Abstract 5012
Background
RAS wt unresectable mCRC pts were randomized to FOLFOX + Pan (8 cycles) followed by maintenance with Pan (arm B) or Pan + 5FU/LV (arm A). A prespecified translational endpoint was the evaluation of PRESSING panel, that groups rare genomic markers beyond RAS/BRAFto predict anti-EGFR resistance in addition to primary tumor location (PTL) (Cremolini, Ann Oncol ’17).
Methods
Primary endpoint was PFS. A sample size of 224 pts had 90% power to detect 50% 10-month PFS in arm A, max 15% less in arm B, significance level 0.1 (non-inferiority margin of arm B vs A: 1.515). PRESSING panel analyses: ISH for HER2/METamplification, IHC +/- RNA-seq for ALK/ROS/TRKs/RETfusions, NGS (Hotspot Cancer Panel, Ion Torrent®) for HER2/PI3K/PTEN/low % RAS mutations, PCR for MSI.
Results
229 pts randomized (117 arm A/112 arm B). At updated median follow-up of 18 mos, the upper boundary of 1-sided 90% CI of HR was 1.857. 10-m PFS was 49% in arm B vs 59.9% in arm A (HR=1.51 [1.11-2.07]; p=0.009).
A subgroup of 189 RAS/BRAF wt evaluable pts had available tumor tissue for PRESSING analyses, with 46 (24%) PRESSING-pos tumors.
Table 1 shows PFS according to PTL and PRESSING panel, overall and by treatment arm.
| Number | Median PFS (95% CI), months | HR (95% CI) | log-rank test p | interaction test p | |
| Right- vs left-sided | 40 vs 189 | 7.4 (6.4-9.3) vs 11.2 (10.5-13.2) | 1.83 (1.26-2.68) | 0.002 | - |
| Right-sided: arm B vs A | 21 vs 19 | 7.0 (4.5-8.9) vs 8.7 (5.9-NE) | 2.10 (1.96-4.16) | - | 0.369 |
| Left-sided: arm B vs A | 91 vs 98 | 10.6 (9.4-12.6) vs 12.9 (10.6-15.3) | 1.45 (1.03-2.05) | - | |
| PRESSING-positive vs -negative | 46 vs 143 | 7.7 (6.9-10.3) vs 12.1 (10.8-14.2) | 2.07 (1.43-2.99) | 0.0001 | - |
| PRESSING-positive: arm B vs A | 22 vs 24 | 7.5 (5.5-8.8) vs 11.1 (6.9-14.6) | 2.32 (1.12-4.81) | - | 0.118 |
| PRESSING-negative: arm B vs A | 67 vs 76 | 11.1 (10.6-13.4) vs 13.4 (10.8-18.7) | 1.61 (1.07-2.44) | - |
In post-hoc combined analyses of PTL and PRESSING, right-sided and/or PRESSING-pos tumors were “predicted resistant (R)” (arm B/A: 31/32); left-sided + PRESSING-neg “predicted sensitive (S)” (arm B/A: 58/68). mPFS: 8.1 vs 13.2 mos for predicted R vs S (HR=2.08 [1.47-2.93]; p<0.0001); 7.7 vs 9.9 mos for arm B vs A in predicted R (HR=2.12 [1.16-3.89]), 12.4 vs 14.2 mos for arm B vs A in predicted S (HR=1.54 [0.98-2.40]) (interaction p=0.126).
Conclusions
RAS/BRAFwt, right-sided and/or PRESSING-pos pts receiving maintenance with Pan alone had extremely poor PFS. The PFS benefit of 5FU/LV added to Pan was consistent in all subgroups.
Clinical trial identification
NCT02476045
Editorial Acknowledgement
None