Plasma RAS dynamics and anti-EGFR rechallenge efficacy in patients with RAS/BRAF wild-type metastatic colorectal cancer: REMARRY and PURSUIT trials.

Abstract

3518 Background: Rechallenge with anti-EGFR monoclonal antibody (EGFR mAb) showed certain activities in patients (pts) with RAS/ BRAF V600E wild-type (wt) metastatic colorectal cancer (mCRC), particularly in pts with negative plasma RAS (p RAS) mutation by circulating-tumor DNA (ctDNA) assay at ‘just before’ the rechallenge therapy. However, the efficacy is unknown in pts with RAS/ BRAF wt mCRC whose p RAS was converted to positive once during or after EGFR mAb. Therefore, we conducted REMARRY, a prospective longitudinal study to investigate the p RAS dynamics, and PURSUIT trials, a phase II trial to investigate the efficacy of EGFR mAb rechallenge in pts with p RAS wt just before rechallenge therapy. Methods: The eligibility criteria of REMARRY trial included RAS/ BRAF V600E wt mCRC; ECOG PS 0-1; CR or PR during EGFR mAb; and a refractory ≤ 2 months from the last administration of EGFR mAb. p RAS status by the BEAMing method was prospectively monitored at timepoints of progression on EGFR mAb and each subsequent therapy. The eligibility criteria of PURSUIT trial included enrollment in the REMARRY trial with confirmed p RAS wt prior to enrollment in PURSUIT trial; being refractory or intolerant to fluoropyrimidine, oxaliplatin, and irinotecan; and ≥ 4 months of EGFR mAb-free interval. Study treatment was rechallenge with panitumumab + irinotecan (6 mg/kg + 150 mg/m2 q2wks). Primary endpoint was a confirmed objective response rate (ORR) according to RECIST v1.1. The required number of pts was 45, with a null ORR of 10%, an expected ORR of 25%, power of 85%, and one-sided α of 0.05. Results: Between May 2019 and May 2021, 183 pts with 343 timepoints (median, 2) were enrolled in REMARRY trial from 27 institutions, and 50 pts were enrolled in PURSUIT trial; median age, 68 years; left-sided primary, 44 pts; prior EGFR mAb, 1st/2nd/≥3rd lines was 28/6/16 pts; and p RAS status at progression on prior EGFR mAb, wt/mutant (mt)/unknown in 31/7/12 pts. Confirmed ORR and disease control rate were 14% (90% CI, 7.8%–23.9%) and 80% (95% CI, 67.0%–88.8%), respectively. In addition, 4 pts showed an unconfirmed PR. With a median follow-up time of 8.7 months, median progression-free survival was 3.6 months (95% CI, 3.0 – 4.7 months). The subgroup analysis showed a significantly higher confirmed ORR in pts with a longer EGFR mAb-free interval than a shorter one (> vs. < 365 days, 44.4% vs. 7.3%, p = 0.0037). Without any unexpected safety signals, 58.5% of pts had ≥ grade 3 adverse events. Of 31 patients with wt p RAS at progression on prior EGFR mAb, 5 had a confirmed response (ORR, 16%), whereas no response was observed in patients with 7 p RAS mt (ORR, 0%) (p = 0.25). Conclusions: The primary endpoint of confirmed ORR was not met; however, pts with p RAS wt at progression on prior EGFR mAb may benefit from rechallenge with, implying a lack of or worse response if p RAS becomes positive even once during or after EGFR mAb. Clinical trial information: REMARRY: UMIN000036424 PURSUIT: jRCTs031190096.

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

“…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). Consistent with the observation of previous studies, patients with longer (>365 days) intervals show an increased probability of obtaining a clinical benefit from this anti‐EGFR retreatment with an ORR of 33.3% and a median PFS of >8 months in the overall evaluable population as well as in the subgroup of prior responders, in contrast with those with shorter interval (<365 days, ORR: 20.0%, mPFS: 4.7 months in the overall population; ORR: 16.7%, mPFS: 3.3 months in prior‐responders).…”

“…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.…”

New developments in targeted therapy for metastatic colorectal cancer

“…Furthermore, patients with an EGFR antibody-free interval of over 1 year had a significantly higher ORR (44.4% versus 7.3%, p = 0.0037). 45 The ongoing FIRE-4 phase III randomized controlled trial (RCT) will compare the efficacy of re-challenge cetuximab-chemotherapy treatment with regorafenib in the third-line setting, following disease progression after first-line cetuximab plus FOLFIRI and second-line bevacizumab plus FOLFOX (NCT02934529).…”