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.

SARS-CoV-2 omicron (B.1.1.529)-related COVID-19 sequelae in vaccinated and unvaccinated patients with cancer: results from the OnCovid registry.

BACKGROUND: COVID-19 sequelae can affect about 15% of patients with cancer who survive the acute phase of SARS-CoV-2 infection and can substantially impair their survival and continuity of oncological care. We aimed to investigate whether previous immunisation affects long-term sequelae in the context of evolving variants of concern of SARS-CoV-2. METHODS: OnCovid is an active registry that includes patients aged 18 years or older from 37 institutions across Belgium, France, Germany, Italy, Spain, and the UK with a laboratory-confirmed diagnosis of COVID-19 and a history of solid or haematological malignancy, either active or in remission, followed up from COVID-19 diagnosis until death. We evaluated the prevalence of COVID-19 sequelae in patients who survived COVID-19 and underwent a formal clinical reassessment, categorising infection according to the date of diagnosis as the omicron (B.1.1.529) phase from Dec 15, 2021, to Jan 31, 2022; the alpha (B.1.1.7)-delta (B.1.617.2) phase from Dec 1, 2020, to Dec 14, 2021; and the pre-vaccination phase from Feb 27 to Nov 30, 2020. The prevalence of overall COVID-19 sequelae was compared according to SARS-CoV-2 immunisation status and in relation to post-COVID-19 survival and resumption of systemic anticancer therapy. This study is registered with ClinicalTrials.gov, NCT04393974. FINDINGS: At the follow-up update on June 20, 2022, 1909 eligible patients, evaluated after a median of 39 days (IQR 24-68) from COVID-19 diagnosis, were included (964 [50·7%] of 1902 patients with sex data were female and 938 [49·3%] were male). Overall, 317 (16·6%; 95% CI 14·8-18·5) of 1909 patients had at least one sequela from COVID-19 at the first oncological reassessment. The prevalence of COVID-19 sequelae was highest in the pre-vaccination phase (191 [19·1%; 95% CI 16·4-22·0] of 1000 patients). The prevalence was similar in the alpha-delta phase (110 [16·8%; 13·8-20·3] of 653 patients, p=0·24), but significantly lower in the omicron phase (16 [6·2%; 3·5-10·2] of 256 patients, p<0·0001). In the alpha-delta phase, 84 (18·3%; 95% CI 14·6-22·7) of 458 unvaccinated patients and three (9·4%; 1·9-27·3) of 32 unvaccinated patients in the omicron phase had sequelae. Patients who received a booster and those who received two vaccine doses had a significantly lower prevalence of overall COVID-19 sequelae than unvaccinated or partially vaccinated patients (ten [7·4%; 95% CI 3·5-13·5] of 136 boosted patients, 18 [9·8%; 5·8-15·5] of 183 patients who had two vaccine doses vs 277 [18·5%; 16·5-20·9] of 1489 unvaccinated patients, p=0·0001), respiratory sequelae (six [4·4%; 1·6-9·6], 11 [6·0%; 3·0-10·7] vs 148 [9·9%; 8·4-11·6], p=0·030), and prolonged fatigue (three [2·2%; 0·1-6·4], ten [5·4%; 2·6-10·0] vs 115 [7·7%; 6·3-9·3], p=0·037). INTERPRETATION: Unvaccinated patients with cancer remain highly vulnerable to COVID-19 sequelae irrespective of viral strain. This study confirms the role of previous SARS-CoV-2 immunisation as an effective measure to protect patients from COVID-19 sequelae, disruption of therapy, and ensuing mortality. FUNDING: UK National Institute for Health and Care Research Imperial Biomedical Research Centre and the Cancer Treatment and Research Trust.

Definitive study shows no association between ARID1A mutation status and clinical outcome in endometriosis-related ovarian cancers‡.

