Publications by authors named "Matteo S Carlino"

118 Publications

Risk of radiation necrosis after stereotactic radiosurgery for melanoma brain metastasis by anatomical location.

Strahlenther Onkol 2021 Jun 10. Epub 2021 Jun 10.

Royal Prince Alfred Hospital, Camperdown, NSW, Australia.

Purpose: In this retrospective study, we have explored the anatomical factors that lead to the development of radiation necrosis (RN) in the setting of stereotactic radiosurgery (SRS) for melanoma brain metastases (MBM).

Methods: Between 2014 and 2018, 137 patients underwent SRS for 311 MBM. Lesions were assessed according to anatomical zones: zone 1-peripheral grey-white matter junction and cortical mantle, zone 2-deep white matter, including tumours located at base of sulci, zone 3-tumours adjacent to ependymal lining or in deep locations such as brainstem, basal ganglia and thalamus. Other anatomical factors including lobes, medial-peripheral, supra or infratentorial locations were also recorded.

Results: In all, 12.4% (n = 17) of patients and 6.1% (n = 20) of lesions developed RN, actuarial incidence of RN at 12 and 24 months was 10% and 14.2% respectively. Zone 2 lesions recorded the highest rate of development of RN (n = 7/19; 36%), zone 3 (N = 4/24; 16%) and zone 1 (n = 9/268; 3%). Five of 17 patients developed symptomatic RN and 7/17 patients underwent surgery for RN.

Conclusion: This study raises awareness of the increased likelihood of deep lesions particularly in white matter structures to develop RN after SRS. Further studies including larger cohorts would be useful in identifying statistical differences in the rate of development of RN in different anatomical zones.
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http://dx.doi.org/10.1007/s00066-021-01798-xDOI Listing
June 2021

Immunotherapy in advanced Merkel cell carcinoma: Sydney west cancer network experience.

J Med Imaging Radiat Oncol 2021 May 30. Epub 2021 May 30.

Sydney Medical School, Faculty of Medicine and Health Sciences, University of Sydney, Camperdown, New South Wales, Australia.

Introduction: Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with no survival benefit demonstrated using palliative cytotoxic chemotherapy in the setting of metastatic MCC. Recently, immune checkpoint inhibitors (anti-PD-L1/PD1) have been approved in this setting after durable clinical response was demonstrated in several clinical trials. In this series, we present a multicentre real-world experience in using anti-PD-L1/PD1 in advanced MCC.

Methods: A retrospective review was performed of all patients with metastatic MCC who were treated with at least one dose of anti-PD-L1/PD1 presenting to Sydney West Cancer Network (Westmead, Nepean and Blacktown hospitals) was performed between 2016 and 2020. Treatment response was assessed based on morphologic and/or metabolic changes of the disease on FDG-PET/CT scans. Primary end point investigated was objective response rate. Secondary outcomes included therapy toxicity, disease control and overall survival.

Results: Thirteen patients received anti-PD-L1/PD1 with a median age of 82 (range 62-89). Two patients had undergone prior palliative chemotherapy. The median follow-up time was 17 months (range 2-34). The overall, complete and partial response rates were 77% (10), 54% (7) and 23% (3), respectively. Treatment-related grade 1 or 2 toxicity was experienced by 69% with only 2 cases of greater severity. The median progression-free survival and overall survival were 18 months (95% CI 10-26 months) and 33 months (95% CI range 7.6-58.4 months), respectively.

Conclusions: Consistent with clinical trial results, anti-PD-L1/PD1 therapy in this small series demonstrated efficacy and safety in patients with metastatic MCC.
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http://dx.doi.org/10.1111/1754-9485.13243DOI Listing
May 2021

Ipilimumab alone or ipilimumab plus anti-PD-1 therapy in patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy: a multicentre, retrospective, cohort study.

Lancet Oncol 2021 06 11;22(6):836-847. Epub 2021 May 11.

Melanoma Institute Australia, University of Sydney, Sydney, NSW, Australia; Royal North Shore Hospital, Sydney, NSW, Australia; Mater Hospital, Sydney, NSW, Australia. Electronic address:

Background: Anti-PD-1 therapy (hereafter referred to as anti-PD-1) induces long-term disease control in approximately 30% of patients with metastatic melanoma; however, two-thirds of patients are resistant and will require further treatment. We aimed to determine the efficacy and safety of ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab) compared with ipilimumab monotherapy in patients who are resistant to anti-PD-(L)1 therapy (hereafter referred to as anti-PD-[L]1).

Methods: This multicentre, retrospective, cohort study, was done at 15 melanoma centres in Australia, Europe, and the USA. We included adult patients (aged ≥18 years) with metastatic melanoma (unresectable stage III and IV), who were resistant to anti-PD-(L)1 (innate or acquired resistance) and who then received either ipilimumab monotherapy or ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab), based on availability of therapies or clinical factors determined by the physician, or both. Tumour response was assessed as per standard of care (CT or PET-CT scans every 3 months). The study endpoints were objective response rate, progression-free survival, overall survival, and safety of ipilimumab compared with ipilimumab plus anti-PD-1.

Findings: We included 355 patients with metastatic melanoma, resistant to anti-PD-(L)1 (nivolumab, pembrolizumab, or atezolizumab), who had been treated with ipilimumab monotherapy (n=162 [46%]) or ipilimumab plus anti-PD-1 (n=193 [54%]) between Feb 1, 2011, and Feb 6, 2020. At a median follow-up of 22·1 months (IQR 9·5-30·9), the objective response rate was higher with ipilimumab plus anti-PD-1 (60 [31%] of 193 patients) than with ipilimumab monotherapy (21 [13%] of 162 patients; p<0·0001). Overall survival was longer in the ipilimumab plus anti-PD-1 group (median overall survival 20·4 months [95% CI 12·7-34·8]) than with ipilimumab monotherapy (8·8 months [6·1-11·3]; hazard ratio [HR] 0·50, 95% CI 0·38-0·66; p<0·0001). Progression-free survival was also longer with ipilimumab plus anti-PD-1 (median 3·0 months [95% CI 2·6-3·6]) than with ipilimumab (2·6 months [2·4-2·9]; HR 0·69, 95% CI 0·55-0·87; p=0·0019). Similar proportions of patients reported grade 3-5 adverse events in both groups (59 [31%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 54 [33%] of 162 patients in the ipilimumab group). The most common grade 3-5 adverse events were diarrhoea or colitis (23 [12%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 33 [20%] of 162 patients in the ipilimumab group) and increased alanine aminotransferase or aspartate aminotransferase (24 [12%] vs 15 [9%]). One death occurred with ipilimumab 26 days after the last treatment: a colon perforation due to immune-related pancolitis.

