Prognostic value of liver metastases in colorectal cancer treated by systemic therapy: An ARCAD pooled analysis.

BACKGROUND: The liver is the most frequent site of metastases in colorectal cancer (CRC). This study aimed to assess the response rate and survival outcomes in metastatic CRC patients with non-liver metastases (NLM) compared to those with liver metastases (LM) across different lines of treatment. METHODS: A total of 17,924 mCRC patients included in 26 trials from the ARCAD CRC database were analyzed. The analysis was conducted based on the presence or absence of LM across different treatment groups: chemotherapy (CT) alone, CT + anti-VEGF, CT + anti-EGFR in KRAS wild-type tumors, within the first-line (1 L) and second-line (2 L), and patients enrolled in third-line (≥3 L) trials treated with trifluridine/tipiracil or regorafenib or placebo. The endpoints were overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). RESULTS: Out of the 17,924 patients, 14,066 had LM (30.6 % with only liver involvement and 69.4 % with liver and other metastatic sites), while 3858 patients had NLM. In the CT alone and CT + anti-VEGF subgroups, NLM patients showed better OS and PFS in the 1 L and 2 L settings. However, in the CT + anti-EGFR 1 L and 2 L subgroups, there was no significant difference in OS and PFS between NLM and LM patients. In the ≥ 3 L subgroups, better OS and PFS were observed in NLM patients. ORRs were higher in LM patients than in NLM patients across all cohorts treated in the 1 L and only in the anti-EGFR cohort in the 2 L. CONCLUSION: LM is a poor prognostic factor for mCRC increasing from 1 L to ≥ 3 L except for patients in 1 L and 2 L receiving CT+anti-EGFR. These data justify using LM as a stratification factor in future trials for patients with unresectable mCRC.

First-Line Nivolumab and Relatlimab Plus Chemotherapy for Gastric or Gastroesophageal Junction Adenocarcinoma: The Phase II RELATIVITY-060 Study.

PURPOSE: Open-label phase II study (RELATIVITY-060) to investigate the efficacy and safety of first-line nivolumab, a PD-1-blocking antibody, plus relatlimab, a lymphocyte-activation gene 3 (LAG-3)-blocking antibody, plus chemotherapy in patients with previously untreated advanced gastric cancer (GC) or gastroesophageal junction cancer (GEJC). METHODS: Patients with unresectable, locally advanced or metastatic GC/GEJC were randomly assigned 1:1 to nivolumab + relatlimab (fixed-dose combination) + chemotherapy or nivolumab + chemotherapy. The primary end point was objective response rate (ORR; per RECIST v1.1 by blinded independent central review [BICR]) in patients whose tumors had LAG-3 expression ≥1%. RESULTS: Of 274 patients, 138 were randomly assigned to nivolumab + relatlimab + chemotherapy and 136 to nivolumab + chemotherapy. Median follow-up was 11.9 months. In patients with LAG-3 expression ≥1%, BICR-assessed ORR (95% CI) was 48% (38 to 59) in the nivolumab + relatlimab + chemotherapy arm and 61% (51 to 71) in the nivolumab + chemotherapy arm; median progression-free survival (95% CI) by BICR was 7.0 months (5.8 to 8.4) versus 8.3 months (6.9 to 12.1; hazard ratio [HR], 1.41 [95% CI, 0.97 to 2.05]), and median overall survival (95% CI) was 13.5 months (11.9 to 19.1) versus 16.0 months (10.9 to not estimable; HR, 1.04 [95% CI, 0.70 to 1.54]), respectively. Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 69% and 61% of all treated patients, and 42% and 36% of patients discontinued because of any-grade TRAEs in the nivolumab + relatlimab + chemotherapy and nivolumab + chemotherapy arms, respectively. CONCLUSION: RELATIVITY-060 did not meet its primary end point of improved ORR in patients with LAG-3 expression ≥1% when relatlimab was added to nivolumab + chemotherapy compared with nivolumab + chemotherapy. Further studies are needed to address whether adding anti-LAG-3 to anti-PD-1 plus chemotherapy can benefit specific GC/GEJC patient subgroups.

Safety and tolerability of radiotherapy in combination with systemic targeted therapies for treatment of hepatocellular carcinoma: a narrative review.

