CFI-402257, a TTK inhibitor, effectively suppresses hepatocellular carcinoma.

Deregulation of cell cycle is a typical feature of cancer cells. Normal cells rely on the strictly coordinated spindle assembly checkpoint (SAC) to maintain the genome integrity and survive. However, cancer cells could bypass this checkpoint mechanism. In this study, we showed the clinical relevance of threonine tyrosine kinase (TTK) protein kinase, a central regulator of the SAC, in hepatocellular carcinoma (HCC) and its potential as therapeutic target. Here, we reported that a newly developed, orally active small molecule inhibitor targeting TTK (CFI-402257) effectively suppressed HCC growth and induced highly aneuploid HCC cells, DNA damage, and micronuclei formation. We identified that CFI-402257 also induced cytosolic DNA, senescence-like response, and activated DDX41-STING cytosolic DNA sensing pathway to produce senescence-associated secretory phenotypes (SASPs) in HCC cells. These SASPs subsequently led to recruitment of different subsets of immune cells (natural killer cells, CD4+ T cells, and CD8+ T cells) for tumor clearance. Our mass cytometry data illustrated the dynamic changes in the tumor-infiltrating immune populations after treatment with CFI-402257. Further, CFI-402257 improved survival in HCC-bearing mice treated with anti-PD-1, suggesting the possibility of combination treatment with immune checkpoint inhibitors in HCC patients. In summary, our study characterized CFI-402257 as a potential therapeutic for HCC, both used as a single agent and in combination therapy.

Dual CTLA-4 and PD-1 checkpoint blockade using CS1002 and CS1003 (nofazinlimab) in patients with advanced solid tumors: A first-in-human, dose-escalation, and dose-expansion study.

BACKGROUND: This study investigated the safety and efficacy of an anti-CTLA-4 monoclonal antibody (CS1002) as monotherapy and in combination with an anti-PD-1 monoclonal antibody (CS1003) in patients with advanced/metastatic solid tumors. METHODS: The phase 1 study involved phase 1a monotherapy dose-escalation (part 1) and phase 1b combination therapy dose escalation (part 2) and expansion (part 3). Various dosing schedules of CS1002 (0.3, 1, or 3 mg/kg every 3 weeks, or 3 mg/kg every 9 weeks) were evaluated with 200 mg CS1003 every 3 weeks in part 3. RESULTS: Parts 1, 2, and 3 included a total of 13, 18, and 61 patients, respectively. No dose-limiting toxicities or maximum tolerated doses were observed. Treatment-related adverse events (TRAEs) were reported in 30.8%, 83.3%, and 75.0% of patients in parts 1, 2, and 3, respectively. Grade ≥3 TRAEs were experienced by 15.4%, 50.0%, and 18.3% of patients in each part. Of 61 patients evaluable for efficacy, 23 (37.7%) achieved objective responses in multiple tumor types. Higher objective response rates were observed with conventional and high-dose CS1002 regimens (1 mg/kg every 3 weeks or 3 mg/kg every 9 weeks) compared to low-dose CS1002 (0.3 mg/kg every 3 weeks) in microsatellite instability-high/mismatch repair-deficient tumors, melanoma, and hepatocellular carcinoma (50.0% vs. 58.8%, 14.3% vs. 42.9%, and 0% vs. 16.7%). CONCLUSION: CS1002, as monotherapy, and in combination with CS1003, had a manageable safety profile across a broad dosing range. Promising antitumor activities were observed in patients with immune oncology (IO)-naive and IO-refractory tumors across CS1002 dose levels when combined with CS1003, supporting further evaluation of this treatment combination for solid tumors. PLAIN LANGUAGE SUMMARY: CS1002 is a human immunoglobulin (Ig) G1 monoclonal antibody that blocks the interaction of CTLA-4 with its ligands and increases T-cell activation/proliferation. CS1003, now named nofazinlimab, is a humanized, recombinant IgG4 monoclonal antibody that blocks the interaction between human PD-1 and its ligands. In this original article, we determined the safety profile of CS1002 as monotherapy and in combination with CS1003. Furthermore, we explored the antitumor activity of the combination in anti-programmed cell death protein (ligand)-1 (PD-[L]1)-naive microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) pan tumors, and anti-PD-(L)1-refractory melanoma and hepatocellular carcinoma (HCC). CS1002 in combination with CS1003 had manageable safety profile across a broad dosing range and showed promising antitumor activities across CS1002 dose levels when combined with CS1003. This supports further assessment of CS1002 in combination with CS1003 for the treatment of solid tumors.

Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Biliary tract cancers, which arise from the intrahepatic or extrahepatic bile ducts and the gallbladder, generally have a poor prognosis and are rising in incidence worldwide. The standard-of-care treatment for advanced biliary tract cancer is chemotherapy with gemcitabine and cisplatin. Because most biliary tract cancers have an immune-suppressed microenvironment, immune checkpoint inhibitor monotherapy is associated with a low objective response rate. We aimed to assess whether adding the immune checkpoint inhibitor pembrolizumab to gemcitabine and cisplatin would improve outcomes compared with gemcitabine and cisplatin alone in patients with advanced biliary tract cancer. METHODS: KEYNOTE-966 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 175 medical centres globally. Eligible participants were aged 18 years or older; had previously untreated, unresectable, locally advanced or metastatic biliary tract cancer; had disease measurable per Response Evaluation Criteria in Solid Tumours version 1.1; and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks (maximum 35 cycles), in combination with gemcitabine (1000 mg/m2 intravenously on days 1 and 8 every 3 weeks; no maximum duration) and cisplatin (25 mg/m2 intravenously on days 1 and 8 every 3 weeks; maximum 8 cycles). Randomisation was done using a central interactive voice-response system and stratified by geographical region, disease stage, and site of origin in block sizes of four. The primary endpoint of overall survival was evaluated in the intention-to-treat population. The secondary endpoint of safety was evaluated in the as-treated population. This study is registered at ClinicalTrials.gov, NCT04003636. FINDINGS: Between Oct 4, 2019, and June 8, 2021, 1564 patients were screened for eligibility, 1069 of whom were randomly assigned to pembrolizumab plus gemcitabine and cisplatin (pembrolizumab group; n=533) or placebo plus gemcitabine and cisplatin (placebo group; n=536). Median study follow-up at final analysis was 25·6 months (IQR 21·7-30·4). Median overall survival was 12·7 months (95% CI 11·5-13·6) in the pembrolizumab group versus 10·9 months (9·9-11·6) in the placebo group (hazard ratio 0·83 [95% CI 0·72-0·95]; one-sided p=0·0034 [significance threshold, p=0·0200]). In the as-treated population, the maximum adverse event grade was 3 to 4 in 420 (79%) of 529 participants in the pembrolizumab group and 400 (75%) of 534 in the placebo group; 369 (70%) participants in the pembrolizumab group and 367 (69%) in the placebo group had treatment-related adverse events with a maximum grade of 3 to 4. 31 (6%) participants in the pembrolizumab group and 49 (9%) in the placebo group died due to adverse events, including eight (2%) in the pembrolizumab group and three (1%) in the placebo group who died due to treatment-related adverse events. INTERPRETATION: Based on a statistically significant, clinically meaningful improvement in overall survival compared with gemcitabine and cisplatin without any new safety signals, pembrolizumab plus gemcitabine and cisplatin could be a new treatment option for patients with previously untreated metastatic or unresectable biliary tract cancer. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

Polo-like kinase 4 inhibitor CFI-400945 suppresses liver cancer through cell cycle perturbation and eliciting antitumor immunity.

BACKGROUND AND AIMS: Prognosis of HCC remains poor due to lack of effective therapies. Immune checkpoint inhibitors (ICIs) have delayed response and are only effective in a subset of patients. Treatments that could effectively shrink the tumors within a short period of time are idealistic to be employed together with ICIs for durable tumor suppressive effects. HCC acquires increased tolerance to aneuploidy. The rapid division of HCC cells relies on centrosome duplication. In this study, we found that polo-like kinase 4 (PLK4), a centrosome duplication regulator, represents a therapeutic vulnerability in HCC. APPROACH AND RESULTS: An orally available PLK4 inhibitor, CFI-400945, potently suppressed proliferating HCC cells by perturbing centrosome duplication. CFI-400945 induced endoreplication without stopping DNA replication, causing severe aneuploidy, DNA damage, micronuclei formation, cytosolic DNA accumulation, and senescence. The cytosolic DNA accumulation elicited the DEAD box helicase 41-stimulator of interferon genes-interferon regulatory factor 3/7-NF-κß cytosolic DNA sensing pathway, thereby driving the transcription of senescence-associated secretory phenotypes, which recruit immune cells. CFI-400945 was evaluated in liver-specific p53/phosphatase and tensin homolog knockout mouse HCC models established by hydrodynamic tail vein injection. Tumor-infiltrated immune cells were analyzed. CFI-400945 significantly impeded HCC growth and increased infiltration of cluster of differentiation 4-positive (CD4 + ), CD8 + T cells, macrophages, and natural killer cells. Combination therapy of CFI-400945 with anti-programmed death-1 showed a tendency to improve HCC survival. CONCLUSIONS: We show that by targeting a centrosome regulator, PLK4, to activate the cytosolic DNA sensing-mediated immune response, CFI-400945 effectively restrained tumor progression through cell cycle inhibition and inducing antitumor immunity to achieve a durable suppressive effect even in late-stage mouse HCC.

Plain language summary of the HIMALAYA study: tremelimumab and durvalumab for unresectable hepatocellular carcinoma (liver cancer).

WHAT IS THIS SUMMARY ABOUT?: This is a summary of results from a phase 3 clinical study called HIMALAYA. HIMALAYA looked at treatment with one dose of a medication called tremelimumab combined with multiple doses of a medication called durvalumab (the STRIDE regimen) or multiple doses of durvalumab alone. These treatments were compared with a medication called sorafenib in participants with unresectable hepatocellular carcinoma (HCC). HCC is a type of liver cancer that is difficult to treat because it is often diagnosed when it is unresectable, meaning it can no longer be removed with surgery. Sorafenib has been the main treatment for unresectable HCC since 2007. However, people who take sorafenib may experience side effects that can reduce their quality of life, so alternative medicines are being trialed. Tremelimumab and durvalumab are types of drugs called immunotherapies, and they both work in different ways to help the body's immune system fight cancer. WHAT WERE THE RESULTS OF THE STUDY?: Participants who took STRIDE lived longer than participants who took sorafenib, whilst participants who took durvalumab alone lived a similar length of time as participants who took sorafenib. Participants who took STRIDE or durvalumab had a lower relative risk of experiencing worsening in their quality of life than participants who took sorafenib. The side effects that participants who received STRIDE or durvalumab experienced were expected for these types of treatments and could mostly be managed. WHAT DO THE RESULTS OF THE STUDY MEAN?: Overall, STRIDE is more effective than sorafenib for people with unresectable HCC.

