Neoantigen-targeted CD8+ T cell responses with PD-1 blockade therapy.

Neoantigens are peptides derived from non-synonymous mutations presented by human leukocyte antigens (HLAs), which are recognized by antitumour T cells1-14. The large HLA allele diversity and limiting clinical samples have restricted the study of the landscape of neoantigen-targeted T cell responses in patients over their treatment course. Here we applied recently developed technologies15-17 to capture neoantigen-specific T cells from blood and tumours from patients with metastatic melanoma with or without response to anti-programmed death receptor 1 (PD-1) immunotherapy. We generated personalized libraries of neoantigen-HLA capture reagents to single-cell isolate the T cells and clone their T cell receptors (neoTCRs). Multiple T cells with different neoTCR sequences (T cell clonotypes) recognized a limited number of mutations in samples from seven patients with long-lasting clinical responses. These neoTCR clonotypes were recurrently detected over time in the blood and tumour. Samples from four patients with no response to anti-PD-1 also demonstrated neoantigen-specific T cell responses in the blood and tumour to a restricted number of mutations with lower TCR polyclonality and were not recurrently detected in sequential samples. Reconstitution of the neoTCRs in donor T cells using non-viral CRISPR-Cas9 gene editing demonstrated specific recognition and cytotoxicity to patient-matched melanoma cell lines. Thus, effective anti-PD-1 immunotherapy is associated with the presence of polyclonal CD8+ T cells in the tumour and blood specific for a limited number of immunodominant mutations, which are recurrently recognized over time.

Long-term avelumab in advanced non-small-cell lung cancer: summaries and post hoc analyses from JAVELIN Solid Tumor.

Background: This study examined patients with advanced non-small-cell lung cancer who received long-term avelumab (anti-PD-L1) in a large phase Ib trial (JAVELIN Solid Tumor). Methods: Patients receiving >2 years of avelumab were reviewed and exploratory descriptive analyses were conducted. Results: Individuals with varying baseline characteristics who had received up to 6 years of avelumab were reviewed. Overall, 37/340 (10.9%) had received ≥2 years of treatment; in this subgroup, best response was complete response in 5.4%, partial response in 59.5% and stable disease in 29.7%; 51.4% had continued treatment beyond disease progression. Conclusions: In this study, 11% of patients with advanced non-small-cell lung cancer received ≥2 years of avelumab treatment and experienced prolonged response or continued clinical benefit. Clinical Trial Registration: NCT02395172 (ClinicalTrials.gov).

Need for numbers: assessing cancer survivors' needs for personalized and generic statistical information.

BACKGROUND: Statistical information (e.g., on long-term survival or side effects) may be valuable for healthcare providers to share with their patients to facilitate shared decision making on treatment options. In this pre-registered study, we assessed cancer survivors' need for generic (population-based) versus personalized (tailored towards patient/tumor characteristics) statistical information after their diagnosis. We examined how information coping style, subjective numeracy, and anxiety levels of survivors relate to these needs and identified statistical need profiles. Additionally, we qualitatively explored survivors' considerations for (not) wanting statistical information. METHODS: Cancer survivors' need for statistics regarding incidence, survival, recurrence, side effects and quality of life were assessed with an online questionnaire. For each of these topics, survivors were asked to think back to their first cancer diagnosis and to indicate their need for generic and personalized statistics on a 4-point scale ('not at all'- 'very much'). Associations between information coping style, subjective numeracy, and anxiety with need for generic and personalized statistics were examined with Pearson's correlations. Statistical need profiles were identified using latent class analysis. Considerations for (not) wanting statistics were analyzed qualitatively. RESULTS: Overall, cancer survivors (n = 174) had a higher need for personalized than for generic statistics (p < .001, d = 0.74). Need for personalized statistics was associated with higher subjective numeracy (r = .29) and an information-seeking coping style (r = .41). Three statistical need profiles were identified (1) a strong need for both generic and personalized statistics (34%), (2) a stronger need for personalized than for generic statistics (55%), and (3) a little need for both generic and personalized statistics (11%). Considerations for wanting personalized cancer statistics ranged from feelings of being in control to making better informed decisions about treatment. Considerations for not wanting statistics related to negative experience with statistics and to the unpredictability of future events for individual patients. CONCLUSIONS: In light of the increased possibilities for using personalized statistics in clinical practice and decision aids, it appears that most cancer survivors want personalized statistical information during treatment decision-making. Subjective numeracy and information coping style seem important factors influencing this need. We encourage further development and implementation of data-driven personalized decision support technologies in oncological care to support patients in treatment decision making.

Pembrolizumab plus cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma: an open-label, multi-arm, non-randomised, multicentre, phase 2 trial.