The ARID1A tumour suppressor protein is a component of the SWI/SNF chromatin remodelling complex, which is mutated in approximately 20% of all human cancers. ARID1A mutational status is considered to hold prognostic significance in a range of solid malignancies, yet in endometriosis-related ovarian carcinomas there has been a lack of clarity of its prognostic role. Moreover, the relationship between ARID1A status and immune infiltrate is also poorly understood. In a recent issue of The Journal of Pathology, a large comprehensive study by Heinze, Nazeran et al addressed these areas by reviewing 1,623 endometriosis-associated ovarian carcinomas and correlating ARID1A status using standardised immunohistochemistry to infer mutation status, with comprehensive clinicopathological features, mismatch repair status and CD8+ tumour infiltrating lymphocytes. The study definitively showed that ARID1A status does not provide any independent prognostic value in endometriosis-associated ovarian carcinomas. ARID1A loss was, however, shown to be associated with mismatch repair deficiency and increased CD8+ tumour infiltrating lymphocytes in endometrioid ovarian carcinoma, which may be relevant for future studies. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Identification of RAD51 foci in cancer-associated circulating cells of patients with high-grade serous ovarian cancer: association with treatment outcomes.

OBJECTIVE: Fifty percent of patients with high-grade serous ovarian cancer harbor defects in the homologous recombination repair pathway. RAD51 foci form where DNA is damaged, indicating its involvement in repairing double-stranded breaks. High levels of RAD51 in ovarian cancer tissue have been associated with a poorer prognosis. OBJECTIVE: To demonstrate RAD51 foci in circulating cancer-associated cells of patients with ovarian cancer and their association with clinical outcomes. METHODS: One hundred and twenty-four patients with high-grade serous ovarian cancer had blood samples taken at strategic points during treatment and follow-up. Cells were stained using WT1 and RAD51 antibodies with immunofluorescence and reviewed under Leica camera microscopy; RAD51 foci were counted. Correlations were made between numbers of RAD51 foci and treatment response, BRCA status, and progression-free survival. RESULTS: RAD51 foci were identified in all patients (n=42) with wild-type BRCA. BRCA mutant/homologous recombination deficiency-positive patients (n=8) had significantly lower numbers of RAD51 foci (p=0.009). Responders to treatment (n=32) had a reduction in circulating cells (p=0.02) and RAD51 foci (p=0.0007). Numbers of RAD51 foci were significantly higher in the platinum-resistant population throughout treatment: at the start of treatment, in 56 platinum-sensitive patients there was a mean of 3.6 RAD51 foci versus 6.2 in 15 platinum-resistant patients (p=0.02). Patients with a high number of RAD51 foci had worse median progression-free survival: in 39 patients with a mean of <3 RAD51 foci at treatment start, median progression-free survival had not been reached, compared with 32 patients with >3 RAD51 foci whose progression-free survival was 13 months (p=0.04). CONCLUSIONS: Levels of RAD51 foci in circulating cancer-associated cells of patients with high-grade serous ovarian cancer are associated with clinical outcomes and may be a more pragmatic method of determining a homologous repair-deficient population.

Outcomes of the SARS-CoV-2 omicron (B.1.1.529) variant outbreak among vaccinated and unvaccinated patients with cancer in Europe: results from the retrospective, multicentre, OnCovid registry study.

