Relationship of the emergence of KRAS mutations and resistance to panitumumab in second-line treatment of colorectal cancer (CRC).

e14592 Background: Multiple analyses have concluded anti-EGFR antibodies are detrimental to a majority of patients (pts) whose CRCs harbor mutant KRAS. While panitumumab may benefit some pts with tumors harboring WT KRAS, in the majority the added benefit is small and transient. Recent studies have claimed emergence of KRAS mutations mediates acquired resistance to EGFR inhibitors. Methods: We analyzed published and unpublished data to assess this possibility, calculating growth and regression rate constants and estimating doubling times of CRC. Results: Amongst 24 pts with CRC whose tumors were initially KRAS WT, circulating mutant KRAS transcripts were detected in 9 treated in second line with panitumumab plus chemotherapy [Diaz et al, Nature 2012]. The growth rate of tumor in the 9 pts with circulating MT KRAS was 0.0019 days -1 . This value is statistically indistinguishable [p = .2439] from the growth rate of 0.0021 days -1 calculated for tumors in 15 pts with no detectable circulating MT KRAS transcripts. Both values were also statistically indistinguishable [p = .3055 for MT KRAS; p = .7688 for WT KRAS] from the growth rate [0.002 days -1 ] of tumors in a cohort treated in second line with the same chemotherapy without an EGFR inhibitor. Similar results were observed when growth rates were calculated using CEA values [WT, 0.00087 days -1 ; MT, 0.0024 days -1 ; p = .1265] and similar regression rate constants were also calculated [WT, 0.0114 days -1 ; MT, 0.0117 days -1 ; p = .858]. Furthermore, in pts with detectable serum MT KRAS transcripts the growth rate remained constant even as MT KRAS transcripts appeared to increase. The growth rates allowed us to estimate tumor doubling times of 110 to 124 days in these pts receiving second line therapies, consistent with clinical data for disease progression in second line; and similar to the estimated doubling time of 116 days in the cohort that did not receive panitumumab. Conclusions: Resistance to panitumumab in tumors harboring WT KRAS cannot be explained by overgrowth of cells with MT KRAS. Other mechanisms must be sought to explain the limited efficacy of panitumumab. The data suggest such mechanism(s) are inherent and likely present in the majority of cells.