Overall survival result and outcomes by KRAS, BRAF, and DNA mismatch repair in relation to primary tumor site in colon cancers from a randomized trial of adjuvant chemotherapy: NCCTG (Alliance) N0147.

En el presente trabajo presentado en ASCO 2014 se analizan los resultados negativos de asociar el Cetuximab al Folfox6 en adyuvancia de colon, estadío III.

Author(s): Frank A. Sinicrope, Harry H. Yoon, Michelle R. Mahoney, Garth D. Nelson, Stephen N. Thibodeau, Richard M. Goldberg, Daniel J. Sargent, Steven R. Alberts, Alliance for Clinical Trials in Oncology; Mayo Clinic, Rochester, MN; Mayo Clinic College of Medicine, Rochester, MN; The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH

Abstract:

Background: We report mature overall survival (OS) data in stage III colon cancers from a phase III trial of adjuvant mFOLFOX6 ± cetuximab. Biomarkers were analyzed in relation to primary tumor site and OS, and include additional non randomized patients (pts) with KRASmutant tumors. Methods: Cancers (N= 3,018) were analyzed prospectively forBRAF^V600E (exon 15) and KRAS (exon 2;codons 12, 13) mutations, and expression of DNA mismatch repair (MMR) proteins (MLH1, MSH2, and MSH6). Loss of an MMR protein indicated deficient (d) MMR. Tumor site was categorized as proximalvsdistal (inclusive of the splenic flexure). Median follow-up was 4.9 yrs. Cox proportional hazards models were adjusted for covariates including treatment. Results: Consistent with our previously reported DFS data, the addition of cetuximab was associated with worse OS in pts with wild type KRAS (p=.0073). Activating BRAF^V600E or KRAS mutations were detected in 346/2831 (12.2%) and 1042/2905 (35.9%) tumors, respectively; dMMR was found in 329/2906 (11.3%). dMMR or mutations in BRAF^V600E or KRAS were more likely to occur in proximal vs distal tumors [all p<.0001]. BRAF^V600E mutations were associated with older age, female sex, high grade histology, dMMR, and higher T and N stage (all p< 0.01). A tumor site interaction was observed for OS with KRAS (p=.0435) and MMR (p=.0097), but not BRAF. KRAS mutations [HR 1.98 (1.49-2.63); p<.0001] and dMMR [HR 1.85 (0.99-3.46); p=.054] were each associated with worse OS in distal (vs proximal) cancers. dMMR predicted favorable OS in proximal tumors [HR 0.71 (0.53-0.97); p=.030]. Tumors with wild type copies of both BRAFand KRAS showed better OS within proximal [HR 0.74 (0.59-0.93); p=.009] and distal [HR 0.51 (0.39-0.67); p<.0001] cancers compared to those with a BRAF^V600E or KRASmutation. Conclusions: The addition of cetuximab to mFOLFOX6 resulted in significantly poorer OS. The prognostic impact of biomarkers on OS differed significantly by tumor site. Novel findings include poor OS of KRAS mutant tumors that was restricted to the distal colon, and a divergent prognosis for dMMR by primary tumor site. 

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.

Cost-effectiveness analysis (CEA) of bevacizumab (Bev) in first- and second-line treatment of metastatic colorectal cancer (mCRC).

Se transcribe un abstract que va a ser presentado en el Meeting de ASCO de este año, en el cual se hace un análisis de los costos del bevacizumab indicados en primera y segunda línea, mostrando los gastos excesivos para pobres resulados.

