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BackgroundReduced-dose nivolumab in combination with standard-dose ipilimumab improves objective response and progression-free survival compared with standard-dose ipilimumab alone, but increases toxicity. We assessed the safety and anti-tumour activity of standard-dose pembrolizumab in combination with reduced-dose ipilimumab.MethodsIn this open-label, phase 1b trial, we recruited patients from 12 medical centres in Australia, New Zealand, and the USA. Eligible patients were aged at least 18 years, had advanced melanoma, had an Eastern Coooperative Oncology Group performance status of 0 or 1, had measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, had adequate organ function, had resolution of toxic effects of the most recent previous chemotherapy to grade 1 or less, had no active autoimmune disease requiring systemic steroids or immunosuppressive agents, had no active non-infectious pneumonitis, had no uncontrolled thyroid dysfunction or diabetes, had no active brain metastases, and had not received previous immune checkpoint inhibitor therapy. Patients received intravenous pembrolizumab 2 mg/kg plus intravenous ipilimumab 1 mg/kg every 3 weeks for four doses, followed by intravenous pembrolizumab 2 mg/kg every 3 weeks for up to 2 years or disease progression, intolerable toxicity, withdrawal of consent, or investigator decision. The primary endpoint was safety and tolerability. The proportion of patients achieving an objective response assessed per RECIST version 1.1 by independent central review and overall survival were secondary endpoints. We also assessed progression-free survival. The primary endpoint was assessed in all patients who received at least one dose of combination therapy. Activity was assessed in all enrolled patients. This trial is registered with ClinicalTrials.gov, number NCT02089685. Enrolment into this cohort is closed, but patients are still being monitored for safety and anti-tumour activity.FindingsBetween Jan 13, 2015, and Sept 17, 2015, we enrolled and treated 153 patients. As of the Oct 17, 2016, cutoff date, median follow-up was 17·0 months (IQR 14·8-18·8). 110 (72%) of 153 patients received all four pembrolizumab plus ipilimumab doses; 64 (42%) remained on pembrolizumab monotherapy. 110 grade 3-4 treatment-related adverse events occurred in 69 (45%) patients. No treatment-related deaths occurred. Treatment-related adverse events led to discontinuation of pembrolizumab and ipilimumab in 22 (14%) patients, including 17 (11%) who discontinued both treatments for the same event and five (3%) who discontinued ipilimumab for one event and later discontinued pembrolizumab for another. 12 (8%) patients discontinued ipilimumab only and 14 (9%) discontinued pembrolizumab only because of treatment-related adverse events. 158 immune-mediated adverse events of any grade occurred in 92 (60%) patients, and 50 immune-mediated adverse events of grade 3-4 occurred in 42 (27%) patients; the most common immune-mediated adverse events were hypothyroidism (25 [16%]) and hyperthyroidism (17 [11%]). 93 (61% [95% CI 53-69]) patients achieved an objective response. Estimated 1 year progression-free survival was 69% (95% CI 60-75), and estimated 1 year overall survival was 89% (95% CI 83-93).InterpretationStandard-dose pembrolizumab given in combination with four doses of reduced-dose ipilimumab followed by standard-dose pembrolizumab has a manageable toxicity profile and provides robust anti-tumour activity in patients with advanced melanoma. These data suggest that standard-dose pembrolizumab plus reduced-dose ipilimumab might be a tolerable, efficacious treatment option for patients with advanced melanoma. A randomised phase 2 trial of alternative dosing strategies of this combination is underway.FundingMerck & Co, Inc.

