Oral PD-L1 inhibitor GS-4224 selectively engages PD-L1 high cells and elicits pharmacodynamic responses in patients with advanced solid tumors.

BACKGROUND: Checkpoint inhibitors targeting the programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) pathway are effective therapies in a range of immunogenic cancer types. Blocking this pathway with an oral therapy could benefit patients through greater convenience, particularly in combination regimens, and allow flexible management of immune-mediated toxicities. METHODS: PD-L1 binding activity was assessed in engineered dimerization and primary cell target occupancy assays. Preclinical antitumor activity was evaluated in ex vivo and in vivo human PD-L1-expressing tumor models. Human safety, tolerability, pharmacokinetics, and biomarker activity were evaluated in an open-label, multicenter, sequential dose-escalation study in patients with advanced solid tumors. Biomarkers evaluated included target occupancy, flow cytometric immunophenotyping, plasma cytokine measurements, and T-cell receptor sequencing. RESULTS: GS-4224 binding caused dimerization of PD-L1, blocking its interaction with PD-1 and leading to reversal of T-cell inhibition and increased tumor killing in vitro and in vivo. The potency of GS-4224 was dependent on the density of cell surface PD-L1, with binding being most potent on PD-L1-high cells. In a phase 1 dose-escalation study in patients with advanced solid tumors, treatment was well tolerated at doses of 400-1,500 mg once daily. Administration of GS-4224 was associated with a dose-dependent increase in plasma GS-4224 exposure and reduction in free PD-L1 on peripheral blood T cells, an increase in Ki67 among the PD-1-positive T-cell subsets, and elevated plasma cytokines and chemokines. CONCLUSIONS: GS-4224 is a novel, orally bioavailable small molecule inhibitor of PD-L1. GS-4224 showed evidence of expected on-target biomarker activity, including engagement of PD-L1 and induction of immune-related pharmacodynamic responses consistent with PD-L1 blockade. TRIAL REGISTRATION NUMBER: NCT04049617.

Complementary and Alternative Medicine (CAM): use and views among patients with solid organ and haematological malignancies in Northland, New Zealand.

AIMS: Complementary Alternative Medicine (CAM) use among patients with malignant diagnosis has been rising globally. This study assesses the prevalence of CAM among patients with solid organ or haematological malignancy at a regional outpatient cancer and blood service in Northland, New Zealand. Secondary objectives include determining: i) types of CAM used, ii) sources of information, and iii) patient perspectives on CAM. METHOD: In this single-centre cross-sectional study, patients attending treatment or follow-up appointments at the Jim Carney Cancer Treatment Centre (JCC) between 25 September to 20 October 2017 were invited to complete an anonymous self-administered questionnaire. RESULTS: Of the 306 assessable entries, 29% (n=89) respondents were using CAM, 10% had intentions to use CAM in the future, while 45% were undecided. Word-of-mouth (58%) was the most common source of CAM information, followed by internet sources (36%) and healthcare professionals (27%). Biologically based therapies were the most popular form of CAM used. Common reasons for CAM use include symptom relief (65%), perceived lower toxicity (62%), holistic (52%), natural (51%) and potential for cure (45%). Only 49% of CAM users felt comfortable discussing their CAM use with their oncologist/ haematologist. CONCLUSION: CAM use is common and has relevance across oncology treatment centres nationwide. Local research into CAM use can serve to raise awareness and to assist healthcare professional training in addressing CAM use in a specific patient population.

Survival Outcomes and Care Equity among Patients with Advanced Breast Cancer in Auckland, New Zealand.

Aim: The Auckland Advanced Breast Cancer Review (AABC) was a review of patients diagnosed with advanced inoperable/metastatic breast cancer (ABC) within the Auckland region of New Zealand, commissioned in response to a Breast Cancer Registry report (BCFNZR) that showed poor and inequitable survival outcomes. The review was aimed at assessing equity of care and identifying healthcare delivery gaps for patients with ABC in the Auckland region. Method: In this retrospective study, patients living within the Auckland region, diagnosed with ABC between the 1st January 2013 to the 31st December 2015 were identified from the Breast Cancer Registry. Data censorship date was 30th January 2019 to allow a minimum of 3 years of follow-up. Demographic, diagnostic, treatment, and survival data were extracted from electronic records for statistical analysis. Results: Of the 388 patients that met inclusion criteria for this study, median overall survival (medOS) was 18.9 months in the total population, with no difference between patients with de novo metastatic disease (dnMBC -18.9 m) and recurrent metastatic disease (rMBC -18.7 m). No statistically significant differences in medOS was found amongst Maori (16.2 m), Pacific People (17.3 m), and NZ European (18.9 m) or when patients were stratified according domicile district health board. Median number of lines of systemic treatment was two, with similar treatment exposure between ethnic groups. Conclusion: While treatment uptake and survival outcomes were generally comparable across ethnicity and district health boards, dnMBC survival outcomes were considerably poorer than expected, earmarking this subset of patients with ABC for more in-depth research.

Re-thinking the possible interaction between proton pump inhibitors and capecitabine.