Author(s): Daniel A. Goldstein, Qiushi Chen, David H. Howard, Joseph Lipscomb, Turgay Ayer, Bassel F. El-Rayes, Christopher Flowers; Winship Cancer Institute of Emory University, Atlanta, GA; H. Milton Stewart School of Industrial & Systems Engineering, Georgia Institute of Technology, Atlanta, GA; Emory University Department of Health Policy and Management, Atlanta, GA; Rollins School of Public Health; Winship Cancer Institute, Atlanta, GA; H. Milton Stewart School of Industrial and Systems Engineering, Georgia Institute of Technology, Atlanta, GA; The Winship Cancer Institute of Emory University, Atlanta, GA; Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA

Abstract:

Background: The addition of Bev to 5-Fluorouracil (5-FU)-based chemotherapy is the standard of care for previously untreated mCRC. A recent randomized trial demonstrated a 1.4 month increase in median overall survival (OS) when Bev is continued beyond the first progression, thus making it standard practice to use Bev with 5-FU based chemotherapy in both first- and second-line. International CEAs have evaluated Bev in the 1st-line setting. The objective of this study is to determine the cost effectiveness of Bev in the 1st line setting and when continued beyond progression from the US-payer perspective.Methods: We developed two Markov models to compare the cost and effectiveness of 5-FU, leucovorin and oxaliplatin (FOLFOX) with or without Bev in the first-line treatment, and subsequent chemotherapy with or without Bev in the second-line treatment of mCRC. Weibull models were fitted to the published survival curves, and were used to extrapolate the cause-specific mortality and progression risks. Costs for administration and management of adverse events were based on Medicare reimbursement rates for hospital and physician services, and drug costs based on the Medicare average sale prices (all in 2013 US $). Health outcomes were measured in life years (LY) and quality-adjusted life years (QALYS). The simulated OS and progression free survival (PFS) were validated by the fitted survival models. Model robustness was addressed by univariate and probabilistic sensitivity analyses (PSA). Results: Using Bev in first-line therapy provided an additional 0.289 QALYs (0.412 LYs) at a cost of $69,381. The incremental cost-effectiveness ratio (ICER) was $240,195/QALY. Continuing Bev beyond progression provided an additional 0.108 QALYs (0.167 LYs) at a cost of $23,788. The ICER was $219,742/QALY. In all one way sensitivity analyses, the ICER of Bev was > $100,000/QALY. The ICER of Bev was greater than $100,000/QALY in > 99.9% of PSAs. Conclusions: This is the first US based CEA of Bev in mCRC. Bev provides minimal incremental benefit at high incremental cost per QALY in both the first and second-line setting. The ICER of Bev could be improved by use of an effective biomarker to select patients most likely to benefit.

POBRES RESULTADOS DEL REGORAFENIB EN CÁNCER COLORRECTAL METASTÁTICO

Si bien los estudios preclínicos demuestran utilidad de esta molécula mutiinhibidora de kinasas y agente antiangiogénico, independientemente de lo que transcribiré mas adelante los resultados son muy escasos como para tomar en consideración este tratamiento  en los pacientes. Estos paupérrimos resultados se logran a expensas de una importante toxicidad.

The CORRECT Study: Regorafenib vs Best Supportive Care in Patients With Colorectal Cancer Who Have Progressed on Standard Therapy

Thomas H. Cartwright, MD:
For oncologists, finding more effective therapies for patients with advanced, metastatic colorectal cancer that has progressed on standard therapy is a high unmet clinical need—the vast majority of patients with metastatic colorectal cancer receives only palliative care. We all see patients who fail first-, second-, and third‑line therapy. These patients have few options for salvage therapy other than a clinical trial.

Regorafenib is an oral agent similar to sorafenib but targets a wider, slightly different group of tyrosine kinases including angiogenic kinases (VEGFR1-3, TIE2), stromal kinases (PDGFR-β, FGFR), and oncogenic kinases (KIT, PDGFR, RET). Grothey and colleagues^[1] presented results from CORRECT, a large, randomized, phase III trial of regorafenib 160 mg/day vs best supportive care in 760 patients with metastatic colorectal cancer that progressed on standard therapy. Slightly more than 50% had KRASmutations, and 60% had received 4 or more previous lines of systemic therapies. All patients had previously received bevacizumab. Treatment cycles were 3 weeks on and 1 week off. Encouragingly, regorafenib produced statistically significant benefits in the endpoints of overall survival (OS) and progression-free survival (PFS).