Interpretation: In patients who are resistant to anti-PD-(L)1, ipilimumab plus anti-PD-1 seemed to yield higher efficacy than ipilimumab with a higher objective response rate, longer progression-free, and longer overall survival, with a similar rate of grade 3-5 toxicity. Ipilimumab plus anti-PD-1 should be favoured over ipilimumab alone as a second-line immunotherapy for these patients with advanced melanoma.

Funding: None.
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http://dx.doi.org/10.1016/S1470-2045(21)00097-8DOI Listing
June 2021

The role of local therapy in the treatment of solitary melanoma progression on immune checkpoint inhibition: A multicentre retrospective analysis.

Eur J Cancer 2021 Jul 7;151:72-83. Epub 2021 May 7.

Department of Medical Oncology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; Department of Internal Medicine, Leiden University Medical Center, Albinusdreef 2, 2333 AZ Leiden, the Netherlands.

Introduction: In patients with metastatic melanoma, progression of a single tumour lesion (solitary progression) after response to immune checkpoint inhibition (ICI) is increasingly treated with local therapy. We evaluated the role of local therapy for solitary progression in melanoma.

Patients And Methods: Patients with metastatic melanoma treated with ICI between 2010 and 2019 with solitary progression as first progressive event were included from 17 centres in 9 countries. Follow-up and survival are reported from ICI initiation.

Results: We identified 294 patients with solitary progression after stable disease in 15%, partial response in 55% and complete response in 30%. The median follow-up was 43 months; the median time to solitary progression was 13 months, and the median time to subsequent progression after treatment of solitary progression (TTSP) was 33 months. The estimated 3-year overall survival (OS) was 79%; median OS was not reached. Treatment consisted of systemic therapy (18%), local therapy (36%), both combined (42%) or active surveillance (4%). In 44% of patients treated for solitary progression, no subsequent progression occurred. For solitary progression during ICI (n = 143), the median TTSP was 29 months. Both TTSP and OS were similar for local therapy, ICI continuation and both combined. For solitary progression post ICI (n = 151), the median TTSP was 35 months. TTSP was higher for ICI recommencement plus local therapy than local therapy or ICI recommencement alone (p = 0.006), without OS differences.

Conclusion: Almost half of patients with melanoma treated for solitary progression after initial response to ICI had no subsequent progression. This study suggests that local therapy can benefit patients and is associated with favourable long-term outcomes.
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http://dx.doi.org/10.1016/j.ejca.2021.04.003DOI Listing
July 2021

Combination anti-PD1 and ipilimumab therapy in patients with advanced melanoma and pre-existing autoimmune disorders.

J Immunother Cancer 2021 May;9(5)

Department of Medical Oncology, Westmead and Blacktown Hospital, New South Wales, New South Wales, Australia

Background: Clinical trials of immunotherapy have excluded patients with pre-existing autoimmune disease. While the safety and efficacy of single agent ipilimumab and anti-PD1 antibodies in patients with autoimmune disease has been examined in retrospective studies, no data are available for combination therapy which has significantly higher toxicity risk. We sought to establish the safety and efficacy of combination immunotherapy for patients with advanced melanoma and pre-existing autoimmune diseases.

Methods: We performed a retrospective study of patients with advanced melanoma and pre-existing autoimmune disease who received combination ipilimumab and anti-PD1 at 10 international centers from March 2015 to February 2020. Data regarding the autoimmune disease, treatment, toxicity and outcomes were examined in patients.

Results: Of the 55 patients who received ipilimumab and anti-PD1, the median age was 63 years (range 23-83). Forty-six were treated with ipilimumab and nivolumab and nine with ipilimumab and pembrolizumab.Eighteen patients (33%) had a flare of their autoimmune disease including 4 of 7 with rheumatoid arthritis, 3 of 6 with psoriasis, 5 of 10 with inflammatory bowel disease, 3 of 19 with thyroiditis, 1 of 1 with Sjogren's syndrome, 1 of 1 with polymyalgia and 1 of 1 with Behcet's syndrome and psoriasis. Eight (44%) patients ceased combination therapy due to flare. Thirty-seven patients (67%) had an unrelated immune-related adverse event (irAE), and 20 (36%) ceased combination immunotherapy due to irAEs. There were no treatment-related deaths. Patients on immunosuppression (OR 4.59; p=0.03) had a higher risk of flare.The overall response rate was 55%, with 77% of responses ongoing. Median progression free survival and overall survival were 10 and 24 months, respectively. Patients on baseline immunosuppression had an overall survival of 11 months (95% CI 3.42 to 18.58) compared with 31 months without (95% CI 20.89 to 41.11, p=0.005).

Conclusions: In patients with pre-existing autoimmune disease, not on immunosuppression and advanced melanoma, combination ipilimumab and anti-PD1 has similar efficacy compared with previously reported trials. There is a risk of flare of pre-existing autoimmune disorders, particularly in patients with inflammatory bowel disease and rheumatologic conditions, and patients on baseline immunosuppression.
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http://dx.doi.org/10.1136/jitc-2020-002121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108669PMC
May 2021

Evaluation of TMB as a predictive biomarker in patients with solid cancers treated with anti-PD-1/CTLA-4 combination immunotherapy.

Cancer Cell 2021 May 29;39(5):592-593. Epub 2021 Apr 29.