BACKGROUND: Pembrolizumab (PD-1 inhibitor) and cetuximab (EGFR inhibitor) are active as single agents and in combination with cytotoxic chemotherapy for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Given each drug's single agent activity and unique mechanism of action, we aimed to evaluate the anti-tumour activity of PD-1 blockade with EGFR inhibition in recurrent or metastatic HNSCC. METHODS: This study is an open-label, non-randomised, multi-arm, phase 2 trial done at four academic centres in the USA. Participants were required to have platinum-resistant or platinum-ineligible, recurrent or metastatic HNSCC, be at least 18 years old, have an Eastern Cooperative Oncology Group performance status 0-1, have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and to have received no previous immunotherapy or EGFR inhibition. All participants received pembrolizumab 200 mg intravenously every 3 weeks, combined with an initial loading dose of cetuximab 400 mg/m2 intravenously followed by 250 mg/m2 intravenously weekly (21 day cycle). The primary endpoint was overall response rate defined as the proportion of participants with a partial or complete responses (per RECIST version 1.1) by 6 months in the intention-to-treat population. The safety population included all participants who received at least one dose of pembrolizumab. Herein, the final analysis of cohort 1 (no previous PD-1, PD-L1, or EGFR inhibition for recurrent or metastatic HNSCC) is reported. Three additional cohorts (two for participants with a previous response to immunotherapy followed by relapse or progression, with or without previous cetuximab exposure, and one for cutaneous HNSCC) will be reported separately once fully accrued. This study is registered with ClinicalTrials.gov, NCT03082534, and remains open as the three additional cohorts are actively accruing participants. FINDINGS: Between March 22, 2017, and July 16, 2019, 33 participants were enrolled to cohort 1. All 33 participants received at least one dose of pembrolizumab. Median follow-up duration was 7·3 months (IQR 3·9-10·9). By 6 months, the overall response rate was 45% (95% CI 28-62), with 15 of 33 participants achieving a partial response. The most common grade 3-4 treatment-related adverse event was oral mucositis (three [9%] of 33 participants), and serious treatment-related adverse events occurred in five (15%) participants. No treatment-related deaths occurred. INTERPRETATION: Pembrolizumab combined with cetuximab shows promising clinical activity for recurrent or metastatic HNSCC, and merits further investigation. FUNDING: Merck Sharp & Dohme.

Pegilodecakin as monotherapy or in combination with anti-PD-1 or tyrosine kinase inhibitor in heavily pretreated patients with advanced renal cell carcinoma: Final results of cohorts A, G, H and I of IVY Phase I study.

Interleukin (IL)-10 has anti-inflammatory and CD8+ T-cell-stimulating properties. Pegilodecakin (pegylated recombinant human IL-10) induces intratumoral antigen-specific CD8 + T-cells and upregulates IFNγ and major histocompatibility complexes (MHC) I and II. Pegilodecakin has single-agent activity with manageable toxicity in advanced renal cell carcinama (aRCC) (data cutoff 24 March 2016). Pegilodecakin with pembrolizumab or nivolumab revealed clinical activity in aRCC (data cutoff 1 July 2018). Here, we report for the first time the results of pegilodecakin+ pazopanib, and final results for monotherapy and long-term follow-up with pegilodecakin + anti-programmed cell death 1 (anti-PD-1) inhibitors (data cutoff 19 February 2019). Phase 1/1b multi-cohort dose escalation IVY study enrolled 353 patients. Sixty-six patients with aRCC were treated with pegilodecakin alone or with pazopanib or anti-PD-1 inhibitor in cohorts A, G, H and I (data cutoff 19 February 2019). Primary endpoints included safety and tolerability. Secondary endpoint was tumor response by immune-related response criteria (irRC). Pegilodecakin plus nivolumab or pembrolizumab yielded median progression-free survival (mPFS) of 13.9 months and 6-month PFS probability of 60%, 76% 1-year overall survival (OS) probability and 61% 2-year OS probability. Pegilodecakin monotherapy produced mPFS of 1.8 months, 6-month PFS probability 25%, 1-year OS 50%, and 2-year OS 17%. Median OS was not reached in both combinations. Objective response rates (ORRs) were 33% with pazopanib and 43% with anti-PD-1. Most common Grade 3/4 treatment-related adverse events included anemia, thrombocytopenia and hypertriglyceridemia. In these heavily pretreated renal cell carcinama cohorts of IVY, pegilodecakin+anti-PD-1 inhibitor showed promising clinical activity. Safety profile of pegilodecakin alone and with anti-PD-1 inhibitors was consistent as previously reported.

Immunologic and tumor responses of pegilodecakin with 5-FU/LV and oxaliplatin (FOLFOX) in pancreatic ductal adenocarcinoma (PDAC).