BACKGROUND AND OBJECTIVE: Palliative radiotherapy (RT) and systemic immuno- or targeted therapy both play significant roles in the treatment of advanced hepatocellular carcinoma (HCC). Concurrent application of these therapies is increasing, however, no guidelines exist regarding the combination of systemic therapy with RT. This narrative review summarises the existing literature reporting toxicity observed after concurrent treatment with RT and immuno- or targeted therapeutic agents commonly used in HCC. METHODS: The PubMed database was searched for studies published between 2011 and 2023 reporting toxicity data on patients treated concurrently with RT and targeted agents used in HCC. Due to the paucity of relevant literature in HCC, the inclusion criteria were expanded to include non-HCC cohorts treated with targeted therapies commonly used in advanced HCC. KEY CONTENT AND FINDINGS: Sixty-seven articles were included in this review. Twenty-two articles reported combined RT with sorafenib, one with regorafenib, 22 with bevacizumab, three with lenvatinib and 19 with immune checkpoint inhibitors. Significant findings include a high rate severe hepatotoxicity with combination RT and sorafenib, ranging from 0-19% with liver stereotactic body radiotherapy (SBRT) and 3-18% with conventionally fractionated liver RT. Severe gastrointestinal (GI) toxicities including perforation and ulceration were seen with combination bevacizumab and RT, ranging from 0-27% in the acute setting and 0-23% in the late setting. The safety profile of combination immune checkpoint blockade agents and RT was similar to that seen in monotherapy. CONCLUSIONS: Existing data suggests that combination RT and targeted therapy given the risk of severe adverse events including hepatotoxicity and GI toxicity. There is an urgent need for future studies specifically examining the impact of combination therapy in HCC patients to guide clinical decision-making in the evolving landscape of immune- and targeted therapies.

The association of healthcare contact days with physical function and survival in CCTG/AGITG CO.17.

INTRODUCTION: While contact days-days with healthcare contact outside home-are increasingly adopted as a measure of time toxicity and treatment burden, they could also serve as a surrogate of treatment-related harm. We sought to assess the association between contact days and patient-reported outcomes, and the prognostic ability of contact days. METHODS: We conducted a secondary analysis of CO.17 that evaluated cetuximab vs supportive care in patients with advanced colorectal cancer. CO.17 collected EORTC-QLQ-C30 instrument data. We assessed the association between number of contact days in a window and changes in physical function and global health status, and the association between number of contact days in the first 4 weeks with overall survival (OS). RESULTS: There was a negative association between the number of contact days and change in physical function (per each additional contact day at 4 weeks, 1.50 point decrease; and 8 weeks, 1.06 point decrease, p < .0001 for both), but not with global health status. This negative association was seen in patients receiving cetuximab, but not supportive care. More contact days in the first 4 weeks was associated with worse OS for all comers and patients receiving cetuximab (per each additional contact day; all comers, aHR 1.07, 95% CI, 1.05- 1.10; and cetuximab, aHR 1.08, 95%CI 1.05- 1.11, p < .0001 for both). CONCLUSIONS: In this secondary analysis of a clinical trial, more contact days early in the course was associated with declines in physical function and worse survival in all-comers and in participants receiving cancer-directed treatment. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT00079066.

Peritoneal Tumor DNA as a Prognostic Biomarker in Gastric Cancer: A Systematic Review and Meta-Analysis.

