Panitumumab in Wild-Type KRAS mCRC Trial

Recent biomarker analyses of studies involving the anti-EGFR antibody panitumumab combined with chemotherapy for treatment of metastatic colorectal cancer (mCRC) have advanced clinicians’ ability to prospectively identify patients who are, more or less, likely to respond to this agent.^1-3

In one recent retrospective analysis of three randomized phase III studies with panitumumab—as first-line, secondline, and monotherapy—across each of the three regimens, patients with mutantKRAScodon 12 or 13 mCRC tumors were found to be unlikely to benefit from panitumumab therapy.¹The authors recommended that panitumumab therapy currently be limited to patients with wild-typeKRASmCRC.

Another recently reported, prospectively defined, retrospective biomarker analysis evaluated the effect of panitumumab plus FOLFOX versus FOLFOX alone on overall survival (OS) in patients with mCRC in the phase III PRIME study.²The analysis looked atRAS(KRASorNRAS) orBRAFmutations.

These findings indicated that patients with wild-type RAS mCRC who were treated with the combination regimen containing panitumumab had a statistically significant 6-month survival benefit over patients receiving FOLFOX alone. Patients whose tumors hadRASmutations had significantly worse progression-free survival (PFS) and OS.BRAFmutations displayed no predictive value in this analysis.²

Further evidence emerged from an analysis of PRIME data, reflecting the most mature OS results at the time of its reporting at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting (82% of patients with a survival event), and reinforcing the same findings.³

Activating RAS Mutations Appear Predictive of Panitumumab Effect

Median OS was 23.8 months in patients with wild-typeKRASexon 2 tumors who were treated with panitumumab versus 19.4 months in patients receiving FOLFOX2 alone (hazard ratio [HR] = 0.83;P=.03). As in previous analyses, patients with mutantKRASexon 2 tumors displayed a trend of worse survival following panitumumab treatment (15.5 vs 19.2 months; HR = 1.16;P=.16).³In the first prospective trial comparing an anti-EGFR agent to an anti-VEGF agent in combination with chemotherapy for first-line treatment of mCRC with wild-typeRAS, the phase II PEAK trial⁴randomized 285 treatment-naïve patients with unresectable mCRC.

Results demonstrated that the panitumumab arm significantly prolonged PFS relative to the bevacizumab-plus-FOLFOX6 arm (9.6 months vs 8 months; HR = 0.90; 95% CI, 0.66-0.97;P=.02) and OS. By contrast, the panitumumab regimen had an adverse effect on patients with mutatedKRAS, reducing median PFS and OS (15.5 months vs 19.3 months; HR = 1.24; 95% CI, 1.04-1.62;P=.68).4

PEAK trial investigator Lee Schwartzberg, MD, and colleagues, who had reported these results at the 2012 ASCO Gastrointestinal Cancers Symposium, updated the PEAK data along with analysis ofKRAS/NRASmutations at the 2013 ASCO Annual Meeting.

In a prospective-retrospective analysis of PEAK data, Schwartzberg and colleagues⁵assessed the effects of panitumumab plus FOLFOX6 or bevacizumab plus FOLFOX6 on PFS and OS in wild-typeRAS(KRAS/NRASexons 2, 3, 4) mCRC. (Enrolled patients were required to have wild-typeKRASexon 2 tumors.)

At the same time, the researchers conducted sequencing analyses to detect mutations inKRASexon 3 (codons 59/61), exon 4 (codons 117/146);NRASexon 2 (codons 12/13), exon 3 (codons 59/61), exon 4 (codons 117/146); andBRAFexon 15 (codon 600) among banked specimens.

Median PFS for panitumumab plus FOLFOX6 in this June 2013 report from the PEAK trial was 13.1 months and 9.5 months for bevacizumab plus FOLFOX6 (P=.02). Median OS was not reached at the time of reporting for the panitumumab arm and 29 months for the bevacizumab arm (P=.06).⁵

Heinz-Josef Lenz, MD, codirector of the Colorectal Center and GI Oncology Program at the USC Norris Comprehensive Cancer Center, reflected on the future potential impact of extendedKRAStesting on treatment choices and management of patients with mCRC. “Up to nowKRAStesting has been limited to codons 12 and 13. Now we have learned from the presentation from the PEAK trial at ASCO and in Barcelona [at ESMO 2013] that if we add codons 61, 117, and 146 inKRASandNRAS[we] may actually include up to 20% more patients who [we know] would not benefit from EGFR inhibitors. These are early data from a PEAK trial analysis, so I don’t think that we can say that these are validated data. But we are hoping that extendedKRAStesting can be applied in the FIRE-3 and the CALGB 8045 trials to see if these findings can be further validated. If they can be validated, this might have a dramatic impact on how we screen patients with metastatic colorectal cancer.”

Meanwhile, Amgen, the manufacturer of panitumumab, recently took steps to directly communicate these new data to clinicians, saying that panitumumab “…is not indicated for the treatment of patients withKRASmutation-positive mCRC or for whomKRASmCRC status is unknown. Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix in patients whose tumors hadKRASmutations in codon 12 or 13.”⁶The company also said that it is working with regulatory agencies globally regarding appropriate safety communication to the healthcare community regarding the outcomes of these analyses.

ASCO, ahead of its 2013 Annual Meeting at which these data were to be reported, granted an exception to its policy so that physicians and patients may begin to make treatment decisions based on the new information.

References

1. Peeters M, Douillard J-Y, Van Cutsem E, et al. Mutant KRAS codon 12 and 13 alleles in patients with metastatic colorectal cancer: assessment as a prognostic and predictive biomarkers of response to panitumumab.J Clin Oncol. 2013;31(6):759-765.
2. Oliner KS, Douillard J-Y, Siena S, et al. Analysis of KRAS/NRAS and BRAF mutations in the phase III PRIME study of panitumumab (pmab) plus FOLFOX versus FOLFOX as first-line treatment (tx) for metastatic colorectal cancer (mCRC).J Clin Oncol. 2013;31(suppl; abstr 3511).
3. Douillard J-Y, Siena S, Tabernero J, et al. Overall survival (OS) analysis from PRIME: randomized phase III study of panitumumab (pmab) with FOLFOX4 for first-line metastatic colorectal cancer (mCRC).J Clin Oncol. 2013;31(suppl; abstr 3620).
4. Schwartzberg LS, Rivera F, Karthaus M, et al. PEAK (study 20070509): a randomized phase II study of mFOLFOX6 with either panitumumab (pmab) or bevacizumab (bev) as first-line treatment (tx) in patients (pts) with unresectable wild-type (WT) KRAS metastatic colorectal cancer (mCRC).J Clin Oncol. 2012;30(suppl 34; abstr 446).
5. Schwartzberg LS, Rivera F, Karthaus M, et al. Analysis of KRAS/NRAS mutations in PEAK: a randomized study of FOLFOX6 plus panitumumab (pmab) or bevacizumab (bev) as first-line treatment (tx) for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC).J Clin Oncol. 2013;31(suppl; abstr 3631).
6. Amgen. New analyses identify predictive biomarkers for Vectibix® (panitumumab) in patients with metastatic colorectal cancer [press release]. Available at: http:// wwwext.amgen.com/media/media_pr_detail.jsp?year=2013&releaseID=1820728 Accessed August 27, 2013.