Placental growth factor promotes tumour desmoplasia and treatment resistance in intrahepatic cholangiocarcinoma.

OBJECTIVE: Intrahepatic cholangiocarcinoma (ICC)-a rare liver malignancy with limited therapeutic options-is characterised by aggressive progression, desmoplasia and vascular abnormalities. The aim of this study was to determine the role of placental growth factor (PlGF) in ICC progression. DESIGN: We evaluated the expression of PlGF in specimens from ICC patients and assessed the therapeutic effect of genetic or pharmacologic inhibition of PlGF in orthotopically grafted ICC mouse models. We evaluated the impact of PlGF stimulation or blockade in ICC cells and cancer-associated fibroblasts (CAFs) using in vitro 3-D coculture systems. RESULTS: PlGF levels were elevated in human ICC stromal cells and circulating blood plasma and were associated with disease progression. Single-cell RNA sequencing showed that the major impact of PlGF blockade in mice was enrichment of quiescent CAFs, characterised by high gene transcription levels related to the Akt pathway, glycolysis and hypoxia signalling. PlGF blockade suppressed Akt phosphorylation and myofibroblast activation in ICC-derived CAFs. PlGF blockade also reduced desmoplasia and tissue stiffness, which resulted in reopening of collapsed tumour vessels and improved blood perfusion, while reducing ICC cell invasion. Moreover, PlGF blockade enhanced the efficacy of standard chemotherapy in mice-bearing ICC. Conclusion PlGF blockade leads to a reduction in intratumorous hypoxia and metastatic dissemination, enhanced chemotherapy sensitivity and increased survival in mice-bearing aggressive ICC.

Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: Cabozantinib has shown clinical activity in combination with checkpoint inhibitors in solid tumours. The COSMIC-312 trial assessed cabozantinib plus atezolizumab versus sorafenib as first-line systemic treatment for advanced hepatocellular carcinoma. METHODS: COSMIC-312 is an open-label, randomised, phase 3 trial that enrolled patients aged 18 years or older with advanced hepatocellular carcinoma not amenable to curative or locoregional therapy and previously untreated with systemic anticancer therapy at 178 centres in 32 countries. Patients with fibrolamellar carcinoma, sarcomatoid hepatocellular carcinoma, or combined hepatocellular cholangiocarcinoma were not eligible. Tumours involving major blood vessels, including the main portal vein, were permitted. Patients were required to have measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), Barcelona Clinic Liver Cancer stage B or C disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, adequate organ and marrow function, and Child-Pugh class A. Previous resection, tumour ablation, radiotherapy, or arterial chemotherapy was allowed if more than 28 days before randomisation. Patients were randomly assigned (2:1:1) via a web-based interactive response system to cabozantinib 40 mg orally once daily plus atezolizumab 1200 mg intravenously every 3 weeks, sorafenib 400 mg orally twice daily, or single-agent cabozantinib 60 mg orally once daily. Randomisation was stratified by disease aetiology, geographical region, and presence of extrahepatic disease or macrovascular invasion. Dual primary endpoints were progression-free survival per RECIST 1.1 as assessed by a blinded independent radiology committee in the first 372 patients randomly assigned to the combination treatment of cabozantinib plus atezolizumab or sorafenib (progression-free survival intention-to-treat [ITT] population), and overall survival in all patients randomly assigned to cabozantinib plus atezolizumab or sorafenib (ITT population). Final progression-free survival and concurrent interim overall survival analyses are presented. This trial is registered with ClinicalTrials.gov, NCT03755791. FINDINGS: Analyses at data cut-off (March 8, 2021) included the first 837 patients randomly assigned between Dec 7, 2018, and Aug 27, 2020, to combination treatment of cabozantinib plus atezolizumab (n=432), sorafenib (n=217), or single-agent cabozantinib (n=188). Median follow-up was 15·8 months (IQR 14·5-17·2) in the progression-free survival ITT population and 13·3 months (10·5-16·0) in the ITT population. Median progression-free survival was 6·8 months (99% CI 5·6-8·3) in the combination treatment group versus 4·2 months (2·8-7·0) in the sorafenib group (hazard ratio [HR] 0·63, 99% CI 0·44-0·91, p=0·0012). Median overall survival (interim analysis) was 15·4 months (96% CI 13·7-17·7) in the combination treatment group versus 15·5 months (12·1-not estimable) in the sorafenib group (HR 0·90, 96% CI 0·69-1·18; p=0·44). The most common grade 3 or 4 adverse events were alanine aminotransferase increase (38 [9%] of 429 patients in the combination treatment group vs six [3%] of 207 in the sorafenib group vs 12 [6%] of 188 in the single-agent cabozantinib group), hypertension (37 [9%] vs 17 [8%] vs 23 [12%]), aspartate aminotransferase increase (37 [9%] vs eight [4%] vs 18 [10%]), and palmar-plantar erythrodysaesthesia (35 [8%] vs 17 [8%] vs 16 [9%]); serious treatment-related adverse events occurred in 78 (18%) patients in the combination treatment group, 16 (8%) patients in the sorafenib group, and 24 (13%) in the single-agent cabozantinib group. Treatment-related grade 5 events occurred in six (1%) patients in the combination treatment group (encephalopathy, hepatic failure, drug-induced liver injury, oesophageal varices haemorrhage, multiple organ dysfunction syndrome, and tumour lysis syndrome), one (<1%) patient in the sorafenib group (general physical health deterioration), and one (<1%) patient in the single-agent cabozantinib group (gastrointestinal haemorrhage). INTERPRETATION: Cabozantinib plus atezolizumab might be a treatment option for select patients with advanced hepatocellular carcinoma, but additional studies are needed. FUNDING: Exelixis and Ipsen.

Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial.

BACKGROUND: Single-agent nivolumab showed durable responses, manageable safety, and promising survival in patients with advanced hepatocellular carcinoma in the phase 1-2 CheckMate 040 study. We aimed to investigate nivolumab monotherapy compared with sorafenib monotherapy in the first-line setting for patients with advanced hepatocellular carcinoma. METHODS: In this randomised, open-label, phase 3 trial done at medical centres across 22 countries and territories in Asia, Australasia, Europe, and North America, patients at least 18 years old with histologically confirmed advanced hepatocellular carcinoma not eligible for, or whose disease had progressed after, surgery or locoregional treatment; with no previous systemic therapy for hepatocellular carcinoma, with Child-Pugh class A and Eastern Cooperative Oncology Group performance status score of 0 or 1, and regardless of viral hepatitis status were randomly assigned (1:1) via an interactive voice response system to receive nivolumab (240 mg intravenously every 2 weeks) or sorafenib (400 mg orally twice daily) until disease progression or unacceptable toxicity. The primary endpoint was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT02576509. FINDINGS: Between Jan 11, 2016, and May 24, 2017, 743 patients were randomly assigned to treatment (nivolumab, n=371; sorafenib, n=372). At the primary analysis, the median follow-up for overall survival was 15·2 months (IQR 5·7-28·0) for the nivolumab group and 13·4 months (5·7-25·9) in the sorafenib group. Median overall survival was 16·4 months (95% CI 13·9-18·4) with nivolumab and 14·7 months (11·9-17·2) with sorafenib (hazard ratio 0·85 [95% CI 0·72-1·02]; p=0·075; minimum follow-up 22·8 months); the protocol-defined significance level of p=0·0419 was not reached. The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysaesthesia (1 [<1%] of 367 patients in the nivolumab group vs 52 [14%] of patients in the sorafenib group), aspartate aminotransferase increase (22 [6%] vs 13 [4%]), and hypertension (0 vs 26 [7%]). Serious treatment-related adverse events were reported in 43 (12%) patients receiving nivolumab and 39 (11%) patients receiving sorafenib. Four deaths in the nivolumab group and one death in the sorafenib group were assessed as treatment related. INTERPRETATION: First-line nivolumab treatment did not significantly improve overall survival compared with sorafenib, but clinical activity and a favourable safety profile were observed in patients with advanced hepatocellular carcinoma. Thus, nivolumab might be considered a therapeutic option for patients in whom tyrosine kinase inhibitors and antiangiogenic drugs are contraindicated or have substantial risks. FUNDING: Bristol Myers Squibb in collaboration with Ono Pharmaceutical.

Ramucirumab for Patients with Advanced Hepatocellular Carcinoma and Elevated Alpha Fetoprotein Following Non-Sorafenib Systemic Therapy: An Expansion Cohort of REACH-2.

BACKGROUND: Ramucirumab is indicated for patients with advanced hepatocellular carcinoma (HCC) and α-fetoprotein (AFP) ≥400 ng/mL following sorafenib. Here, we prospectively studied ramucirumab following non-sorafenib systemic therapies. MATERIALS AND METHODS: This open-label, non-comparative cohort of REACH-2 enrolled patients with advanced HCC, Child-Pugh class-A liver disease, and AFP ≥400 ng/mL who had received 1-2 lines of therapy, excluding sorafenib or chemotherapy. Ramucirumab was administered 8 mg/kg intravenously Q2W. The primary endpoint was safety. Secondary endpoints were overall survival, progression-free survival, objective response rate (RECIST v1.1), time to progression, pharmacokinetics, and patient-reported outcomes. Final analysis occurred after all enrolled patients completed ≥3 treatment cycles or discontinued treatment. RESULTS: Between April 27, 2018, and March 29, 2021, 47 patients were treated at 21 investigative sites in Asia, Europe, and USA. The most frequently reported grade ≥3 adverse events, regardless of causality, were hypertension (11%), proteinuria (6%), hyponatremia (6%), and AST increased (6%). Two patients died from adverse events (myocardial infarction and upper gastrointestinal hemorrhage), deemed related to treatment. Median progression-free survival, time to progression, and overall survival were 1.7 months, 2.8 months, and 8.7 months, respectively. The objective response rate was 10.6% with a median duration response of 8.3 months. Median time to deterioration in FHSI-8 total score was 4.4 months. CONCLUSION: Ramucirumab demonstrated consistent and meaningful clinical activity with no new safety signals following non-sorafenib therapies in patients with advanced HCC and AFP ≥400 ng/mL. This represents one of the first sequencing studies for patients with advanced HCC not treated with sorafenib.