Background Treatment options for pancreatic ductal adenocarcinoma (PDAC) are limited and checkpoint blockade inhibitors have been disappointing in this disease. Pegilodecakin has demonstrated single agent anti-tumor activity in immune-sensitive tumors. Phase 1 and preclinical data indicate synergy of pegilodecakin with 5-FU and platins. We assessed the safety and activity of pegilodecakin+FOLFOX in patients with PDAC. Methods IVY (NCT02009449) was an open-label phase 1b trial in the United States. Here we report on all enrolled patients from cohort C. Heavily pretreated patients were treated with pegilodecakin (self-administered subcutaneously daily at 2.5, 5, or 10 µg/kg) + 5-flurouracil/leucovorin/oxaliplatin (FOLFOX), dosed per manufacturers prescribing information, until tumor progression. Eligible patients had measurable disease per immune-related response criteria (irRC), were ≥ 18 years of age, and had ECOG performance status of 0 or 1. Patients were evaluated for primary(safety) and secondary (tumor response per irRC) endpoints. Results From 5 August 2014-12 July 2016, 39 patients enrolled in cohort C. All patients were evaluable for safety. In this advanced population, regimen had manageable toxicities with no immune-related adverse events (irAEs) greater than grade 1. The most common grade 3/4/5 TEAEs were thrombocytopenia (21[53.8%] of 39) and anemia (17[43.6%] of 39). In evaluable PDAC patients, the best overall response of pegilodecakin+FOLFOX was 3(14%) with CRs in 2(9%) patients. Conclusions Pegilodecakin+FOLFOX had an acceptable tolerability profile in PDAC, with no substantial irAEs seen, and promising efficacy with the combination yielding a 2-year OS of 24% (95% CI 10-42). These data led to the phase 3 study with pegilodecakin+FOLFOX as second-line therapy of PDAC (SEQUOIA).

Medical and dental characteristics of children with chromosome 22q11.2 deletion syndrome at the Royal Children's Hospital, Melbourne.

BACKGROUND: Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a multifaceted syndrome with a variable phenotype. Few studies have described the associated dental characteristics and their relationship with medical co-morbidities; and no Australian data exist. AIM: To determine the clinical manifestations and correlations between oral and medical conditions in children with 22q11.2DS. DESIGN: A retrospective observational study. Children genetically diagnosed with 22q11.2DS at the Royal Children's Hospital Melbourne were selected; their medical and dental characteristics were collated and analysed. RESULTS: The study population (n = 57; mean age 11.5 years, range 2-27 years) experienced a range of medical conditions involving multiple medical systems; of whom 44 (77.2%) had caries experience, 7 (12.3%) developmentally missing teeth, and 31 (54.4%) developmental defects of enamel (DDE). Smaller proportions of primary teeth were affected by DDE in children with congenital heart disease (2.2% vs 9.7%; P = .02), and cardiac surgery (0.2% vs 9%; P = .001). Conversely, children with hypoparathyroidism (n = 2) had significantly higher proportions of primary teeth affected by DDE (27.5% vs 4%; P = .02). CONCLUSIONS: Significant associations existed between medical conditions (congenital heart disease, history of cardiac surgery, and hypoparathyroidism) and primary dentition DDE in children with 22q11.2 DS.

Cemiplimab in locally advanced cutaneous squamous cell carcinoma: results from an open-label, phase 2, single-arm trial.

BACKGROUND: Cemiplimab has shown substantial antitumour activity in patients with metastatic cutaneous squamous cell carcinoma. Patients with locally advanced cutaneous squamous cell carcinoma have poor prognosis with conventional systemic therapy. We present a primary analysis of the safety and antitumour activity of cemiplimab in patients with locally advanced cutaneous squamous cell carcinoma. METHODS: This pivotal open-label, phase 2, single-arm trial was done across 25 outpatient clinics, primarily at academic medical centres, in Australia, Germany, and the USA. Eligible patients (aged ≥18 years with histologically confirmed locally advanced cutaneous squamous cell carcinoma and an Eastern Cooperative Oncology Group performance status of 0-1) received cemiplimab 3 mg/kg intravenously over 30 min every 2 weeks for up to 96 weeks. Tumour measurements were done every 8 weeks. The primary endpoint was objective response, defined as the proportion of patients with complete or partial response, according to independent central review as per Response Evaluation Criteria in Solid Tumors version 1.1 for radiological scans and WHO criteria for medical photography. Data cutoff was Oct 10, 2018, when the fully enrolled cohort reached the prespecified timepoint for the primary analysis. Analyses were done as per the intention-to-treat principle. The safety analysis comprised all patients who received at least one dose of cemiplimab. This study is registered with ClinicalTrials.gov, number NCT02760498. FINDINGS: Between June 14, 2016, and April 25, 2018, 78 patients were enrolled and treated with cemiplimab. The median duration of study follow-up was 9·3 months (IQR 5·1-15·7) at the time of data cutoff. An objective response was observed in 34 (44%; 95% CI 32-55) of 78 patients. The best overall response was ten (13%) patients with a complete response and 24 (31%) with a partial response. Grade 3-4 treatment-emergent adverse events occurred in 34 (44%) of 78 patients; the most common were hypertension in six (8%) patients and pneumonia in four (5%). Serious treatment-emergent adverse events occurred in 23 (29%) of 78 patients. One treatment-related death was reported that occurred after onset of aspiration pneumonia. INTERPRETATION: Cemiplimab showed antitumour activity and an acceptable safety profile in patients with locally advanced cutaneous squamous cell carcinoma for whom there was no widely accepted standard of care. FUNDING: Regeneron Pharmaceuticals and Sanofi.