Olivia Newton-John Cancer Research Institute, Melbourne, Australia; School of Cancer Medicine, La Trobe University, Australia.

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http://dx.doi.org/10.1016/j.ccell.2021.04.005DOI Listing
May 2021

Circulating Tumor DNA Reflects Uveal Melanoma Responses to Protein Kinase C Inhibition.

Cancers (Basel) 2021 Apr 6;13(7). Epub 2021 Apr 6.

Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia.

The prognosis for patients with UM is poor, and recent clinical trials have failed to prolong overall survival (OS) of these patients. Over 95% of UM harbor activating driver mutations, and this allows for the investigation of ctDNA. In this study, we investigated the value of ctDNA for adaptive clinical trial design in metastatic UM. Longitudinal plasma samples were analyzed for ctDNA in 17 metastatic UM patients treated with PKCi-based therapy in a phase 1 clinical trial setting. Plasma ctDNA was assessed using digital droplet PCR (ddPCR) and a custom melanoma gene panel for targeted next generation sequencing (NGS). Baseline ctDNA strongly correlated with baseline lactate dehydrogenase (LDH) ( < 0.001) and baseline disease burden ( = 0.002). Early during treatment (EDT) ctDNA accurately predicted patients with clinical benefit to PKCi using receiver operator characteristic (ROC) curves (AUC 0.84, [95% confidence interval 0.65-1.0, = 0.026]). Longitudinal ctDNA assessment was informative for establishing clinical benefit and detecting disease progression with 7/8 (88%) of patients showing a rise in ctDNA and targeted NGS of ctDNA revealed putative resistance mechanisms prior to radiological progression. The inclusion of longitudinal ctDNA monitoring in metastatic UM can advance adaptive clinical trial design.
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http://dx.doi.org/10.3390/cancers13071740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038771PMC
April 2021

Combination immunotherapy with ipilimumab and nivolumab in patients with advanced adrenocortical carcinoma: a subgroup analysis of CA209-538.

Oncoimmunology 2021 Apr 12;10(1):1908771. Epub 2021 Apr 12.

Department of Medical Oncology, Austin Health, Melbourne, Australia.

: Adrenocortical carcinoma is a rare malignancy, with poor prognosis and limited treatment options for patients with advanced disease. Chemotherapy is the current standard first-line treatment, providing only a modest survival benefit. There is only limited treatment experience with immunotherapy using single-agent anti-PD-1/PD-L1 therapy. To date no clinical trials have been reported using combination immunotherapy with anti-CTLA-4 and anti-PD-1 blockade in this patient population. : CA209-538 is a prospective multicentre clinical trial in patients with advanced rare cancers. Participants received the anti-PD-1 antibody nivolumab (3 mg/kg IV) and the anti-CTLA-4 antibody ipilimumab (1 mg/kg IV) every three weeks for four doses, followed by nivolumab (3 mg/kg IV) every two weeks and continued for up to 96 weeks, until disease progression or unacceptable toxicity. Response was assessed every 12 weeks by RECIST version 1.1. Primary endpoint was clinical benefit rate (complete response, partial response, stable disease at 12 weeks). : Six patients with adrenocortical carcinoma were enrolled and received treatment. Two patients (33%) have an ongoing partial response (10 and 25 months +) and two patients (33%) stable disease leading to a disease control rate of 66%. Both responders had tumors with a microsatellite instable phenotype. One patient rapidly progressed shortly after enrollment into the trial and did not undergo restaging. Immunotherapy-related toxicity was reported in all patients, with four patients (67%) experiencing grade 3/4 hepatitis leading to discontinuation of treatment. : This is the first treatment experience using ipilimumab and nivolumab combination immunotherapy in patients with advanced adrenocortical carcinoma. Durable responses have been observed in a subset of patients suggesting that this treatment regimen should be further investigated in this patient population.
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http://dx.doi.org/10.1080/2162402X.2021.1908771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043165PMC
April 2021

Thyroid immune-related adverse events following immune checkpoint inhibitor treatment.

J Clin Endocrinol Metab 2021 Apr 20. Epub 2021 Apr 20.

Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.

Background: Thyroid dysfunction occurs commonly following immune checkpoint inhibition. The etiology of thyroid immune-related adverse events (irAEs) remains unclear and clinical presentation can be variable. This study sought to define thyroid irAEs following immune checkpoint inhibitor (ICI) treatment and describe their clinical and biochemical associations.

Methods: We performed a retrospective cohort study of thyroid dysfunction in patients with melanoma undergoing CTLA-4 and/or PD-1 based ICI treatment from Nov 1, 2009 to Dec 31, 2019. Thyroid function was measured at baseline and at regular intervals following the start of ICI-treatment. Clinical and biochemical features were evaluated for associations with ICI-associated thyroid irAEs. The prevalence of thyroid autoantibodies and the effect of thyroid irAEs on survival were analysed.

Results: A total of 1246 patients were included with a median follow-up of 11.3 months. 518 (42%) patients developed an ICI-associated thyroid irAE. Subclinical thyrotoxicosis (n=234) was the most common thyroid irAE, followed by overt thyrotoxicosis (n=154), subclinical hypothyroidism (n=61), and overt hypothyroidism (n=39). Onset of overt thyrotoxicosis occurred a median of 5 weeks (IQR 2-8) after receipt of first dose of ICI. Combination immunotherapy was strongly associated with development of overt thyrotoxicosis (OR 10.8, 95% CI 4.51-25.6 vs. CTLA-4 monotherapy; p<0.001), as was female sex (OR 2.02, 95% CI 1.37-2.95; p<0.001) and younger age (OR 0.83 per 10-years, 95% CI 0.72-0.95; p=0.007). By comparison, median onset of overt hypothyroidism was 14 weeks (IQR 8-25). The frequency of overt hypothyroidism did not differ between different ICI-types. The strongest associations for hypothyroidism were higher baseline TSH (OR 2.33 per mIU/L, 95% CI 1.61-3.33; p<0.001) and female sex (OR 3.31, 95% CI 1.67-6.56; p=0.01). Overt thyrotoxicosis was associated with longer progression free survival (HR 0.68, 95% CI 0.49-0.94; p=0.02) and overall survival (HR 0.57, 95% CI 0.39-0.84; p=0.005). There was no association between hypothyroidism and cancer outcomes.

