In the phase 3 randomized CORRECT trial, REG improved survival vs placebo in treatment-refractory mCRC; 19% of REG-treated patients had PFS >4 m. In the single-arm phase 3b CONSIGN trial (NCT01538680) of REG, adverse events (AEs) and PFS were consistent with phase 3 trials in mCRC. We performed a retrospective analysis of CONSIGN patients with PFS >4 m (long PFS) and ≤4 m (short PFS).
Patients with treatment-refractory mCRC received REG 160 mg QD for 3 wks on/1 wk off until disease progression, death, or unacceptable toxicity. Treatment beyond progression was at the investigator's discretion. PFS (investigator assessed) was the time from treatment assignment to progression or death. Of 2872 patients assigned to REG, 674 (23%) had long PFS and 2198 (77%) had short PFS. Descriptive statistics are reported.
Compared to the short PFS group, the long PFS group had a higher proportion of patients with ECOG PS 0, with no liver metastases, and ≥18 m since diagnosis of metastatic disease (Table). Long PFS patients received a median of 7 cycles (2–29); 75% ≥6 cycles; 34% ≥9 cycles. Short PFS patients received a median of 2 cycles (1–33). Dose reductions due to AEs (long PFS, short PFS) were 65%, 40%; actual mean daily doses were 136 mg, 149 mg, respectively. The most common drug-related NCI-CTCAE v4 grade ≥3 AEs (long PFS, short PFS) were hypertension (20%, 14%), hand–foot skin reaction (19%, 12%), fatigue (13%, 13%), diarrhea (8%, 4%), and hypophosphatemia (8%, 4%).
|Long PFS (n = 674)||Short PFS (n = 2198)|
|Median age, yrs (range)||62 (27–86)||62 (19–89)|
|Age, % ≥70 yrs ≥75 yrs||19 8||23 10|
|ECOG PS, % 0 1||58 41||44 56|
|Liver metastases, % No Yes||32 67||20 80|
|KRAS status, % mutant wild-type||47 49||52 43|
|Primary site of disease, % Colon Rectum Both||66 28 6||64 28 8|
|No. of prior regimens on or after diagnosis of metastatic disease, % 0–2 3 ≥4||22 28 50||28 27 45|
|Time since first diagnosis of metastatic disease to treatment assignment, % |
This exploratory analysis suggests that among patients with mCRC treated with regorafenib, the long PFS (>4 months) subgroup tended to have a higher proportion of patients with better performance status, with no liver involvement, and a longer time since diagnosis of metastatic disease. Higher rates of some AEs and dose reductions in the long PFS group may be related to longer treatment duration.
Clinical trial identification
Legal entity responsible for the study
R. Garcia-Carbonero: Advisory board: Roche, Amgen, Merck, Sanofi, Lilly, Boehringer Ingelheim, Bayer, Novartis, Ipsen. E. Van Cutsem: Corporate-sponsored research: Bayer. F. Ciardiello: Advisory board: Bayer, Roche, Merck Serono, Lilly, Sanofi, AstraZeneca. Corporate-sponsored research: AstraZeneca, Merck Serono, Roche, Bayer. M. Ychou: Advisory board: Bayer, Roche, Merck. J-F. Seitz: Advisory board: Roche, Sanofi-Aventis. R.D. Hofheinz: Corporate-sponsored research: Amgen, Medac, Merck, Roche, Sanofi. U. Verma: Advisory board: Bayer. Speakers bureau: Intramed. A. Grothey: Advisory board: Bayer Corporate-sponsored research: Bayer (institute). A. Miriyala, J. Kalmus, C. Kappeler: Stock ownership: Bayer. Other substantive relationships: Bayer (employee). A. Falcone: Advisory board: Amgen, Roche, Bayer, Lilly, Sanofi, Servier, Merck. Corporate-sponsored research: Roche, Amgen, Bayer, Merck, Sanofi. All other authors have declared no conflicts of interest.