Neoadjuvant chemoradiation (CRT) with or without panitumumab (Pan) in patients with K-ras-unmutated, locally advanced rectal cancer (LARC): A randomized multicenter phase II trial (SAKK 41/07).

Abstract

3546 Background: Disappointingly low rates of pathologic complete remission (pCR) have been noted in several phase II studies in patients (pts) with LARC and unselected K-ras tumor status when combining CRT with the epidermal growth factor receptor (EGFR) inhibitor cetuximab. Pan is a fully human monoclonal antibody binding to the EGFR. Methods: Patients with centrally tested K-ras unmutated, mrT3-4 and/or mrN+ disease, without distant metastases were recruited in 19 centers. Treatment consisted of CRT (1.8 Gy for 25 days) with capecitabine (825mg/m2 bid day1-35) in the standard arm (arm B). Pan (6mg/m2) was added on days -7, 7, 21, 35, 49 in arm A. Surgical resection was performed on day 77 (+/- 7 days). All pts received preemptive treatment including doxycyline and skin care. Primary endpoint was pathological complete tumour response (pCR) prospectively defined as grade 3 (near complete regression) or 4 (complete regression) in the histological grading of regression according to Dworak classification (DC). Central pathology review for DC grade 2 or 3 was performed (completed for all pts arm B, all but 3 arm A). Early secondary endpoints were sphincter preservation, R0 resection, downstaging and safety. Results: 68 pts (40 arm A, 28 arm B) were randomized into two parallel treatment groups. Median CRT doses were similar in both arms (45 Gy RT, capecitabine 92.7% vs. 94.0%). Median Pan dose was 88%. Most common CTC (v 3.0) grade 3/4 toxicities in arm A/B (% of pts) were: diarrhea 20/6, hand-foot-syndrome 2/0, fatigue 2/0, acneiform skin rash 2/0, anastomotic leaks 15/4. One death of unknown reason occurred in arm A, one pts was ineligible in arm B. pCR-rate was was 56% (arm A, based on 36 pts, CI 95% [38, 72]%) and 44 % (arm B, based on 27 pts, CI 95% [25, 65]%); 4/5 pts had DC 4 and 16/5 pts had DC3. Sphincter preservation was achieved in 71/70%, R0 resection 87/93% and downstaging in 87/85%. Conclusions: Addition of Pan to CRT in K-ras unmutated LARC pts is feasible at increased toxicity and resulted in a higher than expected pCR rate, mostly due to grade 3 DC. Further investigations of this active regimen in K-ras selected LARC tumours are warranted.