IMPORTANCE Few studies are available on the role of maintenance strategies after induction treatment regimens based on anti-epidermal growth factor receptors, and the optimal regimen for an anti-epidermal growth factor receptors-based maintenance treatment in patients with RAS wild-type metastatic colorectal cancer is still to be defined. OBJECTIVETo determine whether maintenance therapy with single-agent panitumumab was noninferior to panitumumab plus fluorouracil and leucovorin after a 4-month induction treatment regimen. DESIGN, SETTING, AND PARTICIPANTSThis open-label, randomized phase 2 noninferiority trial was conducted from July 7, 2015, through October 27, 2017, at multiple Italian centers. Patients with RAS wild-type, unresectable metastatic colorectal adenocarcinoma who had not received previous treatment for metastatic disease were eligible. Induction therapy consisted of panitumumab plus FOLFOX-4 (panitumumab, 6 mg/kg, oxaliplatin, 85 mg/m 2 at day 1, leucovorin calcium, 200 mg/m 2 , and fluorouracil, 400-mg/m 2 bolus, followed by 600-mg/m 2 continuous 24-hour infusion at days 1 and 2, every 2 weeks). Cutoff date for analyses was July 30, 2018. INTERVENTIONSPatients were randomized (1:1) to first-line panitumumab plus FOLFOX-4 for 8 cycles followed by maintenance therapy with panitumumab plus fluorouracil-leucovorin (arm A) or panitumumab (arm B) until progressive disease, unacceptable toxic effects, or consent withdrawal. The minimization method was used to stratify randomization by previous adjuvant treatment and number of metastatic sites. MAIN OUTCOMES AND MEASURESThe prespecified primary end point was 10-month progression-free survival (PFS) analyzed on an intention-to-treat basis with a noninferiority margin of 1.515 for the upper limit of the 1-sided 90% CI of the hazard ratio (HR) of arm B vs A. RESULTSOverall, 229 patients (153 male [66.8%]; median age, 64 years [interquartile range (IQR), 56-70 years]) were randomly assigned to arm A (n = 117) or arm B (n = 112). At a median follow-up of 18.0 months (IQR, 13.1-23.3 months]), a total of 169 disease progression or death events occurred. Arm B was inferior (upper limit of 1-sided 90% CI of the HR, 1.857). Ten-month PFS was 59.9% (95% CI, 51.5%-69.8%) in arm A vs 49.0% (95% CI, 40.5%-59.4%) in arm B (HR, 1.51; 95% CI, 1.11-2.07;P = .01).Duringmaintenance,armAhadahigherincidenceofgrade3orgreatertreatment-related adverse events (36 [42.4%] vs 16 [20.3%]) and panitumumab-related adverse events (27 [31.8%] vs 13 [16.4%]), compared with arm B. CONCLUSIONS AND RELEVANCEIn patients with RAS wild-type metastatic colorectal cancer, maintenance therapy with single-agent panitumumab was inferior in terms of PFS compared with panitumumab plus fluorouracil-leucovorin, which slightly increased the treatment toxic effects. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02476045

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Refining the selection of HER2-positive metastatic gastric cancer patient candidates for trastuzumab is a challenge of precision oncology. Preclinical studies have suggested several genomic mechanisms of primary resistance, leading to activation of tyrosine kinase receptors other than HER2 or downstream signaling pathways. We carried out this multicenter, prospective, case-control study to demonstrate the negative predictive impact of a panel of candidate genomic alterations (AMNESIA panel), including mutations and amplifications. Hypothesizing a prevalence of candidate alterations of 30% and 0% in resistant and sensitive HER2-positive patients, respectively, 20 patients per group were needed. AMNESIA panel alterations were significantly more frequent in resistant (11 of 20, 55%) as compared with sensitive (0% of 17) patients ( < 0.001), and in HER2 IHC 2 (7 of 13, 53.8%) than 3 (4 of 24, 16.7%) tumors ( = 0.028). Patients with tumors bearing no candidate alterations had a significantly longer median progression-free [5.2 vs. 2.6 months; HR, 0.34; 95% confidence interval (CI), 0.07-0.48; = 0.001] and overall survival (16.1 vs. 7.6 months; HR, 0.38; 95% CI, 0.09-0.75; = 0.015). The predictive accuracy of the AMNESIA panel and HER2 IHC was 76% and 65%, respectively. The predictive accuracy of the combined evaluation of the AMNESIA panel and HER2 IHC was 84%. Our panel of candidate genomic alterations may be clinically useful to predict primary resistance to trastuzumab in patients with HER2-positive metastatic gastric cancer and should be further validated with the aim of molecularly stratifying HER2-addicted cancers for the development of novel treatment strategies. .