A phase 1 study of pegylated recombinant arginase (PEG-BCT-100) in combination with systemic chemotherapy (capecitabine and oxaliplatin)[PACOX] in advanced hepatocellular carcinoma patients.

INTRODUCTION: We investigated the safety and efficacy of a pegylated arginase (PEG-BCT-100) in combination with chemotherapy (oxaliplatin and capecitabine) [PACOX] in advanced HCC patients. METHODS: This was a single centre phase 1 trial to assess the safety and tolerability of PACOX. All the enrolled subjects received treatment in 3-weekly cycles: intravenous PEG-BCT-100 2.7 mg/kg on days 1, 8 and 15 of each cycle; oral capecitabine 1000 mg/m2 twice daily on day 1-14 of each cycle and intravenous oxaliplatin on day 1. Three dose levels of oxaliplatin (85 mg/m2, 100 mg/m2 or 130 mg/m2) were studied to define the maximum tolerated dose (MTD). Adverse events (AEs), efficacy by RECIST v1.1, time to progression (TTP), progression-free survival (PFS) and overall survival (OS) were studied. RESULTS: Seventeen patients were enrolled at 3 dose levels of oxaliplatin: 85 mg/m2 (8 patients), 100 mg/m2 (3 patients), and 130 mg/m2 (6 patients). The median age was 55 years; all had had locoregional chemotherapy or targeted therapy such as sorafenib, but no systemic chemotherapy. The most common AEs were nausea (82%), injection site reaction (76%), palmar-plantar erythrodysesthesia (59%), oral mucositis (53%) and vomiting (53%). There was no dose-limiting toxicity (DLT). Median duration on study was 8 weeks overall. In 14 evaluable cases, one achieved partial response (PR), 4 had stable disease (SD); disease control rate was 36%; most responses were observed in the 130 mg/m2 cohort with 1 PR and 2 SDs. Median TTP and PFS were both 7.0 weeks. Overall median OS was 10.7 months; the median OS was not reached at 19.4 months of follow-up in the 130 mg/m2 cohort. CONCLUSION: The PACOX regimen demonstrated good anti-cancer activity and survival advantage in advanced pre-treated HCC with favourable safety profile. It warrants further phase II/III studies.

Malignancies in spondyloarthritis with and without concomitant psoriasis, and the effect of disease modifying anti-rheumatic drugs.

OBJECTIVES: To determine the risk of 6 types of malignancies in spondyloarthritis (SpA) with and without psoriasis (PsO) and on disease-modifying anti-rheumatic drugs (DMARDs), compared to non-specific back pain (NSBP). METHODS: Medical records were retrieved. Patients with SpA with and without PsO were identified and compared to those with NSBP. Clinical data; follow-up duration; comorbidities; dates and types of cancer diagnosed; types and duration of DMARD therapy were collected. Propensity score adjustment was used to compare the risks of malignancies between SpA, SpA with and without PsO, and NSBP. Cox regression analysis was used to determine the risk of malignancy in DMARD therapy. RESULTS: A total of 3020 patients with SpA and 2527 patients with NSBP were studied. The mean follow-up duration in patients with SpA and NSBP was 9.6 years and 13.5 years respectively. Incidence and risk of malignancies were compatible between SpA and NSBP. The incidences of various carcinomas (per 1000 patient-years) in SpA were: 1.37 for colorectal carcinoma; 0.30 for carcinoma of pancreas; 0.30 for carcinoma of stomach; and 0.91 for lymphomas. Risk of colorectal carcinoma (HR 2.46; p=0.03) and lymphomas (HR 2.86; p=0.04) was increased in SpA with concomitant PsO. DMARD therapy was not associated with increased risks of malignancies after adjustment for confounding factors. CONCLUSIONS: Risk of malignancy was increased in SpA with PsO but not in other subtypes of SpA or DMARD therapy.

Safety and tolerability of subcutaneous trastuzumab and intravenous pertuzumab as adjuvant treatment for HER2 positive breast cancer: a pilot study.

BACKGROUND: Subcutaneous (SC) trastuzumab is similar to intravenous trastuzumab in terms of pharmacokinetics, efficacy and tolerability. The use of dual anti-HER2 agents trastuzumab and pertuzumab has become the new standard for node-positive HER2-positive breast cancers at adjuvant setting, but the safety and tolerability of combining SC trastuzumab and intravenous pertuzumab is not well studied. METHODS: This was a prospective single-arm pilot study with locally advanced HER2-positive breast cancer who received adjuvant SC trastuzumab and intravenous pertuzumab after standard anti-HER2 treatment with chemotherapy. Primary outcomes included adverse events (AEs), severe AEs and cardiac AEs. Secondary outcome was invasive disease-free survival (iDFS). RESULTS: With a median follow-up of 21.7 months, 20 patients were enrolled. One patient (5%) developed asymptomatic drop in left ventricular ejection fraction from 69% to 53%. Two patients (10%) developed grade 1 injection site reaction related to SC trastuzumab. There were no grade 2 or above AEs. All AEs were transient. No new AEs were observed. The 1-year iDFS was 90% (95% CI 0.656 to 0.974). CONCLUSIONS: Combination of SC trastuzumab and intravenous pertuzumab for HER2-positive breast cancer is a safe and well-tolerated option in adjuvant setting.

