a multicenter multicohort phase ii study of trastuzumab deruxtecan ds 8201a in subjects with her2 expressing metastatic colorectal cancer

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a multicenter multicohort phase 2 study of trastuzumab deruxtecan ds 8201a in subjects with her2 expressing metastatic colorectal cancer trial in progress

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Landscape of KRASG12C, Associated Genomic Alterations, and Interrelation With Immuno-Oncology Biomarkers in KRAS-Mutated Cancers

Genomic alterations; Mutated cancers; Immuno-oncologyAlteraciones genómicas; Cánceres mutados; Inmuno-oncologíaAlteracions genòmiques; Càncers mutats; Immuno-oncologiaPURPOSE Promising single-agent activity from sotorasib and adagrasib in KRASG12C-mutant tumors has provided clinical evidence of effective KRAS signaling inhibition. However, comprehensive analysis of KRAS-variant prevalence, genomic alterations, and the relationship between KRAS and immuno-oncology biomarkers is lacking. MATERIALS AND METHODS Retrospective analysis of deidentified records from 79,004 patients with various cancers who underwent next-generation sequencing was performed. Fisher's exact test evaluated the association between cancer subtypes and KRAS variants. Logistic regression assessed KRASG12C comutations with other oncogenes and the association between KRAS variants and immuno-oncology biomarkers. RESULTS Of the 79,004 samples assessed, 13,758 (17.4%) harbored KRAS mutations, with 1,632 (11.9%) harboring KRASG12C and 12,126 (88.1%) harboring other KRAS variants (KRASnon-G12C). Compared with KRASnon-G12C across all tumor subtypes, KRASG12C was more prevalent in females (56% v 51%, false discovery rate-adjusted P value [FDR-P] = .0006), current or prior smokers (85% v 56%, FDR-P 60 years (73% v 63%, FDR-P ≤ .0001). The most frequent KRAS variants across all subtypes were G12D (29.5%), G12V (23.0%), G12C (11.9%), G13D (6.5%), and G12R (6.2%). KRASG12C was most prevalent in patients with non–small-cell lung cancer (9%), appendiceal (3.9%), colorectal (3.2%), tumor of unknown origin (1.6%), small bowel (1.43%), and pancreatic (1.3%) cancers. Compared with KRASnon-G12C-mutated, KRASG12C-mutated tumors were significantly associated with tumor mutational burden-high status (17.9% v 8.4%, odds ratio [OR] = 2.38; FDR-P < .0001). KRASG12C-mutated tumors exhibited a distinct comutation profile from KRASnon-G12C-mutated tumors, including higher comutations of STK11 (20.59% v 5.95%, OR = 4.10; FDR-P < .01) and KEAP1 (15.38% v 4.61%, OR = 3.76; FDR-P < .01). CONCLUSION This study presents the first large-scale, pan-cancer genomic characterization of KRASG12C. The KRASG12C mutation was more prevalent in females and older patients and appeared to be associated with smoking status. KRASG12C tumors exhibited a distinct comutation profile and were associated with tumor mutational burden-high status

Top-percentile traffic routing problem by dynamic programming

Multi-homing is a technology used by Internet Service Provider (ISP) to connect to the Internet via different network providers. To make full use of the underlying networks with minimum cost, an optimal routing strategy is required by ISPs. This study investigates the optimal routing strategy in case where network providers charge ISPs according to top-percentile pricing. We call this problem the Top-percentile Traffic Routing Problem (TpTRP). The TpTRP is a multistage stochastic optimisation problem in which routing decision should be made before knowing the amount of traffic that is to be routed in the following time period. The stochastic nature of the problem forms the critical difficulty of this study. In this paper several approaches are investigated in modelling and solving the problem. We begin by modelling the TpTRP as a multi-stage stochastic programming problem, which is hard to solve due to the integer variables introduced by top-percentile pricing. Several simplifications of the original TpTRP are then explored in the second part of this work. Some of these allow analytical solutions which lead to bounds on the achievable optimal solution. We also establish bounds by investigation several "naive" routing policies. In the end, we explore the solution of the TpTRP as a stochastic dynamic programming problem by a discretization of the state space. This SDP model gives us achievable routing policies on medium size instances of TpTRP, which of course improve the naive routing policies. With a classification of the SDP decision table, a crude routing policy for realistic size instances can be developed from the smaller size SDP model. © 2011 Springer Science+Business Media, LLC

canstem303c trial a phase 3 study of napabucasin napa in combination with 5 fluorouracil 5 fu leucovorin and irinotecan folfiri in adult patients pts with previously treated metastatic colorectal cancer mcrc trial in progress