PURPOSE: Gastric cancers commonly spread to the peritoneum. Its presence significantly alters patient prognosis and treatment-intent; however, current methods of peritoneal staging are inaccurate. Peritoneal tumor DNA (ptDNA) is tumor-derived DNA detectable in peritoneal lavage fluid. ptDNA positivity may indicate peritoneal micrometastasis and may be more sensitive than cytology in staging the peritoneum. In this meta-analysis, we evaluated the prognostic potential of ptDNA in gastric cancer. METHODS: PubMed, Embase, Scopus, and Web of Science databases were searched using PRISMA guidelines. Studies published between January 1, 1990, and April 30, 2023, containing quantitative data relating to ptDNA in gastric cancer were meta-analyzed. RESULTS: Six studies were analyzed. Of the total 757 patients with gastric adenocarcinoma, 318 (42.0%) were stage I, 311 (41.0%) were stage II/III, 116 (15.3%) were stage IV, and 22 (2.9%) were undetermined. Overall, ptDNA detected cytology-positive cases with a sensitivity and specificity of 85.2% (95% CI, 66.5 to 100.0) and 91.5% (95% CI, 86.5 to 96.6), respectively. Additionally, ptDNA was detected in 54 (8.5%) of 634 cytology-negative patients. The presence of ptDNA negatively correlated with pathological stage I (relative risk [RR], 0.29 [95% CI, 0.13 to 0.66]) and positively correlated with pathological stage IV (RR, 8.61 [95% CI, 1.86 to 39.89]) disease. Importantly, ptDNA positivity predicted an increased risk of peritoneal-specific metastasis (RR, 13.81 [95% CI, 8.11 to 23.53]) and reduced 3-year progression-free (RR, 5.37 [95% CI, 1.39 to 20.74]) and overall (hazard ratio, 4.13 [95% CI, 1.51 to 11.32]) survival. CONCLUSION: ptDNA carries valuable prognostic information and can detect peritoneal micrometastases in patients with gastric cancer. Its clinical utility in peritoneal staging for gastric cancer deserves further investigation.

BCL-XL inhibitors enhance the apoptotic efficacy of BRAF inhibitors in BRAFV600E colorectal cancer.

Metastatic BRAFV600E colorectal cancer (CRC) carries an extremely poor prognosis and is in urgent need of effective new treatments. While the BRAFV600E inhibitor encorafenib in combination with the EGFR inhibitor cetuximab (Enc+Cet) was recently approved for this indication, overall survival is only increased by 3.6 months and objective responses are observed in only 20% of patients. We have found that a limitation of Enc+Cet treatment is the failure to efficiently induce apoptosis in BRAFV600E CRCs, despite inducing expression of the pro-apoptotic protein BIM and repressing expression of the pro-survival protein MCL-1. Here, we show that BRAFV600E CRCs express high basal levels of the pro-survival proteins MCL-1 and BCL-XL, and that combining encorafenib with a BCL-XL inhibitor significantly enhances apoptosis in BRAFV600E CRC cell lines. This effect was partially dependent on the induction of BIM, as BIM deletion markedly attenuated BRAF plus BCL-XL inhibitor-induced apoptosis. As thrombocytopenia is an established on-target toxicity of BCL-XL inhibition, we also examined the effect of combining encorafenib with the BCL-XL -targeting PROTAC DT2216, and the novel BCL-2/BCL-XL inhibitor dendrimer conjugate AZD0466. Combining encorafenib with DT2216 significantly increased apoptosis induction in vitro, while combining encorafenib with AZD0466 was well tolerated in mice and further reduced growth of BRAFV600E CRC xenografts compared to either agent alone. Collectively, these findings demonstrate that combined BRAF and BCL-XL inhibition significantly enhances apoptosis in pre-clinical models of BRAFV600E CRC and is a combination regimen worthy of clinical investigation to improve outcomes for these patients.

SCORE: a randomised controlled trial evaluating shared care (general practitioner and oncologist) follow-up compared to usual oncologist follow-up for survivors of colorectal cancer.