The improvement in PFS was fairly modest, a median of two tenths of a month. However, that does not accurately reflect efficacy as the curves spread out and show a significant difference after the median—the hazard ratio (HR) for PFS was .049 (P < .000001) (Figure 1). More importantly, the median OS benefit was approximately a month and a half (5.0 months with placebo vs 6.4 months with regorafenib), which was significant (HR: 0.77; P = .0052). Disease control (a few partial responses plus stable disease) was achieved in 45% of regorafenib-treated patients vs 15% of those who received placebo (P < .000001).

In the oral presentation, there appeared to be a subgroup of patients who experienced longer benefit, but at this point, we do not have any way of identifying those patients.

Toxicities were relatively tolerable; although many patients experienced grade 1/2 toxicities, there were few grade 3/4 events. However, grade 3 hand-foot reaction was seen in 17% of patients receiving regorafenib vs 0.4% of those receiving placebo. Grade 3 fatigue, hypertension, diarrhea, and rash were also seen with regorafenib but in fewer than 10% of patients. 

 

Alan P. Venook, MD:
One caveat is that this was designed to be a randomized, double‑blind trial, but there was enough toxicity with regorafenib that it could not be effectively blinded. In other words, I think that the patients and doctors knew who was receiving the drug and who was receiving placebo. Due to toxicity, approximately 10% of the patients stopped treatment with regorafenib, even though presumably they were benefiting or, at least, remained alive and without progression. Therefore, although I concur there is an unmet need, my concern is that additional toxicity may be seen, and I am not sure how popular it will be with patients who are receiving supportive care.

In addition, there are issues with the study and its design. As you point out, the PFS benefit was minimal, yet statistically significant, at 1.7 months vs 1.9 months (P < .000001), but there was a large separation between the curves after the median was reached. Because the study met its endpoint at a prespecified interim analysis (1.5 months), the study was unblinded and patients receiving placebo were allowed to cross over to regorafenib. This helped to identify a subset that clearly had benefit with regorafenib. Biomarker analyses of plasma and tissue samples are ongoing and should be aided by the study’s clear cutoff point where patients either benefit or do not benefit.

Thomas H. Cartwright, MD:
Of note, the patients who experienced a benefit had a somewhat better performance score.

Alan P. Venook, MD:
One caveat is that this study employed a 2:1 randomization, and the results did not indicate whether the patients’ rate of progression coming on study was the same. Eligibility included progression within 3 months of or during previous therapy, and those are different criteria. Assuming those are matched, then it is a modest benefit. If they are not matched, then it may not even be that much of a benefit.

Again, I think it is an advance, but it also may impede future research because regorafenib is yet another drug that has to be accounted for in a population of patients where, in my opinion, we ought to be putting more emphasis on biomarker‑driven decisions (eg, tumor mutations) and treating patients accordingly. Therefore, I am not sure how much impact this modest advance will really have.

Thomas H. Cartwright, MD:
My conclusion is that this agent potentially meets an unmet need, although the benefit is relatively modest. I would not be surprised if regorafenib were approved. In future trials, the investigators may look at ways to select patients and minimize the toxicity, and may evaluate different dosing regimens (eg, continuous vs 3 weeks on and 1 week off).

OTRA MIRADA DE LAS TERAPIAS DIRIGIDAS EN CÁNCER COLORRECTAL METASTÁTICO: AFLIBERCEPT

Esta es una transcripción del Comité del NICE (National Institute for Health and Care Exellence) Inglés, en el cual analizan las terapias dirigidas en cáncer de colon y su relación con el costo que tienen y los pocos beneficios que se obtienen. Es de hacer notar que no analizan los pacientes que se benefician, ya que esto se sabría si se publicara el NNT (Número de pacientes a tratar, para obtener un resultado). Esta Institución basa sus resultados en comparar los resultados de los grupos de tratamiento en conjunto y los gastos que de ello se derivan.

