Phase II study of anti-EGFR rechallenge therapy with panitumumab driven by circulating tumor DNA molecular selection in metastatic colorectal cancer: The CHRONOS trial.

Abstract

3506 Background: Despite advances in molecular segmentation of metastatic colorectal cancer (mCRC), beyond RAS status therapeutic actionability remains confined to the limited subgroups of ERBB2 amplified, BRAF mutated and MSI-H patients. Optimization of available treatments is therefore warranted. Rechallenge with anti-EGFR monoclonal antibodies is often empirically used with some benefit as late-line therapy. We previously found that mutant RAS and EGFR ectodomain clones, which emerge in blood during EGFR blockade, decline upon antibody withdrawal leading to regain drug sensitivity. Based on this rationale, we designed CHRONOS, a multicenter phase II trial of anti-EGFR therapy rechallenge guided by monitoring of the mutational status of RAS, BRAF and EGFR in circulating tumor DNA (ctDNA). To our knowledge, this is the first interventional clinical trial of liquid biopsy for driving anti-EGFR rechallenge therapy in mCRC. Methods: Eligible patients were PS ECOG 0-2 RAS/BRAF WT mCRC having first achieved an objective response and then progression in any treatment line with an anti-EGFR antibody containing regimen, displaying RAS, BRAF and EGFR ectodomain WT status in ctDNA at molecular screening after progression to the last anti-EGFR-free regimen. Clonal evolution in ctDNA was analyzed by ddPCR and next generation sequencing. Panitumumab 6 mg/kg was administered IV every two weeks until progression. The primary endpoint was objective response rate (ORR) by RECIST version 1.1 with independent central review. 27 total patients and 6 responses were required to declare the study positive (power = 85%, type I error = 0.05). Results: Between Aug 19, 2019 and Nov 6, 2020 52 patients were screened by liquid biopsy and 36 (69%) were negative in ctDNA for RAS/BRAF/EGFR mutations. Of these, 27 patients were enrolled in 4 centers. Median age was 64 years (range: 42-80). PS ECOG was 0/50%, 1/46%, 2/4%. Previous anti-EGFR was administered in 1st line in 63%, 2nd in 15% and > 2nd in 22%. Median number of previous treatments was 3. The primary endpoint was met, with 8/27 partial responses (PR) observed (2 unconfirmed) (ORR = 30%, 95% CI: 12-47%). Stable disease (SD) was obtained in 11/27 (40%, 95% CI: 24-59%), lasting > 4 months in 8/11. Disease control rate (PR plus SD > 4 months) was therefore obtained in 16/27 (59%, 95% CI: 41-78%). Median progression-free survival was 16 weeks. Median duration of response was 17 weeks (1 ongoing). Maximal grade toxicity was G3, limited to dermatological and occurring in 19% of patients. ctDNA dynamics were studied in all patients. Conclusions: Liquid biopsy-driven rechallenge with anti-EGFR antibodies leads to further objective responses in one third of patients. Genotyping tumor DNA in the blood to direct therapy can be effectively incorporated in the management of advanced CRCs. Clinical trial information: 2016-002597-12.

Tackling Refractory Metastatic Colorectal Cancer: Future Perspectives

“…The phase II CRICKET trial tested the cetuximab rechallenge in 28 irinotecan-pretreated, RAS/BRAF wild-type mCRC patients who had received an anti-EGFR-based first-line therapy, with at least PR for > 6 months, followed by PD [35]. After progression to the second-line therapy, patients were retreated with an irinotecan-based chemotherapy and cetuximab.…”

Role of Circulating Tumor DNA in Gastrointestinal Cancers: Current Knowledge and Perspectives

“…Among them, 16 (31%) were mutated in ctDNA for RAS, BRAF or EGFR ectodomain and avoided a useless treatment by anti-EGFR. Of the 36 (39%) triple wild-type patients, 27 were re-challenged by anti-EGFR and obtained an ORR of 30% [155]. Some ongoing studies, such as the prospective RASINTRO study (NCT-03259009) or the randomized FIRE4 trial (NCT02934529) are currently ongoing to confirm the clinical use of liquid biopsy-driven re-challenge and the predictive impact of RAS mutations in ctDNA for the efficacy of anti-EGFR reintroduction treatment in patients with mCRC (Table 3).…”

Integrating Molecular Biomarker Inputs Into Development and Use of Clinical Cancer Therapeutics

“…In CRC, postoperative serial ctDNA detection identified recurrence before radiological imaging and was predictive of high relapse risk ( Chen et al, 2021 ). ctDNA has suggested a novel therapeutic rechallenge strategy for CRC based on evidence that resistance mechanisms to anti-EGFR therapy extinguish over time off of that therapy ( Misale et al, 2014 ; Parseghian et al, 2019 ; Sartore-Bianchi et al, 2021 ). Moreover, in a prospective real-world study of NSCLC, ctDNA clearance during treatment was correlated with better OS ( Song et al, 2020 ).…”