The use of pembrolizumab monotherapy for the management of head and neck squamous cell carcinoma (HNSCC) in the UK.

Pembrolizumab has received approval in the UK as first-line monotherapy for recurrent and/or metastatic HNSCC (R/M HNSCC) following the results of the KEYNOTE-048 trial, which demonstrated a longer overall survival (OS) in comparison to the EXTREME chemotherapy regimen in patients with a combined positive score (CPS) ≥1. In this article, we provide retrospective real-world data on the role of pembrolizumab monotherapy as first-line systemic therapy for HNSCC across 18 centers in the UK from March 20, 2020 to May 31, 2021. 211 patients were included, and in the efficacy analysis, the objective response rate (ORR) was 24.7%, the median progression-free survival (PFS) was 4.8 months (95% confidence interval [CI]: 3.6-6.1), and the median OS was 10.8 months (95% CI 9.0-12.5). Pembrolizumab monotherapy was well tolerated, with 18 patients having to stop treatment owing to immune-related adverse events (irAEs). 53 patients proceeded to second-line treatment with a median PFS2 of 10.2 months (95% CI: 8.8-11.5). Moreover, patients with documented irAEs had a statistically significant longer median PFS (11.3 vs. 3.3 months; log-rank p value = <.001) and median OS (18.8 vs. 8.9 months; log-rank p value <.001). The efficacy and safety of pembrolizumab first-line monotherapy for HNSCC has been validated using real-world data.

Ibrutinib as first-line therapy for mantle cell lymphoma: a multicenter, real-world UK study.

ABSTRACT: During the COVID-19 pandemic, ibrutinib with or without rituximab was approved in England for initial treatment of mantle cell lymphoma (MCL) instead of immunochemotherapy. Because limited data are available in this setting, we conducted an observational cohort study evaluating safety and efficacy. Adults receiving ibrutinib with or without rituximab for untreated MCL were evaluated for treatment toxicity, response, and survival, including outcomes in high-risk MCL (TP53 mutation/deletion/p53 overexpression, blastoid/pleomorphic, or Ki67 ≥ 30%). A total of 149 patients from 43 participating centers were enrolled: 74.1% male, median age 75 years, 75.2% Eastern Cooperative Oncology Group status of 0 to 1, 36.2% high-risk, and 8.9% autologous transplant candidates. All patients received ≥1 cycle ibrutinib (median, 8 cycles), 39.0% with rituximab. Grade ≥3 toxicity occurred in 20.3%, and 33.8% required dose reductions/delays. At 15.6-month median follow-up, 41.6% discontinued ibrutinib, 8.1% due to toxicity. Of 104 response-assessed patients, overall (ORR) and complete response (CR) rates were 71.2% and 20.2%, respectively. ORR was 77.3% (low risk) vs 59.0% (high risk) (P = .05) and 78.7% (ibrutinib-rituximab) vs 64.9% (ibrutinib; P = .13). Median progression-free survival (PFS) was 26.0 months (all patients); 13.7 months (high risk) vs not reached (NR) (low risk; hazard ratio [HR], 2.19; P = .004). Median overall survival was NR (all); 14.8 months (high risk) vs NR (low risk; HR, 2.36; P = .005). Median post-ibrutinib survival was 1.4 months, longer in 41.9% patients receiving subsequent treatment (median, 8.6 vs 0.6 months; HR, 0.36; P = .002). Ibrutinib with or without rituximab was effective and well tolerated as first-line treatment of MCL, including older and transplant-ineligible patients. PFS and OS were significantly inferior in one-third of patients with high-risk disease and those unsuitable for post-ibrutinib treatment, highlighting the need for novel approaches in these groups.

A Phase I/II Trial of Oral SRA737 (a Chk1 Inhibitor) Given in Combination with Low-Dose Gemcitabine in Patients with Advanced Cancer.

PURPOSE: This was a Phase I/II trial of the novel checkpoint kinase 1 (Chk1) inhibitor SRA737 given in combination with gemcitabine. Its objectives were to establish the safety profile, recommended Phase 2 dose (RP2D), pharmacokinetics profile, and clinical activity of SRA737. PATIENTS AND METHODS: Patients with advanced solid tumors were enrolled into dose-escalation cohorts and treated in 28-day cycles with oral SRA737 on days 2, 3, 9, 10, 16, and 17, and intravenous gemcitabine on days 1, 8, and 15. Treatment was continued until progression. Each expansion cohort included up to 20 patients with specific genetically defined tumors. RESULTS: The RP2D was determined to be 500 mg SRA737 combined with low-dose (250 mg/m2) gemcitabine. Of 143 enrolled patients, 77 were treated at doses of at least 500 mg SRA737 combined with 250 mg/m2 gemcitabine. Common toxicities of nausea, vomiting, fatigue, and diarrhea were primarily mild to moderate, and rarely led to treatment discontinuation. Anemia, neutropenia, and thrombocytopenia were grade ≥3 in 11.7%, 16.7%, and 10% of patients treated at the RP2D, respectively. The objective response rate (ORR) was 10.8% overall and notably the ORR in anogenital cancer was 25%. Partial tumor responses were observed in anogenital cancer, cervical cancer, high-grade serous ovarian cancer, rectal cancer, and small cell lung cancer. CONCLUSIONS: SRA737 in combination with low-dose gemcitabine was well tolerated with lower myelotoxicity than has been seen at standard doses of gemcitabine or with other combinations of Chk1 inhibitors with gemcitabine. Tumor responses were observed in anogenital and other solid tumors.