Health-related quality-of-life impact of pembrolizumab versus best supportive care in previously systemically treated patients with advanced hepatocellular carcinoma: KEYNOTE-240.

BACKGROUND: Health-related quality of life (HRQoL) is an important outcome measure and prognostic indicator in hepatocellular carcinoma (HCC). KEYNOTE-240 (NCT02702401) assessed the efficacy and safety of pembrolizumab plus best supportive care (BSC) versus placebo plus BSC in patients with HCC who previously received sorafenib. This study presents the results of a prespecified exploratory analysis of patient-reported outcomes. METHODS: Patients completed the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) and its HCC supplement (EORTC QLQ-HCC18) electronically at baseline; at weeks 2, 3, 4, 6, 9, 12, and 18; and then every 9 weeks until 1 year or end of treatment, and at the 30-day safety follow-up visit. RESULTS: The HRQoL population included 271 and 127 patients randomly assigned to pembrolizumab and placebo, respectively. From baseline to week 12, changes in both scores were similar between pembrolizumab and placebo; global health status/QoL scores were stable. The proportions of patients who improved, remained stable, or deteriorated across all functional domain and symptom scores were generally similar between pembrolizumab and placebo. Time to deterioration was similar between the 2 arms based on the prespecified analysis of EORTC QLQ-HCC18 domains of abdominal swelling, fatigue, and pain. CONCLUSION: Pembrolizumab preserved HRQoL during treatment for advanced HCC. Combined with efficacy and safety results from KEYNOTE-240, these findings support a positive benefit/risk profile for pembrolizumab in a second-line treatment setting for patients with HCC who previously received sorafenib.

Hepatocellular Carcinoma Cells Up-regulate PVRL1, Stabilizing PVR and Inhibiting the Cytotoxic T-Cell Response via TIGIT to Mediate Tumor Resistance to PD1 Inhibitors in Mice.

BACKGROUND & AIMS: Immune checkpoint inhibitors are effective in the treatment of some hepatocellular carcinomas (HCCs), but these tumors do not always respond to inhibitors of programmed cell death 1 (PDCD1, also called PD1). We investigated mechanisms of resistance of liver tumors in mice to infiltrating T cells. METHODS: Mice were given hydrodynamic tail vein injections of clustered regularly interspaced short palindromic repeats-Cas9 (CRISPR-Cas9) and transposon vectors to disrupt Trp53 and overexpress C-Myc (Trp53KO/C-MycOE mice). Pvrl1 and Pvrl3 were knocked down in Hepa1-6 cells by using short hairpin RNAs. Hepa1-6 cells were injected into livers of C57BL/6 mice; some mice were given intraperitoneal injections of antibodies against PD1, T-cell immunoreceptor with Ig and ITIM domains (TIGIT), or CD8 before the cancer cells were injected. Liver tissues were collected from mice and analyzed by histology, immunohistochemistry, and quantitative real-time polymerase chain reaction; tumors were analyzed by mass cytometry using markers to detect T cells and other lymphocytes. We obtained HCC and nontumorous liver tissues and clinical data from patients who underwent surgery in Hong Kong and analyzed the tissues by immunohistochemistry. RESULTS: Trp53KO/C-MycOE mice developed liver tumors in 3-5 weeks; injections of anti-PD1 did not slow tumor development. Tumors from mice given anti-PD1 had larger numbers of memory CD8+ T cells (CD44+CD62L-KLRG1int) and T cells that expressed PD1, lymphocyte activating 3 (LAG3), and TIGIT compared with mice not given the antibody. HCC tissues from patients had higher levels of PVRL1 messenger RNA and protein than nontumorous tissues. Increased PVRL1 was associated with shorter times of disease-free survival. Knockdown of Pvrl1 in Hepa1-6 cells caused them to form smaller tumors in mice, infiltrated by higher numbers of CD8+ T cells that expressed the inhibitory protein TIGIT; these effects were not observed in mice with depletion of CD8+ T cells. In Hepa1-6 cells, PVRL1 stabilized cell surface PVR, which interacted with TIGIT on CD8+ T cells; knockdown of Pvrl1 reduced cell-surface levels of PVR but not levels of Pvr messenger RNA. In Trp53KO/C-MycOE mice and mice with tumors grown from Hepa1-6 cells, injection of the combination of anti-PD1 and anti-TIGIT significantly reduced tumor growth, increased the ratio of cytotoxic to regulatory T cells in tumors, and prolonged survival. CONCLUSIONS: PVRL1, which is up-regulated by HCC cells, stabilizes cell surface PVR, which interacts with TIGIT, an inhibitory molecule on CD8+ effector memory T cells. This suppresses the ant-tumor immune response. Inhibitors of PVRL1/TIGIT, along with anti-PD1 might be developed for treatment of HCC.

Analysis of the pan-Asian subgroup of patients in the NALA Trial: a randomized phase III NALA Trial comparing neratinib+capecitabine (N+C) vs lapatinib+capecitabine (L+C) in patients with HER2+metastatic breast cancer (mBC) previously treated with two or more HER2-directed regimens.