Tipifarnib in recurrent, metastatic HRAS-mutant salivary gland cancer.

BACKGROUND: To the authors' knowledge, there are no approved therapies for recurrent, metastatic (R/M) salivary gland carcinoma (SGC), but molecularly targeted therapies warrant ongoing investigation. In the current study, the authors have reported on the efficacy of tipifarnib in patients with aggressive HRAS-mutant, R/M SGC. METHODS: The current prospective, nonrandomized, multicenter, international cohort study involved 8 centers and was conducted from May 2015 to June 2019. The median follow-up was 22 months (range, 6-55 months). Subjects with HRAS-mutant R/M SGC (any histology) and disease progression within the last 6 months were enrolled. Tipifarnib was dosed orally twice daily. The authors determined the objective response rate using Response Evaluation Criteria in Solid Tumors (version 1.1), duration of response, and molecular predictors of response. RESULTS: A total of 13 patients with R/M SGC were enrolled; all had received prior systemic therapy (1-3 regimens). One objective response was observed; an additional 7 of 12 evaluable patients (58%) had stable disease as their best response with a median duration of 9 months (range, 3-14 months). Five of 7 patients had >10% tumor regression and 6 of 7 had stable disease lasting >6 months. Q61R was the most frequent activating HRAS mutation noted (7 of 13 patients; 54%), but gene variant and allele frequency did not correlate with outcomes. The median progression-free survival was 7 months (95% confidence interval, 5.9-10.1 months), and the median overall survival was 18 months (95% confidence interval, 9.6-22.4 months) with approximately 58.6% of patients alive at 1 year. Survival was similar regardless of HRAS mutant variant or co-occurring PIK3CA alterations. No participant discontinued treatment because of toxicity. CONCLUSIONS: Tipifarnib resulted in modest clinical activity with a promising disease control rate among patients with HRAS-mutant, R/M SGC who developed disease progression within the last 6 months.

Risk factors of unmet needs among women with breast cancer in the post-treatment phase.

OBJECTIVE: Unmet health care needs require additional care resources to achieve optimal patient well-being. In this nationwide study we examined associations between a number of risk factors and unmet needs after treatment among women with breast cancer, while taking into account their health care practices. We expected that more care use would be associated with lower levels of unmet needs. METHODS: A multicenter, prospective, observational design was employed. Women with primary breast cancer completed questionnaires 6 and 15 months post-diagnosis. Medical data were retrieved from medical records. Direct and indirect associations between sociodemographic and clinical risk factors, distress, care use, and unmet needs were investigated with structural equation modeling. RESULTS: Seven hundred forty-six participants completed both questionnaires (response rate 73.7%). The care services received were not negatively associated with the reported levels of unmet needs after treatment. Comorbidity was associated with higher physical and daily living needs. Higher age was associated with higher health system-related and informational needs. Having had chemotherapy and a mastectomy were associated with higher sexuality needs and breast cancer-specific issues, respectively. A higher level of distress was associated with higher levels of unmet need in all domains. CONCLUSIONS: Clinicians may use these results to timely identify which women are at risk of developing specific unmet needs after treatment. Evidence-based, cost-effective (online) interventions that target distress, the most influential risk factor, should be further implemented and disseminated among patients and clinicians.

Cardiovascular disease risk assessment for Aboriginal and Torres Strait Islander adults aged under 35 years: a consensus statement.

Cardiovascular disease (CVD) is a leading cause of preventable morbidity and mortality in Aboriginal and Torres Strait Islander peoples. This statement from the Australian Chronic Disease Prevention Alliance, the Royal Australian College of General Practitioners, the National Aboriginal Community Controlled Health Organisation and the Editorial Committee for Remote Primary Health Care Manuals communicates the latest consensus advice of guideline developers, aligning recommendations on the age to commence Aboriginal and Torres Strait Islander CVD risk assessment across three guidelines. MAIN RECOMMENDATIONS: In Aboriginal and Torres Strait Islander peoples without existing CVD: CVD risk factor screening should commence from the age of 18 years at the latest, including for blood glucose level or glycated haemoglobin, estimated glomerular filtration rate, serum lipids, urine albumin to creatinine ratio, and other risk factors such as blood pressure, history of familial hypercholesterolaemia, and smoking status. Individuals aged 18-29 years with the following clinical conditions are automatically conferred high CVD risk: ▶type 2 diabetes and microalbuminuria; ▶moderate to severe chronic kidney disease; ▶systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 110 mmHg; ▶familial hypercholesterolaemia; or ▶serum total cholesterol > 7.5 mmol/L. Assessment using the National Vascular Disease Prevention Alliance absolute CVD risk algorithm should commence from the age of 30 years at the latest - consider upward adjustment of calculated CVD risk score, accounting for local guideline use, risk factor and CVD epidemiology, and clinical discretion. Assessment should occur as part of an annual health check or opportunistically. Subsequent review should be conducted according to level of risk. CHANGES IN MANAGEMENT AS A RESULT OF THIS STATEMENT: From age 18 years (at the latest), Aboriginal and Torres Strait Islander adults should undergo CVD risk factor screening, and from age 30 years (at the latest), they should undergo absolute CVD risk assessment using the NVDPA risk algorithm.