Objectives: To review the outcomes of immune checkpoint inhibitor (ICI) treatment of advanced cutaneous squamous cell carcinoma (CSCC) outside clinical trials. Study design: Retrospective observational study; review of patient records in fifteen Australian institutions. Setting, participants: All Australian adults with locally advanced or metastatic CSCC not amenable to curative surgery or radiotherapy treated with ICIs, 5 May 2017 – 23 May 2022, through a cemiplimab compassionate access scheme (Therapeutic Goods Administration Special Access Scheme) or who personally covered the cost of pembrolizumab prior to the start of the access scheme. Main outcome measures: Best overall response rate (ORR) according to standardised assessment criteria using the hierarchy: Response Evaluation Criteria in Solid Tumors (RECIST 1.1), the modified World Health Organization clinical response criteria, and the Positron Emission Tomography Response Criteria (PERCIST 1.0); overall and progression‐free survival. Results: A total of 286 people with advanced CSCC received ICI therapy during May 2017 – May 2022 (cemiplimab, 270; pembrolizumab, 16). Their median age was 75.2 years (range, 39.3–97.5 years) and 232 were men (81%); median follow‐up time was 12.2 months (interquartile range, 5.5–20.5 months). Eighty‐eight people (31%) were immunocompromised, 27 had autoimmune disease, and 59 of 277 (21%) had ECOG performance scores of 2 or 3. The ORR was 60% (166 of 278 evaluable patients): complete responses were recorded for 74 (27%) and partial responses for 92 patients (33%). Twelve‐month overall survival was 78% (95% confidence interval [CI], 72–83%); progression‐free survival was 65% (95% CI, 58–70%). Poorer ECOG performance status was associated with poorer overall survival (per unit: adjusted hazard ratio [aHR], 3.0; 95% CI, 2.0–4.3) and progression‐free survival (aHR, 2.4; 95% CI, 1.8–3.3), as was being immunocompromised (overall: aHR, 1.8; 95% CI, 1.1–3.0; progression‐free: aHR, 1.8; 95% CI, 1.2–2.7). Fifty‐five people (19%) reported immune‐related adverse events of grade 2 or higher; there were no treatment‐related deaths. Conclusion: In our retrospective study, the effectiveness and toxicity of ICI therapy were similar to those determined in clinical trials. Our findings suggest that ICIs could be effective and well tolerated by people with advanced CSCC who are ineligible for clinical trials. [ABSTRACT FROM AUTHOR]

Background: Patients with advanced malignancies have historically been considered poor candidates for admission to the intensive care unit (ICU); however, prognosis is continually improving, and requirements for ICU access are increasing. Aim: To understand the characteristics and outcomes of oncology unit patients admitted to an Australian ICU and identify potential prognostic factors. Methods: A single‐centre, retrospective, cohort study conducted at a tertiary public hospital with a quaternary ICU in Sydney, Australia. All patients admitted under the medical oncology team requiring ICU admission between June 2014 and June 2016 were evaluated. Clinical outcomes were determined including mortality, ICU requirements (ventilation, dialysis, vasopressors, infection) and prognostic scores (Acute Physiologic and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) score). Results: There were 96 patients with mean age 61 years, 58% were male and 76% had metastatic disease. Most were receiving palliative treatment (89%), with recent chemotherapy (43%), immunotherapy (10%) and other therapies (5%). Of the 10 patients with recent immunotherapy, three (all with melanoma) required ICU admission due to immunotoxicity; 13% were admitted due to an oncological emergency. Mean APACHE II score was 17 (standard deviation (SD) 5.33), mean SOFA score was 3.99 (SD 2.70), ICU mortality was 5% and hospital mortality was 22%. Using multivariate logistic regression analysis, cancer stage, infection during ICU admission, intracranial mass effect on ICU admission and SOFA score were associated with 30‐day mortality. Conclusion: Our patient population had good short‐term survival outcomes despite most receiving palliative treatment. Cancer patients can achieve positive outcomes after ICU admission, and appropriate selection of patients is crucial. [ABSTRACT FROM AUTHOR]

Summary: Historically, the prognosis of patients with melanoma brain metastases is poor, with median overall survival (OS) of 4‐6 months. Little is known of OS in the era of modern systemic therapies and local therapy with stereotactic radiosurgery (SRS) or surgery. Patients diagnosed with melanoma brain metastases at Melanoma Institute Australia from January 2011 to December 2014 were included. OS and prognostic factors were analysed using Cox regression and Kaplan‐Meier survival analyses.355 patients were included. The median OS was 7.1 months (95% confidence interval [CI] 6.0‐8.1). Median OS differed by treatment modality: systemic therapy and SRS and/or surgery 14.9 months (95% CI 10.7‐19.0), SRS and/or surgery with or without whole brain radiotherapy (WBRT) 6.4 months (95% CI 5.4‐7.5), systemic therapy 5.4 months (95% CI 3.1‐7.7), systemic therapy and WBRT 5.2 months (95% CI 4.1‐6.4), WBRT 4.4 months (95% CI 2.4‐6.3), and best supportive care 1.8 months (95% CI 1.2‐2.3). OS for patients with melanoma brain metastases appears improved in the modern era, particularly for patients who are candidates for systemic therapy with SRS and/or surgery. [ABSTRACT FROM AUTHOR]