Eribulin Treatment for Patients with Metastatic Breast Cancer: The UK Experience - A Multicenter Retrospective Study.

INTRODUCTION: This study examined real-world data from patients who received eribulin for metastatic breast cancer (MBC) collected from 14 hospitals across the UK. METHODS: Anonymized data were collected retrospectively from patients with MBC who had received eribulin. The data included the hormone-receptor status, histological diagnosis, age, prior chemotherapy, response to eribulin, progression-free survival (PFS), and overall survival (OS). RESULTS: Among 577 patients analyzed, the median age was 56 years, and most patients (73%) were estrogen-receptor positive. The median OS was 288 days (95% confidence interval [CI]: 261-315), and the PFS was 117 days (95% CI: 105-129). The median OS was higher among older patients (≥65 vs. <65 years: 325 days [95% CI: 264-385] vs. 285 days [95% CI: 252-317]; p = 0.028). The median OS was also higher in patients who received eribulin after fewer prior lines of chemotherapy (≤2 vs. >2 prior: 328 days [95% CI: 264-385] vs. 264 days [95% CI: 229-298]; p = 0.042). DISCUSSION/CONCLUSION: These retrospective data suggest that eribulin can be successfully used in older patients with MBC. Eribulin treatment was more effective in earlier-line settings, which, while predictable, supports consideration of eribulin as a second-line treatment option.

Inequalities in cancer screening, prevention and service engagement between UK ethnic minority groups.

More people in the UK are living with cancer than ever before. With an increasingly ethnically diverse population, greater emphasis must be placed on understanding factors influencing cancer outcomes. This review seeks to explore UK-specific variations in engagement with cancer services in minority ethnic groups and describe successful interventions. The authors wish to highlight that, despite improvement to engagement and education strategies, inequalities still persist and work to improve cancer outcomes across our communities still needs to be prioritised. There are many reasons why cancer healthcare inequities exist for minority communities, reported on a spectrum ranging from cultural beliefs and awareness, through to racism. Strategies that successfully enhanced engagement included language support; culturally-sensitive reminders; community-based health workers and targeted outreach. Focusing on the diverse city of Leicester the authors describe how healthcare providers, researchers and community champions have worked collectively, delivering targeted community-based strategies to improve awareness and access to cancer services.

Comparison of PET-CT, CT and MRI scan in initial staging and management of head and neck cancers.

BACKGROUND: To evaluate the utility of positron-emission tomography (FDG PET) in initial staging and management of head and neck cancers. METHODS: This is a retrospective study of 99 treatment naïve head and neck cancer patients treated between January 2017 and December 2020 at a tertiary teaching centre. Change in initial staging and management was noted based on PET scan compared to cross-sectional imaging (CT and MRI). RESULTS: There were 73 (73.7%) males and 26 (26.2%) females with male-to-female ratio of 2.8:1.Overall, change in management was seen in 36/99 (36.4%) patients due to PET scan. With regards to initial staging, T, N and M stage was changed in 14/99 (14.1%), 19/99 (19.1%) and 3/99 (3%) patients, respectively. These changes were significantly higher in patients with unknown primary (63.3%, p value -0.001) and N3 (41%, p -0.045) nodal disease. CONCLUSION: PET-CT plays an important role in appropriate initial staging and subsequent treatment planning of head and neck cancers. ADVANCES IN KNOWLEDGE: Initial staging PETCT changes management in 36.4% cases. Accuracy of various different imaging modalities have been compared.

Centralised RECIST Assessment and Clinical Outcomes with Lenvatinib Monotherapy in Recurrent and Metastatic Adenoid Cystic Carcinoma.