Health care use and remaining needs for support among women with breast cancer in the first 15 months after diagnosis: the role of the GP.

BACKGROUND: The number of women with breast cancer in general practice is rising. To address their needs and wishes for a referral, GPs might benefit from more insight into women's health care practices and need for additional support. OBJECTIVE: To examine the prevalence of health care use and remaining needs among women with breast cancer in the first 15 months after diagnosis. METHODS: In this multicentre, prospective, observational study women with breast cancer completed a questionnaire at 6 and 15 months post-diagnosis. Medical data were retrieved through chart reviews. The prevalence of types of health care used and remaining needs related to medical, psychosocial, paramedical and supplementary service care (such as home care), was examined with descriptive analyses. RESULTS: Seven hundred forty-six women completed both questionnaires. At both assessments patients reported that they had most frequent contact with medical and paramedical providers, independent of types of treatment received. Three to fifteen percent of the patients expressed a need for more support. Prominent needs included a wish for more frequent contact with a physiotherapist, a clinical geneticist and a psychologist. Patients also wanted more help for chores around the house, particularly in the early post-treatment phase. CONCLUSION: A small but relevant percentage of women with breast cancer report having unmet needs. GPs may need to be particularly watchful of their need for more support from specific providers. Future research into the necessity of structural needs assessment among cancer patients in general practice is warranted.

Pegilodecakin combined with pembrolizumab or nivolumab for patients with advanced solid tumours (IVY): a multicentre, multicohort, open-label, phase 1b trial.

BACKGROUND: IL-10 has anti-inflammatory and CD8+ T-cell stimulating activities. Pegilodecakin (pegylated IL-10) is a first-in-class, long-acting IL-10 receptor agonist that induces oligoclonal T-cell expansion and has single-agent activity in advanced solid tumours. We assessed the safety and activity of pegilodecakin with anti-PD-1 monoclonal antibody inhibitors in patients with advanced solid tumours. METHODS: We did a multicentre, multicohort, open-label, phase 1b trial (IVY) at 12 cancer research centres in the USA. Patients were assigned sequentially into cohorts. Here, we report on all enrolled patients from two cohorts treated with pegilodecakin combined with anti-PD-1 inhibitors. Eligible patients were aged at least 18 years with histologically or cytologically confirmed advanced malignant solid tumours refractory to previous therapies, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients with uncontrolled infectious diseases were excluded. Pegilodecakin was provided in single-use 3 mL vials and was self-administered subcutaneously by injection at home at 10 µg/kg or 20 µg/kg once per day in combination with pembrolizumab (2 mg/kg every 3 weeks or 200 mg every 3 weeks) or nivolumab (3 mg/kg every 2 weeks or 240 mg every 2 weeks or 480 mg every 4 weeks at the approved dosing), both of which were given intravenously at the study site. Patients received pembrolizumab or nivolumab with pegilodecakin until disease progression, toxicity necessitating treatment discontinuation, patient withdrawal of consent, or study end. The primary endpoints were safety and tolerability, assessed in all patients enrolled in the study who received any amount of study medication including at least one dose of pegilodecakin, and pharmacokinetics (previously published). Secondary endpoints included objective response by immune-related response criteria in all patients who were treated and had evaluable measurements. The study is active but no longer recruiting, and is registered with ClinicalTrials.gov, NCT02009449. FINDINGS: Between Feb 13, 2015, and Sept 12, 2017, 111 patients were enrolled in the two cohorts. 53 received pegilodecakin plus pembrolizumab, and 58 received pegilodecakin plus nivolumab. 34 (31%) of 111 patients had non-small-cell lung cancer, 37 (33%) had melanoma, and 38 (34%) had renal cell carcinoma; one (<1%) patient had triple-negative breast cancer and one (<1%) had bladder cancer. Data cutoff was July 1, 2018. Median follow-up was 26·9 months (IQR 22·3-31·5) for patients with non-small-cell lung cancer, 33·0 months (29·2-35·1) for those with melanoma, and 22·7 months (20·9-27·0) for those with renal cell carcinoma. At least one treatment-related adverse event occurred in 103 (93%) of 111 patients. Grade 3 or 4 events occurred in 73 (66%) of 111 patients (35 [66%] of 53 in the pembrolizumab group and 38 [66%] of 58 in the nivolumab group), the most common of which were anaemia (12 [23%] in the pembrolizumab group and 16 [28%] in the nivolumab group), thrombocytopenia (14 [26%] in the pembrolizumab group and 12 [21%] in the nivolumab group), fatigue (11 [21%] in the pembrolizumab group and 6 [10%] in the nivolumab group) and hypertriglyceridaemia (three [6%] in the pembrolizumab group and eight [14%] in the nivolumab group). There were no fatal adverse events determined to be related to the study treatments. Of the patients evaluable for response, objective responses were 12 (43%) of 28 (non-small-cell lung cancer), three (10%) of 31 (melanoma), and 14 (40%) of 35 (renal cell carcinoma). INTERPRETATION: In this patient population, pegilodecakin with anti-PD-1 monoclonal antibodies had a manageable toxicity profile and preliminary antitumour activity. Pegilodecakin with pembrolizumab or nivolumab could provide a new therapeutic opportunity for previously treated patients with renal cell carcinoma and non-small-cell carcinoma. FUNDING: ARMO BioSciences, a wholly owned subsidiary of Eli Lilly and Company.