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Encorafenib Plus Cetuximab as a New Standard of Care for Previously Treated BRAF V600E–Mutant Metastatic Colorectal Cancer: Updated Survival Results and Subgroup Analyses from the BEACON Study

PURPOSE: BEACON CRC evaluated encorafenib plus cetuximab with or without binimetinib versus investigators' choice of irinotecan or FOLFIRI plus cetuximab in patients with BRAFV600E-mutant metastatic colorectal cancer (mCRC), after progression on 1-2 prior regimens. In the previously reported primary analysis, encorafenib, binimetinib plus cetuximab (ENCO/BINI/CETUX; triplet) and encorafenib plus cetuximab (ENCO/CETUX; doublet) regimens improved overall survival (OS) and objective response rate (ORR; by blinded central review) versus standard of care. The purpose of this analysis was to report updated efficacy and safety data. METHODS: In this open-label, phase III trial, 665 patients with BRAF V600E-mutant mCRC were randomly assigned 1:1:1 to receive triplet, doublet, or control. Primary end points were OS and independently reviewed ORR comparing triplet to control. OS for doublet versus control was a key secondary end point. Updated analyses include 6 months of additional follow-up and ORR for all randomized patients. RESULTS: Patients received triplet (n = 224), doublet (n = 220), or control (n = 221). Median OS was 9.3 months (95% CI, 8.2 to 10.8) for triplet and 5.9 months (95% CI, 5.1 to 7.1) for control (hazard ratio [HR], 0.60 [95% CI, 0.47 to 0.75]). Median OS for doublet was 9.3 months (95% CI, 8.0 to 11.3) (HR v control, 0.61 [95% CI, 0.48 to 0.77]). Confirmed ORR was 26.8% (95% CI, 21.1% to 33.1%) for triplet, 19.5% (95% CI, 14.5% to 25.4%) for doublet, and 1.8% (95% CI, 0.5% to 4.6%) for control. Adverse events were consistent with the prior primary analysis, with grade ≥ 3 adverse events in 65.8%, 57.4%, and 64.2% for triplet, doublet, and control, respectively. CONCLUSION: In the BEACON CRC study, encorafenib plus cetuximab improved OS, ORR, and progression-free survival in previously treated patients in the metastatic setting compared with standard chemotherapy. Based on the primary and updated analyses, encorafenib plus cetuximab is a new standard care regimen for previously treated patients with BRAF V600E mCRC

Subgroup analysis of patients with metastatic colorectal cancer (mCRC) treated with regorafenib (REG) in the CORRECT trial who had progression-free survival (PFS) longer than 4 months

No abstract availabl

Cetuximab and irinotecan as third-line therapy in advanced colorectal cancer patients: a single centre phase II trial

The epidermal growth factor receptor (EGFR), which participates in signalling pathways that are deregulated in cancer cells, is frequently mutated in colorectal-cancer cells. Cetuximab is a monoclonal antibody that specifically blocks the EGFR. We evaluated the efficacy of cetuximab in weekly combination with irinotecan in metastatic colorectal cancer patients refractory to previous treatments based on oxaliplatin or irinotecan. We included 55 heavily pretreated patients (colon/rectum: 34/11, M/F: 16/29, median age 63 years, range: 27–79) whose disease had progressed during or within an oxaliplatin-based first-line chemotherapy and a irinotecan-based second-line regimen. Patients were followed for tumour response and were also evaluated for the time to tumour progression, and safety of treatment. Cetuximab was given at an initial dose of 400 mg m−2, followed by weekly infusions of 250 mg m−2. Irinotecan was administered weekly at the dose of 90 mg m−2. All patients were assessable for treatment efficacy and safety response rate was 25.4% (95% CI: 21.7–39.6%); 38.2% (95 CI: 18.6–39.8%) of patients showed a disease stability as the best response. As a consequence, the overall tumour control rate was 63.6% (95% CI: 46.4–70.6%). The median time to progression was 4.7 months (95% CI: 2.5–7.1 months) and the median survival time was 9.8 months (95% CI: 3.9–10.1 months). The most common G3-4 noncutaneous side toxicities were: diarrhoea (16.4%), fatigue (12.7%) and stomatitis (7.3%). 89.1% of patients developed skin toxicity and 32.6% of cases was of grade 3–4. No allergic reactions were identified at any courses in any patients. Fever was documented in 27.3% of patients and was most commonly recorded after the first administration. Cetuximab has clinically significant activity even in heavily pretreated colorectal cancer patients progressed after both oxaliplatin and irinotecan-based chemotherapy regimens