Adenoid cystic carcinoma (ACC) is a rare cancer of secretory glands. Recurrent or metastatic (R/M) ACC is generally considered resistant to cytotoxic chemotherapy. Recent phase II studies have reported improved objective response rates (ORR) with the use of the multi-kinase inhibitor lenvatinib. We sought to evaluate real-world experience of R/M ACC patients treated with lenvatinib monotherapy within the UK National Health Service (NHS) to determine the response rates by Response Evaluation Criteria of Solid Tumour (RECIST) and clinical outcomes. Twenty-three R/M ACC patients from eleven cancer centres were included. All treatment assessments for clinical decision making related to drug therapy were undertaken at the local oncology centre. Central radiology review was performed by an independent clinical trial radiologist and blinded to the clinical decision making. In contrast to previously reported ORR of 12-15%, complete or partial response was not observed in any patients. Eleven patients (52.4%) had stable disease and 5 patients (23.8%) had progression of disease as the best overall response. The median time on treatment was 4 months and the median survival from discontinuation was 1 month. The median PFS and OS from treatment initiation were 4.5 months and 12 months respectively. Multicentre collaborative studies such as this are required to evaluate rare cancers with no recommended standard of care therapy and variable disease courses.

Allogeneic stem cell transplantation for chronic lymphocytic leukemia in the era of novel agents.

Although novel agents (NAs) have improved outcomes for patients with chronic lymphocytic leukemia (CLL), a subset will progress through all available NAs. Understanding outcomes for potentially curative modalities including allogeneic hematopoietic stem cell transplantation (alloHCT) following NA therapy is critical while devising treatment sequences aimed at long-term disease control. In this multicenter, retrospective cohort study, we examined 65 patients with CLL who underwent alloHCT following exposure to ≥1 NA, including baseline disease and transplant characteristics, treatment preceding alloHCT, transplant outcomes, treatment following alloHCT, and survival outcomes. Univariable and multivariable analyses evaluated associations between pre-alloHCT factors and progression-free survival (PFS). Twenty-four-month PFS, overall survival (OS), nonrelapse mortality, and relapse incidence were 63%, 81%, 13%, and 27% among patients transplanted for CLL. Day +100 cumulative incidence of grade III-IV acute graft-vs-host disease (GVHD) was 24%; moderate-severe GVHD developed in 27%. Poor-risk disease characteristics, prior NA exposure, complete vs partial remission, and transplant characteristics were not independently associated with PFS. Hematopoietic cell transplantation-specific comorbidity index independently predicts PFS. PFS and OS were not impacted by having received NAs vs both NAs and chemoimmunotherapy, 1 vs ≥2 NAs, or ibrutinib vs venetoclax as the line of therapy immediately pre-alloHCT. AlloHCT remains a viable long-term disease control strategy that overcomes adverse CLL characteristics. Prior NAs do not appear to impact the safety of alloHCT, and survival outcomes are similar regardless of number of NAs received, prior chemoimmunotherapy exposure, or NA immediately preceding alloHCT. Decisions about proceeding to alloHCT should consider comorbidities and anticipated response to remaining therapeutic options.

Outcomes of COVID-19 in patients with CLL: a multicenter international experience.

Given advanced age, comorbidities, and immune dysfunction, chronic lymphocytic leukemia (CLL) patients may be at particularly high risk of infection and poor outcomes related to coronavirus disease 2019 (COVID-19). Robust analysis of outcomes for CLL patients, particularly examining effects of baseline characteristics and CLL-directed therapy, is critical to optimally manage CLL patients through this evolving pandemic. CLL patients diagnosed with symptomatic COVID-19 across 43 international centers (n = 198) were included. Hospital admission occurred in 90%. Median age at COVID-19 diagnosis was 70.5 years. Median Cumulative Illness Rating Scale score was 8 (range, 4-32). Thirty-nine percent were treatment naive ("watch and wait"), while 61% had received ≥1 CLL-directed therapy (median, 2; range, 1-8). Ninety patients (45%) were receiving active CLL therapy at COVID-19 diagnosis, most commonly Bruton tyrosine kinase inhibitors (BTKi's; n = 68/90 [76%]). At a median follow-up of 16 days, the overall case fatality rate was 33%, though 25% remain admitted. Watch-and-wait and treated cohorts had similar rates of admission (89% vs 90%), intensive care unit admission (35% vs 36%), intubation (33% vs 25%), and mortality (37% vs 32%). CLL-directed treatment with BTKi's at COVID-19 diagnosis did not impact survival (case fatality rate, 34% vs 35%), though the BTKi was held during the COVID-19 course for most patients. These data suggest that the subgroup of CLL patients admitted with COVID-19, regardless of disease phase or treatment status, are at high risk of death. Future epidemiologic studies are needed to assess severe acute respiratory syndrome coronavirus 2 infection risk, these data should be validated independently, and randomized studies of BTKi's in COVID-19 are needed to provide definitive evidence of benefit.

Phase Ib Study of Tirabrutinib in Combination with Idelalisib or Entospletinib in Previously Treated Chronic Lymphocytic Leukemia.