Conclusions: Thyroid irAEs are common and there are multiple distinct phenotypes. Different thyroid irAE subtypes have unique clinical and biochemical associations, suggesting potentially distinct etiologies for thyrotoxicosis and hypothyroidism arising in this context.
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http://dx.doi.org/10.1210/clinem/dgab263DOI Listing
April 2021

Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): health-related quality-of-life results from a double-blind, randomised, controlled, phase 3 trial.

Lancet Oncol 2021 05 12;22(5):655-664. Epub 2021 Apr 12.

EORTC Headquarters, Brussels, Belgium.

Background: The European Organisation for Research and Treatment of Cancer (EORTC) 1325-MG/KEYNOTE-054 trial in patients with resected, high-risk stage III melanoma demonstrated improved recurrence-free survival with adjuvant pembrolizumab compared with placebo (hazard ratio 0·57 [98·4% CI 0·43-0·74]; p<0·0001). This study reports the results from the health-related quality-of-life (HRQOL) exploratory endpoint.

Methods: This double-blind, randomised, controlled, phase 3 trial was done at 123 academic centres and community hospitals across 23 countries. Patients aged 18 years or older with previously untreated histologically confirmed stage IIIA, IIIB, or IIIC resected cutaneous melanoma, and an Eastern Cooperative Oncology Group performance status score of 1 or 0 were eligible. Patients were randomly assigned (1:1) using a central interactive voice-response system on the basis of a minimisation technique stratified for stage and geographic region to receive intravenously 200 mg pembrolizumab or placebo. Treatment was administered every 3 weeks for 1 year, or until disease recurrence, unacceptable toxicity, or death. The primary endpoint of the trial was recurrence-free survival (reported elsewhere). HRQOL was a prespecified exploratory endpoint, with global health/quality of life (GHQ) over 2 years measured by the EORTC QLQ-C30 as the primary analysis. Analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37, and long-term follow-up is ongoing.

Findings: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to pembrolizumab (n=514) or placebo (n=505). Median follow-up was 15·1 months (IQR 12·8-16·9) at the time of this analysis. HRQOL compliance was greater than 90% at baseline, greater than 70% during the first year, and greater than 60% thereafter for both groups. Because of low absolute compliance numbers at later follow-up, the analysis was truncated to week 84. Baseline GHQ scores were similar between groups (77·55 [SD 18·20] in the pembrolizumab group and 76·54 [17·81] in the placebo group) and remained stable over time. The difference in average GHQ score between the two groups over the 2 years was -2·2 points (95% CI -4·3 to -0·2). The difference in average score during treatment was -1·1 points (95% CI -3·2 to 0·9) and the difference in average score after treatment was -2·2 points (-4·8 to 0·4). These differences are within the 5-point clinical relevance threshold for the QLQ-C30 and are therefore clinically non-significant.

Interpretation: Pembrolizumab does not result in a clinically significant decrease in HRQOL compared with placebo when given as adjuvant therapy for patients with resected, high-risk stage III melanoma. These results support the use of adjuvant pembrolizumab in this setting.

Funding: Merck Sharp & Dohme.
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http://dx.doi.org/10.1016/S1470-2045(21)00081-4DOI Listing
May 2021

Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial.

Lancet Oncol 2021 05 12;22(5):643-654. Epub 2021 Apr 12.

EORTC Headquarters, Brussels, Belgium.

Background: The European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial assessed pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. At 15-month median follow-up, pembrolizumab improved recurrence-free survival (hazard ratio [HR] 0·57 [98·4% CI 0·43-0·74], p<0·0001) compared with placebo, leading to its approval in the USA and Europe. This report provides the final results for the secondary efficacy endpoint, distant metastasis-free survival and an update of the recurrence-free survival results.

Methods: This double-blind, randomised, controlled, phase 3 trial was done at 123 academic centres and community hospitals across 23 countries. Patients aged 18 years or older with complete resection of cutaneous melanoma metastatic to lymph node, classified as American Joint Committee on Cancer staging system, seventh edition (AJCC-7) stage IIIA (at least one lymph node metastasis >1 mm), IIIB, or IIIC (without in-transit metastasis), and with an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) via a central interactive voice response system to receive intravenous pembrolizumab 200 mg or placebo every 3 weeks for up to 18 doses or until disease recurrence or unacceptable toxicity. Randomisation was stratified according to disease stage and region, using a minimisation technique, and clinical investigators, patients, and those collecting or analysing the data were masked to treatment assignment. The two coprimary endpoints were recurrence-free survival in the intention-to-treat (ITT) population and in patients with PD-L1-positive tumours. The secondary endpoint reported here was distant metastasis-free survival in the ITT and PD-L1-positive populations. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37.

Findings: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to receive either pembrolizumab (n=514) or placebo (n=505). At an overall median follow-up of 42·3 months (IQR 40·5-45·9), 3·5-year distant metastasis-free survival was higher in the pembrolizumab group than in the placebo group in the ITT population (65·3% [95% CI 60·9-69·5] in the pembrolizumab group vs 49·4% [44·8-53·8] in the placebo group; HR 0·60 [95% CI 0·49-0·73]; p<0·0001). In the 853 patients with PD-L1-positive tumours, 3·5-year distant metastasis-free survival was 66·7% (95% CI 61·8-71·2) in the pembrolizumab group and 51·6% (46·6-56·4) in the placebo group (HR 0·61 [95% CI 0·49-0·76]; p<0·0001). Recurrence-free survival remained longer in the pembrolizumab group 59·8% (95% CI 55·3-64·1) than the placebo group 41·4% (37·0-45·8) at this 3·5-year follow-up in the ITT population (HR 0·59 [95% CI 0·49-0·70]) and in those with PD-L1-positive tumours 61·4% (56·3-66·1) in the pembrolizumab group and 44·1% (39·2-48·8) in the placebo group (HR 0·59 [95% CI 0·49-0·73]).

