Neoadjuvant chemotherapy and radiation followed by surgical resection of the rectum is a standard treatment for locally advanced rectal cancer. A subset of rectal cancer is caused by a deficiency in ...mismatch repair. Because mismatch repair-deficient colorectal cancer is responsive to programmed death 1 (PD-1) blockade in the context of metastatic disease, it was hypothesized that checkpoint blockade could be effective in patients with mismatch repair-deficient, locally advanced rectal cancer.
We initiated a prospective phase 2 study in which single-agent dostarlimab, an anti-PD-1 monoclonal antibody, was administered every 3 weeks for 6 months in patients with mismatch repair-deficient stage II or III rectal adenocarcinoma. This treatment was to be followed by standard chemoradiotherapy and surgery. Patients who had a clinical complete response after completion of dostarlimab therapy would proceed without chemoradiotherapy and surgery. The primary end points are sustained clinical complete response 12 months after completion of dostarlimab therapy or pathological complete response after completion of dostarlimab therapy with or without chemoradiotherapy and overall response to neoadjuvant dostarlimab therapy with or without chemoradiotherapy.
A total of 12 patients have completed treatment with dostarlimab and have undergone at least 6 months of follow-up. All 12 patients (100%; 95% confidence interval, 74 to 100) had a clinical complete response, with no evidence of tumor on magnetic resonance imaging,
F-fluorodeoxyglucose-positron-emission tomography, endoscopic evaluation, digital rectal examination, or biopsy. At the time of this report, no patients had received chemoradiotherapy or undergone surgery, and no cases of progression or recurrence had been reported during follow-up (range, 6 to 25 months). No adverse events of grade 3 or higher have been reported.
Mismatch repair-deficient, locally advanced rectal cancer was highly sensitive to single-agent PD-1 blockade. Longer follow-up is needed to assess the duration of response. (Funded by the Simon and Eve Colin Foundation and others; ClinicalTrials.gov number, NCT04165772.).
Although a minority of colorectal cancers exhibit mismatch repair deficiency and associated sensitivity to immune checkpoint inhibitors (ICI), the vast majority of colorectal cancers arise in a ...tolerogenic microenvironment with mismatch repair proficiency, low tumor-intrinsic immunogenicity, and negligible immunotherapy responsiveness. Treatment strategies to augment tumor immunity with combination ICIs and chemotherapy have broadly failed in mismatch repair-proficient tumors. Similarly, although several small single-arm studies have shown that checkpoint blockade plus radiation or select tyrosine kinase inhibition may show improved outcomes compared with historical controls, this finding has not been clearly validated in randomized trials. An evolving next generation of intelligently engineered checkpoint inhibitors, bispecific T-cell engagers, and emerging CAR-T cell therapies may improve immunorecognition of colorectal tumors. Across these modalities, ongoing translational efforts to better define patient populations and biomarkers associated with immune response, as well as combine biologically sound and mutually amplifying therapies, show promise for a new era of immunotherapy in colorectal cancer.
This Phase 1 study assessed the safety and efficacy of the Porcupine inhibitor, WNT974, in patients with advanced solid tumours.
Patients (n = 94) received oral WNT974 at doses of 5-30 mg once-daily, ...plus additional dosing schedules.
The maximum tolerated dose was not established; the recommended dose for expansion was 10 mg once-daily. Dysgeusia was the most common adverse event (50% of patients), likely resulting from on-target Wnt pathway inhibition. No responses were seen by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1; 16% of patients had stable disease (median duration 19.9 weeks). AXIN2 expression by RT-PCR was reduced in 94% of paired skin biopsies (n = 52) and 74% of paired tumour biopsies (n = 35), confirming inhibition of the Wnt pathway. In an exploratory analysis, an inverse association was observed between AXIN2 change and immune signature change in paired tumour samples (n = 8).
Single-agent WNT974 treatment was generally well tolerated. Biomarker analyses suggest that WNT974 may influence immune cell recruitment to tumours, and may enhance checkpoint inhibitor activity.
NCT01351103.
