Abstract 3700: Genomic alterations on first-line panitumumab plus FOLFIRI in metastatic colorectal cancer
Authors: Avallone Antonio , Giuliani Francesco , Nasti Guglielmo , Montesarchio Vincenzo , Santabarbara Giuseppe , Leo Silvana , Malapelle Umberto , Rosati Gerardo , Lotesoriere Claudio , Tamburini Emiliano , Colombo Alfredo , Pepe Francesco , Cardone Claudia , Leone Alessandra , Vitagliano Carlo , Russo Gianluca , Troncone Giancarlo , Giannarelli Diana , De Stefano Alfonso , Budillon Alfredo 
Published: March 2024

Background: IMPROVE is a randomized, non-comparative multicenter, phase 2 study evaluating continuous or intermittent FOLFIRI/PANI, in first-line in patients (pts) with unresectable RAS/BRAF wild-type metastatic colorectal cancer (mCRC). In this trial intermittent FOLFIRI/PANI strategy produced a longer progression-free survival (PFS) on treatment, 17.6 months (mts) vs 11.3 mts, a reduced skin severe toxicity, 18% vs 30%, without any detrimental effect on overall survival (OS), 36.2 mts vs 36.2 mts. The trial also included a prospective genomic alterations (GAs) analysis on circulating tumor DNA with the aim to explore emergence of GAs under the selective pressure of FOLFIRI/PANI.

Methods: We analyzed paired plasma samples (basal and PD) by a commercially available NGS panel enabled to simultaneously analyze KRAS, NRAS, BRAF and PIK3CA hotspot mutations from blood samples. Among them, inspecting default calling parameters on proprietary analysis software (Ion Reporter software 5.2.0), only variants with ⩾5X allele coverage and a quality score ⩾20, within an amplicon that covered at least 1000X alleles was considered. As clonality, the threshold of 0.5% of variant allele frequency (VAF) was established to classify mutations as clonal (VAF⩾0.5%) or subclonal (VAF&lt;0.5%).

Results: Of the 137 pts enrolled in the trial, GAs basal analyses were available for 84 pts. Among these, in 55 (65.5%) no GAs were detected (ND). In the remaining cases, the analysis relieved the presence of mutations for PIK3CA (N=14), KRAS (N=12), NRAS (N=2) and BRAF (N=1). According to the clonality threshold, these GAs were classified as subclonal (SC) in 12 cases (14.3%) and clonal (CL) in 17 (20.2%) cases. Survival analysis according to basal GAs clonality showed a median PFS of 16.6 mts (95% IC 13.0-20.2), 12 mts (95% IC 9.1-14.9) and 25.8 mts (95% IC 17.2-34.5) for ND, CL and SC group, respectively. Median OS was 47.7 mts for ND group (95% IC 34.9-60.5), 26.8 mts for CL (95% IC 25.8-27.8) and not reached for SC group. Moreover, we performed GAs analysis on 61 cases of which basal and PD samples were available. Forty-two cases (68.9%) resulted ND, 7 (11.5%) with SC and 12 (19.7%) with CL GAs.At PD, among 42 ND basal cases, 29 remained ND (69%), 8 (19%) and 5 cases (11.9%) developed SC and CL GAs, respectively. In the SC group, 1 kept SC (14.3%), 4 (57.1%) and 2 (28.6%) cases became ND and CL GAs, respectively. In the CL group, 10 (83.3%) kept CL GAs, 1 (8.3%) case became ND and 1 (8.3%) CL.

Conclusions: These findings suggest that classical GAs associated with anti-EGFR resistance are infrequent with up-front use of anti-EGFR/chemotherapy. Moreover, our data show that basal SC GAs rarely evolve to CL GAs at progression disease and do not affect survival of pts with anti-EGFR/chemotherapy treatment. An update will be provided at the congress. NCT04425239

Citation Format: Antonio Avallone, Francesco Giuliani, Guglielmo Nasti, Vincenzo Montesarchio, Giuseppe Santabarbara, Silvana Leo, Umberto Malapelle, Gerardo Rosati, Claudio Lotesoriere, Emiliano Tamburini, Alfredo Colombo, Francesco Pepe, Claudia Cardone, Alessandra Leone, Carlo Vitagliano, Gianluca Russo, Giancarlo Troncone, Diana Giannarelli, Alfonso De Stefano, Alfredo Budillon. Genomic alterations on first-line panitumumab plus FOLFIRI in metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3700.