Si quiere tener una visión más amplia siga el link  http://guidance.nice.org.uk

Appraisal title: Aflibercept in combination with irinotecan and fluorouracil-based therapy for treating metastatic colorectal cancer that has progressed following prior oxaliplatin-based chemotherapy

Key conclusion

Aflibercept in combination with irinotecan and fluorouracil-based therapy is not recommended within its marketing authorisation for treating metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing regimen.

Given the considerable uncertainty around extrapolating overall survival and its implementation within the model, and in the absence of other evidence, the Committee was not satisfied that the estimates from fitting parametric functions to Kaplan–Meier data or those produced by the model were sufficiently robust to accept that the 3-month life extension criterion is fulfilled.

The Committee concluded that the most plausible ICER was higher than the normally acceptable maximum ICER range of £20,000–30,000 per QALY gained

Current practice
Clinical need of patients, including the availability  of alternative treatments	The Committee noted that the current treatment options for patients with metastatic colorectal cancer are limited, and that treatment is determined individually. The Committee heard that resecting tumours surgically may be a treatment option in some patients with metastatic disease, noting that systemic therapy can make resection possible in some patients.
The technology
Proposed benefits of the  technology How innovative is the technology in its potential to make a significant and s ubstantial impact on health-related benefits?	The Committee noted that patients consider biologic therapies such as aflibercept to improve quality of life compared with chemotherapy.
	The Committee heard that, because the overall   survival curves continued to separate for both patients who had or had not stopped treatment, the survival curves might reflect a disease modifying effect in that aflibercept might have altered the natural course of the disease whereby, despite the disease progressing, patients lived longer even after treatment stopped. The Committee agreed that there was no robust evidence to make firm conclusions about the likely cause of the different shapes of the overall survival and progression-free survival curves.
	The Committee acknowledged that aflibercept   represented a novel recombinant fusion protein. However, the Committee concluded that all benefits of a substantial nature relating to treatment with aflibercept plus FOLFIRI had been captured in the QALY calculation.
What is the position of the  treatment in the pathway of care for the condition?	Aflibercept in combination with FOLFIRI has a UK marketing authorisation 'for the treatment of adults with metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing regimen'.
Adverse reactions	The Committee concluded that treatment with   aflibercept plus FOLFIRI was associated with a considerable burden of adverse effects, but that, being a new treatment, less is known about its adverse effects profile than for other available treatments.
Evidence for clinical effectiveness
Availability, nature and quality of evidence	The Committee noted that the evidence on the   clinical effectiveness of aflibercept was derived from the VELOUR trial. The Committee agreed that the VELOUR trial was of good quality and directly relevant to the decision problem. However, the Committee would have liked the manufacturer to have collected and presented trial data relating to health-related quality of life, and would have liked the manufacturer to have followed and presented event data for all patients after the end of the trial as defined. The Committee concluded that the results from the VELOUR trial are generalisable to UK clinical practice.
Relevance to general clinical practice in the NHS	No specific Committee considerations on the relevance to general clinical practice in the NHS.
Uncertainties generated  by the evidence	The Committee noted that, to estimate aflibercept's mean survival benefit of 4.7 months, the manufacturer extrapolated the survival curves from a trial with a median follow-up of just under 2 years up to 15 years. Although the Committee agreed that a small proportion of patients, with as yet undefined characteristics, appeared to derive greater benefit from aflibercept than most patients in the trial, it considered that the manufacturer's extrapolation of overall survival based on a population with a very few patients at risk of dying after 30 months' follow-up over a further 12 years was associated with great uncertainty.
