Abstract
BackgroundTargeted agents are standard treatment for RAS wild-type metastatic colorectal cancer in the first- and second-line settings. This phase 2 study determined the benefit of targeting the epidermal growth factor receptor (EGFR) with panitumumab plus irinotecan in irinotecan-refractory patients.MethodsKRAS exon-2 wild-type patients failing prior irinotecan received panitumumab (6 mg/kg) and irinotecan (180 mg/m²) every 2 weeks. The primary endpoint was the overall response rate (ORR). Secondary endpoints included safety, progression-free survival (PFS) and overall survival (OS). KRAS exon-2 status was evaluated centrally, along with NRAS, BRAF mutations, epiregulin, amphiregulin, PTEN and EGFR copy number status, and correlated with efficacy.ResultsSixty-one patients were treated. Among the 46 wild-type RAS patients, the ORR was 15.2% (seven partial responses), with median PFS of 3.8 months (95% CI 2.7–4.3) and median OS of 12.5 months (95% CI 6.7–15.9). Wild-type BRAF patients showed a 13.0% response rate. No significant correlations between response and baseline biomarker expression were identified. Common grade 3–4 adverse events were diarrhoea and rash (18.0% each), hypomagnesaemia and asthenia (8.2% each).ConclusionsThe addition of panitumumab to irinotecan as salvage therapy is feasible but has limited activity in irinotecan-refractory metastatic colorectal cancer. No biomarkers predictive of response were identified.
Highlights
Targeted agents are standard treatment for RAS wild-type metastatic colorectal cancer in the first- and second-line settings
The success of blocking epidermal growth factor receptor (EGFR) signalling is dependent on Kirsten rat sarcoma viral (KRAS) mutational status, with the efficacy benefits of cetuximab treatment in metastatic colorectal cancer (CRC) patients being confined to tumours wildtype for KRAS codons 12 and 13, while RAS mutations predict adverse outcomes with panitumumab-FOLFOX treatment.[5,6]
In this single-arm combination study, the addition of panitumumab to irinotecan in irinotecan-refractory wild-type KRAS exon-2 metastatic CRC (mCRC) patients gave a 15% response rate. This falls well short of the protocol’s statistical hypothesis threshold of 30%, which was considered to demonstrate an efficacy benefit. It is notably lower than the 35% response rate reported in heavily pre-treated patients harbouring wild-type KRAS treated with panitumumab and irinotecan in the one-arm phase 2 French GERCOR study, as was progression-free survival (PFS)
Summary
Targeted agents are standard treatment for RAS wild-type metastatic colorectal cancer in the first- and second-line settings. Cetuximab was the first to show benefit when added to single-agent irinotecan after fluoropyrimidine-based therapy.[2] Subsequently, two large phase 3 studies demonstrated that the addition of panitumumab to irinotecan as monotherapy or FOLFIRI in wild-type Kirsten rat sarcoma viral (KRAS) patients failing fluoropyrimidine-based therapy improved progressionfree survival (PFS) and response rate, without a significant impact on overall survival (OS).[3,4] The success of blocking EGFR signalling is dependent on KRAS mutational status, with the efficacy benefits of cetuximab treatment in metastatic CRC (mCRC) patients being confined to tumours wildtype for KRAS codons 12 and 13, while RAS mutations predict adverse outcomes with panitumumab-FOLFOX treatment.[5,6] benefit with anti-EGFR antibodies in combination with chemotherapy as front-line therapy in patients with RAS
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