There is a worldwide growing use of chemicals by our developed, industrialized, and technological society. More than 100,000 chemical substances are thus commonly used both by industry and ...households. Depending on the amount produced, physical-chemical properties, and mode of use, many of them may reach the environment and, notably, the aquatic receiving systems. This may result in undesirable and harmful side-effects on both the human and the ecosystem's health. Mediterranean rivers are largely different from Northern and Central European rivers in terms of hydrological regime, climate conditions (e.g. air temperature, solar irradiation, precipitation), and socio-economics (e.g. land use, tourism, crop types, etc.), with all these factors leading to differences in the relative importance of the environmental stressors, in the classes and levels of the pollutants found and their environmental fate. Furthermore, water scarcity might be critical in affecting water pollution because of the lowered dilution capacity of chemicals.
This work provides raw chemical data from different families of microcontaminants identified in three selected Mediterranean rivers (the Sava, Evrotas, and Adige) collected during two sampling campaigns conducted in 2014 and 2015 in three different matrices, namely, water, sediments, and biota (fish). More than 200 organic micropollutants were analyzed, including relevant groups like pharmaceuticals, personal care products, perfluorinated compounds, pesticides, pyrethroid insecticides, flame retardants, and persistent organic pollutants. Data obtained were summarized with some basic statistics for all compound families and matrices analyzed. Observed occurrence and spatial patterns were interpreted both in terms of compound physical-chemical properties and local environmental pressures. Finally, their spatial distribution was examined and their ecotoxicological risk in the water phase was assessed. This allowed locating, at each basin, the most polluted sites (“hot spots”) and identifying the respective river basin specific pollutants (RBSPs), prioritizing them in terms of the potential ecotoxicological risk posed to the aquatic ecosystems.
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•More than 200 emerging contaminants monitored in three Mediterranean River Basins•Three environmental compartments (water, sediments, biota) investigated•River basin “hot spots” characterized through ecotoxicological risk assessment•River basin specific pollutants identified
Colorectal cancer (CRC) is a heterogeneous disease representing a therapeutic challenge, which is further complicated by the common occurrence of several molecular alterations that confer resistance ...to standard chemotherapy and targeted agents. Mechanisms of resistance have been identified at multiple levels in the epidermal growth factor receptor (EGFR) pathway, including mutations in KRAS, NRAS, and BRAFV600E, and in the HER2 and MET receptors. These alterations represent oncogenic drivers that may co-exist in the same tumor with other primary and acquired alterations via a clonal selection process. Other molecular alterations include DNA damage repair mechanisms and rare kinase fusions, potentially offering a rationale for new therapeutic strategies. In recent years, genomic analysis has been expanded by a more complex study of epigenomic, transcriptomic, and microenvironment features. The Consensus Molecular Subtype (CMS) classification describes four CRC subtypes with distinct biological characteristics that show prognostic and potential predictive value in the clinical setting. Here, we review the panorama of actionable targets in CRC, and the developments in more recent molecular tests, such as liquid biopsy analysis, which are increasingly offering clinicians a means of ensuring optimal tailored treatments for patients with metastatic CRC according to their evolving molecular profile and treatment history.
Pre-clinical data have shown that combining trifluridine/tipiracil with oxaliplatin enhances anti-tumour activity compared with either monotherapy. A phase I dose-escalation study was conducted to ...determine the maximum tolerated dose (MTD), recommended dose (RD) for phase II and pharmacokinetic profile of this combination in patients with metastatic colorectal cancer (mCRC) who had progressed after at least 1 prior line of treatment.
Using a 3 + 3 design, patients received escalating trifluridine/tipiracil doses from 25, then 30 and to 35 mg/m2 twice daily, days 1–5, q14 days, together with a fixed dose of 85 mg/m2 of oxaliplatin day 1, q14 days. An intermediate cohort with a lower oxaliplatin dose (65 mg/m2) was also investigated. After MTD determination, additional patients were treated to define the RD.
Twenty-four patients were enrolled. One dose-limiting toxicity of grade 3 febrile neutropenia was observed at the highest dose level, which was established as the MTD and subsequently the RD. The most common drug-related adverse events (AEs) were asthenia, nausea, diarrhoea, peripheral neuropathy, neutropenia, decreased appetite, thrombocytopenia, vomiting, anaemia and peripheral sensory neuropathy. Most drug-related AEs (93.0%) were of grade 1–2. Pharmacokinetic parameters of trifluridine/tipiracil were not influenced by oxaliplatin co-administration. Best overall responses at the RD (n = 14) included 1 patient with partial response (7.1%) and 7 patients with stable disease (50.0%).