BACKGROUND: The omicron (B.1.1.529) variant of SARS-CoV-2 is highly transmissible and escapes vaccine-induced immunity. We aimed to describe outcomes due to COVID-19 during the omicron outbreak compared with the prevaccination period and alpha (B.1.1.7) and delta (B.1.617.2) waves in patients with cancer in Europe. METHODS: In this retrospective analysis of the multicentre OnCovid Registry study, we recruited patients aged 18 years or older with laboratory-confirmed diagnosis of SARS-CoV-2, who had a history of solid or haematological malignancy that was either active or in remission. Patient were recruited from 37 oncology centres from UK, Italy, Spain, France, Belgium, and Germany. Participants were followed up from COVID-19 diagnosis until death or loss to follow-up, while being treated as per standard of care. For this analysis, we excluded data from centres that did not actively enter new data after March 1, 2021 (in France, Germany, and Belgium). We compared measures of COVID-19 morbidity, which were complications from COVID-19, hospitalisation due to COVID-19, and requirement of supplemental oxygen and COVID-19-specific therapies, and COVID-19 mortality across three time periods designated as the prevaccination (Feb 27 to Nov 30, 2020), alpha-delta (Dec 1, 2020, to Dec 14, 2021), and omicron (Dec 15, 2021, to Jan 31, 2022) phases. We assessed all-cause case-fatality rates at 14 days and 28 days after diagnosis of COVID-19 overall and in unvaccinated and fully vaccinated patients and in those who received a booster dose, after adjusting for country of origin, sex, age, comorbidities, tumour type, stage, and status, and receipt of systemic anti-cancer therapy. This study is registered with ClinicalTrials.gov, NCT04393974, and is ongoing. FINDINGS: As of Feb 4, 2022 (database lock), the registry included 3820 patients who had been diagnosed with COVID-19 between Feb 27, 2020, and Jan 31, 2022. 3473 patients were eligible for inclusion (1640 [47·4%] were women and 1822 [52·6%] were men, with a median age of 68 years [IQR 57-77]). 2033 (58·5%) of 3473 were diagnosed during the prevaccination phase, 1075 (31·0%) during the alpha-delta phase, and 365 (10·5%) during the omicron phase. Among patients diagnosed during the omicron phase, 113 (33·3%) of 339 were fully vaccinated and 165 (48·7%) were boosted, whereas among those diagnosed during the alpha-delta phase, 152 (16·6%) of 915 were fully vaccinated and 21 (2·3%) were boosted. Compared with patients diagnosed during the prevaccination period, those who were diagnosed during the omicron phase had lower case-fatality rates at 14 days (adjusted odds ratio [OR] 0·32 [95% CI 0·19-0·61) and 28 days (0·34 [0·16-0·79]), complications due to COVID-19 (0·26 [0·17-0·46]), and hospitalisation due to COVID-19 (0·17 [0·09-0·32]), and had less requirements for COVID-19-specific therapy (0·22 [0·15-0·34]) and oxygen therapy (0·24 [0·14-0·43]) than did those diagnosed during the alpha-delta phase. Unvaccinated patients diagnosed during the omicron phase had similar crude case-fatality rates at 14 days (ten [25%] of 40 patients vs 114 [17%] of 656) and at 28 days (11 [27%] of 40 vs 184 [28%] of 656) and similar rates of hospitalisation due to COVID-19 (18 [43%] of 42 vs 266 [41%] of 652) and complications from COVID-19 (13 [31%] of 42 vs 237 [36%] of 659) as those diagnosed during the alpha-delta phase. INTERPRETATION: Despite time-dependent improvements in outcomes reported in the omicron phase compared with the earlier phases of the pandemic, patients with cancer remain highly susceptible to SARS-CoV-2 if they are not vaccinated against SARS-CoV-2. Our findings support universal vaccination of patients with cancer as a protective measure against morbidity and mortality from COVID-19. FUNDING: National Institute for Health and Care Research Imperial Biomedical Research Centre and the Cancer Treatment and Research Trust.

Translational genomics of ovarian clear cell carcinoma.

Ovarian clear cell carcinomas (OCCC) are rare aggressive, chemo-resistant tumours comprising approximately 13% of all epithelial ovarian cancers, which have distinct clinical and molecular features, when compared to other gynaecological malignancies. At present, there are no specific licensed targeted therapies for OCCC, although a number of candidate targets have been identified. This review focuses on recent knowledge underpinning our understanding of the pathogenesis of OCCC including direct and synthetic-lethal therapeutic strategies in particular focussing on ARID1A deficiency. We also discuss current targeted clinical trials and immunotherapeutic approaches.

ATARI trial: ATR inhibitor in combination with olaparib in gynecological cancers with ARID1A loss or no loss (ENGOT/GYN1/NCRI).

