We have previously reported modest activity for the combination of regorafenib and nivolumab (REGONIVO) in chemotherapy resistant MSS mCRC. Given the importance of CTLA-4 inhibition in T-cell priming, we explored the addition of ipilimumab to REGONIVO in a similar patient (pt) population.
Pts with chemotherapy resistant MSS mCRC were enrolled. The first-dose level (DL) consisted of regorafenib (R) at 80 mg QD x 21 days in 4-week cycles while ipilimumab (I) was administered at 1mg/kg Q6 weeks and nivolumab (N) at 240 mg Q 2 weeks. Dose-de-escalation was allowed (decreased in R) if the 1st dose was not tolerated. A 20-pt expansion was enrolled at the recommended dose to establish safety and to explore efficacy.
9 pts were enrolled on the safety cohort and established DL1 as the recommended dose level (RDL). 29 pts were enrolled at the RDL. 7 pts had liver metastases. Overall response rate (ORR), disease control rate (DCR) and progression free survival (PFS) are summarized in Table and are stratified by liver involvement, RAS, and BRAF status. With a median follow-up of 16 months (mo), the median overall survival (OS) was 7 mo in pts with liver mCRC, 14 mo in the overall population, and has exceeded 15 mo (not reached) in pts without liver disease. 5 pts remain on study without PD (12 – 19 mo since treatment start). 18/29 pts had paired ctDNA (baseline and 6 weeks), 8 pts had ctDNA clearance and experienced either PR or PFS > 8 mo. Immune-related toxicities included hepatitis (G3-4, 13.8%, n=4), skin rash (G3, 34.5%, n=10), colitis (G3, 6.9%, n=2), meningitis (G3, 3.4%, n=1), pneumonitis (G2, 3.4%, n=1), hypophysitis (G2, 3.4%, n=1), arthritis (G2, 13.8%, n=4), hypothyroidism (G2, 13.8%, n=4), and hyperthyroidism (G2, 3.4%, n=1). Table: 320MO
|N||ORR% (N)||DCR% (N)||PFS (mo)||ORR% (N)||DCR% (N)||PFS (mo)|
|Overall||29||27.6 (8)||62.1 (18)||4||27.6 (8)||72.4 (21)||5|
|Liver||7||0 (0)||42.9 (3)||2||0 (0)||42.9 (3)||2|
|Non-Liver||22||36.4 (8)||68.2 (15)||5||36.4 (8)||81.8 (18)||6|
|BRAF-MT||3||66.7 (2)||66.7 (2)||66.7 (2)||100.0 (3)|
|RAS-MT||21||28.6 (6)||61.2 (13)||28.6 (6)||71.4 (15)|
|BRAF/RAS-WT||5||0 (0)||60.0 (3)||0 (0)||60.0 (3)|
RIN has substantial activity in MSS mCRC patients without liver involvement with an iRECIST ORR of 36%, iDCR of 82%, and an iRECIST mPFS of 6 mo. Clinical benefits were seen irrespective of BRAF and RAS status.
Clinical trial identification
Legal entity responsible for the study
Institutional funding with drugs provided by BMS.
M.G. Fakih: Other, Research Grant: Amgen, AstraZeneca, Novartis; Other, Speaker’s Bureau: Amgen; Other, Advisory Role: Array, Bayer, GSK, Taiho, Incyte, Pfizer.
All other authors have declared no conflicts of interest.