FOLFOX/Cetuximab Prolonged Survival in Mutation-Free Colorectal Cancer

Se presentó en ESMO World Congress on Gastrointestinal Cancer 2015, un trabajo de cetuximab mas FOLFOX en el cual se seleccionan los pacientes para no tener ninguna mutación RAS. El ENORME BENEFICIO ES DE 1.9 MESES. Por favor no engañar más a los médicos desprevenidos.

Combination treatment with FOLFOX plus cetuximab resulted in improved progression-free survival compared with FOLFOX alone in patients with metastatic colorectal cancer with “all-RAS” wild-type tumors who had progressed after first-line FOLFIRI plus cetuximab.

However, patients who had tumors with a mutation in KRAS, NRAS, BRAF, and/or PIK3CA genes had a detrimental effect from the combination of FOLFOX plus cetuximab, according to the results of the CAPRI-GOIM study (abstract LBA-09) presented at the European Society for Medical Oncology (ESMO) 17th World Congress on Gastrointestinal Cancer in Barcelona.

“A word of caution: these results generate a very important signal that deserves to be further explored in a larger, randomized, phase III study, that continuing anti-EGFR treatment while switching the chemotherapy backbone in second line is feasible past progression and by identifying patients whose tumor is EGFR-dependent; that by identifying wild-type status for KRAS, NRAS, BRAF, and PIK3CA genes, also identifies patients responsive to this treatment,” said Fortunato Ciardiello, MD, PhD, from Seconda Università degli Studi di Napoli in Naples Italy, in a prepared statement.

The phase II trial included 340 patients with metastatic colorectal cancer and KRAS exon 2 wild-type tumors treated with first-line FOLFIRI plus cetuximab until disease progression or unacceptable toxicity. After progression, these patients were randomly assigned to treatment with FOLFOX plus cetuximab (n = 74) or FOLFOX alone (n = 79). The primary endpoint was progression-free survival.

According to the study results, the median progression-free survival of the intention-to-treat population was 6.4 months for FOLFOX plus cetuximab compared with 4.5 months for FOLFOX alone (hazard ratio [HR] = 0.81; 95% confidence interval [CI], 0.58–1.12; P = .19).

The researchers performed next-generation sequencing in about 75% of cases; 66 patients had “all-RAS” wild-type tumors with no mutations in KRAS, NRAS, BRAF, or PIK3CA genes and 51 patients had tumors harboring a mutation in at least one of these genes.

The median progression-free survival for patients identified as all-RAS wild-type was 6.8 months with combination treatment compared with 5.5 months for FOLFOX alone (HR = 0.80; 95% CI, 0.50–1.29; P = .36). Median progression-free survival in the RAS-mutated population was 2.7 months for FOLFOX plus cetuximab compared with 4.1 months for FOLFOX alone (HR = 1.53; 95% CI, 0.79–2.96; P = .2).

When the researchers looked at those patients considered to be quadruple wild-type, the median progression-free survival was 6.9 months for combination therapy compared with 5.3 months for FOLFOX alone, a significant difference (HR = 0.56; 95% CI, 0.33–0.94; P = .025). In contrast, for patients with any mutation in KRAS, NRAS, BRAF, or PIK3CA, the median progression-free survival was longer for FOLFOX alone compared with combination treatment (4.4 months vs 2.7 months; HR = 1.70; 95% CI, 0.94–3.05; P = .07).

ESMO spokesperson Andrés Cervantes, of University Hospital Valencia in Spain, who was not involved in the study, commented in a press release: “This is a new understanding of how to treat a select group of patients that are wild-type for the KRAS, NRAS, BRAF, and PIK3CA genes who can be treated with the same anti-EGFR antibody and a change in chemotherapy following progression. In the intent-to-treat analysis there is no benefit from this treatment, however, the patients showing no mutation do benefit from this approach.”

Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer

Yo creo que un tratamiento que provee menos de 2 meses en cuanto a período libre de enfermedad y supervivencia es realmente inútil. Si a ello le agregamos que es tóxico y caro, ya es un forma de actuar del laboratorio muy poco ética y extremadamente comercial. Es una pena ver a personas que tienen un nombre en la oncología, prestarse, dinero de por medio a esta farsa.
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Heterogeneity of KRAS, NRAS, BRAF and PIK3CA mutations in metastatic colorectal cancer and potential effects on therapy in the CAPRI GOIM trial

Una mejoría en el tiempo medio a la progresión de menos de un mes en pocos pacientes en segunda línea después de descartar todos los tipos de Ras mutados realmente es una vergüenza. Se leyó y se publica.

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Anti-EGFR Therapy Worsens Survival in Patients With RAS Mutations

There might now be a better way to predict clinical response to panitumumab (Vectibix), according to a new study.

In patients with metastatic colorectal cancer, KRAS mutations have been established as a predictive biomarker of resistance to antiepidermal growth-factor receptor (EGFR) therapy, but other RAS mutations are also predictive.

In fact, the data suggest that patients with other RAS mutations have worse survival when panitumumab is added to a standard chemotherapy regimen.

Patients with nonmutated wild-type KRAS exon 2 who harbored other RAS mutations had inferior progression-free and overall survival when treated with panitumumab plus oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) than when treated with FOLFOX4 alone.

This is consistent with findings in patients with KRAS mutations in exon 2, report Jean-Yves Douillard, MD, PhD, from the Institut de Cancérologie de l'Ouest in Nantes, France, and colleagues. In other words, when a patient has a KRAS mutation in exon 2 or other RAS mutations, they will not benefit from panitumumab.

Conversely, for those without RAS mutations, progression-free and overall survival were better with panitumumab plus FOLFOX4 than with FOLFOX4 alone.

Results from the Panitumumab Randomized Trial in Combination with Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME) were published in the September 12 issue of the New England Journal of Medicine.

Detrimental Effect

In PRIME, the researchers looked at the effect of RAS (KRAS or NRAS) or BRAF mutations on the efficacy and safety of panitumumab plus FOLFOX4 and FOLFOX4 alone.

For patients with no RAS mutations, progression-free survival was better when panitumumab was added to FOLFOX4 (10.1 vs 7.9 months; hazard ratio [HR] for progression or death, 0.72; P = .004). Overall survival was also better with panitumumab (25.8 vs 20.2 months; HR for death, 0.78; P = .04).

However, panitumumab did not improve survival in patients with RAS mutations; it actually had a detrimental effect.

For patients with no KRAS mutation in exon 2 who had other RAS mutations, progression-free survival was worse when panitumumab was added to FOLFOX4 (7.3 vs 8.0 months). Overall survival was also worse (17.1 vs 17.8 months).

Clinical Implications

So what does this mean clinically?

In an accompanying editorial, Jordan Berlin, MD, from the Vanderbilt–Ingram Cancer Center in Nashville, Tennessee, notes that the benefit of excluding patients with RAS mutations from anti-EGFR antibody therapy is "logical and expected," but the harm was not anticipated.

Even though data from this study are "not definitive enough to require a change from the limited KRASexon 2 testing currently performed" to broadly assess RAS status, "presuming other analyses support these results, it would be difficult to justify taking a long time to change practices," writes Dr. Berlin.

He adds that because the PRIME results show that panitumumab plus FOLFOX4 is less effective than FOLFOX4 alone in the presence of other RAS mutations, the need to quickly confirm or refute these data is "even greater."

"The PRIME study aroused concern that a subgroup of patients may be harmed by the combination of an anti-EGFR therapy with FOLFOX4," he continues. "Thus, it will be difficult to recommend incorporation of these regimens into first-line therapy in metastatic colorectal cancer."