BACKGROUND: ARID1A (AT-rich interactive domain containing protein 1A) loss-of-function mutations have been reported in gynecological cancers, including rarer subtypes such as clear cell carcinoma. Preclinical studies indicate that ARID1A mutant cancers display sensitivity to ATR inhibition while tumors without ARID1A mutations may be sensitive to Ataxia telangiectasia and Rad3 related (ATR) inhibitors in combination with poly-ADP ribose polymerase (PARP) inhibitors. PRIMARY OBJECTIVE: To determine whether the ATR inhibitor, ceralasertib, has clinical activity as a single agent and in combination with the PARP inhibitor, olaparib, in patients with ARID1A 'loss' and 'no loss' clear cell carcinomas and other relapsed gynecological cancers. STUDY HYPOTHESIS: ARID1A deficient clear cell carcinoma of the ovary or endometrium is sensitive to ATR inhibition, while the combination of ATR and PARP inhibition has activity in other gynecological tumors, irrespective of ARID1A status. TRIAL DESIGN: ATARI (ENGOT/GYN1/NCRI) is a multicenter, international, proof-of-concept, phase II, parallel cohort trial assessing ceralasertib activity as a single agent and in combination with olaparib in ARID1A stratified gynecological cancers. Patients with relapsed ovarian/endometrial clear cell carcinoma with ARID1A loss will receive ceralasertib monotherapy (cohort 1A). Relapsed ovarian/endometrial clear cell carcinoma patients with no ARID1A loss (cohort 2) or patients with other histological subtypes (endometrioid, carcinosarcoma, cervical) (cohort 3) will receive combination therapy (olaparib/ceralasertib). Treatment will continue until disease progression. MAJOR INCLUSION/EXCLUSION CRITERIA: Patients with histologically confirmed recurrent clear cell (ovarian, endometrial, or endometriosis related), endometrioid (ovarian, endometrial, or endometriosis related), cervical (adenocarcinomas or squamous), or carcinosarcomas (ovarian or endometrial) are eligible. Patients progressing after ≥1 prior platinum with evidence of measurable (RECIST v1.1) radiological disease progression since last systemic anticancer therapy and prior to trial entry are eligible. Previous ATR or PARP inhibitor treatment is not permissible. PRIMARY ENDPOINT: Best overall objective response rate (RECIST v1.1). SAMPLE SIZE: A minimum of 40 and a maximum of 116. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Accrual is anticipated to be complete by the second quarter of 2022, with reporting of results by the fourth quarter of 2022. Overall accrual targets and reporting timelines are dependent on individual cohort progression to stage 2. TRIAL REGISTRATION NUMBER: NCT0405269.

Maintenance therapy in ovarian cancer.

PURPOSE OF REVIEW: Targeted therapies are being used as maintenance therapy to improve the outcome of ovarian cancer following standard treatment in the first-line setting and in recurrent disease. We review the different approaches being used, trial design, and the impact of maintenance treatment on survival and quality of life. RECENT FINDINGS: The greatest experience of maintenance therapy is with antiangiogenic agents. Several trials targeting vascular endothelial growth factor with bevacizumab or vascular endothelial growth factor receptor with oral tyrosine kinase inhibitors have demonstrated a prolongation in progression-free survival (PFS) following first or second-line treatment. Maintenance therapy with olaparib, a poly ADP ribose polymerase inhibitor given post-platinum therapy for recurrent disease, has led to a prolongation in PFS, particularly, in patients with a BRCA mutation. The results of immunotherapy maintenance studies, based on using cancer antigen 125 as an antigen, have been disappointing. A benefit in PFS often does not translate into overall survival improvement, largely because of crossover and postprogression therapies. This makes clinical interpretation of results more difficult. SUMMARY: The principle of using molecular targeted therapy to prolong the control of ovarian cancer has been clearly demonstrated. The greatest effect is on prolongation of PFS and, by adding to the effects of standard treatments, maintenance therapy is likely to help incrementally extend the 5-year survival of women with ovarian cancer.