Safety profile of avelumab in patients with advanced solid tumors: A pooled analysis of data from the phase 1 JAVELIN solid tumor and phase 2 JAVELIN Merkel 200 clinical trials.

BACKGROUND: Antibodies targeting the programmed death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) checkpoint may cause adverse events (AEs) that are linked to the mechanism of action of this therapeutic class and unique from those observed with conventional chemotherapy. METHODS: Patients with advanced solid tumors who were enrolled in the phase 1 JAVELIN Solid Tumor (1650 patients) and phase 2 JAVELIN Merkel 200 (88 patients) trials received avelumab, a human anti-PD-L1 IgG1 antibody at a dose of 10 mg/kg every 2 weeks. Treatment-related AEs (TRAEs) were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). In post hoc analyses, immune-related AEs (irAEs) were identified via an expanded AE list and medical review, and infusion-related reactions (IRRs) occurring ≤2 days after infusion and symptoms occurring ≤1 day after infusion and resolving ≤2 days after onset were identified based on prespecified Medical Dictionary for Regulatory Activities (MedDRA) terms. RESULTS: Of the 1738 patients analyzed, grade ≥3 TRAEs occurred in 177 (10.2%); the most common were fatigue (17 patients; 1.0%) and IRR (10 patients; 0.6%). TRAEs led to discontinuation in 107 patients (6.2%) and death in 4 patients (0.2%). Grade ≥3 irAEs occurred in 39 patients (2.2%) and led to discontinuation in 34 patients (2.0%). IRRs or related symptoms occurred in 439 patients (25.3%; grade 3 in 0.5% [9 patients] and grade 4 in 0.2% [3 patients]). An IRR occurred at the time of first infusion in 79.5% of 439 patients who had an IRR, within the first 4 doses in 98.6% of 439 patients who had an IRR, and led to discontinuation in 35 patients (2.0%). CONCLUSIONS: Avelumab generally was found to be well tolerated and to have a manageable safety profile. A minority of patients experienced grade ≥3 TRAEs or irAEs, and discontinuation was uncommon. IRRs occurred mainly at the time of first infusion, and repeated events were infrequent. Cancer 2018;124:2010-7. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Patient-reported quality-of-life outcomes after de-escalated chemoradiation for human papillomavirus-positive oropharyngeal carcinoma: Findings from a phase 2 trial.

BACKGROUND: The current study represents a subset analysis of quality-of-life (QOL) outcomes among patients treated on a phase 2 trial of de-escalated chemoradiation for human papillomavirus (HPV)-associated oropharyngeal cancer. METHODS: Eligibility included newly diagnosed, (American Joint Committee on Cancer, 7th edition) stage III or IV oropharyngeal squamous cell carcinoma, p16 positivity, age ≥ 18 years, and a Zubrod performance status of 0 to 1. Treatment was induction paclitaxel at a dose of 175 mg/m2 and carboplatin at an area under the curve of 6 for 2 cycles followed by response-adapted, dose-reduced radiation of 54 Gy or 60 Gy with weekly concurrent paclitaxel at a dose of 30 mg/m2 . The University of Washington Quality of Life (UW-QOL) and the Functional Assessment of Cancer Therapy-Head and Neck questionnaires were used to assess patient-reported QOL as a secondary endpoint. RESULTS: A total of 45 patients were registered, 40 of whom completed QOL surveys and were evaluable. Nadirs for overall UW-QOL and Functional Assessment of Cancer Therapy-Head and Neck scores were reached at 4 weeks after treatment but returned to baseline at 3 months. Nearly all functional indices returned to baseline levels by 6 to 9 months. The mean overall UW-QOL score was 71.6 at baseline compared with 70.8, 73.0, 83.3, and 81.1, respectively, at 3 months, 6 months, 1 year, and 2 years after therapy. The percentage of patients rating their overall QOL as "very good" or "outstanding" at 6 months, 1 year, and 2 years using the UW-QOL was 50%, 77%, and 84%, respectively. CONCLUSIONS: This de-escalation regimen achieved QOL outcomes that were favorable compared with historical controls. These results serve as powerful evidence that ongoing de-escalation efforts lead to tangible gains in function and QOL. Cancer 2018;124:521-9. © 2017 American Cancer Society.

A human microdose study of the antimalarial drug GSK3191607 in healthy volunteers.