Proton Pump Inhibitors (PPI) rank within the top ten most prescribed medications in Europe and USA. A high frequency of PPI use has been reported amongst patients undergoing chemotherapy, to mitigate treatment-induced gastritis or gastro-oesophageal reflux. Several recent, mostly retrospective, observational studies have reported inferior survival outcomes among patients on capecitabine who concomitantly use PPI. Whilst this association is yet to be definitively established, given the prominence of capecitabine as an anti-cancer treatment with multiple indications, these reports have raised concern within the oncological community and drug regulatory bodies worldwide. Currently, the leading mechanism of interaction postulated in these reports has focussed on the pH altering effects of PPI and how this could diminish capecitabine absorption, leading to a decrease in its bioavailability. In this discourse, we endeavour to summarise plausible pharmacokinetic interactions between PPI and capecitabine. We provide a basis for our argument against the currently proposed mechanism of interaction. We also highlight the long-term effects of PPI on health outcomes, and how PPI use itself could lead to poorer outcomes, independent of capecitabine.

Cardiac Troponin I and T in Checkpoint Inhibitor-associated Myositis and Myocarditis.

Checkpoint inhibitor-associated myocarditis (ir-myocarditis) and myositis (ir-myositis) may occur concurrently among patients on checkpoint inhibitor immunotherapy. While cardiac-specific troponin I (cTnI) and troponin T (cTnT) are regarded to have similar sensitivities and specificities in conditions such as acute coronary syndrome, the cardiac specificity of cTnT has been challenged following observation that patients with neuromuscular diseases, including myositis, may have elevated cTnT without apparent clinical evidence of myocardial injury. Consequently, in the context of concurrent ir-myositis, cTnI may be a more appropriate biomarker for diagnosing and monitoring ir-myocarditis. To illustrate this point, we report a case of a patient with severe ir-myositis while on adjuvant programmed cell death protein 1 inhibitor immunotherapy for stage III melanoma, with accompanying elevation in cTnT.

Neoadjuvant chemotherapy in non-metastatic breast cancer: a study on practice trends in a regional cancer treatment service.

BACKGROUND: Neoadjuvant chemotherapy (NACT) is increasingly used for managing locally advanced and high risk non-metastatic breast cancer. AIMS: To describe trends in NACT use, assess compliance to best practice recommendations and determine treatment response rates in a regional cancer treatment service. METHODS: In this retrospective cross- sectional study, electronic records of patients who underwent NACT in centres covered by the MidCentral Regional Cancer Treatment Service in 2013 and 2017 were reviewed. Data pertaining to patient demographics, disease status, compliance to best practice recommendations and treatment outcomes were extracted and analysed. RESULTS: Of a total of 502 referrals for non-metastatic breast cancer, 34 underwent NACT with the estimated NACT rate rising from 3.85% (2013) to 9.92% (2017). Compliance to practice recommendations improved in all domains (pre-treatment tumour and axillary evaluation, marker placement, multidisciplinary discussion). Overall, NACT was well tolerated with only three patients experiencing treatment limiting toxicity. Response rates mirror published data (complete response: 29.4%, partial: 61.8%) with higher responses registered in HER2 positive and triple negative subtypes. Discordance between radiological and pathological response was 28%, with imaging overestimating response in five out of seven cases. Of the 11 (32%) patients who initially underwent breast conserving surgery, six required a second surgery. CONCLUSION: NACT is increasingly used in the Regional Cancer Treatment Service, with improving compliance to practice recommendations. These results are reassuring and can be used to help patients develop a realistic expectation towards NACT.

Thirty-day mortality after systemic anticancer treatment as a real-world, quality-of-care indicator: the Northland experience.

BACKGROUND: Systemic anticancer treatment (SACT) at the end of life is considered poor practice due to its futility and associated toxicities. Consequently, 30-day mortality after SACT is increasingly recognised as a potential real-world quality-of-care indicator in medical oncology. AIMS: Whangarei Base Hospital (WBH) provides outpatient SACT treatment to all patients living in the Northland region of New Zealand. The goal of this study was to report our 30-day mortality after SACT and to contribute to the experience of its use in Australasia. METHODS: In this retrospective study, the WBH electronic database was searched to identify all patients who had received SACT in WBH from 1 January 2012 to 31 December 2016. Patients who died within 30 days of their last treatment were shortlisted. Records were reviewed identifying key demographic, disease, treatment and mortality data. Composite 30-day mortality index and that of each tumour stream were calculated. Key findings were described using descriptive statistics. RESULTS: Over 5 years, 1103 patients received SACT in WBH, with 57 patients dying within 30 days of treatment, resulting in a composite 30-day mortality rate of 5.17%. One patient died receiving curative intent SACT. More deaths occurred in SACT-naïve patients and during the first two cycles of therapy. Of the deaths, 28% was attributed to SACT, while 59.7% was attributed to cancer progression. CONCLUSION: Thirty-day mortality rates were comparable to studies from larger institutions. We demonstrated the feasibility of this index for auditing practice in smaller oncology units over a longer timeframe.