Tumors bearing homologous recombination deficiency are extremely sensitive to DNA double strand breaks induced by several chemotherapeutic agents. ATM gene, encoding a protein involved in DNA damage response, is frequently mutated in colorectal cancer (CRC), but its potential role as predictive and prognostic biomarker has not been fully investigated. We carried out a multicenter effort aimed at defining the prognostic impact of ATM mutational status in metastatic CRC (mCRC) patients. Mutational profiles were obtained by means of next-generation sequencing. Overall, 35 out of 227 samples (15%) carried an ATM mutation. At a median follow-up of 56.6 months, patients with ATM mutated tumors showed a significantly longer median overall survival (OS) versus ATM wild-type ones (64.9 vs 34.8 months; HR, 0.50; 95% CI, 0.29–0.85; P = 0.01). In the multivariable model, ATM mutations confirmed the association with longer OS (HR, 0.57; 95% CI, 0.33–0.98; P = 0.04). The prognostic impact of ATM mutations was independent from TP53 mutational status and primary tumor location. High heterogeneity score for ATM mutations, possibly reflecting the loss of wild-type allele, was associated with excellent prognosis. In conclusion, we showed that ATM mutations are independently associated with longer OS in patients with mCRC.

These "real-life" efficacy data on ramucirumab treatment are in line with previous randomized trials. Ramucirumab is well tolerated in daily clinical practice.

TEMIRI regimen is a safe and active option in pre-treated, irinotecan-sensitive mCRC patients with MGMT methylation.

Background Patients with high microsatellite instability (MSI) gastric cancer (GC) show improved survival and no benefit or harm from adjuvant and/or perioperative chemotherapy. The role of immune microenvironment in GC is largely unknown. Materials and Methods In the present study, 256 tumor tissue blocks were centrally collected from patients enrolled in ITACA‐S, a randomized adjuvant trial of 5‐FU/LV versus sequential FOLFIRI and cisplatin‐docetaxel. MSI status was assessed by multiplex PCR, inflammatory reaction by H&E morphological assessment, and programmed death‐ligand 1 (PD‐L1) expression by immunohistochemistry. Results Overall, 9% patients had MSI‐high tumors, 23% had high inflammatory reaction, 11% had tumor PD‐L1 ≥ 1%, and 11% had stromal PD‐L1 ≥ 1%. A significant association with disease‐free survival (DFS) and overall survival (OS) was found for MSI‐high (hazard ratio [HR], 0.43; p = .02; HR, 0.40; p = .02) and high inflammatory reaction (HR, 0.55; p = .010; HR, 0.53; p = .008) but not for PD‐L1. At multivariable analysis, only MSI showed an independent association with both DFS (p = .02) and OS (p = .01), whereas inflammatory reaction showed an independent association only with OS (p = .04). Patients with tumor PD‐L1 ≥ 1% had a significantly longer DFS in sequential chemotherapy than in than 5‐FU/LV arm (interaction p = .04) and a trend for OS (interaction p = .12). Conclusion Our data suggest that MSI status could be a useful prognostic biomarker in patients with radically resected stage II–III GC and should be used as stratification factor in future trials. Tumor PD‐L1 ≥ 1% should be further investigated as a potential predictor of benefit from intensive chemotherapy. Implications for Practice In this post hoc analysis of patients with radically resected gastric cancer randomized to an intensive sequential chemotherapy regimen versus 5‐FU/LV monotherapy as adjuvant treatment in the ITACA‐S trial, MSI‐high status was independently associated with better disease‐free survival and overall survival (OS) and inflammatory reaction was independently associated with better OS. Moreover, tumor PD‐L1 expression ≥1% was associated with greater benefit from intensive sequential chemotherapy compared with 5‐fluorouracil plus leucovorin (5‐FU/LV), whereas PD‐L1 expression <1% was not, conditioning a statistically significant interaction between such biomarker and treatment arms. The meta‐analysis of individual patients’ data from available studies could yield data on the role of MSI status that could inform clinical decisions.

The HER2 splice variant characterized by the deletion of exon 16 and denominated as d16HER2, is associated with HER2-positive breast cancer (BC) aggressiveness, stemness, and trastuzumab susceptibility and is considered to be a “flag” of HER2 dependence. However, with the exception of quantitative real-time PCR analysis, easily reproducible assays are still lacking to clinically detect and quantify the d16HER2 expression. Further, no data on d16HER2 expression and its potential role are available in HER2-positive gastrointestinal malignancies. Here, we used a novel RNA in situ hybridization technique (BaseScope) to discriminate d16HER2 variant expression from the wild type isoform (WTHER2) and to assess their levels across different HER2-positive histological samples. Our results demonstrate the existence of outliers, with d16HER2 mRNA high scores restricted to HER2-positive gastric cancer (GC) and colorectal cancer (CRC) coupled with increased d16HER2 expression compared with BC. Consistent with previously reported data on BC, experiments performed in HER2-positive GC patient-derived xenografts suggest that increased d16HER2 expression is associated with a clinical benefit/response to single-agent trastuzumab. Therefore, d16HER2 may be considered as a “flag” of HER2 dependence in GC and can be clinically investigated as a marker of trastuzumab susceptibility in several other HER2-driven cancers, including CRC. As a clinical proof-of-concept, we indicate that high d16HER2 mRNA scores are exclusively found in patients with a long-term benefit from trastuzumab exceeding 12 months (clinical “outliers”), and that d16HER2 expression is also increased in circulating tumor-released exosomes obtained from baseline plasma samples of long-term responders.