A Phase II study comparing front-line treatment with anti-EGFR drug Vectibix against anti-VEGF therapy Avastin in a genetically defined subset of metastatic colorectal cancer patients has yielded promising results in favor of the anti-EGFR agent.
According to the study authors, which included researchers from Vectibix (panitumumab) sponsor Amgen and from several other institutions, the PEAK trial is the first comparison of an anti-EGFR drug and an anti-VEGF treatment in metastatic colorectal cancer patients with a variety of RAS mutations. Published in the Journal of Clinical Oncology this week, around 280 patients with wild-type KRAS exon 2 tumors were randomized to receive Vectibix plus modified FOLFOX6 (fluorouracil, leucovorin, oxaliplatin) or Roche/Genentech's Avastin (bevacizumab) plus modified FOLFOX6.
The primary analysis of median progression-free survival was similar between the two arms, 10.9 months in the Vectibix arm versus 10.1 months in the Avastin arm. However, median overall survival was 34.2 months for Vectibix-treated patients and 24.3 months for Avastin-treated patients, a statistically significant difference.
Additionally, the researchers led by Lee Schwartzberg of the West Clinic in Memphis, Tenn., conducted a pre-specified expanded genetic analysis on banked patient samples to identify additional RAS mutations in KRAS and NRAS exons 2, 3, and 4 using tests from Qiagen and Roche or local laboratory assays. Additional mutational analysis was performed using bidirectional Sanger sequencing and Transgenomic's Surveyor CRC RAScan Kit. In 170 RAS wild-type patients, there was a 3.5 month improvement in median progression-free survival among those treated with Vectibix versus Avastin, but median overall survival was greatly improved – 41.3 months versus 28.9 months.
"To our knowledge, 41.3 months is the longest reported median overall survival for the use of systemic therapies in the treatment of patients with mCRC," the researchers reported in the paper, noting that the small size of the study limits definitive conclusions. While further investigation in larger trials will be needed to figure out why Vectibix had a limited impact on progression-free survival but a robust effect on overall survival, Schwartzberg and colleagues believe the data suggests that anti-EGFR therapy in combination with chemotherapy may be a better option than anti-VEGF therapy as first-line treatment for metastatic colorectal cancer patients – not just for those who have wild-type KRAS exon 2 tumors but also a broader population that harbor wild-type RAS tumors.
"The results of PEAK offer provocative data suggesting that first-line treatment with an anti-EGFR antibody in conjunction with chemotherapy could be a preferred choice for metastatic colorectal cancer patients with wild-type KRAS tumors," Thomas Abrams, an oncologist at Dana-Farber Cancer Institute, said in reviewing the data from PEAK in a JCO podcast. "While the effect on progression-free survival may have been negligible, there was a significant improvement in overall survival compared to FOLFOX and bevacizumab."
Abrams added that the study also makes a strong case for expanded RAS mutational testing in metastatic colorectal cancer patients, rather than the current standard of care testing restricted to KRAS exon 2 mutations in codons 12 and 13. "If PEAK data suggest KRAS mutations in exons 3 and 4 and NRAS mutations confer at least some degree of resistance to anti-EGFR antibodies, our current standard of testing only for mutations in KRAS exon 2 codons 12 and 13 is insufficient," he said. "By expanding our palate of routine mutational testing, we will be closer to realizing our goal of truly personalized medicine."
Based on this study and data from other trials that have similarly suggested that patients with RAS mutations may have limited response to Vectibix, Amgen has announced plans to develop a next-generation sequencing-based companion diagnostic for the drug. Earlier this year, Amgen announced that it will work with Illumina to advance a companion test for Vectibix on the MiSeqDx platform. Specifically, the test will identify patients' RAS mutation status.
Data from the PRIME trial also support the findings in PEAK suggesting that broader RAS mutation testing should be conducted in metastatic colorectal cancer patients. In PRIME, researchers from Amgen and elsewhere randomized metastatic colorectal cancer patients to receive either Vectibix and FOLFOX4 or just FOLFOX4. The study, published in September in the New England Journal of Medicine, showed that among approximately 500 patients without RAS mutations (KRAS or NRAS), overall survival was 26 months on Vectibix/FOLFOX4 versus 20.2 months on FOLFOX4.
In PRIME, researchers used Transgenomic's RAScan test to gauge molecular markers in patients. Approximately 17 percent of the patients with wild-type KRAS had other RAS mutations. “These mutations were associated with inferior progression-free survival and overall survival with panitumumab–FOLFOX4 treatment, which was consistent with the findings in patients with KRAS mutations in exon 2,” reported researchers led by Jean-Yves Douillard of Institut de Cancérologie de l'Ouest in France.
PEAK researchers believe that the negative impact of additional RAS markers in patients receiving Vectibix is what's behind the seemingly strange results seen in the study with regard to the drug's impact on progression-free and overall survival. In the JCO paper, Schwartzberg and colleagues posit that when the primary progression-free analysis considered the overall wild-type KRAS exon 2 patients, it failed to show significant benefit over the Avastin arm likely because patients had other RAS mutations limiting their response.
Alternatively, the advantage seen in overall survival may be due to the effect of subsequent chemotherapy or anti-VEGF treatment, which 83 percent and 50 percent of patients received, respectively.
"Although the sample size was small, results are consistent with reports suggesting that the combination of anti-EGFR antibodies with oxaliplatin-containing regimens may be predictive of negative outcomes for patients with any mutant RAS metastatic colorectal cancer," the authors wrote. Indeed, in the FIRE3 Phase III study, where wild-type KRAS exon 2 patients were randomized to receive anti-EGFR therapy Erbitux (cetuximab) or Avastin in combination with FOLFIRI (leucovorin, fluorouracil, irinotecan), there was no statistical difference in progression-free survival, but those receiving Erbitux has median overall survival of 28.8 months versus 25 months with Avastin.
"While it is indeed difficult to square the lack of progression-free survival to the significant overall survival benefit, it is reassuring to know that the FIRE 3 results are virtually identical despite a different chemotherapy backbone, FOLFIRI, and a different anti-EGFR antibody, cetuximab," Abrams said. "Further inquiry into the possible reasons for such unexpected findings is clearly needed, including defining the impact of second- and third-line therapies following either first-line anti-EGFR or first-line bevacizumab therapies."
Schwartzberg and colleagues are hoping that the randomized, Phase III CALGB 80405 trial -- which compares Erbitux or Avastin or Erbitux and Avastin in combination with chemotherapy in nearly 3,000 metastatic colorectal cancer patients – will support the results they've generated in PEAK.