PURPOSE: The randomized PANAMA trial investigated the efficacy of panitumumab (Pmab) when added to maintenance therapy with fluorouracil and folinic acid (FU/FA) in patients with RAS wild-type metastatic colorectal cancer. METHODS: Following first-line induction therapy with six cycles of FU/FA and oxaliplatin plus Pmab, responding patients (stable disease or partial or complete remission) were randomly assigned (1:1, open-label) to maintenance treatment with either FU/FA plus Pmab or FU/FA alone. The primary objective was to demonstrate superiority of progression-free survival (PFS, time from random assignment until progression or death) in favor of FU/FA plus Pmab with a hazard ratio (HR) of 0.75, a power of 80%, and a significance level of 10%. Secondary end points included overall survival, objective response rate of maintenance therapy, and toxicity. Survival end points were analyzed by the Kaplan-Meier method and compared by log-rank test and Cox regressions. Dichotomous variables were compared by Fisher's exact test; odds ratios were indicated when appropriate. The trial is registered with ClinicalTrials.gov ( NCT01991873 ). RESULTS: Overall, 248 patients were randomly assigned and received maintenance therapy with either FU/FA plus Pmab (125 patients) or FU/FA alone (123 patients). At data cutoff, with 218 events (of 218 needed), PFS of maintenance therapy was significantly improved with FU/FA plus Pmab (8.8 months v 5.7 months; HR, 0.72; 80% CI, 0.60 to 0.85; P = .014). Overall survival (event rate 54%) numerically favored the FU/FA plus Pmab arm (28.7 months v 25.7 months; HR, 0.84; 95% CI, 0.60 to 1.18; P = .32). Objective response rates were 40.8% in patients receiving FU/FA plus Pmab versus 26.0% in patients receiving FU/FA alone (odds ratio, 1.96; 95% CI, 1.14 to 3.36; P = .02). The most frequent Common Terminology Criteria for Adverse Event grade ≥ 3 event during maintenance therapy was skin rash (7.2%). CONCLUSION: In RAS wild-type metastatic colorectal cancer, maintenance therapy with FU/FA plus Pmab induced a significantly superior PFS compared with FU/FA alone. If active maintenance therapy is aspired following induction therapy with FU/FA and oxaliplatin plus Pmab, FU/FA plus Pmab appears to be the most favorable option.

Christopher Maximilian Arends, Savvina Dimitriou, Arndt Stahler, Raphael Hablesreiter, Paulina M Strzelecka, Catarina M Stein, Marlon Tilgner, Ryunosuke Saiki,

Most metastatic colorectal cancer (mCRC) patients succumb to refractory disease due to secondary chemotherapy resistance. To elucidate the molecular changes associated with secondary resistance, we recruited 64 patients with mCRC and hepatic metastases before standard first-line chemotherapy between 2014 and 2018. We subjected DNA from primary tumor specimens (P), hepatic metastasis specimens after treatment (M), and liquid biopsies (L) taken prior to (pre), during (intra), and after (post) treatment to next generation sequencing. We performed Nanostring expression analysis in P and M specimens. Comparative bioinformatics and statistical analysis revealed typical mutational patterns with frequent alterations in TP53, APC, and KRAS in P specimens (n = 48). P and pre-L (n = 42), as well as matched P and M (n = 30), displayed a similar mutation spectrum. In contrast, gene expression profiles classified P (n = 31) and M (n = 23), distinguishable by up-regulation of immune/cytokine receptor and autophagy programs. Switching of consensus molecular subtypes from P to M occurred in 58.3% of cases. M signature genes SFRP2 and SPP1 associated with inferior survival, as validated in an independent cohort. Molecular changes during first-line treatment were detectable by expression profiling rather than by mutational tumor and liquid biopsy analyses. SFRP2 and SPP1 may serve as biomarkers and/or actionable targets.

Background: Amphiregulin (AREG) and epiregulin (EREG) are ligands of the epidermal growth factor receptor (EGFR). Predictive information for anti-EGFR treatment in metastatic colorectal cancer (mCRC) was observed, but data for other agents is limited. Methods: Ligand mRNA expression, RAS, BRAF, PIK3CA mutations and EGFR expression were assessed by RTqPCR, pyrosequencing and immunohistochemistry, respectively, in mCRC tumor tissue of patients participating in the randomized controlled trials FIRE-1, CIOX and FIRE-3. Normalized mRNA expression was dichotomized using median and 3rd quartile. Overall (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier method including univariate and multivariate Cox regression analyses. Penalised spline regression analysis tested interaction of mRNA expression and outcome. Results: Of 688 patients with available material, high AREG expression was detected in 343 (> median) and 172 (> 3^rd quartile) patients, respectively. High AREG expression was associated with significantly higher OS (26.2 vs. 21.5 months, HR 0.80 [95% CI 0.68 - 0.94], p = 0.007), PFS (10.0 vs. 8.1 months, HR 0.74 [95% CI 0.63 - 0.86], p = 0.001) and ORR (63.1 % vs. 51.6 %, p = 0.004) compared to low expression at both threshold values. This effect remained significant in multivariate Cox regression analysis (OS: p = 0.01, PFS: p = 0.002). High AREG mRNA expression interacted significantly with the efficacy of cetuximab compared to bevacizumab (OS: p = 0.02, PFS: p = 0.04) in RAS WT mCRC. Conclusions: High AREG mRNA expression is a favorable prognostic biomarker for mCRC which interacted significantly with efficacy of anti-EGFR treatment.

Purpose: We evaluated additional mutations in RAS wild-type (WT) metastatic colorectal cancer (mCRC) as prognostic and predictive biomarkers for the efficacy of added panitumumab to a 5-fluorouracil plus folinic acid (FU/FA) maintenance as pre-specified analysis of the randomized PanaMa trial. Patients and Methods: Mutations (MUT) were identified using targeted next-generation sequencing (NGS; Illumina Cancer Hotspot Panel v2) and IHC. RAS/BRAF V600E/PIK3CA/AKT1/ALK1/ERBB2/PTEN MUT and HER2/neu overexpressions were negatively hyperselected and correlated with median progression-free survival (PFS) and overall survival (OS) since start of maintenance treatment, and objective response rates (ORR). Univariate/multivariate Cox regression estimated hazard ratios (HR) and 95% confidence intervals (CI). Results: 202 of 248 patients (81.5%) of the full analysis set (FAS) had available NGS data: hyperselection WT, 162 (80.2%); MUT, 40 (19.8%). From start of maintenance therapy, hyperselection WT tumors were associated with longer median PFS as compared with hyperselection MUT mCRC (7.5 vs. 5.4 months; HR, 0.75; 95% CI, 0.52–1.07; P = 0.11), OS (28.7 vs. 22.2 months; HR, 0.53; 95% CI, 0.36–0.77; P = 0.001), and higher ORR (35.8% vs. 25.0%, P = 0.26). The addition of panitumumab to maintenance was associated with significant benefit in hyperselection WT tumors for PFS (9.2 vs. 6.0 months; HR, 0.66; 95% CI, 0.47–0.93; P = 0.02) and numerically also for OS (36.9 vs. 24.9 months; HR, 0.91; 95% CI, 0.61–1.36; P = 0.50), but not in hyperselection MUT tumors. Hyperselection status interacted with maintenance treatment arms in terms of PFS (P = 0.06) and OS (P = 0.009). Conclusions: Extended molecular profiling beyond RAS may have the potential to improve the patient selection for anti-EGFR containing maintenance regimens.