	The Committee was aware that the manufacturer estimated the mean survival benefit of 4.7 months by fitting the log-logistic function to the observed data, and extrapolating the survival curves over 15 years. The Committee noted that the estimates using other parametric functions ranged from 3.0–5.3 months. The Committee was aware that a longer than 5-year survival for patients with metastatic colorectal cancer is very unusual. Having considered the estimates obtained using different parametric functions and extrapolation periods, the Committee was concerned that the log-logistic function had a very 'heavy tail', and that this is likely to have overestimated the survival benefit of aflibercept. The Committee was also concerned that the manufacturer did not characterise the uncertainty around any of the estimates. The Committee concluded that extrapolating overall survival with the log-logistic function over 15 years did not provide a plausible mean overall survival benefit.
Are there any clinically relevant subgroups for  which there is evidence of differential effectiveness?	The Committee agreed that there was no evidence to suggest that aflibercept would be more effective in patients with liver metastases only than in patients with metastases confined to other organs. The Committee was not presented with evidence about rates of resection and cure with aflibercept in the subgroup of patients with liver metastases only. The Committee therefore agreed that aflibercept cannot be considered an effective treatment option to make liver metastases resectable, concluding that this subgroup should not be considered further.
	The Committee heard from the clinical specialists that, in clinical practice, patients who had received oxaliplatin-based therapy in the adjuvant setting and relapsed within the following 6 months would not be treated differently to the overall trial population. In addition, the Committee noted that the analysis for this subgroup was planned after the trial results had been compiled (post hoc), and that the test for interaction did not show that the treatment effect in this subgroup differed from the effect in the rest of the trial population. The Committee therefore concluded that it did not need to consider further the subgroup that excluded patients whose disease had relapsed 6 months or less after starting oxaliplatin-based adjuvant therapy.
Estimate of the size of the  clinical effectiveness including strength of supporting evidence	The Committee agreed that the difference in median overall survival of 1.44 months reflects a statistically significant but clinically small benefit.
	The Committee considered that the manufacturer's extrapolation of overall survival from a population with very few patients at risk of dying after 30 months' follow-up, over a further 12 years, was associated with great uncertainty.
Availability and nature of evidence	The Committee concluded that overall the manufacturer's model adhered to the NICE reference case for assessing cost effectiveness.
Uncertainties around and plausibility of assumptions and inputs in the economic  model	The Committee considered that the manufacturer's assumption that the treatment benefit continues beyond the trial period and until 15 years is highly uncertain given that most patients had died during the 3-year follow-up period of the trial. The Committee considered that the ERG's analysis that allows the hazard ratio to become greater than 1.0 could be considered implausible. The Committee agreed that the ERG's scenario, which assumes equal risk of death for all patients beyond the trial period (hazard ratio equals 1.0), represents an acceptable compromise between the 2 extremes of assuming continuing treatment effect (manufacturer's base case) and allowing for a reversed treatment effect (ERG's second scenario). The Committee noted that, in response to consultation, the manufacturer implemented a new scenario in its revised base case in which the hazard ratio begins to taper to 1.0 36 months after starting treatment, over a 12‑month period. The Committee agreed that as a means to extrapolate overall survival both its preferred scenario (that is, the ERG's first scenario) and the manufacturer's new scenario were associated with some degree of uncertainty. In the absence of further evidence to validate the manufacturer's new approach, the Committee maintained its preference for the ERG's first scenario.
Incorporation of health-related  quality-of-life benefits and utility values Have any potential significant  and substantial   health-related benefits been identified that  were not included in the economic model, and how have  they been considered?	The Committee was aware that the manufacturer got the utility value for the stable-disease state from the 'mCRC utilities study' and revised it after consultation to a value derived from the ASQoP. The Committee noted that the ERG preferred another value from the ASQoP study for the stable-disease state. The Committee concluded that either value could be considered appropriate.
