Cetuximab–Irinotecan Rechallenge Success Reported For Metastatic CRC Patients

Phase II results suggest that patients with RAS and BRAF wild-type metastatic colorectal cancer resistant to first-line cetuximab plus irinotecan may benefit from third-line use

medwireNews: Rechallenge with cetuximab–irinotecan therapy has achieved disease responses in patients with metastatic colorectal cancer (CRC) that have previously developed resistance to the regimen, preliminary research demonstrates. 

However, only patients who were wild-type for both RAS and BRAF in their circulating tumour (ct)DNA responded to the third-line treatment, the investigators report in JAMA Oncology

“These findings lay the foundation for further evaluating the efficacy of anti–epidermal growth factor receptor rechallenge in larger studies including only patients with no mechanisms of acquired resistance detectable in circulating tumor DNA”, say Alfredo Falcone, from Azienda Ospedaliero-Universitaria Pisana in Italy, and co-authors.

The phase II trial included 28 patients with liquid biopsy results available for ctDNA, all of whom had initially responded and achieved at least 6 months of progression-free survival (PFS) following first-line cetuximab plus irinotecan but progressed within 4 weeks of their last cetuximab dose. The patients had also received second-line treatment with oxaliplatin plus bevacizumab.

Rechallenge consisted of biweekly cetuximab 500 mg/m2 plus irinotecan 180 mg/m2 until disease progression, the researchers explain.

The RECIST overall response rate was 21%, meeting the primary endpoint of a 5% lower limit of the 95% confidence interval; this included six partial responses, four of which were confirmed, and nine patients achieved stable disease. The disease control rate was 54%.

When ctDNA taken before rechallenge was assessed, RAS mutations were detected in 48% of the cohort but not in any of the patients who achieved a partial response to the third-line regimen.

And PFS was significantly longer in patients whose ctDNA tested wild-type for RAS than those with a RAS mutation, at 4.0 versus 1.9 months and a hazard ratio for disease progression or death of 0.44.

Discussing their proof-of-concept study findings, the investigators admit that the recruitment of patients at time of rechallenge, after second disease progression, prevents any conclusions about how many patients with RAS and BRAF wild-type disease who respond to initial chemotherapy plus anti-EGFR therapy may be suitable for this third-line approach. 

“Although markers of EGFR dependency are still lacking, patients with RAS and BRAF wild-type left-sided tumors, possibly not showing other molecular mechanisms of intrinsic resistance to EGFR inhibition, who derived clinically meaningful benefit from first-line anti-EGFR–containing therapy, and with undetectable markers of acquired resistance to anti-EGFR monoclonal antibodies in tissue and/or liquid biopsy samples at the time of retreatment, might be the optimal candidates for rechallenge”, they conclude.



Cremolini C, Rossini D, Dell’Aquila E, et al. Rechallenge for patients with RAS and BRAF wild-type metastatic colorectal cancer with acquired resistance to first-line cetuximab and irinotecan. A phase 2 single-arm clinical trial . JAMA Oncol; Advance online publication 21 November 2018.

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