Rechallenge with cetuximab, irinotecan may benefit mCRC patients
medwireNews: Approximately one-fifth of patients with RAS and BRAF wild-type metastatic colorectal cancer (mCRC) derive clinical benefit from rechallenge with cetuximab plus irinotecan, Italian researchers report.
Alfredo Falcone (Azienda Ospedaliera Universitaria Pisana, Pisa) and co-authors say their findings “lay the foundation for further evaluating the efficacy of anti–epidermal growth factor receptor [EGFR] rechallenge in larger studies including only patients with no mechanisms of acquired resistance detectable in circulating tumor DNA [ctDNA].”
The phase II CRICKET trial included 28 patients (68% men, median age 69 years) with RAS and BRAF wild-type mCRC who had previously achieved at least a partial response and progression-free survival (PFS) of 6 months or more with a first-line irinotecan- and cetuximab-based regimen but progressed within 4 weeks of the last cetuximab dose. They had also received a prior second-line oxaliplatin- and bevacizumab-based treatment.
In this third-line stetting, all patients were treated with cetuximab 500 mg/m2 every 2 weeks plus irinotecan 180 mg/m2.
During a median follow-up of 15.4 months, none of the patients had a complete response according to RECIST criteria but six achieved a partial response (four confirmed), giving an overall response rate of 21%. In addition, nine patients had stable disease, resulting in a disease control rate of 54%.
Median PFS was 3.4 months and median overall survival (OS) was 9.8 months.
A preplanned analysis of ctDNA collected at rechallenge baseline revealed RAS mutations in 12 (48%) of 25 evaluable patients.
Of note, none of the four patients with a confirmed partial response had detectable RAS mutations, compared with 57% of the 21 who did not achieve a partial response.
Furthermore, median PFS was significantly longer among the patients with RAS wild-type ctDNA than among those with RAS mutated ctDNA, at 4.0 versus 1.9 months. Median OS was also longer among patients with RAS wild-type versus mutated ctDNA, at 12.5 versus 5.2 months, but the difference did not reach statistical significance.
Taken together, these findings indicate that “evaluation of RAS mutational status on ctDNA might be helpful in selecting candidate patients” for rechallenge with cetuximab plus irinotecan, Falcone et al remark.
And despite “the intrinsic limitations of a single-arm phase 2 study”, the researchers say their data “provide a clear signal of activity for the anti-EGFR rechallenge in the third-line setting, in patients with strict clinical and molecular criteria for defining acquired resistance to first-line treatment based on anti-EGFR monoclonal antibodies.”
Writing in JAMA Oncology, the team concludes: “Given the increasing amount of evidence of the role of anti-EGFR–based maintenance after first-line induction regimens, the clinical scenario of anti-EGFR rechallenge might be frequently faced in future clinical practice.”
By Laura Cowen
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