A phase II study of daily encorafenib in combination with biweekly cetuximab in patients with BRAF V600E mutated metastatic colorectal cancer: the NEW BEACON study.

BACKGROUND: Patients with BRAF V600E mutated metastatic colorectal cancer (mCRC) have a poor prognosis. The introduction of BRAF targeted therapy with encorafenib and weekly administered cetuximab have shown improved survival with a median progression free survival (PFS) of 4.3 months. However, a regimen with cetuximab given every second week may have comparable efficacy and is more convenient for patients. While BRAF targeted therapy is a new standard therapy in pre-treated patients with BRAF V600E mutated mCRC, resistance invariably occurs and is an emerging challenge. The aim of this study is to investigate the efficacy and tolerability of cetuximab given every second week in combination with daily encorafenib and to explore the correlation between markers of resistance and outcome. METHODS: The study is an open label, single arm, phase II study, investigating the efficacy and tolerability of cetuximab given every second week in combination with encorafenib in patients with BRAF V600E mutated mCRC. Furthermore, we will be investigating mechanisms of response and resistance against BRAF targeted therapy though comprehensive genomic profiling on tumor tissue and blood for circulating tumor DNA analysis. A total of 53 patients (19 + 34 in two steps) will be included according to Simon's optimal two stage design. The primary end point of the study is 2 months PFS rate. DISCUSSION: By combining BRAF inhibitor with cetuximab given every second week we can halve the number of visits in the hospital compared to the currently approved regimen with weekly cetuximab. This seems particularly relevant in a group of patients with a median overall survival of 9.3 months. Resistance after initial response to targeted therapy can be either adaptive (e.g., epigenetic, or transcriptomic alterations) or acquired (selective genetic alterations - e.g., activating de novo mutations) resistance. It is of great importance to untangle these complex mechanisms of resistance in patients with BRAF V600E mutated mCRC to improve treatment strategies in the future potentially even further. TRIAL REGISTRATION: EU Clinical Trial Register, Eudract no. 2020-003283-10 . Registered on 11 November 2020.

TAS-102 with or without bevacizumab in patients with chemorefractory metastatic colorectal cancer: an investigator-initiated, open-label, randomised, phase 2 trial.

BACKGROUND: TAS-102 (trifluridine-tipiracil) has shown a significant overall survival benefit compared with placebo in patients with chemorefractory metastatic colorectal cancer. Inspired by the encouraging results of a small phase 1-2 study, C-TASK FORCE, which evaluated the combination of TAS-102 plus bevacizumab in patients with chemorefractory metastatic colorectal cancer, we aimed to compare the efficacy of TAS-102 plus bevacizumab versus TAS-102 monotherapy in patients receiving refractory therapy for metastatic colorectal cancer . METHODS: This investigator-initiated, open-label, randomised, phase 2 study enrolled patients (aged ≥18 years) with metastatic colorectal from four cancer centres in Denmark. The main inclusion criteria were histopathologically confirmed metastatic colorectal cancer refractory or intolerant to a fluoropyrimidine, irinotecan, oxaliplatin, and cetuximab or panitumumab (only for RAS wild-type), and WHO performance status of 0 or 1. Previous therapy with bevacizumab, aflibercept, ramucirumab, or regorafenib was allowed but not mandatory. Participants were enrolled and randomly assigned (1:1) in block sizes of two, four, or six by a web-based tool to receive oral TAS-102 (35 mg/m2 twice daily on days 1-5 and 8-12 every 28 days) alone or combined with intravenous bevacizumab (5 mg/kg on days 1 and 15) until progression, unacceptable toxicity, or patient decision to withdraw. Treatment assignment was not masked, and randomisation was stratified by institution and RAS mutation status. The primary endpoint was investigator-evaluated progression-free survival. All analyses were based on intention to treat. This trial is registered with EudraCT, 2016-005241-23. FINDINGS: From Aug 24, 2017, to Oct 31, 2018, 93 patients were enrolled and randomly assigned to TAS-102 (n=47) or TAS-102 plus bevacizumab (n=46). The clinical cut-off date was Feb 15, 2019, after a median follow-up of 10·0 months (IQR 6·8-14·0). Median progression-free survival was 2·6 months (95% CI 1·6-3·5) in the TAS-102 group versus 4·6 months (3·5-6·5) in the TAS-102 plus bevacizumab group (hazard ratio 0·45 [95% CI 0·29-0·72]; p=0·0015). The most frequent grade 3 or worse adverse event was neutropenia (18 [38%] of 47 in the TAS-102 monotherapy group vs 31 [67%] of 46 in the TAS-102 plus bevacizumab group). Serious adverse events were observed in 21 (45%) patients in the TAS-102 group and 19 (41%) in the TAS-102 plus bevacizumab group. No deaths were deemed treatment related. INTERPRETATION: In patients with chemorefractory metastatic colorectal cancer, TAS-102 plus bevacizumab, as compared with TAS-102 monotherapy, was associated with a significant and clinically relevant improvement in progression-free survival with tolerable toxicity. The combination of TAS-102 plus bevacizumab could be a new treatment option for patients with refractory metastatic colorectal cancer and could be a practice-changing development. FUNDING: Servier.

Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients with resected stage III colon cancer (PETACC-8): an open-label, randomised phase 3 trial.

BACKGROUND: Since the 1990s, fluorouracil-based adjuvant chemotherapy has significantly reduced the risk of tumour recurrence in patients with stage III colon cancer. We aimed to assess whether the addition of cetuximab to standard adjuvant oxaliplatin, fluorouracil, and leucovorin chemotherapy (FOLFOX4) in patients with stage III colon cancer improved disease-free survival (DFS). METHODS: For this open-label, randomised phase 3 study done in nine European countries, we enrolled patients through an interactive voice response system to the central randomisation centre, with a central stratified permuted block randomisation procedure. We randomly assigned patients with resected (R0) stage III disease (1:1) to receive 12 cycles of FOLFOX4 twice a week with or without cetuximab. Patients were stratified by N-status (N1 vs N2), T-status (T1-3 vs T4), and obstruction or perforation status (no obstruction and no perforation vs obstruction or perforation or both). A protocol amendment (applied in June, 2008, after 2096 patients had been randomly assigned to treatment-restricted enrolment to patients with tumours wild-type at codons 12 and 13 in exon 2 of the KRAS gene (KRAS exon 2 wild-type). The primary endpoint was DFS. Analysis was intention to treat in all patients with KRAS exon 2 wild-type tumours. The study is registered at EudraCT, number 2005-003463-23. FINDINGS: Between Dec 22, 2005, and Nov 5, 2009, 2559 patients from 340 sites in Europe were randomly assigned. Of these patients, 1602 had KRAS exon 2 wild-type tumours (intention-to-treat population), 791 in the FOLFOX4 plus cetuximab group and 811 in the FOLFOX4 group. Median follow-up was 3·3 years (IQR 3·2-3·4). In the experimental and control groups, DFS was similar in the intention-to-treat population (hazard ratio [HR] 1·05; 95% CI 0·85-1·29; p=0·66), and in patients with KRAS exon 2/BRAF wild-type (n=984, HR 0·99; 95% CI 0·76-1·28) or KRAS exon 2-mutated tumours (n=742, HR 1·06; 95% CI 0·82-1·37). We noted heterogeneous responses to the addition of cetuximab in preplanned subgroup analyses. Grade 3 or 4 acne-like rash (in 209 of 785 patients [27%] vs four of 805 [<1%]), diarrhoea (113 [14%] vs 70 [9%]), mucositis (63 [8%] vs 10 [1%]), and infusion-related reactions (55 [7%] vs 30 [4%]) were more frequent in patients treated with FOLFOX4 plus cetuximab than in those patients who received FOLFOX4 alone. INTERPRETATION: The addition of cetuximab to FOLFOX4 did not improve DFS compared with FOLFOX4 alone in patients with KRAS exon 2 wild-type resected stage III colon cancer. This trial cannot conclude on the benefit of cetuximab in the studied population, but the heterogeneity of response suggests that further investigation of the role of FOLFOX4 plus cetuximab in specific patient subgroups is warranted. FUNDING: Fédération Francophone de Cancérologie Digestive (FFCD), Merck KGaA, and Sanofi-Aventis.

Safety and effectiveness of regorafenib in patients with metastatic colorectal cancer in routine clinical practice in the prospective, observational CORRELATE study.

BACKGROUND: Regorafenib prolonged overall survival (OS) versus placebo in patients with treatment-refractory metastatic colorectal cancer (mCRC) in phase III trials. We conducted an observational study of regorafenib for patients with mCRC in real-world clinical practice. METHODS: The international, prospective, CORRELATE study recruited patients with mCRC previously treated with approved therapies, for whom the decision to treat with regorafenib was made by the treating physician according to the local health authority approved label. The primary objective was safety, assessed by treatment-emergent adverse events (TEAEs; National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03). RESULTS: A total of 1037 patients were treated. The median age was 65 years (range: 24-93); 87% of patients had Eastern Cooperative Oncology Group performance status 0-1, 56% of patients had KRAS, 7% had NRAS and 4% had BRAF mutations. The initial regorafenib dose was 160 mg/day in 57% of patients. The most common grade III or IV drug-related TEAEs were fatigue (9%), hand-foot skin reaction (7%) and hypertension (6%). Drug-related grade V (fatal) TEAEs occurred in 1% of patients. Dose reductions for drug-related TEAEs occurred in 24% of patients. Median OS was 7.7 months (95% confidence interval [CI]: 7.2-8.3), and median progression-free survival (PFS) was 2.9 months (95% CI: 2.8-3.0). CONCLUSIONS: In this real-world, observational study of patients with mCRC, the regorafenib toxicity profile was similar to that reported in phase III trials. The starting dose for almost half of patients was less than the approved 160-mg dose, and the median OS and PFS were in the range observed in phase III trials. TRIAL REGISTRATION: NCT02042144.

DNA repair rate and etoposide (VP16) resistance of tumor cell subpopulations derived from a single human small cell lung cancer.