PURPOSE: Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has demonstrated systemic efficacy and intracranial activity in various stages of HER2+breast cancer. NALA was a phase III randomized trial that assessed the efficacy and safety of neratinib+capecitabine (N+C) against lapatinib+capecitabine (L+C) in HER2+ metastatic breast cancer (mBC) patients who had received ≥ 2 HER2-directed regimens. Descriptive analysis results of the Asian subgroup in the NALA study are reported herein. METHODS: 621 centrally assessed HER2+ mBC patients were enrolled, 202 of whom were Asian. Those with stable, asymptomatic brain metastases (BM) were eligible for study entry. Patients were randomized 1:1 to N (240 mg qd) + C (750 mg/m2 bid, day 1-14) with loperamide prophylaxis or to L (1250 mg qd) + C (1000 mg/m2 bid, day 1-14) in 21-day cycles. Co-primary endpoints were centrally assessed progression-free survival (PFS) and overall survival (OS). Secondary endpoints included time to intervention for central nervous system (CNS) disease, objective response rate, duration of response (DoR), clinical benefit rate, and safety. RESULTS: 104 and 98 Asian patients were randomly assigned to receive N+C or L+C, respectively. Median PFS of N+C and L+C was 7.0 and 5.4 months (P = 0.0011), respectively. Overall cumulative incidence of intervention for CNS disease was lower with N+C (27.9 versus 33.8%; P = 0.039). Both median OS (23.8 versus 18.7 months; P = 0.185) and DoR (11.1 versus 4.2 months; P < 0.0001) were extended with N+C, compared to L+C. The incidences of grade 3/4 treatment emergent adverse events (TEAEs) and TEAEs leading to treatment discontinuation were mostly comparable between the two arms. Diarrhea and palmar-plantar erythrodysesthesia were the most frequent TEAEs in both arms, similar to the overall population in incidence and severity. CONCLUSION: Consistent with the efficacy profile observed in the overall study population, Asian patients with HER2+ mBC, who had received ≥ 2 HER2-directed regimens, may also benefit from N+C. No new safety signals were noted. CLINICAL TRIAL REGISTRATION: NCT01808573.

The Effects of COVID-19 on Cancer Care Provision: A Systematic Review.

This systematic review aims to gather primary data from cancer institutions that have implemented changes to cancer service provision amid the COVID-19 outbreak to inform future intervention and health care facility response strategies. A comprehensive literature search was done on Global Health Medline and EMBASE using pertinent key words and MeSH terms relating to COVID-19 and Cancer service provision. A total of 72 articles were selected for inclusion in this systematic review. Following the narrative synthesis that was conducted of the literature, 6 core themes that encompassed common cancer service intervention adopted by institutions were identified: (1) Testing and Tracking, (2) Outreach and Communication, (3) Protection, (4) Social Distancing (5) Treatment Management, (6) Service Restructuring. Since cancer patients are a high-risk population amid the COVID-19 pandemic, these areas of targeted intervention can be used to inform necessary actions in institutions facing similar risks, based on previous learning from numerous cancer centers globally.

Programmed cell death-ligand 1 expression in hepatocellular carcinoma and its correlation with clinicopathological characteristics.

BACKGROUND AND AIM: Programmed cell death-ligand 1 (PD-L1) immunohistochemistry score has been approved as the predictive biomarker for anti-PD1/PD-L1 therapy in several advanced malignancies. Although its predictive role remained inconclusive in hepatocellular carcinoma, ongoing study of anti-PD1/PD-L1 therapy showed promising results. However, less is known about the PD-L1 immunohistochemistry score and factors correlated with it in hepatocellular carcinoma. We investigated PD-L1 immunohistochemistry scores in a large cohort of hepatocellular carcinoma, as well as its correlation with various clinical and genomic factors. METHODS: Immunohistochemistry was performed to detect the expression of PD-L1 protein in 315 hepatocellular carcinoma tissues. All slides were independently reviewed by three senior pathologists. Next-generation YS panel (450 genes) sequencing was performed on 309 patients. RESULTS: Higher PD-L1 expression as measured by combined positive score (CPS) was associated with increased Edmondson-Steiner grade (grade III vs II, P = 0.041) and TP53 mutations (P = 0.021). PD-L1 CPS had no correlation with tumor mutational burden (Spearman's correlation coefficient 0.067). PD-L1 CPS was not significantly associated with hepatitis B virus infection. CONCLUSIONS: Our data indicated that patients with higher Edmondson-Steiner grade (grade III) had significantly higher PD-L1 CPS than patients with lower Edmondson-Steiner grade (grade II). Patients with TP53 mutations had significantly higher PD-L1 expression.

Thyroid Immune-Related Adverse Events in Patients with Cancer Treated with anti-PD1/anti-CTLA4 Immune Checkpoint Inhibitor Combination: Clinical Course and Outcomes.