Purpose: Combination therapy with reduced-dose programmed death 1 inhibitor plus standard-dose cytotoxic T-lymphocyte-associated antigen 4 inhibitor demonstrated efficacy, but substantial toxicity, in melanoma. We present long-term results of part 1B of KEYNOTE-029, which assessed safety and efficacy of standard-dose pembrolizumab plus reduced-dose ipilimumab in advanced melanoma., Patients and Methods: Part 1B was an expansion cohort of the open-label, phase Ib portion of KEYNOTE-029. Eligible patients had advanced melanoma and no previous immune checkpoint inhibitor therapy. Patients received pembrolizumab 2 mg/kg (amended to 200 mg) every 3 weeks plus ipilimumab 1 mg/kg every 3 weeks (four cycles), then pembrolizumab alone for up to 2 years. Primary end point was safety; secondary end points included objective response rate (ORR), progression-free survival (PFS), duration of response (DOR), and overall survival (OS)., Results: A total of 153 patients received at least one dose of pembrolizumab plus ipilimumab. At a median follow-up of 36.8 months, 71.9% had received four doses of ipilimumab and 30.7% had completed 2 years of pembrolizumab; 26.1% completed both treatments. Treatment-related adverse events occurred in 96.1% (47.1% grade 3/4; no deaths), leading to discontinuation of one or both study drugs in 35.9%. ORR was 62.1% with 42 (27.5%) complete and 53 (34.6%) partial responses. Median DOR was not reached; 36-month ongoing response rate was 84.2%. Median PFS and OS were not reached; 36-month rates were 59.1% and 73.4%, respectively., Conclusions: Standard-dose pembrolizumab plus reduced-dose ipilimumab demonstrated robust antitumor activity, durable response, and favorable long-term survival with manageable toxicity., (©2020 American Association for Cancer Research.)

Context: Checkpoint inhibitor-associated autoimmune diabetes mellitus (CIADM) is a rare illness, and little is known about its incidence, clinical features, or pathogenesis., Case Series Description: Consecutive patients from a single quaternary melanoma center who developed new-onset insulin-requiring diabetes after commencing anti-programmed cell death-1 (PD-1) immunotherapy were studied to describe CIADM characteristics. Ten (1.9%) of 538 patients with metastatic melanoma treated with anti-PD-1-based immunotherapy from March 2015 to March 2018 developed CIADM. Nine patients had no history of diabetes, and one had pre-existing type 2 diabetes mellitus. Median time from immunotherapy start to CIADM diagnosis was 25 weeks [interquartile range (IQR), 17.5 to 34.5 weeks]. All patients had normal serum C-peptide shortly before CIADM onset and an inappropriately low level when measured soon after. At CIADM diagnosis, median hemoglobin A1c was 7.6% (IQR, 7.15% to 9.75%), median glucose level was 32.5 mmol/L (IQR, 21.6 to 36.7 mmol/L), and median C-peptide concentration was 0.35 nmol/L (IQR, 0.10 to 0.49 mmol/L). Type 1 diabetes (T1D)-associated autoantibodies (DAAs) were present in two patients (both of whom had anti-glutamic acid decarboxylase antibody); all were negative for insulin-associated protein 2, insulin, and ZnT8. Three patients were heterozygous for an HLA class II T1D-risk haplotype; two additional patients also carried protective haplotypes for T1D. All patients continued immunotherapy; eight (80%) had complete or partial oncological response, and all patients required ongoing insulin therapy., Conclusion: CIADM is characterized by sudden permanent β-cell failure occurring after immunotherapy. It is distinct from T1D, usually lacks DAA or T1D-associated HLA-risk haplotypes, and is associated with difficult glycemic control from the onset. As such, CIADM represents a new model of auto-inflammatory β-cell failure., (Copyright © 2019 Endocrine Society.)