Medication use evaluation of tocilizumab implementation in COVID-19 treatment guidelines: A causal inference approach.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: Introduction of new medications to health-system formularies is often not accompanied by assessments of their clinical impact on the local patient population. The growing availability of electronic health record (EHR) data and advancements in pharmacoepidemiology methods offer institutions the opportunity to monitor the medication implementation process and assess clinical effectiveness in the local clinical context. In this study, we applied novel causal inference methods to evaluate the effects of a formulary policy introducing tocilizumab therapy for critically ill patients with coronavirus disease 2019 (COVID-19). METHODS: We conducted a medication use evaluation utilizing EHR data from patients admitted to a large medical center during the 6 months before and after implementation of a formulary policy endorsing the use of tocilizumab for treatment of COVID-19. The impact of tocilizumab on 28-day all-cause mortality was assessed using a difference-in-differences analysis, with ineligible patients serving as a nonequivalent control group, and a matched analysis guided by a target trial emulation framework. Safety endpoints assessed included the incidence of secondary infections and liver enzyme elevations. Our findings were benchmarked against clinical trials, an observational study, and a meta-analysis. RESULTS: Following guideline modification, tocilizumab was administered to 69% of eligible patients. This implementation was associated with a 3.1% absolute risk reduction in 28-day mortality (odds ratio, 0.86; number needed to treat to prevent one death, 32) attributable to the inclusion of tocilizumab in the guidelines and an additional 8.6% absolute risk reduction (odds ratio, 0.65; number needed to treat to prevent one death, 12) linked to its administration. These findings were consistent with estimates from published literature, although the effect estimates from the difference-in-differences analysis exhibited imprecision. CONCLUSION: Evaluating formulary management decisions through novel causal inference approaches offers valuable estimates of clinical effectiveness and the potential to optimize the impact of new medications on population outcomes.

Description of a Retrospective Cohort of Epithelial Ovarian Cancer Patients with Brain Metastases: Evaluation of the Role of PARP Inhibitors in this Setting.

BACKGROUND: The incidence of brain metastases (BM) in patients with epithelial ovarian cancer (EOC) is low: 0.3-11%. The onset of BM has been regarded as a late event with limited treatment options and poor prognosis. This retrospective case series aims to explore the current management strategies with particular emphasis on the use of PARP inhibitors and outcomes, as well as identification of other prognostic indicators. METHODS: A total of 39 ovarian cancer patients with brain metastases were identified from eight cancer centres in the UK. Clinical characteristics, details of management, and survival data were collected. RESULTS: A total of 14/39 had BM as their first site of relapse. The majority (29 patients) received systemic treatments in addition to local radiotherapy (RT)/surgery. Nineteen patients had BRCA mutations (one somatic), one had a RAD51C mutation, and eighteen were BRCA wild type; one was unknown. A total of 14/39 patients received maintenance PARP inhibitors. As is well known, patients who received PARPi had consistently better outcomes. This was no different for those who received PARPi as part of the management of their BM. Platinum sensitivity and receiving more than one modality of therapy (e.g., radiation +/- chemotherapy and PARPi) for BM were also good prognostic indicators. Median PFS/OS for those treated with chemotherapy and either RT or surgery, then PARP inhibitor maintenance, have not been reached after a median of 33 months follow up. CONCLUSIONS: As with abdominal relapse, maintenance treatment with PARP inhibitors also has a valuable role in managing BMs in EOC patients.

Quantitative Assessment and Prognostic Associations of the Immune Landscape in Ovarian Clear Cell Carcinoma.

Ovarian clear cell carcinoma (OCCC) is a rare subtype of epithelial ovarian cancer characterised by a high frequency of loss-of-function ARID1A mutations and a poor response to chemotherapy. Despite their generally low mutational burden, an intratumoural T cell response has been reported in a subset of OCCC, with ARID1A purported to be a biomarker for the response to the immune checkpoint blockade independent of micro-satellite instability (MSI). However, assessment of the different immune cell types and spatial distribution specifically within OCCC patients has not been described to date. Here, we characterised the immune landscape of OCCC by profiling a cohort of 33 microsatellite stable OCCCs at the genomic, gene expression and histological level using targeted sequencing, gene expression profiling using the NanoString targeted immune panel, and multiplex immunofluorescence to assess the spatial distribution and abundance of immune cell populations at the protein level. Analysis of these tumours and subsequent independent validation identified an immune-related gene expression signature associated with risk of recurrence of OCCC. Whilst histological quantification of tumour-infiltrating lymphocytes (TIL, Salgado scoring) showed no association with the risk of recurrence or ARID1A mutational status, the characterisation of TILs via multiplexed immunofluorescence identified spatial differences in immunosuppressive cell populations in OCCC. Tumour-associated macrophages (TAM) and regulatory T cells were excluded from the vicinity of tumour cells in low-risk patients, suggesting that high-risk patients have a more immunosuppressive microenvironment. We also found that TAMs and cytotoxic T cells were also excluded from the vicinity of tumour cells in ARID1A-mutated OCCCs compared to ARID1A wild-type tumours, suggesting that the exclusion of these immune effectors could determine the host response of ARID1A-mutant OCCCs to therapy. Overall, our study has provided new insights into the immune landscape and prognostic associations in OCCC and suggest that tailored immunotherapeutic approaches may be warranted for different subgroups of OCCC patients.