Interpretation: Pembrolizumab adjuvant therapy provided a significant and clinically meaningful improvement in distant metastasis-free survival at a 3·5-year median follow-up, which was consistent with the improvement in recurrence-free survival. Therefore, the results of this trial support the indication to use adjuvant pembrolizumab therapy in patients with resected high risk stage III cutaneous melanoma.

Funding: Merck Sharp & Dohme.
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http://dx.doi.org/10.1016/S1470-2045(21)00065-6DOI Listing
May 2021

Immune-Checkpoint Inhibitors for Advanced Hepatocellular Carcinoma: A Synopsis of Response Rates.

Oncologist 2021 Apr 5. Epub 2021 Apr 5.

Blacktown Clinical School, Western Sydney University, Sydney, New South Wales, Australia.

Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide. A first-line standard of care, sorafenib results in median overall survival of 12 months in patients with Child-Pugh class A disease and 6 months in patients with Child-Pugh class B disease with objective response rates (ORRs) not exceeding 19%. These low efficacy rates have driven research on alternative therapeutic options, particularly immune-checkpoint inhibitors (ICIs). We reviewed the response rates (estimated by RECIST 1.1 criteria) across patients with advanced HCC treated with ICIs in phase I-IV clinical trials published between December 2012 to December 2020; 17 reports were identified as eligible and included in the quantitative analysis. Within the selected studies, pembrolizumab + lenvatinib reached the highest absolute ORR (36%), with first-line atezolizumab + bevacizumab showing the second highest ORR (27.3%). With regard to second-line therapy, nivolumab + ipilimumab reached an ORR of 32%, and pembrolizumab alone resulted in an ORR of 17% among sorafenib-experienced patients with advanced HCC. In summary, current studies show high response rates of ICIs in patients with advanced HCC. Nonetheless, further studies are required in the second-line setting to further evaluate ICI therapeutic superiority. Finally, it is of particular interest to examine the therapeutic potential of ICIs for patients with decompensated liver disease (Child-Pugh class C), currently not eligible for any systemic therapy. IMPLICATIONS FOR PRACTICE: Immune-checkpoint inhibitors (ICIs) can provide high objective response rates (ORR, estimated with RECIST 1.1. criteria) when used as first-line treatment in advanced hepatocellular carcinoma, particularly pembrolizumab + lenvatinib (ORR 36%) or atezolizumab + bevacizumab (ORR 27.3%). In sorafenib-experienced patients, nivolumab + ipilimumab (ORR 32%) provided the highest ORR among ICI-based regimens. These findings emphasize high therapeutic potential of ICI-based therapies in patients with advanced hepatocellular carcinoma, although further studies are required to further validate and define their role in this context.
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http://dx.doi.org/10.1002/onco.13776DOI Listing
April 2021

Chronic Immune-Related Adverse Events Following Adjuvant Anti-PD-1 Therapy for High-risk Resected Melanoma.

JAMA Oncol 2021 May;7(5):744-748

Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.

Importance: Agents targeting programmed cell death 1 (PD-1)/PD ligand 1 (PD-L1) improve long-term survival across many advanced cancers and are now used as adjuvant therapy for resected stage III and IV melanomas. The incidence and spectrum of chronic immune-related adverse events (irAEs) have not been well defined.

Objective: To determine the incidence, time course, spectrum, and associations of chronic irAEs arising from adjuvant anti-PD-1 therapy.

Design, Setting, And Participants: This retrospective multicenter cohort study was conducted between 2015 and 2020 across 8 academic medical centers in the United States and Australia. Patients with stage III to IV melanomas treated with anti-PD-1 in the adjuvant setting were included.

Main Outcomes And Measures: Incidence, types, and time course of chronic irAEs (defined as irAEs persisting at least 12 weeks after therapy cessation).

Results: Among 387 patients, the median (range) age was 63 (17-88) years, and 235 (60.7%) were male. Of these patients, 267 (69.0%) had any acute irAE, defined as those arising during treatment with anti-PD-1, including 52 (19.5%) with grades 3 through 5 events; 1 patient each had fatal myocarditis and neurotoxicity. Chronic irAEs, defined as those that persisted beyond 12 weeks of anti-PD-1 discontinuation, developed in 167 (43.2%) patients, of which most (n = 161; 96.4%) were mild (grade 1 or 2) and most persisted until last available follow-up (n = 143; 85.6%). Endocrinopathies (73 of 88; 83.0%), arthritis (22 of 45; 48.9%), xerostomia (9 of 17; 52.9%), neurotoxicities (11 of 15; 73.3%), and ocular events (5 of 8; 62.5%) were particularly likely to become chronic. In contrast, irAEs affecting visceral organs (liver, colon, lungs, kidneys) had much lower rates of becoming chronic irAEs; for example, colitis became chronic in 6 of 44 (13.6%) cases, of which 4 of 6 (66.7%) resolved with prolonged follow-up. Age, gender, time of onset, and need for steroids were not associated with the likelihood of chronicity of irAEs.

Conclusion And Relevance: In this multicenter cohort study, chronic irAEs associated with anti-PD-1 therapy appear to be more common than previously recognized and frequently persisted even with prolonged follow-up, although most were low grade. The risks of chronic irAEs should be integrated into treatment decision-making.
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http://dx.doi.org/10.1001/jamaoncol.2021.0051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995124PMC
May 2021

Hematological immune related adverse events after treatment with immune checkpoint inhibitors.

Eur J Cancer 2021 Apr 9;147:170-181. Epub 2021 Mar 9.

Department of Dermatology, University Hospital Kiel, Kiel, Germany.