AIMS: GSK3191607, a novel inhibitor of the Plasmodium falciparum ATP4 (PfATP4) pathway, is being considered for development in humans. However, a key problem encountered during the preclinical evaluation of the compound was its inconsistent pharmacokinetic (PK) profile across preclinical species (mouse, rat and dog), which prevented reliable prediction of PK parameters in humans and precluded a well-founded assessment of the potential for clinical development of the compound. Therefore, an open-label microdose (100 µg, six subjects) first time in humans study was conducted to assess the human PK of GSK3191607 following intravenous administration of [14C]-GSK3191607. METHODS: A human microdose study was conducted to investigate the clinical PK of GSK3191607 and enable a Go/No Go decision on further progression of the compound. The PK disposition parameters estimated from the microdose study, combined with preclinical in vitro and in vivo pharmacodynamic parameters, were all used to estimate the potential efficacy of various oral dosing regimens in humans. RESULTS: The PK profile, based on the microdose data, demonstrated a half-life (~17 h) similar to other antimalarial compounds currently in clinical development. However, combining the microdose data with the pharmacodynamic data provided results that do not support further clinical development of the compound for a single dose cure. CONCLUSIONS: The information generated by this study provides a basis for predicting the expected oral PK profiles of GSK3191607 in man and supports decisions on the future clinical development of the compound.

Reduced-dose radiotherapy for human papillomavirus-associated squamous-cell carcinoma of the oropharynx: a single-arm, phase 2 study.

BACKGROUND: Head and neck cancers positive for human papillomavirus (HPV) are exquisitely radiosensitive. We investigated whether chemoradiotherapy with reduced-dose radiation would maintain survival outcomes while improving tolerability for patients with HPV-positive oropharyngeal carcinoma. METHODS: We did a single-arm, phase 2 trial at two academic hospitals in the USA, enrolling patients with newly diagnosed, biopsy-proven stage III or IV squamous-cell carcinoma of the oropharynx, positive for HPV by p16 testing, and with Zubrod performance status scores of 0 or 1. Patients received two cycles of induction chemotherapy with 175 mg/m2 paclitaxel and carboplatin (target area under the curve of 6) given 21 days apart, followed by intensity-modulated radiotherapy with daily image guidance plus 30 mg/m2 paclitaxel per week concomitantly. Complete or partial responders to induction chemotherapy received 54 Gy in 27 fractions, and those with less than partial or no responses received 60 Gy in 30 fractions. The primary endpoint was progression-free survival at 2 years, assessed in all eligible patients who completed protocol treatment. This study is registered with ClinicalTrials.gov, numbers NCT02048020 and NCT01716195. FINDINGS: Between Oct 4, 2012, and March 3, 2015, 45 patients were enrolled with a median age of 60 years (IQR 54-67). One patient did not receive treatment and 44 were included in the analysis. 24 (55%) patients with complete or partial responses to induction chemotherapy received 54 Gy radiation, and 20 (45%) with less than partial responses received 60 Gy. Median follow-up was 30 months (IQR 26-37). Three (7%) patients had locoregional recurrence and one (2%) had distant metastasis; 2-year progression-free survival was 92% (95% CI 77-97). 26 (39%) of 44 patients had grade 3 adverse events, but no grade 4 events were reported. The most common grade 3 events during induction chemotherapy were leucopenia (17 [39%]) and neutropenia (five [11%]), and during chemoradiotherapy were dysphagia (four [9%]) and mucositis (four [9%]). One (2%) of 44 patients was dependent on a gastrostomy tube at 3 months and none was dependent 6 months after treatment. INTERPRETATION: Chemoradiotherapy with radiation doses reduced by 15-20% was associated with high progression-free survival and an improved toxicity profile compared with historical regimens using standard doses. Radiotherapy de-escalation has the potential to improve the therapeutic ratio and long-term function for these patients. FUNDING: University of California.

Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): dose-expansion cohort of a multicentre, open-label, phase 1b trial.