Clinical Pharmacists: An Invaluable Part of the Coronavirus Disease 2019 Frontline Response.

Although coronavirus disease 2019 was first identified in December 2019, it rapidly spread and became a global pandemic. The number of patients infected with the novel coronavirus (severe acute respiratory syndrome coronavirus 2) rose rapidly in New York State, placing great stress on healthcare systems. The traditional roles and practices of healthcare providers were dramatically redefined to meet the demand to care for the large number of ill patients. While literature reports on the experiences of many frontline staff, there is a scarcity of reports on the role of clinical pharmacists during this crisis. We report the role of critical care clinical pharmacists at a large academic medical center in New York City during this pandemic. Effective crisis management required clinical pharmacists to employ a wide array of skills and knowledge. Areas included clinical expertise, education, data analysis, health informatics infrastructure, and inventory management in times of surging medication use and manufacturer shortages. Clinical pharmacists fulfilled an essential service during the coronavirus pandemic by working to ensure the best possible outcomes for the patients they served on the frontline.

Longitudinal analysis of a secondary BRCA2 mutation using digital droplet PCR.

Development of resistance to platinum and poly(ADP-ribose) polymerase inhibitors via secondary BRCA gene mutations that restore functional homologous recombination has been observed in a number of cancer types. Here we report a case of somatic BRCA2 mutation in a patient with high grade serous ovarian carcinoma. A secondary mutation predicted to restore the BRCA2 open reading frame was detected at low frequency (2.3%) in whole exome sequencing of a peritoneal biopsy at disease progression after treatment that included carboplatin and olaparib. We used digital droplet PCR (ddPCR) to verify the presence and frequency of this mutation in the biopsy sample at progression and also used this approach to assess the presence of the secondary mutation in preceding biopsies at diagnosis and first relapse. We found no evidence for the secondary mutation being present prior to the final progression biopsy, suggesting that this mutation was acquired late in the course of treatment. ddPCR provides a sensitive and specific technique to investigate the presence of low frequency mutations in a time series of biopsies.

Phase I Trial of First-in-Class ATR Inhibitor M6620 (VX-970) as Monotherapy or in Combination With Carboplatin in Patients With Advanced Solid Tumors.

PURPOSE: Preclinical studies demonstrated that ATR inhibition can exploit synthetic lethality (eg, in cancer cells with impaired compensatory DNA damage responses through ATM loss) as monotherapy and combined with DNA-damaging drugs such as carboplatin. PATIENTS AND METHODS: This phase I trial assessed the ATR inhibitor M6620 (VX-970) as monotherapy (once or twice weekly) and combined with carboplatin (carboplatin on day 1 and M6620 on days 2 and 9 in 21-day cycles). Primary objectives were safety, tolerability, and maximum tolerated dose; secondary objectives included pharmacokinetics and antitumor activity; exploratory objectives included pharmacodynamics in timed paired tumor biopsies. RESULTS: Forty patients were enrolled; 17 received M6620 monotherapy, which was safe and well tolerated. The recommended phase II dose (RP2D) for once- or twice-weekly administration was 240 mg/m2. A patient with metastatic colorectal cancer harboring molecular aberrations, including ATM loss and an ARID1A mutation, achieved RECISTv1.1 complete response and maintained this response, with a progression-free survival of 29 months at last assessment. Twenty-three patients received M6620 with carboplatin, with mechanism-based hematologic toxicities at higher doses, requiring dose delays and reductions. The RP2D for combination therapy was M6620 90 mg/m2 with carboplatin AUC5. A patient with advanced germline BRCA1 ovarian cancer achieved RECISTv1.1 partial response and Gynecologic Cancer Intergroup CA125 response despite being platinum refractory and PARP inhibitor resistant. An additional 15 patients had RECISTv1.1 stable disease as best response. Pharmacokinetics were dose proportional and exceeded preclinical efficacious levels. Pharmacodynamic studies demonstrated substantial inhibition of phosphorylation of CHK1, the downstream ATR substrate. CONCLUSION: To our knowledge, this report is the first of an ATR inhibitor as monotherapy and combined with carboplatin. M6620 was well tolerated, with target engagement and preliminary antitumor responses observed.