Introduction: With the increasing use of checkpoint inhibitors, rare immune-related adverse events (irAE) are being identified. Haematological irAE (hem-irAE) are difficult to treat and have shown high mortality rates. In order to improve side-effect management for these potentially life-threatening events, we analysed frequency, severity and outcomes.

Patients And Methods: Patients who developed hem-irAE while being treated with immune checkpoint inhibitors (ICI) therapy were retrospectively identified from 18 international cancer centres.

Results: In total, more than 7626 patients treated with ICI were screened, and 50 patients with hem-irAE identified. The calculated incidence amounts to 0.6% and median onset was 6 weeks after the ICI initiation (range 1-128 weeks). Thrombocytopenia and leucopaenia were the most frequent hem-irAE with 34% (17/50) and 34% (17/50), respectively, followed by anaemia 28% (14/50), hemophagocytic lymphohistiocytosis (4% (2/50)), aplastic anaemia (2% (1/50)), acquired haemophilia A (2% (1/50)) and coagulation deficiency (2% (1/50)). Simultaneous thrombocytopenia and neutropenia occurred in two patients, concurrent anaemia and thrombocytopenia in one patient. Other than cessation of ICI (in 60%) and corticosteroids (in 78%), treatment included second-line immunosuppression in 24% of cases. Events resolved in 78% (39/50), while 18% (9/50) had persistent changes, and 2% (1/50) had fatal outcomes (agranulocytosis).

Conclusion: Hem-irAE can affect all haematopoietic blood cell lineages and may persist or even be fatal. Management may require immunosuppression beyond corticosteroids. Although these irAE are rare, treating physicians should be aware, monitor blood counts regularly and promptly act upon detection.
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http://dx.doi.org/10.1016/j.ejca.2021.01.013DOI Listing
April 2021

Reply to E. Hindié.

J Clin Oncol 2021 Mar 25;39(8):944-946. Epub 2021 Jan 25.

Alexander M. M. Eggermont, MD, PhD, Princess Máxima Center, Utrecht, the Netherlands; Christian U. Blank, MD, PhD, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, the Netherlands; Mario Mandala, MD, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy; Georgina V. Long, BSc, MBBS, Melanoma Institute Australia, The University of Sydney, and Mater and Royal North Shore Hospitals, Sydney, New South Wales, Australia; Victoria G. Atkinson, MBBS, Princess Alexandra Hospital, Brisbane, Queensland, Australia; St 00B4ephane Dalle, MD, PhD, Hospices Civils de Lyon Cancer Institute, Lyon, France; Andrew M. Haydon, MBBS, PhD, Alfred Hospital, Melbourne, Victoria, Australia; Andrey Meshcheryakov, MD, PhD, N.N. Blokhin Cancer Research Center, Moscow, Russian Federation; Adnan Khattak, MD, Fiona Stanley Hospital and Edith Cowan University, Perth, Western Australia, Australia; Matteo S. Carlino, BMedSc, MBBS, Westmead and Blacktown Hospitals, Melanoma Institute Australia, and The University of Sydney, Sydney, New South Wales, Australia; Shahneen Sandhu, MD, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; James Larkin, PhD, Royal Marsden Hospital, London, United Kingdom; Susana Puig, MD, PhD, Hospital Clinic Universitari de Barcelona, Barcelona, Spain; Paolo A. Ascierto, MD, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale," Naples, Italy; Piotr Rutkowski, MD, PhD, Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw, Poland; Dirk Schadendorf, MD, PhD, University Hospital Essen, Essen, Germany; German Cancer Consortium, Heidelberg, Germany; Rutger Koornstra, MD, PhD, Radboud University Medical Center Nijmegen, Nijmegen, the Netherlands; Leonel Hernandez-Aya, MD, Washington University School of Medicine, St Louis, MO; Anna Maria Di Giacomo, MD, Center for Immuno-Oncology, University Hospital of Siena, Siena, Italy; Alfonsus J. M. van den Eertwegh, MD, PhD, Amsterdam University Medical Center, location VUMC, Amsterdam, the Netherlands; Jean-Jacques Grob, MD, Aix Marseille University, Hôpital de la Timone, Marseille, France; Ralf Gutzmer, MD, Skin Cancer Center, Hannover Medical School, Hanover, Germany; Rahima Jamal, MD, BSc, Centre Hospitalier de l'Université de Montreal (CHUM), Centre de recherche du CHUM, Montreal, Quebec, Canada; Paul C. Lorigan, MD, Christie NHS Foundation Trust, Manchester, United Kingdom; Alexander C. J. van Akkooi, MD, PhD, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, the Netherlands; Clemens Krepler, MD, Merck & Co, Inc, Kenilworth, NJ; Nageatte Ibrahim, MD, Merck & Co, Inc, Kenilworth, NJ; Sandrine Marreaud, MD, European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium; Michal Kicinski, PhD, European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium; Stefan Suciu, PhD, European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium; and Caroline Robert, MD, PhD, Gustave Roussy and Paris-Saclay University, Villejuif, France.

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http://dx.doi.org/10.1200/JCO.20.03463DOI Listing
March 2021

Clinical impact of COVID-19 on patients with cancer treated with immune checkpoint inhibition.

J Immunother Cancer 2021 01;9(1)

European Institute of Oncology, Milan, Italy.

Background: Patients with cancer who are infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are more likely to develop severe illness and die compared with those without cancer. The impact of immune checkpoint inhibition (ICI) on the severity of COVID-19 illness is unknown. The aim of this study was to investigate whether ICI confers an additional risk for severe COVID-19 in patients with cancer.

Methods: We analyzed data from 110 patients with laboratory-confirmed SARS-CoV-2 while on treatment with ICI without chemotherapy in 19 hospitals in North America, Europe and Australia. The primary objective was to describe the clinical course and to identify factors associated with hospital and intensive care (ICU) admission and mortality.