Two human small cell lung cancer (SCLC) subpopulations, CPH 54A, and CPH 54B, established from the same patient tumor by in vitro cloning, were investigated. The tumor was classified as intermediate-type SCLC. The cellular sensitivity to ionizing radiation (IR) was previously determined in the two sublines both in vivo and in vitro. Here we measured the etoposide (VP16) sensitivity together with the induction and repair of VP16- and IR-induced DNA double-strand breaks (DSBs). The two subpopulations were found to differ significantly in sensitivity to VP16, with the radioresistant 54B subline also being VP16 resistant. In order to explain the VP16 resistant phenotype several mechanisms where considered. The p53 status, P-glycoprotein, MRP, topoisomerase IIalpha, and Mre11 protein levels, as well as growth kinetics, provided no explanations of the observed VP16 resistance. In contrast, a significant difference in repair of both VP16- and IR-induced DSBs, together with a difference in the levels of the DSB repair proteins DNA-dependent protein kinase (DNA-PK(cs)) and RAD51 was observed. The VP16- and radioresistant 54B subline exhibited a pronounced higher repair rate of DSBs and higher protein levels of both DNA-PK(cs) and RAD51 compared with the sensitive 54A subline. We suggest, that different DSB repair rates among tumor cell subpopulations of individual SCLC tumors may be a major determinant for the variation in clinical treatment effect observed in human SCLC tumors of identical histological subtype.

[Lymph node identification in colorectal cancer specimens cases]. / Fund af lymfeknuder ved kolorektal cancer.

Colorectal carcinoma is one of the most prevalent malignancies in Western countries. Lymph node status is a significant prognosticator. The chance of identifying node-positivity is positively correlated with the number of lymph nodes (LN) identified. The present paper discusses various variables that may influence the detection of LNs, including patient- as well as surgeon- and pathologist-related issues. The pathologist-related variable most probably shapes the yield the most. Introduction of guidelines focusing on the most appropriate technique may secure better and more consistent results, and the pathologist's commitment is crucial in this respect.

[Resection time and number of detected colorectal lymph nodes in resection specimens with carcinoma]. / Udskaeringstid og antal påviste lymfeknuder ved kolorektal cancer.

INTRODUCTION: The number of identified lymph nodes (LNs) is an essential element in the pathologist's rapport on colorectal resection specimens with carcinoma (CRSC). A considerable number of papers discuss the acceptable minimum number of identified LNs to secure a correct LN status (LNS). Details as to the most appropriate grossing technique for LN detection are, however, largely lacking. In this paper the influence of the time invested by the pathologist in the pursuit of LN is investigated. MATERIAL AND METHODS: The material comprised 150 CRSCs. The usual gross examination was extended by 15 minutes in an effort to identify additional LNs. Provided this careful analysis failed to produce 12 LNs and all detected LNs were benign (pNx), the specimen was re-sampled for an additional 15-minute period. Data were correlated with a baseline material comprising 100 CRSCs. RESULTS: The intensified search for LNs increased the average number of LNs pr. specimen from 9.1 to 14.9. The number of cases with pNx was reduced from 54% to 18%. Re-sampling performed on 25 specimens resulted in the detection of another 61 LNs in 21 cases, ranging from 1 to 8 LN pr. specimen (median 2), whereby pNx was converted to pN0 in eight cases. In another four cases, additional LNs were not detected. Re-sampling did not uncover metastatic disease. CONCLUSION: This intensified effort in the Department of Pathology resulted in a more reliable LNS.

The role of RAD51 in etoposide (VP16) resistance in small cell lung cancer.

Etoposide (VP16) is a potent inducer of DNA double-strand breaks (DSBs) and is efficiently used in small cell lung cancer (SCLC) therapy. However, acquired VP16 resistance remains an important barrier to effective treatment. To understand the underlying mechanisms for VP16 resistance in SCLC, we investigated DSB repair and cellular VP16 sensitivity of SCLC cells. VP16 sensitivity and RAD51, DNA-PK(cs), topoisomerase IIalpha and P-glycoprotein protein levels were determined in 17 SCLC cell lines. In order to unravel the role of RAD51 in VP16 resistance, we cloned the human RAD51 gene, transfected SCLC cells with RAD51 sense or antisense constructs and measured the VP16 resistance. Finally, we measured VP16-induced DSBs in the 17 SCLC cell lines. Two cell lines exhibited a multidrug-resistant phenotype. In the other SCLC cell lines, the cellular VP16 resistance was positively correlated with the RAD51 protein level. In addition, downregulation or overexpression of the RAD51 gene altered the VP16 sensitivity. Furthermore, the levels of the RAD51 and DNA-PK(cs) proteins were related to VP16-induced DSBs. The results suggest that repair of VP16-induced DSBs is mediated through both RAD51-dependent homologous recombination and DNA-PK(cs)-dependent nonhomologous end-joining and may be a determinant of the variation in clinical treatment effect observed in human SCLC tumors of identical histologic subtype. Finally, we propose RAD51 as a potential target to improve VP16 efficacy and predict tumor resistance in the treatment of SCLC patients.