Angiotensin II (Giapreza): A Distinct Mechanism for the Treatment of Vasodilatory Shock.

Septic shock, a form of vasodilatory shock associated with high morbidity and mortality, requires early and effective therapy to improve patient outcomes. Current management of septic shock includes the use of intravenous fluids, catecholamines, and vasopressin for hemodynamic support to ensure adequate perfusion. Despite these interventions, hospital mortality rates are still greater than 40%. Practitioners are continuously faced with cases of refractory shock that are associated with poor clinical outcomes. In December of 2017, the Food and Drug Administration approved the first synthetic human angiotensin II, a potent vasoconstrictor, to increase blood pressure in adults with septic or other distributive shock. This approval was based (ATHOS) on the results from the Angiotensin II for the Treatment of High Output Shock study. In this randomized, double-blind, placebo-controlled trial, patients in the angiotensin II group achieved higher rates of target mean arterial pressure and had lower catecholamine requirements in the first 3 hours of therapy compared with patients in the placebo group. There was no significant difference in the 28-day mortality. Safety issues including the risk of thromboembolic events, infection, and delirium have made clinicians cautious in adopting angiotensin II into practice. Ongoing studies are needed to more clearly define the role of this agent and its utility in the management of shock.

Optimised ARID1A immunohistochemistry is an accurate predictor of ARID1A mutational status in gynaecological cancers.

ARID1A is a tumour suppressor gene that is frequently mutated in clear cell and endometrioid carcinomas of the ovary and endometrium and is an important clinical biomarker for novel treatment approaches for patients with ARID1A defects. However, the accuracy of ARID1A immunohistochemistry (IHC) as a surrogate for mutation status has not fully been established for patient stratification in clinical trials. Here we tested whether ARID1A IHC could reliably predict ARID1A mutations identified by next-generation sequencing. Three commercially available antibodies - EPR13501 (Abcam), D2A8U (Cell Signaling), and HPA005456 (Sigma) - were optimised for IHC using cell line models and human tissue, and screened across a cohort of 45 gynaecological tumours. IHC was scored independently by three pathologists using an immunoreactive score. ARID1A mutation status was assessed using two independent sequencing platforms and the concordance between ARID1A mutation and protein expression was evaluated using Receiver Operating Characteristic statistics. Overall, 21 ARID1A mutations were identified in 14/43 assessable tumours (33%), the majority of which were predicted to be deleterious. Mutations were identified in 6/17 (35%) ovarian clear cell carcinomas, 5/8 (63%) ovarian endometrioid carcinomas, 2/5 (40%) endometrial carcinomas, and 1/7 (14%) carcinosarcomas. ROC analysis identified greater than 95% concordance between mutation status and IHC using a modified immunoreactive score for all three antibodies allowing a definitive cut-point for ARID1A mutant status to be calculated. Comprehensive assessment of concordance of ARID1A IHC and mutation status identified EPR13501 as an optimal antibody, with 100% concordance between ARID1A mutation status and protein expression, across different gynaecological histological subtypes. It delivered the best inter-rater agreement between all pathologists, as well as a clear cost-benefit advantage. This could allow patients to be accurately stratified based on their ARID1A IHC status into early phase clinical trials.

The Spatiotemporal Evolution of Lymph Node Spread in Early Breast Cancer.

