KRAS mutations, and only those patients originally enrolled who were KRAS wild-type were included (333 patients), along with the post-amendment accrual (804 patients). The combination arm was discontinued.

All patients first were stratified to either FOLFOX (leucovorin/5-fluorouracil/oxaliplatin) or FOLFIRI (leucovorin/5-fluorouracil/irinotecan) based on physician preference. They were then randomly assigned to receive either bevacizumab or cetuximab. In this study, 73% of patients received FOLFOX and 27% received FOLFIRI.

New Survival Standard in mCRC

The OS in the bevacizumab and chemotherapy group was 29.0 months, compared with 29.9 months in the cetuximab and chemotherapy group, for a hazard ratio (HR) of 0.925 (95% [CI 0.78-1.09]; p = 0.34). Dr. Venook noted that this is substantially longer than even 10 years ago when the trial began, when the median OS in this setting tended to be around 21 months.

The progression-free survival rates were also similar, at 10.8 months for bevacizumab and 10.4 months for cetuximab (HR 1.04, 95% CI [0.91-1.17]; p = 0.55)

Among only the patients treated with FOLFOX, the median OS was 30.1 months with cetuximab and 26.9 months with bevacizumab, which again was not significantly different (HR 0.9, 95% CI [0.7-1.0]; p = 0.09). Among patients treated with FOLFIRI, the trend was reversed, with a median OS of 33.4 months with bevacizumab and 28.9 months with cetuximab (HR 1.2, 95% [CI 0.9-1.6]; p = 0.28). Dr. Venook noted that the lower number of patients in the FOLFIRI groups limit any interpretation.

Notably, 124 patients (10.9%) were rendered disease-free by surgery and the study treatment, and Dr. Venook said the median OS in only those patients exceeded 5.5 years. “There is a subset of patients with metastatic CRC who will do exceedingly well, and we need to take that message home with us,” he said during the Plenary Session.

The trial found no surprising or new adverse events for any of the agents. The most frequent grade 3 or higher toxicities associated with bevacizumab included hypertension (7%) and gastrointestinal events (2%); for cetuximab these included acne-like rash (7%) and diarrhea (11%). Only 29.6% of the full cohort discontinued treatment because of progressive disease, with adverse events/withdrawal/change in therapy accounting for another 55.5% of discontinuations.

Dr. Venook said a substantial amount of data from the trial is still pending, and forthcoming analyses will include response rate, duration of therapy, specific surgery undergone by some patients, and details pertaining to therapies received after progression on the study regimens. One analysis already completed showed no major differences in quality of life for these patients; the commonly seen rash with cetuximab did have an effect on a skin satisfaction measure, but this did not translate into a significant difference on the European Organisation for Research and Treatment of Cancer Global Quality of Life Measure.

“There may be some temptation to top-line this as a negative trial, the two arms are the same,” said 2013-2014 ASCO President Clifford A. Hudis, MD,  FACP, of Memorial Sloan Kettering Cancer Center, during a press conference. “But the really important thing is that this sets an entirely new high standard and a new high bar for clinical trials in advanced CRC.”

Subanalyses and Expanded RAS

Josep Tabernero, MD, PhD, of Vall d’Hebron University Hospital and Institute of Oncology, Spain, was the Discussant for the study, and stressed that the remaining analyses of the study’s data will shed more light on who might benefit most from these therapies.

Importantly, this trial defined KRAS wild-type based on codons 12 and 13, but in recent years the suggestion has emerged that using “expanded” RAS could further select patients. Codons 12 and 13 account for approximately 40% of patients with metastatic CRC, but adding in various other genetic markers could exclude more and bring the population for a trial like this down to approximately 45% of patients. Dr. Tabernero speculated that with expanded RAS definitions the 1,137 patients in this trial would drop to approximately 950 patients, and differences between the groups could emerge.

Dr. Tabernero also noted that conflicting data in the past has led some institutions, including the National Comprehensive Cancer Network (NCCN), to question the use of cetuximab with chemotherapy, but “the data presented with FOLFOX/cetuximab may make the NCCN reconsider its position in the metastatic CRC guidelines.”

Even without an answer to the study’s initial question of which treatment is better in this patient setting, Dr. Tabernero also said he was reluctant to label it a negative study. “The median survival of patients with metastatic CRC has reached a new benchmark of around 30 months,” he said.