Cetuximab/Irinotecan Rechallenge Active in Resistant Metastatic Colorectal Cancer

Patients with metastatic colorectal cancer (mCRC) with prior resistance to cetuximab plus irinotecan responded to a third-line rechallenge, particularly if their disease harbored wild-type RAS at rechallenge, according to a study presented at the ESMO World Congress on Gastrointestinal Cancer 2018.¹

The multicenter, single-arm, phase 2 CRICKET trial is evaluating the third-line retreatment of patients with mCRC with cetixumab plus irinotecan after an initial response followed by progression of the same regimen in the first line. The purpose of this analysis was to determine if liquid biopsy could be used to select patients for this approach.

The CRICKET trial enrolled patients with mCRC with wild-type RAS and BRAF at baseline. All patients received first-line treatment with cetuximab and irinotecan–containing regimens and demonstrated at least a partial response (PR) by RECIST criteria. After at least a progression-free survival of 6 months and progression within 4 weeks of the last cetuximab dose, all patients received oxaliplatin- and bevacizumab-based second-line therapy. Following the second progression, all patients received cetuximab plus irinotecan until progressive disease. The primary endpoint was response rate.

Circulating tumor DNA (ctDNA) was analyzed at the rechallenge baseline by droplet digital polymerase chain reaction and ultra-deep next-generation sequencing with Ion Torrent S5 XL (Theremo Fisher Scientific) for specific RAS/BRAF mutations.

This analysis included 28 patients, 6 of whom experienced a PR and 9 demonstrated disease stabilization, which resulted in a response rate of 21% (95% CI, 10%-40%) and a disease control rate of 54% (95% CI, 36%-70%).

At rechallenge, 48% of liquid biopsies demonstrated a RAS mutation, and no BRAF or PIK3CA mutations were detected. RAS mutations, however, were not detected in samples from patients who achieved a confirmed PR. Wild-type RAS ctDNA was significantly associated with prolonged progression-free survival with a median of 3.9 months compared with 1.9 months with a RAS mutation (hazard ratio, 0.48; 95% CI, 0.20-0.98; P = .048).

The authors stated that, among patients with metastatic CRC that were initially sensitive and then resistant to cetuximab- and irinotecan-based therapy, this study was “the first prospective demonstration of the activity of rechallenge.” These studies also suggest that wild-type RAS detected in ctDNA may help identify patients who would derive benefit from this approach.

Read more of Cancer Therapy Advisor‘s coverage of the ESMO World Congress on Gastrointestinal Cancer 2018 meeting by visiting the conference page.

Reference

1. Rossini D, Cremolini C, Conca E, et al. Liquid biopsy allows predicting benefit from  rechallenge with cetuximab(cet)1irinotecan(iri) in RAS/BRAF wild-type mCRC patients(pts) with resistance to 1st-line cet+iri: Final results and translational analyses of the CRICKET study by GONO. Ann Oncol. 2018;29 (suppl 5;abstr O-007):v102. doi: 10.1093/annonc/mdy149.006