	The Committee considered that the utility value chosen by the manufacturer for the progressed-disease state did not reflect the entire duration of progressed disease but only early progressed disease, and so was likely to be an overestimate. The Committee was aware that, in its base case, the ERG used an alternative lower value of 0.60, which had been used in NICE technology appraisal guidance 118. The Committee agreed that no utility values for progressed disease were universally accepted as valid, but that it would be important that the utility value reflected the entire progressed-disease state. The Committee also agreed that adjusting the utility values for age was appropriate. The Committee concluded that the most plausible utility value for the progressed-disease health state would lie between the manufacturer's and the ERG's estimate.
	The Committee concluded that all benefits of a substantial nature relating to treatment with aflibercept plus FOLFIRI had been captured in the QALY calculation.
Are there specific groups  of people for whom the  technology is particularly cost effective?	Having considered the clinical evidence presented by the manufacturer for the 2 subgroups, the Committee concluded that it did not need to consider the cost effectiveness of the technology for any of the subgroups.
What are the key drivers  of cost effectiveness?	The Committee considered the robustness of the mean overall survival benefit, obtained using the log-logistic function, of 3 months (5 years extrapolation time), 4.7 months (15 years extrapolation time) and 6.6 months (without truncating the survival curves.
	The Committee was aware that the longer the time horizon, the greater the influence of the 'tails' of the extrapolation curves, which define the difference in mean overall survival between the treatment arms, and to which the model is highly sensitive.
	The Committee noted that, because approximately three-quarters of the QALY gain in the model was accrued after disease progression, the model is highly sensitive to utility value for the progressed-disease state in the model.
Most likely cost- effectiveness estimate (given as an ICER)	The Committee noted that the manufacturer's ICER closest to its preferred assumptions was £44,000 per QALY gained (for age 60), but would increase for the higher age bracket, if the mean value was used from the manufacturer's survey of clinical oncologists after removing the outlier and if an extrapolation function with a less heavy tail had been used. Because the manufacturer's ICERs incorporated a utility value for progressed disease deemed by the Committee to be high, the Committee considered the ICER produced by the ERG using the Committee's preferred assumptions, but which used a utility value for progressed disease of 0.6. The Committee noted that this was approximately £51,000 per QALY gained and would be higher if an extrapolation function with a less heavy tail had been used. The Committee therefore concluded that the most plausible ICER was higher than the normally acceptable maximum ICER range of £20,000–30,000 per QALY gained.
Additional factors taken into account
Patient access schemes  (PPRS)	The manufacturer of aflibercept (Sanofi) has agreed a patient access scheme with the Department of Health that makes aflibercept available with a discount. The size of the discount is commercial in confidence.
End-of-life considerations	The Committee agreed that, given the considerable uncertainty around extrapolating overall survival and its implementation within the model, it is important to take into account what has actually been observed in the trial and, in the absence of other evidence, the Committee was not satisfied that the estimates from fitting parametric functions to Kaplan–Meier data or those produced by the model were sufficiently robust to accept that the 3-month life extension criterion is fulfilled. The Committee therefore concluded that aflibercept did not meet the criteria for an end-of-life therapy as defined by NICE.
Equalities considerations and social value judgements	No equality issues relevant to the Committee's   recommendations were raised.

i

Additional factors taken into account
Patient access schemes  (PPRS)	The manufacturer of aflibercept (Sanofi) has agreed a patient access scheme with the Department of Health that makes aflibercept available with a discount. The size of the discount is commercial in confidence.
End-of-life considerations	The Committee agreed that, given the considerable uncertainty around extrapolating overall survival and its implementation within the model, it is important to take into account what has actually been observed in the trial and, in the absence of other evidence, the Committee was not satisfied that the estimates from fitting parametric functions to Kaplan–Meier data or those produced by the model were sufficiently robust to accept that the 3-month life extension criterion is fulfilled. The Committee therefore concluded that aflibercept did not meet the criteria for an end-of-life therapy as defined by NICE.
Equalities considerations and social value judgements	No equality issues relevant to the Committee's   recommendations were raised.

En estas diapositivas se muestra el resultado del protocolo VELOSUR, con sus pobrísimos resultados