Purpose Pneumonitis is an uncommon but potentially fatal toxicity of anti-programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) monoclonal antibodies (mAbs). Clinical, radiologic, and pathologic features are poorly described. Methods Patients who received anti-PD-1/PD-L1 monotherapy or in combination with anti-cytotoxic T-cell lymphocyte-4 mAb were identified at two institutions (Memorial Sloan Kettering Cancer Center: advanced solid cancers, 2009 to 2014, and Melanoma Institute of Australia: melanomas only, 2013 to 2015). Pneumonitis was diagnosed by the treating investigator; cases with confirmed malignant lung infiltration or infection were excluded. Clinical, radiologic, and pathologic features of pneumonitis were collected. Associations among pneumonitis incidence, therapy received, and underlying malignancy were examined with Fisher's exact test as were associations between pneumonitis features and outcomes. Results Of 915 patients who received anti-PD-1/PD-L1 mAbs, pneumonitis developed in 43 (5%; 95% CI, 3% to 6%; Memorial Sloan Kettering Cancer Center, 27 of 578 [5%]; Melanoma Institute of Australia, 16 of 337 [5%]). Time to onset of pneumonitis ranged from 9 days to 19.2 months. The incidence of pneumonitis was higher with combination immunotherapy versus monotherapy (19 of 199 [10%] v 24 of 716 [3%]; P < .01). Incidence was similar in patients with melanoma and non-small-cell lung cancer (overall, 26 of 532 [5%] v nine of 209 [4%]; monotherapy, 15 of 417 v five of 152 [ P = 1.0]; combination, 11 of 115 v four of 57 [ P = .78]). Seventy-two percent (31 of 43) of cases were grade 1 to 2, and 86% (37 of 43) improved/resolved with drug holding/immunosuppression. Five patients worsened clinically and died during the course of pneumonitis treatment; proximal cause of death was pneumonitis (n = 1), infection related to immunosuppression (n = 3), or progressive cancer (n = 1). Radiologic and pathologic features of pneumonitis were diverse. Conclusion Pneumonitis associated with anti-PD-1/PD-L1 mAbs is a toxicity of variable onset and clinical, radiologic, and pathologic appearances. It is more common when anti-PD-1/PD-L1 mAbs are combined with anti-cytotoxic T-cell lymphocyte-4 mAb. Most events are low grade and improve/resolve with drug holding/immunosuppression. Rarely, pneumonitis worsens despite immunosuppression, and may result in infection and/or death.

Head and neck squamous cell carcinoma (HNSCC) is characterized by the 5-year survival rate of approximately 50%. Despite aggressive surgical, radiation, and chemotherapeutic interventions, 30% to 40% of patients die from the development of recurrent or disseminated disease that is resistant to chemotherapy. As a model of recurrence, we examined the effects of cisplatin on the ability of head and neck cancer cells to initiate tumors in a xenotransplant model. HNSCC cells were treated in vitro with cisplatin at a concentration that elicited >99% cytotoxicity and assessed for tumorigenic potential in nonobese diabetic/severe combined immunodeficient mice. HNSCC cells that survived cisplatin treatment formed tumors in nonobese diabetic/severe combined immunodeficient mice more efficiently than nontreated cells. Cisplatin-resistant cells were characterized using clonal analysis, in vivo imaging, and transcriptomic profiling. Preliminary functional assessment of a gene, interleukin-6 (IL-6), highly upregulated in cisplatin-treated cells was carried out using clonogenicity and tumorigenicity assays. We show that cisplatin-induced IL-6 expression can contribute to the increase in tumorigenic potential of head and neck cancer cells but does not contribute to cisplatin resistance. Finally, through clonal analysis, we show that cisplatin-induced IL-6 expression and cisplatin-induced tumorigenicity are stochastically derived. We report that cisplatin treatment of head and neck cancer cells results in a transient accumulation of cisplatin-resistant, small, and IL-6-positive cells that are highly tumorigenic. These data also suggest that therapies that reduce IL-6 action may reduce recurrence rates and/or increase disease-free survival times in head and neck cancer patients, and thus, IL-6 represents a promising new target in HNSCC treatment., ((c) 2010 AACR.)

Purpose: The standard of care for ovarian cancer includes platinum-based chemotherapy. It is not possible, however, to predict clinical platinum sensitivity or to design rational strategies to overcome resistance. We used a novel approach to identify altered gene expression associated with high sensitivity to cisplatin, to define novel targets to sensitize tumor cells to platins and ultimately improve the effectiveness of this widely used class of chemotherapeutics., Experimental Design: Using differential display PCR, we identified genes differentially expressed in a mutagenized cell line with unusual sensitivity to cisplatin. The most highly differentially expressed gene was selected, and its role in determining cisplatin sensitivity was validated by gene transfection and small interfering RNA (siRNA) approaches, by association of expression levels with cisplatin sensitivity in cell lines, and by association of tumor expression levels with survival in a retrospective cohort of 71 patients with serous ovarian adenocarcinoma., Results: The most highly differently expressed gene identified was ANKRD1, ankyrin repeat domain 1 (cardiac muscle). ANKRD1 mRNA levels were correlated with platinum sensitivity in cell lines, and most significantly, decreasing ANKRD1 using siRNA increased cisplatin sensitivity >2-fold. ANKRD1 was expressed in the majority of ovarian adenocarcinomas tested (62/71, 87%), and higher tumor levels of ANKRD1 were found in patients with worse outcome (overall survival, P=0.013)., Conclusions: These findings suggest that ANKRD1, a gene not previously associated with ovarian cancer or with response to chemotherapy, is associated with treatment outcome, and decreasing ANKRD1 expression, or function, is a potential strategy to sensitize tumors to platinum-based drugs.