Phase 2 study of anti-EGFR rechallenge therapy with panitumumab with or without trametinib in advanced colorectal cancer.
Authors: Parseghian Christine Megerdichian , Vilar Sanchez Eduardo , Sun Ryan , Eluri Madhulika , Morris Van K. , Johnson Benny , Morelli Maria Pia , Overman Michael J. , Willis Jason , Huey Ryan , Raghav Kanwal Pratap Singh , Dasari Arvind , Kee Bryan K. , Wolff Robert A. , Shen John Paul Y.C. , Kopetz Scott 
Published: June 2022

3520

Background: In RAS/RAF WT colorectal cancer (CRC), rechallenge with anti-EGFR therapy (EGFRi) in patients (pts) with prior response leads to clinical benefit, with response rates up to 30% in prior trials. However, secondary MTs in the MAPK signaling pathway have been implicated in resistance to EGFRi. We designed a phase 2 trial to evaluate the efficacy of EGFRi rechallenge +/- a MEK inhibitor (trametinib) based on pre-treatment ctDNA MTs. Methods: This trial evaluated the efficacy and safety of EGFRi rechallenge +/- trametinib in pts with RAS/BRAF WT, MSS, treatment refractory mCRC who achieved clinical benefit with prior EGFRi based therapy for ≥16 weeks with subsequent progression. Pre study ctDNA was used to enroll in one of 3 arms: Arm A: Pts with an acquired EGFR ECD MT but absence of RAS/BRAF/MAP2K1 or with absence of any acquired resistance MT (Arm C) at time of study initiation received panitumumab 6 mg/kg IV Q2 wks. Arm B: Pts with an acquired RAS/BRAF/MAP2K1 MT received panitumumab 4.8 mg/kg plus trametinib 1.5 mg PO daily. Pts in Arms A and C were allowed to cross over on progression. The primary endpoint was ORR by RECIST v1.1. Results: 54 pts were enrolled, with 52 evaluable for efficacy. Median age is 59 yrs (range, 37-78), and 23 (46%) are female. Median number of prior therapies was 3. Three, 20, and 31 pts were enrolled in Arms A, B, C, respectively. Grade 3 TREAs occurred in 29 (54%) pts (all receiving the doublet regimen) and included acneiform rash in 17 (31%) and others occurring in < 5% of pts. There were no grade 4 TRAEs. In pts with no acquired MTs (Arm C), ORR was 20% (6/30) (95% CI, 0.07-0.37), DCR 67% (20/30) (95% CI, 0.45- 0.81), and median PFS and OS 4.1 mo and 11.2 mo, respectively. The median DOR was 5.5 mo. 22 patients crossed over to add trametinib at time of progression, without any responses. In contrast, in pts with acquired RAS/RAF/MAP2K1 MTs (Arm B), there were no responses, with DCR of 63% (12/19) (95% CI, 0.36-0.81), and median PFS and OS 2.1 mo and 5.9 mo, respectively. Only 3 pts were identified with EGFR ECD MTs (Arm A), and ORR is 0% (0/3) in this cohort, with DCR 67% (2/3) (95% CI, 0.09-0.99). Pts with PR had a longer median interval from prior EGFRi and longer time on prior EGFRi than those with SD+PD (5.5 vs 3.6 mo; p = 0.03, and 9.5 vs. 8.8 mo; p = 0.03, respectively). Conclusions: CtDNA guided rechallenge leads to responses in 20% of pts without acquired resistance MTs, with DCR of 67%. This exceeds current third line standard options. While panitumumab has the potential to block EGFR ECD mutations arising from cetuximab, these mutations in isolation were uncommon and there were no signals of efficacy. Although the acneiform rash induced by the combination of MEK and EGFR inhibition was manageable with close dermatologic management, the combination failed to improve outcomes for pts with acquired resistance. Alternative approaches to downstream MAPK blockade should be explored to improve outcomes. Clinical trial information: NCT03087071.