OBJECTIVE: Thyroid immune-related adverse events (irAEs) have been reported to have prognostic significance among patients with cancer treated with anti-programmed cell death-1 (PD1) and anti-programmed death-ligand 1 monotherapies. We evaluated the clinical course and predictors of thyroid irAEs in relation to outcomes of patients with advanced cancer treated with combination anti-PD1/anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4). METHODS: We conducted a regional study and identified patients with advanced cancer who received ≥1 cycle of combination anti-PD1/anti-CTLA4 between 2015 and 2019 in Hong Kong. Thyroid function tests (TFTs) were monitored every 3 weeks. Thyroid irAE was defined by ≥2 abnormal TFTs after initiation of combination anti-PD1/anti-CTLA4 in the absence of other causes. RESULTS: One hundred and three patients were included (median age: 59 years; 71.8% men). About 45% had prior anti-PD1 exposure. Upon median follow-up of 6.8 months, 17 patients (16.5%) developed thyroid irAEs, where 6 initially presented with thyrotoxicosis (overt, n = 4; subclinical, n = 2) and 11 with hypothyroidism (overt, n = 2; subclinical, n = 9). Eventually, 10 patients (58.8%) required continuous thyroxine replacement. Systemic steroid was not required in all cases. Prior anti-PD1 exposure (odds ratio, 3.67; 95% CI, 1.19-11.4; P = .024) independently predicted thyroid irAEs. Multivariable Cox regression analysis revealed that occurrence of thyroid irAEs was independently associated with better overall survival (adjusted hazard ratio, 0.34; 95% CI, 0.17-0.71; P = .004). CONCLUSION: Thyroid irAEs are common in routine clinical practice among patients with advanced cancer treated with anti-PD1/anti-CTLA4 combination and might have potential prognostic significance. Regular TFT monitoring is advised for timely treatment of thyroid irAEs to prevent potential morbidities.

Association of inflammatory biomarkers with clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma.

BACKGROUND & AIMS: Nivolumab, a programmed death (PD)-1 (PD-1) inhibitor, led to durable responses, manageable safety, and increased survival in patients with advanced hepatocellular carcinoma (HCC). In our retrospective analysis, we studied the immunobiology and potential associations between biomarkers and outcomes with nivolumab in HCC. METHODS: Fresh and archival tumour samples from dose-escalation and dose-expansion phases of the CheckMate 040 trial were analysed by immunohistochemistry and RNA sequencing to assess several inflammatory gene expression signatures, including CD274 (PD-ligand 1 [PD-L1]), CD8A, LAG3, and STAT1. Biomarkers were assessed for association with clinical outcomes (best overall response by blinded independent central review per RECIST v1.1 and overall survival [OS]). RESULTS: Complete or partial tumour responses were observed in PD-L1-positive and PD-L1-negative patients treated with nivolumab monotherapy. Median OS was 28.1 (95% CI 18.2-n.a.) vs. 16.6 months (95% CI 14.2-20.2) for patients with tumour PD-L1 ≥1% vs. <1% (p = 0.03). Increased CD3 and CD8 showed a non-significant trend towards improved OS (both p = 0.08), and macrophage markers were not associated with OS. Tumour PD-1 and PD-L1 expression were associated with improved OS (p = 0.05 and p = 0.03, respectively). An inflammatory gene signature consisting of 4 genes was associated with improved objective response rate (p = 0.05) and OS (p = 0.01). CONCLUSIONS: PD-1 and PD-L1 expression, biomarkers of inflammation, and inflammatory gene signatures trended with improved survival and response. While further confirmation within a larger phase III trial is needed to evaluate predictive value of these biomarkers, these exploratory analyses suggest that anti-tumour immune response may play a role in the treatment benefit of nivolumab in HCC. LAY SUMMARY: Certain tests may be used to provide a picture of how a tumour is escaping the immune system, allowing it to continue to grow and create more tumours. Therapies such as nivolumab are designed to help the immune system fight the tumour. These tests may be used to determine how effective such therapies will be in the treatment of advanced liver cancer. NCT NUMBER: NCT01658878.

Regorafenib in Chinese patients with metastatic colorectal cancer: Subgroup analysis of the phase 3 CONCUR trial.

BACKGROUND AND AIM: In the phase 3 CONCUR trial (NCT01584830), regorafenib improved overall survival (OS) versus placebo in Asian patients with treatment-refractory metastatic colorectal cancer (mCRC). We conducted a post hoc subgroup analysis of Chinese patients in CONCUR. METHODS: Adults with mCRC progressing despite at least two prior treatment regimens and Eastern Cooperative Oncology Group performance status 0-1 were randomized 2:1 to regorafenib 160 mg once daily or placebo for the first 3 weeks of each 4-week cycle. Dose modifications were permitted. The primary endpoint was OS. Secondary endpoints included progression-free survival, objective overall response, disease control rate, and safety. RESULTS: A total of 172 Chinese patients were randomized and treated (regorafenib n = 112, placebo n = 60). OS was significantly improved with regorafenib versus placebo (8.4 vs 6.2 months, respectively; hazard ratio [HR] 0.56, 95% CI 0.39-0.80; one-sided P = 0.000632), as was progression-free survival (HR 0.32, 95% CI 0.22-0.47; one-sided P < 0.000001). The most common drug-related grade ≥ 3 treatment-emergent adverse events (TEAEs; regorafenib, placebo) were hand-foot skin reaction (19%, 0%), hypertension (13%, 3%), hypophosphatemia (7%, 0%), increased alanine aminotransferase (6%, 0%), and increased aspartate aminotransferase (5%, 0%). In patients receiving regorafenib and placebo, respectively, TEAEs led to treatment discontinuation in 14% and 7%, dose reduction in 39% and 0%, and dose interruption in 64% and 20%. CONCLUSIONS: This retrospective analysis showed that regorafenib provided an OS benefit over placebo for Chinese patients with previously treated mCRC. TEAEs were consistent with the regorafenib safety profile and manageable with treatment modifications.