Impact of molecular profile on switch maintenance to paclitaxel plus ramucirumab (PTX-RAM) versus continuation of first-line fluoropyrimidine and oxaliplatin (FOX) chemotherapy (ChT) in patients (pts) with advanced HER2-negative gastric or gastroesophageal junction (G/GEJ) cancer: An exploratory endpoint of the ARMANI phase 3 randomized trial.

4060 Background: The ARMANI trial proved the superiority of PTX-RAM switch maintenance over continuation of FOX first-line ChT in patients with advanced HER2-negative G/GEJ cancer. Here, we present the prognostic and predictive impact of baseline gene alterations. Methods: ARMANI was an Italian, multicenter, open-label, randomized phase 3 trial in which patients with HER2-negative G/GEJ cancer who achieved disease control after 3 months of induction FOX chemotherapy were randomized to either PTX-RAM switch maintenance or continuation of FOX. Pre-induction chemotherapy samples were sequenced by means of FoundationOne CDx, a panel comprising 324 cancer-related genes. Variants of unknown significance were filtered out. Presence of at least one pathogenic alteration was used to classify samples as altered or wild-type for the respective pathway (Cell cycle, PI3K, RAS, RTK, TGFβ, TP53 and WNT). Homologous repair deficiency (HRD) positivity was defined as the presence of a positive HRD signature (HRDsig+) as defined by FoundationOne CDx. Results: Sequencing data was available for 130 patients, with 65 patients treated in each arm, and 103 were evaluable for HRDsig. The most frequently altered pathways were TP53 (69.2%), Cell cycle (43.1%), PI3K (24.6%), RTK (24.6%) and RAS (23.1%). Presence of at least one alteration in the WNT pathway was observed for 22/130 patients (16.9%) and was associated with significantly higher rate of objective response to maintenance regimen (55.6% vs 17.3%, p = 0.002), longer mPFS (8.8 vs 6.0 months; HR = 0.54, 95%CI: 0.33-0.89; p = 0.017) and longer mOS (18.1 vs 14.1 months; HR = 0.53, 95%CI: 0.31-0.91, p = 0.021). TP53 pathway status was predictive for OS as switching maintenance to PTX+RAM improved OS in patients without TP53 pathway alterations (mOS 16.8 vs 8.8 months; HR 0.40, 95% CI 0.20–0.78) but not in those with at least one TP53 pathway alteration (mOS 14.7 vs 17.4 months; HR 0.94, 95% CI 0.60–1.48) (p for treatment interaction = 0.044). Ten out of 103 (9.7%) were HRDsig+. HRDsig+ status was not associated with neither PFS nor OS advantage (p = 0.676 and p = 0.623) and was not predictive of better outcomes in the FOX arm (p for treatment interaction for PFS = 0.919 and p for treatment interaction for OS = 0.558). Conclusions: Alterations in the WNT pathway have a positive prognostic significance in patients with G/GEJ cancer who achieved disease control after 3 months of FOX. TP53 pathway alterations bear potential for guiding the choice of PTX+RAM switch maintenance. HRDsig+ is not predictive of sensitivity of FOX in this setting. Clinical trial information: NCT02934464 .