Datamonitor: ESMO 2009 – new lease of life for Vectibix in colorectal cancer?
Results from two Phase III studies presented at the European Society for Medical Oncology Congress 2009 show statistically significant benefits via the addition of Vectibix to both first- and second-line chemotherapy for wild-type KRAS metastatic colorectal cancer. These positive data could help Vectibix to overcome Erbitux’s first-to-market status and usurp its current position.
The Phase III PRIME study investigated first-line FOLFOX4 (5-fluorouracil, leucovorin and oxaliplatin) with or without Vectibix (panitumumab; Amgen) in 1,183 metastatic colorectal cancer patients The addition of Vectibix to standard chemotherapy resulted in a statistically significant increase in progression-free survival of 9.6 months in wild-type KRAS patients, versus 8.0 months for chemotherapy alone (p=0.0234).
Overall response rate in these patients was also increased with the addition of Vectibix, at 55% versus 48% for chemotherapy alone. Median overall survival was not reached in the Vectibix arm, and was 18.9 months in the chemotherapy alone arm, representing a 17% reduction in the risk of death. However, this is not statistically significant, merely showing a trend towards increased survival for Vectibix. Further follow-up data are needed in order to fully quantify this effect, and will be presented at the American Society for Clinical Oncology Gastrointestinal Cancers Symposium in January 2010.
For patients with mutant KRAS, progression-free survival was 7.3 months in the Vectibix arm versus 8.8 months in the chemotherapy alone arm (p=0.0227), representing a 29% increased risk of progression. In terms of overall survival, the addition of Vectibix to chemotherapy resulted in a 53% increased risk of death. Dr Jean-Yves Douillard, who presented the results at the European Society for Medical Oncology Congress 2009 (ESMO), deemed this "important information", and stressed that mutant KRAS patients should not receive Vectibix alongside chemotherapy due to its detrimental effect.
The rate of adverse events was similar in both treatment arms, with the exception of epidermal growth factor receptor (EGFR)-related toxicities such as diarrhea, skin effects and hypomagnesemia in the Vectibix arm, which were expected. Of particular note is that grade 3 infusion-related reactions were only observed in two patients out of the total 593 treated with Vectibix, emphasizing the advantage of the drug’s fully human composition.
Dr Douillard concluded that Vectibix significantly improves progression-free survival when added to first-line FOLFOX4 chemotherapy for wild-type KRAS metastatic colorectal cancer patients, hence confirming the importance of KRAS as a predictive biomarker for response to EGFR-based therapy in colorectal cancer. While some expressed concern over the lack of survival benefit shown to date, Dr Douillard pointed out that this requires a relatively long follow-up, and that some patients are still receiving therapy.
Meanwhile, it was reported that the Phase III 181 study investigating second-line FOLFIRI (5-fluorouracil, leucovorin and irinotecan) with or without Vectibix in 1,186 metastatic colorectal cancer patients met its primary endpoint, with the addition of Vectibix to FOLFIRI showing a statistically significant increased progression-free survival in wild-type KRAS patients of 5.9 months versus 3.9 months for FOLFIRI alone (p=0.004). Vectibix also resulted in slightly longer overall survival in wild-type KRAS patients with 14.5 months in comparison with 12.5 months for chemotherapy alone (p=0.115), although this was not statistically significant. Overall response rate was higher in the Vectibix arm at 35% compared with 10% in the chemotherapy alone arm.
By contrast, between the two treatment arms for mutant KRAS, there was only a negligible difference in progression-free survival (5.0 months for Vectibix versus 4.9 months for chemotherapy alone), overall survival (11.8 months for Vectibix versus 11.0 months for chemotherapy alone) and overall response rate (13% for Vectibix versus 14% for chemotherapy alone).
Adverse events were comparable across the two treatments arms, again with the exception of EGFR-related toxicities in the Vectibix arm, including diarrhea, skin-related events and hypomagnesemia. Particularly of note is the low rate of grade 3/4 infusion-related reactions, observed in only two patients out of the total 591 who received Vectibix.
Dr Mark Peeters, who presented the 181 study results, confirmed that Vectibix significantly improved progression-free survival and was well tolerated when added to standard FOLFIRI for second-line treatment of wild-type KRAS colorectal cancer. This study also confirmed the importance of KRAS as a predictive biomarker for EGFR therapy in colorectal cancer.
Some raised concerns regarding differentiation of the 181 trial from the Phase III EPIC study investigating FOLFIRI plus Erbitux (cetuximab; Eli Lilly/Merck Serono/Bristol-Myers Squibb), another anti-EGFR monoclonal antibody, in the same patient population. Dr Peeters pointed out that in the 181 study, over 90% of tumors were available for KRAS testing, in comparison with only a quarter in the EPIC study. In addition, the EPIC study experienced a relatively high crossover rate of approximately 31% to the active treatment arm. The two studies are therefore not comparable with regards to the active treatment of wild-type KRAS, although the effect in both studies on mutated KRAS was similar. Dr Peeters also pointed out that the response rate of 35% observed with Vectibix was among the highest reported in a second-line metastatic colorectal cancer study.
These data are likely to breathe new life into Vectibix in colorectal cancer, and could be sufficient to help the drug overcome Erbitux’s first-to-market status. Vectibix’s fully human formulation is clearly associated with fewer infusion-related reactions, a significant drawback associated with Erbitux and its humane-murine chimeric formulation. Dosing of Vectibix at every two weeks is more convenient than Erbitux’s weekly administration, and could serve to drive down treatment costs somewhat.
These advantages associated with Vectibix are particularly relevant in light of conflicting data presented for Erbitux at ESMO 2009. While updated CRYSTAL and OPUS results were positive, the addition of Erbitux to chemotherapy in the COIN study showed no benefit in any patient subgroup, regardless of KRAS status. While Vectibix is unlikely to compete with Avastin’s (bevacizumab; Genentech/Roche) dominance in the first-line colorectal cancer setting, it is likely to pose a significant threat to Erbitux in the treatment of wild-type KRAS patients.