The combination of trifluridine/tipiracil and oxaliplatin in patients with mCRC has a manageable safety profile with some efficacy. The RD is 35 mg/m2 of trifluridine/tipiracil twice daily, days 1–5, q14 days and 85 mg/m2 of oxaliplatin day 1, q14
NCT02848443.
•This phase I dose-escalation study explored the combination of trifluridine/tipiracil and oxaliplatin in patients with CRC.•One dose-limiting toxicity (grade 3 febrile neutropenia) was reported, at the highest dose, and most drug-related adverse events (93.0%) were of grade 1–2.•The maximum tolerated dose/recommended dose was defined as 35 mg/m2 of trifluridine/tipiracil twice daily, days 1–5, q14 days and 85 mg/m2 of oxaliplatin day 1, q14 days.•Pharmacokinetic parameters of trifluridine/tipiracil were not influenced by co-administration of oxaliplatin.•At the recommended dose (n = 14), 1 patient (7.1%) had a partial response and 7 (50.0%) had stable disease.
Abstract
Microsatellite-stable colorectal cancer (MSS-CRC) is highly refractory to immunotherapy. Understanding tumor-intrinsic determinants of immunotherapy resistance is critical to improve MSS-CRC ...patient outcomes. Here, we demonstrate that high tumor expression of the core autophagy gene
ATG16L1
is associated with poor clinical response to anti-PD-L1 therapy in KRAS-mutant tumors from IMblaze370 (NCT02788279), a large phase III clinical trial of atezolizumab (anti-PD-L1) in advanced metastatic MSS-CRC. Deletion of
Atg16l1
in engineered murine colon cancer organoids inhibits tumor growth in primary (colon) and metastatic (liver and lung) niches in syngeneic female hosts, primarily due to increased sensitivity to IFN-γ-mediated immune pressure. ATG16L1 deficiency enhances programmed cell death of colon cancer organoids induced by IFN-γ and TNF, thus increasing their sensitivity to host immunity. In parallel, ATG16L1 deficiency reduces tumor stem-like populations in vivo independently of adaptive immune pressure. This work reveals autophagy as a clinically relevant mechanism of immune evasion and tumor fitness in MSS-CRC and provides a rationale for autophagy inhibition to boost immunotherapy responses in the clinic.
Ramucirumab, a human monoclonal antibody against vascular endothelial growth factor receptor 2 (VEGFR-2), is an antiangiogenic therapy that has been approved in combination with FOLFIRI in ...second-line treatment of metastatic colorectal cancer (mCRC), after progression on or after therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. A thorough review of the safety of ramucirumab in this setting and in the context of other antiangiogenic agents is merited. Areas covered: We provide an overview of activity and summarize in detail the overall safety and tolerability profile of ramucirumab in mCRC patients on the basis of a literature review of all published clinical trials in this setting, including both single-agent and combination studies. A focus on adverse events of interest and specific populations is included, as well as a critical comparison with other antiangiogenic therapies. Expert opinion: As an effective agent in pretreated mCRC patients, the toxicity profile of ramucirumab is similar to those of other angiogenesis inhibitors used in the second-line mCRC setting. The next challenge will be to find biomarkers of response and toxicity to antiangiogenic therapies in order to more effectively implement personalized medicine in these patients.
The cancer burden is rising globally, exerting significant strain on populations and health systems at all income levels. In May 2017, world governments made a commitment to further invest in cancer ...control as a public health priority, passing the World Health Assembly Resolution 70.12 on cancer prevention and control within an integrated approach. In this manuscript, the 2016 European Society for Medical Oncology Leadership Generation Programme participants propose a strategic framework that is in line with the 2017 WHO Cancer Resolution and consistent with the principle of universal health coverage, which ensures access to optimal cancer care for all people because health is a basic human right. The time for action is now to reduce barriers and provide the highest possible quality cancer care to everyone regardless of circumstance, precondition or geographic location. The national actions and the policy recommendations in this paper set forth the vision of its authors for the future of global cancer control at the national level, where the WHO Cancer Resolution must be implemented if we are to reduce the cancer burden, avoid unnecessary suffering and save as many lives as possible.
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