These data might also complicate the integration of forthcoming results from head-to-head comparison trials of bevacizumab and anti-EGFR therapy into daily clinical practice, Dr. Berlin points out.

"Therefore, the reanalysis of the PRIME study is the next important step in the development of a biomarker for the efficacy of anti-EGFR antibody therapy in colorectal cancer," he concludes.

Study Details

Dr. Douillard and colleagues conducted a prospective–retrospective biomarker analysis of 1183 patients with metastatic colorectal cancer.

Of the 1060 patients (90%) with RAS status available, 512 (48%) had tumors with nonmutated RAS and 548 (52%) had tumors with mutated RAS (any KRAS or NRAS mutation in exon 2, 3, or 4). In addition, 108 of the patients who had no KRAS mutations in exon 2 had other RAS mutations.

RAS and BRAF status was ascertained in 1047 of the 1183 patients (89%). Of the 619 patients with noKRAS mutation in exon 2 who were evaluated for BRAF, 53 (9%) had V600E mutations.

For patients with no RAS or BRAF mutation, the improvement in progression-free survival was 1.6 months when panitumumab was added to FOLFOX4, and the improvement in overall survival was 7.4 months.

The researchers note that there were "minor differences" in the 2 treatment groups for patients withBRAF mutations but no RAS mutations, but these were not significant.

In patients treated with panitumumab plus FOLFOX4, adverse events were similar in patients with noRAS mutations and in those with no KRAS mutations in exon 2 (from a previous analysis reported in J Clin Oncol. 2010;28:4697-4705). Similarly, the safety profile was similar in patients with RAS mutations and in those with KRAS mutations in exon 2.

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Editorial

Adjuvant Chemotherapy for Locally Advanced Rectal Cancer: Is It a Given?

Se analiza y se recomienda el uso de la quimioterapia en el cáncer de recto avanzado T 3 o ganglios positivos, ya que es de utilidad, pero no siempre se utiliza en la práctica.

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Phase III Trial of Cetuximab With Continuous or Intermittent Fluorouracil, Leucovorin, and Oxaliplatin (Nordic FLOX) Versus FLOX Alone in First-Line Treatment of Metastatic Colorectal Cancer: The NORDIC-VII Study

No todos los trabajos muestran utilidad del Cetuximab en cáncer colorrectal avanzado.

Abstract

Purpose The NORDIC-VII multicenter phase III trial investigated the efficacy of cetuximab when added to bolus fluorouracil/folinic acid and oxaliplatin (Nordic FLOX), administered continuously or intermittently, in previously untreated metastatic colorectal cancer (mCRC). The influence of KRAS mutation status on treatment outcome was also investigated.

Patients and Methods Patients were randomly assigned to receive either standard Nordic FLOX (arm A), cetuximab and FLOX (arm B), or cetuximab combined with intermittent FLOX (arm C). Primary end point was progression-free survival (PFS). Overall survival (OS), response rate, R0 resection rate, and safety were secondary end points.

Results Of the 571 patients randomly assigned, 566 were evaluable in intention-to-treat (ITT) analyses. KRAS and BRAF mutation analyses were obtained in 498 (88%) and 457 patients (81%), respectively. KRAS mutations were present in 39% of the tumors; 12% of tumors had BRAF mutations. The presence of BRAF mutations was a strong negative prognostic factor. In the ITT population, median PFS was 7.9, 8.3, and 7.3 months for the three arms, respectively (not significantly different). OS was almost identical for the three groups (20.4, 19.7, 20.3 months, respectively), and confirmed response rates were 41%, 49%, and 47%, respectively. In patients withKRAS wild-type tumors, cetuximab did not provide any additional benefit compared with FLOX alone. In patients with KRAS mutations, no significant difference was detected, although a trend toward improved PFS was observed in arm B. The regimens were well tolerated.

Conclusion Cetuximab did not add significant benefit to the Nordic FLOX regimen in first-line treatment of mCRC.

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