Findings: Thirty-five (32%) patients were admitted to hospital and 18 (16%) died. All patients who died had advanced cancer, and only four were admitted to ICU. COVID-19 was the primary cause of death in 8 (7%) patients. Factors independently associated with an increased risk for hospital admission were ECOG ≥2 (OR 39.25, 95% CI 4.17 to 369.2, p=0.0013), treatment with combination ICI (OR 5.68, 95% CI 1.58 to 20.36, p=0.0273) and presence of COVID-19 symptoms (OR 5.30, 95% CI 1.57 to 17.89, p=0.0073). Seventy-six (73%) patients interrupted ICI due to SARS-CoV-2 infection, 43 (57%) of whom had resumed at data cut-off.

Interpretation: COVID-19-related mortality in the ICI-treated population does not appear to be higher than previously published mortality rates for patients with cancer. Inpatient mortality of patients with cancer treated with ICI was high in comparison with previously reported rates for hospitalized patients with cancer and was due to COVID-19 in almost half of the cases. We identified factors associated with adverse outcomes in ICI-treated patients with COVID-19.
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http://dx.doi.org/10.1136/jitc-2020-001931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817383PMC
January 2021

Long-term safety of pembrolizumab monotherapy and relationship with clinical outcome: A landmark analysis in patients with advanced melanoma.

Eur J Cancer 2021 Feb 24;144:182-191. Epub 2020 Dec 24.

Melanoma Institute Australia, The University of Sydney, 40 Rocklands Rd, Wollstonecraft, NSW, 2065, Australia; Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, 610 University Ave, Toronto, ON, M5G2C1, Canada; The Kinghorn Cancer Centre at St Vincent's Hospital, 370 Victoria St, Darlinghurst, NSW, 2010, Australia; St Vincent's Clinical School, UNSW Sydney, Victoria St, Darlinghurst, NSW, 2010, Australia. Electronic address:

Objective: Long-term safety of pembrolizumab in melanoma was analyzed in KEYNOTE-001, KEYNOTE-002, and KEYNOTE-006.

Patients And Methods: Analysis involved patients who received ≥1 pembrolizumab dose. Lead-time bias was addressed via landmark analyses in patients who were progression-free before day 147.

Results: Adverse events (AEs) were analyzed for 1567 patients (median follow-up, 42.4 months). Most AEs were mild/moderate; grade 3/4 treatment-related AEs occurred in 17.7% of patients. Two pembrolizumab-related deaths occurred. Any-grade immune-mediated AEs (imAEs) occurred in 23.0%, most commonly hypothyroidism (9.1%), pneumonitis (3.3%), and hyperthyroidism (3.0%); grade 3/4 imAEs occurred in 6.9% of patients. Most imAEs occurred within 16 weeks of treatment. In landmark analysis, patients who did (n = 79) versus did not (n = 384) develop imAEs had similar objective response rates (ORRs) (64.6% versus 63.0%); median time to response (TTR), 5.6 months for both; median duration of response (DOR), 20.0 versus 25.3 months; median progression-free survival (PFS), 17.0 versus 17.7 months; median overall survival (OS), not reached (NR) versus 43 months (p = 0.1104). Patients who did (n = 17) versus did not (n = 62) receive systemic corticosteroids had similar ORRs (70.6% vs. 62.9%) and median TTR (6.4 vs. 5.6 months) but numerically shorter median PFS (9.9 vs. 17.0 months); median DOR, 14.2 months versus NR; median OS, NR for both.

Conclusions: These results enhance the knowledge base for pembrolizumab in advanced melanoma, with no new toxicity signals after lengthy follow-up of a large population. In landmark analyses, pembrolizumab efficacy was similar regardless of imAEs or systemic corticosteroid use.

Clinical Trial Registry: NCT01295827, NCT01704287, NCT01866319.
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http://dx.doi.org/10.1016/j.ejca.2020.11.010DOI Listing
February 2021

Dosing of BRAK and MEK Inhibitors in Melanoma: No Point in Taking a Break.

Cancer Cell 2020 12;38(6):779-781

Faculty of Medicine, Health and Human Sciences, Macquarie University, NSW, Australia; Melanoma Institute Australia, NSW, Australia. Electronic address:

Resistance to BRAF/MEK inhibitor treatment occurs in most patients with advanced BRAF-mutant melanoma. Intermittent drug dosing had been proposed as a strategy to circumvent resistance. In a clinical trial published in Nature Medicine, continuous dosing of BRAF/MEK inhibitors produced superior progression-free survival compared to intermittent dosing in BRAF-mutant melanoma patients.
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http://dx.doi.org/10.1016/j.ccell.2020.11.010DOI Listing
December 2020

Circulating tumour DNA and melanoma survival: A systematic literature review and meta-analysis.

Crit Rev Oncol Hematol 2021 Jan 27;157:103187. Epub 2020 Nov 27.

Cancer Risk Factors and Lifestyle Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Florence, Italy. Electronic address:

We reviewed and meta-analysed the available evidence (until December 2019) about circulating tumour DNA (ctDNA) levels and melanoma patients survival. We included twenty-six studies (>2000 patients overall), which included mostly stage III-IV cutaneous melanoma patients and differed widely in terms of systemic therapy received and somatic mutations that were searched. Patients with detectable ctDNA before treatment had worse progression-free survival (PFS) (summary hazard ratio (SHR) 2.47, 95 % confidence intervals (CI) 1.85-3.29) and overall survival (OS) (SHR 2.98, 95 % CI 2.26-3.92), with no difference by tumour stage. ctDNA detectability during follow-up was associated with poorer PFS (SHR 4.27, 95 %CI 2.75-6.63) and OS (SHR 3.91, 95 %CI 1.97-7.78); in the latter case, the association was stronger (p = 0.01) for stage IV vs. III melanomas. Between-estimates heterogeneity was low for all pooled estimates. ctDNA is a strong prognostic biomarker for advanced-stage melanoma patients, robust across tumour (e.g. genomic profile) and patients (e.g. systemic therapy) characteristics.
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http://dx.doi.org/10.1016/j.critrevonc.2020.103187DOI Listing
January 2021

Detection of splicing variants in plasma-derived cell-free nucleic acids and extracellular vesicles of melanoma patients failing targeted therapy therapies.

