Background: Despite 1^st-line response rates (RR) in mCRC of > 50% with FOLFOX or FOLFIRI, 2^nd-line RRs are less (FOLFOX ~ 15%; FOLFIRI ~ 4%). Thus, there is a critical need for better 2^nd-line strategies. Although use of anti-EGFR antibodies with chemotherapy has validated EGFR as a target in wt-KRAS mCRC, combining anti-EGFR tyrosine-kinase-inhibitors (TKIs) with chemotherapy has not shown consistent activity/tolerability. In vitro, anti-EGFR TKIs can induce a G0/G1 cell cycle arrest that attenuates chemo-induced apoptosis. However, when we alternately sequenced chemotherapy with erlotinib in HCT116p53+/+ CRC cells (mut-KRAS), we found markedly enhanced apoptosis (compared to chemotherapy alone or concurrent chemo/erlotinib). Based on these results, we initiated a clinical trial to alternately sequence 2^nd-line chemotherapy with erlotinib in mCRC. Methods: Non-randomized, parallel Simon’s two-stage phase II (optimum design) using 2^nd-line (opposite of 1^st-line) mFOLFOX6 or FOLFIRI (d1,2; d14,15) alternating with erlotinib (E) 100 mgs qd (d3-8; d16-21). Primary objective: radiographic RRs by RECIST criteria. Secondary objectives: time to progression (TTP), 2^nd progression free survival (PFS), toxicity and tolerability. 1^st stage analysis at 10 pts/arm: mFOLFOX6/E or FOLFIRI/E arms will continue if >2/10 pts, or >1/10 pts, respectively with CR/PRs. 2^nd-stage analysis at 29 pts/arm: mFOLFOX6/E or FOLFIRI/E will be considered promising if > 4/29 pts, or > 6/29 pts, respectively demonstrate CR/PRs. Results: n=15 pts to date. Of evaluable pts: 2 PR, 4 SD, 3 PD were observed in the FOLFIRI/E arm (n=9) and 1 SD in mFOLFOX6/E arm (n=1). Gr3/4 toxicities (n=10 evaluable pts): neutropenia (7), rash (1), nausea (1), oral pain (1), diarrhea (1), elevated LFTs (1), hyponatremia (1), elevated INR (1), GI bleed (1), abd pain (1). Dose reductions/treatment delays in evaluable pts: FOLFIRI/E (n=4/9); mFOLFOX6/E (n=0/1). Conclusions: The FOLFIRI/E arm demonstrates sufficient responses to expand accrual into the 2^nd-stage. The mFOLFOX6/E arm continues 1^st-stage accrual. Toxicities were generally manageable. Molecular correlates are ongoing.