Background: SCORE is the first randomised controlled trial (RCT) to examine shared oncologist and general practitioner (GP) follow-up for survivors of colorectal cancer (CRC). SCORE aimed to show that shared care (SC) was non-inferior to usual care (UC) on the EORTC QLQ-C30 Global Health Status/Quality of Life (GHQ-QoL) scale to 12 months. Methods: The study recruited patients from five public hospitals in Melbourne, Australia between February 2017 and May 2021. Patients post curative intent treatment for stage I-III CRC underwent 1:1 randomisation to SC and UC. SC replaced two oncologist visits with GP visits and included a survivorship care plan and primary care management guidelines. Assessments were at baseline, 6 and 12 months. Difference between groups on GHQ-QoL to 12 months was estimated from a mixed model for repeated measures (MMRM), with a non-inferiority margin (NIM) of -10 points. Secondary endpoints included quality of life (QoL); patient perceptions of care; costs and clinical care processes (CEA tests, recurrences). Registration ACTRN12617000004369p. Findings: 150 consenting patients were randomised to SC (N = 74) or UC (N = 76); 11 GPs declined. The mean (SD) GHQ-QoL scores at 12 months were 72 (20.2) for SC versus 73 (17.2) for UC. The MMRM mean estimate of GHQ-QoL across the 6 month and 12 month follow-up was 69 for SC and 73 for UC, mean difference -4.0 (95% CI: -9.0 to 0.9). The lower limit of the 95% CI did not cross the NIM. There was no clear evidence of differences on other QoL, unmet needs or satisfaction scales. At 12 months, the majority preferred SC (40/63; 63%) in the SC group, with equal preference for SC (22/62; 35%) and specialist care (22/62; 35%) in UC group. CEA completion was higher in SC. Recurrences similar between arms. Patients in SC on average incurred USD314 less in health costs versus UC patients. Interpretation: SC seems to be an appropriate and cost-effective model of follow-up for CRC survivors. Funding: Victorian Cancer Agency and Cancer Australia.

Unified framework for patient-derived, tumor-organoid-based predictive testing of standard-of-care therapies in metastatic colorectal cancer.

Predictive drug testing of patient-derived tumor organoids (PDTOs) holds promise for personalizing treatment of metastatic colorectal cancer (mCRC), but prospective data are limited to chemotherapy regimens with conflicting results. We describe a unified framework for PDTO-based predictive testing across standard-of-care chemotherapy and biologic and targeted therapy options. In an Australian community cohort, PDTO predictions based on treatment-naive patients (n = 56) and response rates from first-line mCRC clinical trials achieve 83% accuracy for forecasting responses in patients receiving palliative treatments (18 patients, 29 treatments). Similar assay accuracy is achieved in a prospective study of third-line or later mCRC treatment, AGITG FORECAST-1 (n = 30 patients). "Resistant" predictions are associated with inferior progression-free survival; misclassification rates are similar by regimen. Liver metastases are the optimal site for sampling, with testing achievable within 7 weeks for 68.8% cases. Our findings indicate that PDTO drug panel testing can provide predictive information for multifarious standard-of-care therapies for mCRC.

The prognostic impact of peritoneal tumour DNA in gastrointestinal and gynaecological malignancies: a systematic review.

Peritoneal metastases from various abdominal cancer types are common and carry poor prognosis. The presence of peritoneal disease upstages cancer diagnosis and alters disease trajectory and treatment pathway in many cancer types. Therefore, accurate and timely detection of peritoneal disease is crucial. The current practice of diagnostic laparoscopy and peritoneal lavage cytology (PLC) in detecting peritoneal disease has variable sensitivity. The significant proportion of peritoneal recurrence seen during follow-up in patients where initial PLC was negative indicates the ongoing need for a better diagnostic tool for detecting clinically occult peritoneal disease, especially peritoneal micro-metastases. Advancement in liquid biopsy has allowed the development and use of peritoneal tumour DNA (ptDNA) as a cancer-specific biomarker within the peritoneum, and the presence of ptDNA may be a surrogate marker for early peritoneal metastases. A growing body of literature on ptDNA in different cancer types portends promising results. Here, we conduct a systematic review to evaluate the prognostic impact of ptDNA in various cancer types and discuss its potential future clinical applications, with a focus on gastrointestinal and gynaecological malignancies.

Evaluation of Intratumoral Response Heterogeneity in Metastatic Colorectal Cancer and Its Impact on Patient Overall Survival: Findings from 10,551 Patients in the ARCAD Database.