BACKGROUND: Avelumab, a human Ig-G1 monoclonal antibody targeting PD-L1 and approved in the USA for the treatment of metastatic Merkel cell carcinoma, has shown antitumour activity and an acceptable safety profile in patients with advanced solid tumours in a dose-escalation phase 1a trial. In this dose-expansion cohort of that trial, we assess avelumab treatment in a cohort of patients with advanced, platinum-treated non-small-cell lung cancer (NSCLC). METHODS: In this dose-expansion cohort of a multicentre, open-label, phase 1 study, patients with progressive or platinum-resistant metastatic or recurrent NSCLC were enrolled at 58 cancer treatment centres and academic hospitals in the USA. Eligible patients had confirmed stage IIIB or IV NSCLC with squamous or non-squamous histology, measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), tumour biopsy or archival sample for biomarker assessment, and Eastern Cooperative Oncology Group performance status 0 or 1, among other criteria. Patient selection was not based on PD-L1 expression or expression of other biomarkers, including EGFR or KRAS mutation or ALK translocation status. Patients received infusional avelumab monotherapy 10 mg/kg every 2 weeks until disease progression or toxicity. The primary objective was to assess safety and tolerability. This trial is registered with ClinicalTrials.gov, number NCT01772004; enrolment in this cohort is closed and the trial is ongoing. FINDINGS: Between Sept 10, 2013, and June 24, 2014, 184 patients were enrolled and initiated treatment with avelumab. Median follow-up duration was 8·8 months (IQR 7·2-11·9). The most common treatment-related adverse events of any grade were fatigue (46 [25%] of 184 patients), infusion-related reaction (38 [21%]), and nausea (23 [13%]). Grade 3 or worse treatment-related adverse events occurred in 23 (13%) of 184 patients; the most common (occurring in more than two patients) were infusion-related reaction (four [2%] patients) and increased lipase level (three [2%]). 16 (9%) of 184 patients had a serious adverse event related to treatment with avelumab, with infusion-related reaction (in four [2%] patients) and dyspnoea (in two [1%]) occurring in more than one patient. Serious adverse events irrespective of cause occurred in 80 (44%) of 184 patients. Those occurring in more than five patients (≥3%) were dyspnoea (ten patients [5%]), pneumonia (nine [5%]), and chronic obstructive pulmonary disease (six [3%]). Immune-related treatment-related events occurred in 22 patients (12%). Of 184 patients, 22 (12% [95% CI 8-18]) achieved a confirmed objective response, including one complete response and 21 partial responses. 70 (38%) had stable disease. Overall, 92 (50%) of 184 patients achieved disease control (they had a confirmed response or stable disease as their best overall response). One patient was initially thought to have died from grade 5 radiation pneumonitis during the study; however, this adverse event was subsequently regraded to grade 3 and the death was attributed to disease progression. INTERPRETATION: Avelumab showed an acceptable safety profile and antitumour activity in patients with progressive or treatment-resistant NSCLC, providing a rationale for further studies of avelumab in this disease setting. FUNDING: Merck KGaA and Pfizer.

Non-small cell lung cancer clinical trials requiring biopsies with biomarker-specific results for enrollment provide unique challenges.

BACKGROUND: Clinical trials in lung cancer increasingly require patients to provide fresh tumor tissue as a prerequisite to enrollment. The effects of this requirement on enrollment rates, enrollment durations, and patient selection have not been fully elucidated. METHODS: The authors retrospectively reviewed data generated by patients who consented to 1 or more interventional lung cancer clinical trials at the University of California-Los Angeles Jonsson Comprehensive Cancer Center between January 2013 and December 2014. Trials were considered to require a biopsy when enrollment was conditional on the procurement of tissue without intervening therapy between procurement and enrollment. RESULTS: In total, 311 patients underwent 368 screening incidents for 1 or more of 19 trials. Trials that required a new biopsy had a longer median screening duration (34 vs 14 days) than trials that did not require a biopsy (P < .001). Trials that required a biopsy had a greater screen failure rate (49.1% vs 26.5%; P < .001), which was largely driven by patients who did not undergo the required biopsy or lacked the required biomarker. Worsening performance status led to the majority of screen failures (56.5%) among biomarker-eligible patients. CONCLUSIONS: Although the scientific benefits of obtaining a new biopsy and requiring specific results for trial enrollment are clear, these requirements lead to a lengthening of the screening period, which, in some patients, is associated with clinical decline before enrollment. Implications for the interpretation of data from studies of this design should be explored. Cancer 2017;123:4800-7. © 2017 American Cancer Society.

Predictors of enduring clinical distress in women with breast cancer.

To date, little is known about enduring clinical distress as measured with the commonly used distress thermometer. We therefore used the distress thermometer to examine: (a) the prevalence of enduring clinical distress, distress-related problems, and subsequent wish for referral of women with breast cancer, and (b) sociodemographic, clinical, and psychosocial predictors of enduring clinical distress. The study had a multicenter, prospective, observational design. Patients with primary breast cancer completed a questionnaire at 6 and 15 months postdiagnosis. Medical data were retrieved from chart reviews. Enduring clinical distress was defined as heightened distress levels over time. The prevalence of enduring clinical distress, problems, and wish for referral was examined with descriptive analyses. Associations between predictors and enduring clinical distress were examined with multivariate analyses. One hundred sixty-four of 746 patients (22 %) reported having enduring clinical distress at 6 and 15 months postdiagnosis. Of these, 10 % wanted to be referred for care. Fatigue was the most frequently reported problem by patients with and without clinical distress, at both time points. Lack of muscle strength (OR = 1.82, 95 % CI 1.12-2.98), experience of a low level of life satisfaction (OR = 0.77, 95 % CI 0.67-0.89), more frequent cancer worry (OR = 1.40, 95 % CI 1.05-1.89), and neuroticism (OR = 1.09, 95 % CI 1.00-1.18) were predictors of enduring clinical distress. In conclusion, one in five women with breast cancer develops enduring clinical distress. Oncologists, nurse practitioners, and cancer nurses are advised to use single-item questions about distress and distress-related problems to ensure timely detection of high-risk patients. Providers should also routinely assess fatigue and its causes, as fatigue is the most frequently reported distress-related problem over time.