A multicenter single-arm phase II trial evaluating the safety and efficacy of panitumumab and irinotecan in patients with Neo RAS wild-type metastatic colorectal cancer (C-PROWESS trial).

3546 Background: Previous studies have demonstrated favorable efficacy of anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) in metastatic colorectal (mCRC) patients with Neo RAS wild type (WT), ie, conversion of RAS status from mutant to WT following treatment. This multicenter, single-arm, phase II trial evaluated the efficacy and safety of panitumumab plus irinotecan for mCRC patients with Neo RAS WT. Methods: Patients with tissue-confirmed RAS mutant mCRC who developed intolerance to or disease progression after fluoropyrimidine, oxaliplatin, and irinotecan were screened for RAS mutation status in circulating tumor DNA (ctDNA) with the OncoBEAM RAS CRC assay. Those without RAS mutations detected within 28 days before enrollment received panitumumab (6 mg/kg) and irinotecan (150 mg/m 2 ) biweekly. The primary endpoint was a response rate (RR) per RECIST 1.1. Secondary endpoints included disease control rate (DCR; response or stable disease), progression-free survival (PFS), overall survival (OS), safety, and biomarker analysis using next-generation sequencing (NGS) of ctDNA (Guardant360). The null hypothesis was a RR of < 4%, and the alternative hypothesis was ≥ 15%, with 80% power and a one-sided 10% significance level. The required sample size is 30. Results: Among 404 patients screened for RAS status in ctDNA, conversion to Neo RAS WT was observed in 54 (13.3%), and 30 patients were enrolled. Median age was 66.5 years old, and 20 (66.7%) were male. Lung was the most frequent site of metastasis (73.3%), and KRAS exon 2 accounted for 80% of prior tissue RAS MT. RR and DCR were 6.7% (80% CI, 1.8 to 16.8) and 76.7% (95% CI, 57.7 to 90.1), respectively. With median follow-up 22.4 months, median PFS was 4.1 months and median OS was 16.8 months. Grade 3 adverse events were observed in 14 patients (46.7%): skin toxicity (13.3%), hypomagnesemia (10.0%), diarrhea (10.0%), appetite loss (10.0%), and anemia (7.0%). No grade ≥4 adverse event was observed. ctDNA NGS results were available for 27 patients and included KRAS (44.4%), NRAS (3.7%), and PIK3CA (7.4%) mutations and ERBB2 amplification (3.7%). RR for patients with none of these mutations (negative hyper-selection cohort) was 16.7% (2/12) while no patient with any of these alterations achieved a response (0/15). Negative hyper-selection was associated with significantly longer PFS and OS (PFS: 6.1 vs 2.9 months, HR, 0.37, 95%CI, 0.16 to 0.87; OS: 25.5 vs 13.1 months, HR, 0.34, 95% CI, 0.12 to 0.99). In multivariate analysis, negative hyper-selection was an independent factor for PFS (HR, 0.12, 95%CI, 0.03 to 0.41) and OS (HR, 0.30, 95%CI, 0.10 to 0.96). Conclusions: Anti-EGFR mAb with chemotherapy may be effective for Neo RAS WT mCRC, especially for patients hyper-selected for absence of gene mutations related to anti-EGFR mAb resistance. Clinical trial information: s031210565.