Metastatic colorectal cancer (mCRC) is a heterogeneous disease that can evoke discordant responses to therapy among different lesions in individual patients. The Response Evaluation Criteria in Solid Tumors (RECIST) criteria do not take into consideration response heterogeneity. We explored and developed lesion-based measurement response criteria to evaluate their prognostic effect on overall survival (OS). PATIENTS AND METHODS: Patients enrolled in 17 first-line clinical trials, who had mCRC with ≥ 2 lesions at baseline, and a restaging scan by 12 weeks were included. For each patient, lesions were categorized as a progressing lesion (PL: > 20% increase in the longest diameter (LD)), responding lesion (RL: > 30% decrease in LD), or stable lesion (SL: neither PL nor RL) based on the 12-week scan. Lesion-based response criteria were defined for each patient as follows: PL only, SL only, RL only, and varied responses (mixture of RL, SL, and PL). Lesion-based response criteria and OS were correlated using stratified multivariable Cox models. The concordance between OS and classifications was measured using the C statistic. RESULTS: Among 10,551 patients with mCRC from 17 first-line studies, varied responses were noted in 51.6% of patients, among whom, 3.3% had RL/PL at 12 weeks. Among patients with RL/SL, 52% had stable disease (SD) by RECIST 1.1, and they had a longer OS (median OS (mOS) = 19.9 months) than those with SL only (mOS = 16.8 months, HR (95% CI) = 0.81 (0.76, 0.85), p < 0.001), although a shorter OS than those with RL only (mOS = 25.8 months, HR (95% CI) = 1.42 (1.32, 1.53), p < 0.001). Among patients with SL/PL, 74% had SD by RECIST 1.1, and they had a longer OS (mOS = 9.0 months) than those with PL only (mOS = 8.0 months, HR (95% CI) = 0.75 (0.57, 0.98), p = 0.040), yet a shorter OS than those with SL only (mOS = 16.8 months, HR (95% CI) = 1.98 (1.80, 2.18), p < 0.001). These associations were consistent across treatment regimen subgroups. The lesion-based response criteria showed slightly higher concordance than RECIST 1.1, although it was not statistically significant. CONCLUSION: Varied responses at first restaging are common among patients receiving first-line therapy for mCRC. Our lesion-based measurement criteria allowed for better mortality discrimination, which could potentially be informative for treatment decision-making and influence patient outcomes.

Nurse-led emergency department avoidance model of care for patients receiving cancer therapy in the ambulatory setting: a health service improvement initiative.

AIMS: The Symptom and Urgent Review Clinic was a service improvement initiative, which consisted of the implementation and evaluation of a nurse-led emergency department (ED) avoidance model of care. The clinic was developed for patients experiencing symptoms associated with systemic anti-cancer therapy in ambulatory cancer settings. METHODS: The clinic was implemented in four health services in Melbourne, Australia across a six-month period in 2018. Evaluation was by prospective data collection of the frequency and characteristics of patients who used the service, pre- and post-survey of patient reported experience, and a post-implementation survey of clinician engagement and experience. RESULTS: There were 3095 patient encounters in the six-month implementation period; 136 patients were directly admitted to inpatient healthcare services after clinic utilization. Of patients who contacted SURC (n = 2174), a quarter (n = 553) stated they would have otherwise presented to the emergency department and 51% (n = 1108) reported they would have otherwise called the Day Oncology Unit. After implementation, more patients reported having a dedicated point of contact (OR 14.3; 95% CI 5.8-37.7) and ease of contacting the nurse (OR 5.5; 95% CI 2.6-12.1). Clinician reported experience and engagement with the clinic was highly favorable. CONCLUSION: The nurse-led emergency department avoidance model of care addressed a gap in service delivery, while optimizing service utilization by reducing ED presentations. Patients reported improved levels of satisfaction with ease of access to a dedicated nurse and advice provided.

Changing patterns of care for pancreas cancer in Victoria: the 2022 Pancreas Tumour Summit.

