Prof. Dr. med. Bernhard Pestalozzi's statement on the following questions:

• At WCGIC congress 2017, the new ESMO guidelines were presented, what are your recommendations now for the treatment of mCRC RAS wildtype patients in first line?
• Could you please explain the key findings of the CRICKET study and its implications for clinicians?
• Regarding Cetuximab, could a rechallenge be considered in the daily clinical practice?


Rechallenge with cetuximab + irinotecan in 3rd-line in RAS and BRAF wild-type metastatic colorectal cancer (mCRC) patients with acquired resistance to 1st-line cetuximab1irinotecan:

The phase II CRICKET study by GONO

Rossini Daniele, Santini Daniele, Cremolini Chiara, Salvatore Lisa, et al.

Annals of Oncology (2017) 28 (suppl_3): iii1-iii12. 10.1093/annonc/mdx263

Introduction: Clinical benefit from rechallenge with cetuximab based therapy in KRAS wild-type mCRC patients previously treated with the same anti-EGFR-based regimen was suggested in a retrospective study. Molecular data highlighting the dynamism of intratumoral heterogeneity under the pressure of systemic treatments may explain this finding.

Methods: CRICKET (NCT02296203) is a multicenter phase II single-arm study in mCRC patients, who became resistant to 1st-line cetuximab + irinotecan. Main eligibility criteria are: measurable, unresectable mCRC; RAS/BRAF wild-type status; prior 1st-line irinotecan-based, cetuximab-containing regimen with at least RECIST partial response (PR), 1st-line progression-free survival (PFS) 6 months, and progression (PD) within 4 weeks after the last administration of cetuximab; prior 2nd-line oxaliplatin-based and bevacizumab-containing treatment. Patients receive 3rd-line cetuximab + irinotecan until PD. The primary endpoint is response rate (RR) according to RECIST v1.1. Based on the Fleming single-stage design, setting p0 = 5%, and p1 = 20%, with 1-sided-α and ß errors of 0.05 and 0.20, 27 patients were required. The null hypothesis P ≥ p0 would have been rejected if RECIST response had been observed in 4 patients.

Results: Between Jan 2015 and Jan 2017, 22 patients were enrolled in 6 centers. Patients’ characteristics are: median age 70 yrs, ECOG PS 0/1-2 59%/41%, primary location right/left 36%/64%, time from diagnosis of metastases >18 months 77%. At the time of data cut-off (Jan 15, 2017), 20 patients were evaluable for response. The primary endpoint was met. Five PRs (one unconfirmed) were reported (RR: 25%). Four SD (disease control rate: 45%) and 8 PD were observed. Three patients experienced clinical PD before disease assessment. No unexpected adverse events were evident.

Conclusion: Rechallenge with cetuximab + irinotecan is active in some patients with RAS and BRAF wild-type mCRC, initially sensitive and then resistant to first-line irinotecan-based chemotherapy + cetuximab. Analyses on cfDNA collected at study entry are ongoing in order to verify whether the detection of markers of acquired resistance to cetuximab may help to identify patients more likely to benefit from this strategy.

Partially funded by Merck Serono SpA.