A randomized study of KRAS-guided maintenance therapy with bevacizumab, erlotinib or metronomic capecitabine after first-line induction treatment of metastatic colorectal cancer: the Nordic ACT2 trial.
BACKGROUND
Maintenance treatment (mt) with bevacizumab (bev) ± erlotinib (erlo) has modest effect after induction chemotherapy in metastatic colorectal cancer (mCRC). We hypothesized the efficacy of erlo to be dependent on KRAS mutational status and investigated this by exploring mt strategies with bev ± erlo and low-dose capecitabine (cap).


METHODS
Included patients had mCRC scheduled for first-line therapy, Eastern Cooperative Oncology Group (ECOG) 0-1 and no major comorbidities. Treatment with XELOX/FOLFOX or XELIRI/FOLFIRI + bev was given for 18 weeks. After induction, patients without progression were eligible for randomization to mt; KRAS wild-type (wt) patients were randomized to bev ± erlo (arms wt-BE, N = 36 versus wt-B, N = 35), KRAS mutated (mut) patients were randomized to bev or metronomic cap (arms mut-B, N = 34 versus mut-C, N = 33). Primary end point was progression-free survival (PFS) rate (PFSr) at 3 months after start of mt. A pooled analysis of KRAS wt patients from the previous ACT study was performed.


RESULTS
We included 233 patients. Median age was 64 years, 62% male, 68% ECOG 0, 52% with primary tumor in situ. A total of 138 patients started mt after randomization. PFSr was 64.7% versus 63.6% in wt-B versus wt-BE, P = 1.000; and 75% versus 66.7% in mut-B versus mut-C, P = 0.579, with no significant difference in median PFS and overall survival (OS). In the pooled cohort, median PFS was 3.7 months in wt-B (N = 64) and 5.7 months in wt-BE (N = 62) (hazard ratios 1.03, 95% confidence interval 0.70-1.50, P = 0.867). The frequency of any grade 3/4 toxicities during mt was: 28%/58%/18%/15% (wt-B/wt-BE/mut-B/mut-C).


CONCLUSIONS
Addition of erlo to bev as mt in KRAS wt mCRC did not significantly improve PFS or OS, but it did increase toxicity. KRAS status does not seem to influence the outcome of treatment with erlotinib. Metronomic cap warrants further investigation in mt strategies, given our explorative results.


BACKGROUND
NCT01229813.
Department of Oncology, County Hospital Ryhov, Jönköping helga.hagman@med.lu.se.
H
H
Hagman
Department of Oncology, Karolinska University Hospital, Stockholm.
J-E
JE
Frödin
Department of Oncology, Uppsala University Hospital, Uppsala.
Å
Å
Berglund
Department of Oncology, Skåne University Hospital, Lund/Malmö, Sweden.
J
J
Sundberg
Department of Oncology, Odense University Hospital, Odense, Denmark.
L W
LW
Vestermark
Department of Oncology, Linköping University Hospital, Linköping.
M
M
Albertsson
Department of Oncology, Växjö Hospital, Växjö, Sweden.
E
E
Fernebro
Department of Oncology, Skåne University Hospital, Lund/Malmö, Sweden.
A
A
Johnsson
D059250:Administration, Metronomic; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000068258:Bevacizumab / Q000008:administration & dosage*; D000069287:Capecitabine / Q000008:administration & dosage*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D060828:Induction Chemotherapy; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000556:secondary; D060046:Maintenance Chemotherapy; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D016896:Treatment Outcome
C117307:KRAS protein, human; D000068258:Bevacizumab; D000069287:Capecitabine; D000069347:Erlotinib Hydrochloride; D016283:Proto-Oncogene Proteins p21(ras)
bevacizumab; capecitabine; erlotinib; maintenance treatment; metastatic colorectal cancer; metronomic chemotherapy