BACKGROUND: The Victorian Government convened the second Pancreas Cancer Summit in 2021 to identify unwarranted variation in care 2016-2019, and to assess trends compared with the first Summit 2017 (reporting 2011-2015). State-wide administrative data were assessed at population level in alignment with optimal care pathways across all stages of the cancer care continuum. METHODS: Data linkage performed by Centre for Victorian Data Linkage combined data from Victorian Cancer Registry with other administrative data sets including Victorian Admitted Episodes Dataset, Victorian Radiotherapy Minimum Data Set, Victorian Emergency Minimum Dataset and Victorian Death Index. A Cancer Service Performance Indicator audit was carried out providing an in-depth analysis of identified areas of interest. RESULTS: Of 3138 Victorians diagnosed with pancreas ductal adenocarcinoma 2016-2019, 63% were metastatic at diagnosis. One-year survival increased between time periods, from 29.7% overall 2011-2015 (59.1% for non-metastatic, and 15.1% metastatic) to 32.5% overall 2016-2019 (P < 0.001), 61.2% non-metastatic (P = 0.008), 15.7% metastatic (P = NS). A higher proportion of non-metastatic patients progressed to surgery (35% vs. 31%, P = 0.020), and more received neoadjuvant therapy (16% vs. 4%, P < 0.001). Postoperative mortality following pancreatectomy at 30 and 90 days remained low at 2%. Utilization of 5FU-based chemotherapy regimens increased between 2016 and 2020. Multidisciplinary Meeting (MDM) presentation was still below the 85% target (74%) as was supportive care screening (39%, target 80%). CONCLUSIONS: Surgical outcomes remain world-class and there has been an appropriate shift in chemotherapy administration towards neoadjuvant timing with increasing use of 5FU-based regimens. MDM presentation rates, supportive care and overall care coordination remain areas of deficiency.

Evaluating the Time Toxicity of Cancer Treatment in the CCTG CO.17 Trial.

PURPOSE: The time spent in pursuing treatments for advanced cancer can be substantial. We have previously proposed a pragmatic and patient-centered metric of these time costs-which we term time toxicity-as any day with physical health care system contact. This includes outpatient visits (eg, bloodwork, scans, etc), emergency department visits, and overnight stays in a health care facility. Herein, we sought to assess time toxicity in a completed randomized controlled trial (RCT). METHODS: We conducted a secondary analysis of the Canadian Cancer Trials Group CO.17 RCT that evaluated weekly cetuximab infusions versus supportive care alone in 572 patients with advanced colorectal cancer. Initial results reported a 6-week improvement in median overall survival (OS) with cetuximab (6.1 v 4.6 months). Subsequent analyses reported that benefit was restricted to patients with K-ras wild-type tumors. We calculated patient-level time toxicity by analyzing trial forms. We considered days without health care contact as home days. We compared medians of time measures across arms and stratified results by K-ras status. RESULTS: In the overall population, median time toxic days were higher in the cetuximab arm (28 v 10, P < .001) although median home days were not statistically different between arms (140 v 121, P = .09). In patients with K-ras-mutated tumors, cetuximab was associated with almost numerically equal home days (114 days v 112 days, P = .571) and higher time toxicity (23 days v 11 days, P < .001). In patients with K-ras wild-type tumors, cetuximab was associated with more home days (186 v 132, P < .001). CONCLUSION: This proof-of-concept feasibility study demonstrates that measures of time toxicity can be extracted through secondary analyses of RCTs. In CO.17, despite an overall OS benefit with cetuximab, home days were statistically similar across arms. Such data can supplement traditional survival end points in RCTs. Further work should refine and validate the measure prospectively.[Media: see text].

INTEGRATE II: randomised phase III controlled trials of regorafenib containing regimens versus standard of care in refractory Advanced Gastro-Oesophageal Cancer (AGOC): a study by the Australasian Gastro-Intestinal Trials Group (AGITG).

BACKGROUND: Advanced gastro-oesophageal cancer (AGOC) carries a poor prognosis. No standard of care treatment options are available after first and second-line therapies. Regorafenib is an oral multi-targeted tyrosine kinase inhibitor targeting angiogenic, stromal, and oncogenic receptor tyrosine kinases. Regorafenib 160 mg daily prolonged progression free survival compared to placebo (INTEGRATE, phase 2). Regorafenib 80 mg daily in combination with nivolumab 3 mg/kg showed promising objective response rates (REGONIVO). METHODS/DESIGN: INTEGRATE II (INTEGRATE IIa and IIb) platform comprises two international phase III randomised controlled trials (RCT) with 2:1 randomisation in favor of experimental intervention. INTEGRATE IIa (double-blind) compares regorafenib 160 mg daily on days 1 to 21 of each 28-day cycle to placebo. INTEGRATE IIb (open label) compares REGONIVO, regorafenib 90 mg days 1 to 21 in combination with intravenous nivolumab 240 mg days 1 and 15 each 28-day cycle with investigator's choice of chemotherapy (control). Treatment continues until disease progression or intolerable adverse events as per protocol. Eligible participants include adults with AGOC who have failed two or more lines of treatment. Stratification is by location of tumour (INTEGRATE IIa only), geographic region, prior VEGF inhibitor and prior immunotherapy use (INTEGRATE IIb only). Primary endpoint is overall survival. Secondary endpoints are progression free survival, objective response rate, quality of life, and safety. Tertiary/correlative objectives include biomarker and pharmacokinetic evaluation. DISCUSSION: INTEGRATE II provides a platform to evaluate the clinical utility of regorafenib alone, as well as regorafenib in combination with nivolumab in treatment of participants with refractory AGOC. TRIAL REGISTRATION: INTEGRATE IIa prospectively registered 1 April 2016 Australia New Zealand Clinical Trial Registry: ACTRN12616000420448 (ClinicalTrials.gov NCT02773524). INTEGRATE IIb prospectively registered 10 May 2021 ClinicalTrials.gov: NCT04879368.

