Phase 2 study of anti-EGFR rechallenge therapy with panitumumab with or without trametinib in advanced colorectal cancer.

Abstract

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.

China special issue on gastrointestinal tumors‐Cetuximab retreatment plus camrelizumab and liposomal irinotecan in patients with RAS wild‐type metastatic colorectal cancer: Cohort B of the phase II CRACK study

“…Previously, a retrospective study demonstrated a nonsignificant but clear trend that prior responders with longer interval lengths were more likely to respond to anti‐EGFR retreatment 23 . Recently, Parseghian et al also reported that patients who responded to panitumumab as an anti‐EGFR rechallenge therapy had a longer median interval from prior anti‐EGFR therapy than those nonresponders 4 . In the PURSUIT study, 5 rechallenge with panitumumab and irinotecan resulted in a higher confirmed ORR of 37.5% in patients with a longer anti‐EGFR‐free interval (>365 days) than in those with a shorter interval (<365 days, ORR: 9.5%, P = .0037).…”

“…23 Recently, Parseghian et al also reported that patients who responded to panitumumab as an anti-EGFR rechallenge therapy had a longer median interval from prior anti-EGFR therapy than those nonresponders. 4 In the PURSUIT study, 5 rechallenge with panitumumab and irinotecan resulted in a higher confirmed ORR of 37.5% in patients with a longer anti-EGFR-free interval (>365 days) than in those with a T A B L E 3 Treatment-related adverse events (TRAEs). In addition to efficacy, toxicity is the most important factor in choosing third-line or later-line therapies.…”

“…The combination of anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody (mAb) with chemotherapy is one of the frontline treatment options for patients with RAS and BRAF wild-type (wt) mCRC. In some recently reported prospective studies, [4][5][6][7][8][9] rechallenge with anti-EGFR-based therapies has shown activity in RASwt mCRC patients, with response rates ranging from 2.9% to 31% and progression inevitably develops within 4 months. However, these studies mainly focused on patients who were prior anti-EGFR responders with at least one anti-EGFR-free intervening line of therapy after progression.…”

CtDNA-guided rechallenge with anti-EGFR therapy in RASwt metastatic colorectal cancer: Evidence from clinical practice

“…However, data from two additional prospective studies presented at the 2022 ASCO Meeting reported a less-than-expected ORR of 15% and 20% for blood-based rechallenge with anti-EGFR therapy, even in patients without any acquired resistance mutations. 24,25 More interestingly, recently available data looked at the optimal timing for EGFR-directed rechallenge, suggesting that eight months (corresponding to two half-lives) could reasonably be the best time for reintroducing this treatment strategy in the path of RAS-wild-type mCRC. 16 In our study, the patient population was consistent with the standard population of pretreated mCRC since all patients were exposed to both oxaliplatin and irinotecan in previous lines.…”

Circulating Tumor DNA to Drive Treatment in Metastatic Colorectal Cancer

“…ctDNA may rapidly identify these alterations and allow strategies of “enhanced rechallenge” encompassing not only EGFR blockade but also the prevention or treatment of the escaping refractory clones. This approach was recently investigated by Parseghian and colleagues by adopting a vertical double blockade with EGFR and MEK inhibitors ( 73 ). In this study, rechallenge with panitumumab monotherapy or panitumumab-trametinib was provided according to ctDNA status for RAS , BRAF or MAP2K1 mutant clones.…”