PURPOSE: Bruton tyrosine kinase (BTK) inhibition alone leads to incomplete responses in chronic lymphocytic leukemia (CLL). Combination therapy may reduce activation of escape pathways and deepen responses. This open-label, phase Ib, sequential dose-escalation and dose-expansion study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the selective BTK inhibitor tirabrutinib alone, in combination with the PI3K delta (PI3Kδ) inhibitor idelalisib, or with the spleen tyrosine kinase (SYK) inhibitor entospletinib in patients with relapsed/refractory CLL. PATIENTS AND METHODS: Patients received either tirabrutinib monotherapy (80 mg every day) or tirabrutinib 20-150 mg every day in combination with either idelalisib (50 mg twice a day or 100 mg every day) or entospletinib (200 mg or 400 mg every day). RESULTS: Fifty-three patients were included. Systemic tirabrutinib exposure was comparable between monotherapy and combination therapy. No MTD was identified. Across all treatment groups, the most common adverse event was diarrhea (43%, 1 patient grade ≥3); discontinuation due to adverse events was uncommon (13%). Objective response rates were 83%, 93%, and 100%, and complete responses were 7%, 7%, and 10% in patients receiving tirabrutinib, tirabrutinib/idelalisib, and tirabrutinib/entospletinib, respectively. As of February 21, 2019, 46 of 53 patients continue to receive treatment on study. CONCLUSIONS: Tirabrutinib in combination with idelalisib or entospletinib was well tolerated in patients with CLL, establishing an acceptable safety profile for concurrent selective inhibition of BTK with either PI3Kδ or SYK. This small study did not establish a superior efficacy of the combinations over tirabrutinib alone. This trial is registered at www.clinicaltrials.gov (NCT02457598).

Acalabrutinib monotherapy in patients with Waldenström macroglobulinemia: a single-arm, multicentre, phase 2 study.

BACKGROUND: Chemoimmunotherapy is typically the standard of care for patients with Waldenström macroglobulinemia; however, infectious and hematologic toxic effects are problematic. Acalabrutinib is a selective, potent Bruton tyrosine-kinase inhibitor. The aim of this trial was to evaluate the activity and safety of acalabrutinib in patients with Waldenström macroglobulinemia. METHODS: This single-arm, multicentre, phase 2 trial was done in 19 European academic centres in France, Italy, Greece, the Netherlands, and the UK, and eight academic centres in the USA. Eligible patients were 18 years or older and had treatment naive (declined or not eligible for chemoimmunotherapy) or relapsed or refractory (at least one previous therapy) Waldenström macroglobulinemia that required treatment, an Eastern Cooperative Oncology Group performance status of 2 or less, and received no previous Bruton tyrosine-kinase inhibitor therapy. Patients received 100 mg oral acalabrutinib twice per day in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed overall response (at least a minor response) according to the 6th International Workshop for Waldenström Macroglobulinemia (IWWM) and the modified 3rd IWWM workshop criteria. The primary outcome and safety were assessed in all patients who received at least one dose of treatment. This study is registered with ClinicalTrials.gov, number NCT02180724, and is ongoing, but no longer enrolling. FINDINGS: Between Sept 8, 2014, and Dec 24, 2015, 122 patients were assessed for eligibility, of which 106 (87%) patients were given acalabrutinib (14 were treatment naive and 92 had relapsed or refractory disease). With a median follow-up of 27·4 months (IQR 26·0-29·7), 13 (93% [95% CI 66-100]) of 14 treatment naive patients achieved an overall response and 86 (93% [86-98]) of 92 relapsed or refractory patients per both the modified 3rd and 6th IWWM criteria. Seven (50%) of 14 treatment naive patients and 23 (25%) of 92 relapsed or refractory patients discontinued treatment on study. Grade 3-4 adverse events occurring in more than 5% of patients were neutropenia (17 [16%] of 106 patients) and pneumonia (7 [7%]). Grade 3-4 atrial fibrillation occurred in one (1%) patient and grade 3-4 bleeding occurred in three (3%) patients. The most common serious adverse events were lower respiratory tract infection (n=7 [7%]), pneumonia (n=7 [7%]), pyrexia (n=4 [4%]), cellulitis (n=3 [3%]), fall (n=3 [3%]), and sepsis (n=3 [3%]). Pneumonia (n=5 [5%]) and lower respiratory tract infection (n=4 [4%]) were considered treatment related. One treatment-related death was reported (intracranial hematoma). INTERPRETATION: This study provides evidence that acalabrutinib is active as single-agent therapy with a manageable safety profile in patients with treatment-naive, or relapse or refractory Waldenström macroglobulinemia. Further studies are needed to establish its efficacy against current standard treatments and to investigate whether outcomes can be improved with combination therapies. FUNDING: Acerta Pharma.