In colon cancer cells fascin1 regulates adherens junction remodeling.

Adherens junctions (AJs) are a defining feature of all epithelial cells. They regulate epithelial tissue architecture and integrity, and their dysregulation is a key step in tumor metastasis. AJ remodeling is crucial for cancer progression, and it plays a key role in tumor cell survival, growth, and dissemination. Few studies have examined AJ remodeling in cancer cells consequently, it remains poorly understood and unleveraged in the treatment of metastatic carcinomas. Fascin1 is an actin-bundling protein that is absent from the normal epithelium but its expression in colon cancer is linked to metastasis and increased mortality. Here, we provide the molecular mechanism of AJ remodeling in colon cancer cells and identify for the first time, fascin1's function in AJ remodeling. We show that in colon cancer cells fascin1 remodels junctional actin and actomyosin contractility which makes AJs less stable but more dynamic. By remodeling AJs fascin1 drives mechanoactivation of WNT/ß-catenin signaling and generates "collective plasticity" which influences the behavior of cells during cell migration. The impact of mechanical inputs on WNT/ß-catenin activation in cancer cells remains poorly understood. Our findings highlight the role of AJ remodeling and mechanosensitive WNT/ß-catenin signaling in the growth and dissemination of colorectal carcinomas.

A Phase Ib/II Trial of Combined BRAF and EGFR Inhibition in BRAF V600E Positive Metastatic Colorectal Cancer and Other Cancers: The EVICT (Erlotinib and Vemurafenib In Combination Trial) Study.

PURPOSE: BRAF V600E mutant metastatic colorectal cancer represents a significant clinical problem, with combination approaches being developed clinically with oral BRAF inhibitors combined with EGFR-targeting antibodies. While compelling preclinical data have highlighted the effectiveness of combination therapy with vemurafenib and small-molecule EGFR inhibitors, gefitinib or erlotinib, in colorectal cancer, this therapeutic strategy has not been investigated in clinical studies. PATIENTS AND METHODS: We conducted a phase Ib/II dose-escalation/expansion trial investigating the safety/efficacy of the BRAF inhibitor vemurafenib and EGFR inhibitor erlotinib. RESULTS: Thirty-two patients with BRAF V600E positive metastatic colorectal cancer (mCRC) and 7 patients with other cancers were enrolled. No dose-limiting toxicities were observed in escalation, with vemurafenib 960 mg twice daily with erlotinib 150 mg daily selected as the recommended phase II dose. Among 31 evaluable patients with mCRC and 7 with other cancers, overall response rates were 32% [10/31, 16% (5/31) confirmed] and 43% (3/7), respectively, with clinical benefit rates of 65% and 100%. Early ctDNA dynamics were predictive of treatment efficacy, and serial ctDNA monitoring revealed distinct patterns of convergent genomic evolution associated with acquired treatment resistance, with frequent emergence of MAPK pathway alterations, including polyclonal KRAS, NRAS, and MAP2K1 mutations, and MET amplification. CONCLUSIONS: The Erlotinib and Vemurafenib In Combination Trial study demonstrated a safe and novel combination of two oral inhibitors targeting BRAF and EGFR. The dynamic assessment of serial ctDNA was a useful measure of underlying genomic changes in response to this combination and in understanding potential mechanisms of resistance.