Increasing evidence indicates that gut microbiota may influence colorectal cancer risk. Diet, particularly fibre intake, may modify gut microbiota composition, which may affect cancer risk. We investigated the relationship between dietary fibre intake and gut microbiota in adults. Using 16S rRNA gene sequencing, we assessed gut microbiota in faecal samples from 151 adults in two independent study populations: National Cancer Institute (NCI),n75, and New York University (NYU),n76. We calculated energy-adjusted fibre intake based on FFQ. For each study population with adjustment for age, sex, race, BMI and smoking, we evaluated the relationship between fibre intake and gut microbiota community composition and taxon abundance. Total fibre intake was significantly associated with overall microbial community composition in NYU (P=0·008) but not in NCI (P=0·81). In a meta-analysis of both study populations, higher fibre intake tended to be associated with genera of class Clostridia, including higher abundance ofSMB53(fold change (FC)=1·04,P=0·04),Lachnospira(FC=1·03,P=0·05) andFaecalibacterium(FC=1·03,P=0·06), and lower abundance ofActinomyces(FC=0·95,P=0·002),Odoribacter(FC=0·95,P=0·03) andOscillospira(FC=0·96,P=0·06). A species-level meta-analysis showed that higher fibre intake was marginally associated with greater abundance ofFaecalibacterium prausnitzii(FC=1·03,P=0·07) and lower abundance ofEubacterium dolichum(FC=0·96,P=0·04) andBacteroides uniformis(FC=0·97,P=0·05). Thus, dietary fibre intake may impact gut microbiota composition, particularly class Clostridia, and may favour putatively beneficial bacteria such asF. prausnitzii. These findings warrant further understanding of diet–microbiota relationships for future development of colorectal cancer prevention strategies.

Over the past several years, the therapeutic landscape for patients with advanced, unresectable, or metastatic hepatocellular carcinoma has been transformed by the incorporation of checkpoint inhibitor immunotherapy into the treatment paradigm. Frontline systemic treatment options have expanded beyond anti-angiogenic tyrosine kinase inhibitors, such as sorafenib, to a combination of immunotherapy approaches, including atezolizumab plus bevacizumab and durvalumab plus tremelimumab, both of which have demonstrated superior response and survival to sorafenib. Additionally, combination treatments with checkpoint inhibitors and tyrosine kinase inhibitors have been investigated with variable success. In this review, we discuss these advances in systemic treatment with immunotherapy, with a focus on understanding both the underlying biology and mechanism of these strategies and their efficacy outcomes in clinical trials. We also review challenges in identifying predictive biomarkers of treatments and discuss future directions with novel immunotherapy targets.

Cabozantinib is approved for previously treated advanced hepatocellular carcinoma (aHCC) and has been investigated in gastric cancer (GC) and gastroesophageal junction adenocarcinoma (GEJ). Atezolizumab plus bevacizumab is approved for unresectable or metastatic HCC untreated with prior systemic therapy. We evaluated efficacy and safety of cabozantinib plus atezolizumab in aHCC previously untreated with systemic anticancer therapy or previously treated GC/GEJ. COSMIC-021 (ClinicalTrials.gov, NCT03170960) is an open-label, phase 1b study in solid tumours with a dose-escalation stage followed by tumour-specific expansion cohorts, including aHCC (cohort 14) and GC/GEJ (cohort 15). Eligible patients were aged ≥18 years with measurable locally advanced, metastatic, or recurrent disease per RECIST version 1.1. Patients received oral cabozantinib 40 mg daily and intravenous atezolizumab 1200 mg once every 3 weeks until progressive disease or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate per RECIST version 1.1. Patients were screened between February 14, 2019, and May 7, 2020, and 61 (30 aHCC, 31 GC/GEJ) were enrolled and received at least one dose of study treatment. Median duration of follow-up was 31.2 months (IQR 28.5-32.7) for aHCC and 30.4 months (28.7-31.9) for GC/GEJ. Objective response rate was 13% (4/30, 95% CI 4-31) for aHCC and 0% (95% CI 0-11) for GC/GEJ. Six (20%) aHCC patients and three (10%) GC/GEJ patients had treatment-related adverse events resulting in discontinuation of either study drug. Cabozantinib plus atezolizumab had clinical activity with a manageable safety profile in aHCC previously untreated with systemic anticancer therapy. Clinical activity of cabozantinib plus atezolizumab was minimal in previously treated GC/GEJ. Exelixis, Inc., Alameda, CA, USA.

Background: The phase 3 CheckMate 649 established superior overall survival of nivolumab in combination with chemotherapy (NIVO + chemo) compared with chemotherapy (chemo) alone as a first-line treatment for patients with Her2-negative advanced gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma (GC/GEJC/EAC). This post hoc trial analysis aimed to evaluate the benefit of NIVO + chemo using quality-adjusted time without symptoms or toxicity (Q-TWiST) to further account for quality of life (QoL) in different health states depending on disease progression and treatment toxicity. Methods: Using data from CheckMate 649, we evaluated the quality-adjusted survival gain associated with NIVO + chemo compared with chemo alone among all randomized patients and repeated similar analyses among those with programmed cell death-ligand 1 (PD-L1) combined positive score (CPS) ≥ 5. Relative Q-TWiST gains of ≥ 10% were predefined as clinically important. Results: In all randomized patients, those receiving NIVO + chemo had a mean Q-TWiST gain of 1.8 (95% CI 0.9, 2.7) months compared with those receiving chemo alone. The relative Q-TWiST gain was estimated to be 12.8%. Patients with PD-L1 CPS ≥ 5 had greater quality-adjusted survival gain from NIVO + chemo with an estimated Q-TWiST gain of 2.8 (95% CI 1.5, 4.1) months, representing a relative gain of 20.6%. Subgroup analyses and sensitivity analyses with various QoL utility values yielded consistent findings in favor of NIVO + chemo compared with chemo alone. Q-TWiST gain from NIVO + chemo increased with longer duration of follow-up. Conclusions: NIVO + chemo was associated with a statistically significant and clinically important gain in quality-adjusted survival compared with chemo alone among previously untreated patients with advanced GC/GEJC/EAC.