Purpose: The most significant prognostic factor in early breast cancer is lymph node involvement. This stage between localized and systemic disease is key to understanding breast cancer progression; however, our knowledge of the evolution of lymph node malignant invasion remains limited, as most currently available data are derived from primary tumors.Experimental Design: In 11 patients with treatment-naïve node-positive early breast cancer without clinical evidence of distant metastasis, we investigated lymph node evolution using spatial multiregion sequencing (n = 78 samples) of primary and lymph node deposits and genomic profiling of matched longitudinal circulating tumor DNA (ctDNA).Results: Linear evolution from primary to lymph node was rare (1/11), whereas the majority of cases displayed either early divergence between primary and nodes (4/11) or no detectable divergence (6/11), where both primary and nodal cells belonged to a single recent expansion of a metastatic clone. Divergence of metastatic subclones was driven in part by APOBEC. Longitudinal ctDNA samples from 2 of 7 subjects with evaluable plasma taken perioperatively reflected the two major evolutionary patterns and demonstrate that private mutations can be detected even from early metastatic nodal deposits. Moreover, node removal resulted in disappearance of private lymph node mutations in ctDNA.Conclusions: This study sheds new light on a crucial evolutionary step in the natural history of breast cancer, demonstrating early establishment of axillary lymph node metastasis in a substantial proportion of patients. Clin Cancer Res; 24(19); 4763-70. ©2018 AACR.

Nintedanib in ovarian cancer.

INTRODUCTION: Advanced ovarian cancer remains an unmet clinical need. Angiogenesis is considered a therapeutic target in ovarian cancer, with bevacizumab, a monoclonal antibody against VEGF, being the first drug to show a progression-free survival benefit. Nintedanib is an oral tyrosine kinase inhibitor targeting VEGF receptor 1-3, FGFR 1-3 and PDGFR α and ß, which has entered phase III trial development in ovarian cancer. Areas covered: This article reviews the preclinical and clinical efficacy of nintedanib in ovarian cancer, its pharmacokinetic and pharmacodynamics profile, safety issues, together with an overview of clinical trials carried out so far. A literature search was made in PubMed for nintedanib, ovarian cancer, angiogenesis, and on ClinicalTrials.gov site for clinical trials with nintedanib. Expert opinion: An ongoing phase III trial investigating nintedanib combined with first-line chemotherapy in ovarian cancer has shown a statistically significant progression free survival benefit, although there were toxicity issues. The true clinical benefit of nintedanib in ovarian cancer including its optimal treatment setting and dosage still need to be addressed.

Utilizing Functional Genomics Screening to Identify Potentially Novel Drug Targets in Cancer Cell Spheroid Cultures.

The identification of functional driver events in cancer is central to furthering our understanding of cancer biology and indispensable for the discovery of the next generation of novel drug targets. It is becoming apparent that more complex models of cancer are required to fully appreciate the contributing factors that drive tumorigenesis in vivo and increase the efficacy of novel therapies that make the transition from pre-clinical models to clinical trials. Here we present a methodology for generating uniform and reproducible tumor spheroids that can be subjected to siRNA functional screening. These spheroids display many characteristics that are found in solid tumors that are not present in traditional two-dimension culture. We show that several commonly used breast cancer cell lines are amenable to this protocol. Furthermore, we provide proof-of-principle data utilizing the breast cancer cell line BT474, confirming their dependency on amplification of the epidermal growth factor receptor HER2 and mutation of phosphatidylinositol-4,5-biphosphate 3-kinase (PIK3CA) when grown as tumor spheroids. Finally, we are able to further investigate and confirm the spatial impact of these dependencies using immunohistochemistry.

Drug interaction between clopidogrel and proton pump inhibitors.

Dual antiplatelet therapy with clopidogrel and aspirin has been shown to reduce recurrent cardiac events in patients with acute coronary syndromes or those who have undergone coronary artery stent placement. Clopidogrel, a thienopyridine, is a prodrug that is transformed in vivo to an active metabolite by the cytochrome P450 enzyme system. Due to the increased risk of bleeding in patients on dual antiplatelet therapy, concomitant gastrointestinal ulcer prophylaxis with a proton pump inhibitor (PPI) is frequently prescribed. Data from recent studies show that PPIs, which are extensively metabolized by the cytochrome system, may decrease the antiplatelet activity of clopidogrel. This article reviews the metabolism of various PPIs and existing data regarding the drug-drug interaction between PPIs and clopidogrel.