Oncotarget 2020 Nov 3;11(44):4016-4027. Epub 2020 Nov 3.

School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia.

The analysis of plasma circulating tumour nucleic acids provides a non-invasive approach to assess disease burden and the genetic evolution of tumours in response to therapy. splicing variants are known to confer melanoma resistance to BRAF inhibitors. We developed a test to screen cell-free RNA (cfRNA) for the presence of splicing variants. Custom droplet digital PCR assays were designed for the detection of splicing variants p61, p55, p48 and p41 and then validated using RNA from cell lines carrying these variants. Evaluation of plasma from patients with reported objective response to BRAF/MEK inhibition followed by disease progression was revealed by increased circulating tumour DNA (ctDNA) in 24 of 38 cases at the time of relapse. Circulating splicing variants were detected in cfRNA from 3 of these 38 patients; two patients carried the BRAF p61 variant and one the p55 variant. In all three cases the presence of the splicing variant was apparent only at the time of progressive disease. p61 was also detectable in plasma of one of four patients with confirmed splicing variants in their progressing tumours. Isolation and analysis of RNA from extracellular vesicles (EV) from resistant cell lines and patient plasma demonstrated that splicing variants are associated with EVs. These findings indicate that in addition to plasma ctDNA, RNA carried by EVs can provide important tumour specific information.
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http://dx.doi.org/10.18632/oncotarget.27790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646833PMC
November 2020

Management of melanoma brain metastases: Evidence-based clinical practice guidelines by Cancer Council Australia.

Eur J Cancer 2021 01 15;142:10-17. Epub 2020 Nov 15.

Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; Department of Medical Oncology, Royal North Shore Hospital, NSW, Australia.

Introduction: The brain is a common site of metastatic disease for patients with advanced melanoma. Brain metastasis portends a poor prognosis, often causing deterioration in neurological function and quality of life, and leading to neurological death. Treatment approaches including surgery, radiotherapy and systemic therapy can lead to better control of this problem. Therefore, appropriate guidelines for the management of melanoma brain metastases need to be established, with regular updating when new treatment options become available.

Methods: A multidisciplinary working party established by Cancer Council Australia has produced up-to-date, evidence-based clinical practice guidelines for the management of melanoma. After selecting key clinical questions, a comprehensive literature search for relevant studies was conducted, followed by systematic review of those studies. Data were summarised and the evidence was assessed, leading to the development of recommendations.

Main Recommendations: Symptomatic lesions are best treated with surgery, when possible; this provides safe and effective local control. For patients with single or a small number of asymptomatic brain metastases, stereotactic radiotherapy is recommended, but in asymptomatic patients who have not previously received systemic treatment, drug therapy can be considered as a first-line treatment option. Whole brain radiotherapy may provide palliative benefits in patients with multiple brain metastases. Whenever possible, melanoma patients with brain metastases should be managed by a multidisciplinary team of melanoma specialists that considers the optimal combination and sequencing of surgery, radiotherapy and systemic therapy.
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http://dx.doi.org/10.1016/j.ejca.2020.10.013DOI Listing
January 2021

Tumor MHC Expression Guides First-Line Immunotherapy Selection in Melanoma.

Cancers (Basel) 2020 Nov 14;12(11). Epub 2020 Nov 14.

Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia.

Immunotherapy targeting T-cell inhibitory receptors, namely programmed cell death-1 (PD-1) and/or cytotoxic T-lymphocyte associated protein-4 (CTLA-4), leads to durable responses in a proportion of patients with advanced metastatic melanoma. Combination immunotherapy results in higher rates of response compared to anti-PD-1 monotherapy, at the expense of higher toxicity. Currently, there are no robust molecular biomarkers for the selection of first-line immunotherapy. We used flow cytometry to profile pretreatment tumor biopsies from 36 melanoma patients treated with anti-PD-1 or combination (anti-PD-1 plus anti-CTLA-4) immunotherapy. A novel quantitative score was developed to determine the tumor cell expression of antigen-presenting MHC class I (MHC-I) molecules, and to correlate expression data with treatment response. Melanoma MHC-I expression was intact in all tumors derived from patients who demonstrated durable response to anti-PD-1 monotherapy. In contrast, melanoma MHC-I expression was low in 67% of tumors derived from patients with durable response to combination immunotherapy. Compared to MHC-I high tumors, MHC-I low tumors displayed reduced T-cell infiltration and a myeloid cell-enriched microenvironment. Our data emphasize the importance of robust MHC-I expression for anti-PD-1 monotherapy response and provide a rationale for the selection of combination immunotherapy as the first-line treatment in MHC-I low melanoma.
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http://dx.doi.org/10.3390/cancers12113374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696726PMC
November 2020

Musculoskeletal immune-related adverse events with use of checkpoint inhibitors in malignancy.

Intern Med J 2020 Nov 2. Epub 2020 Nov 2.

Department of Rheumatology, University of Sydney, Royal North Shore Hospital, Sydney, NSW, Australia, 2065.

Background: Immunotherapy has revolutionised the treatment of many malignancies. Along with their success, there have been inflammatory and immune-related adverse events (irAE). There is a paucity of literature describing the Australian experience of rheumatic irAE.

Aims: To describe and characterise the Royal North Shore Hospital and Westmead Hospital cohort with rheumatic irAE.

Methods: This case series reports on seventeen patients with advanced cancer treated at two sites in Sydney, Australia who were referred for rheumatological evaluation from 2013 to 2016. Data was collected retrospectively and inspected for clinical signs, duration of immunotherapy prior to onset of symptoms, management strategies and cancer outcomes.

Results: Patients presented with arthralgias, myalgias, periarticular and systemic symptoms. Onset of rheumatological symptoms was variable, with a median of 4 months (range 0.2- 24) for monotherapy and 5.05 months (range 0.2- 6.9) for combination. The predominant findings were of tenosynovitis (23%) and large joint involvement (65%). All patients were seronegative for RF and anti-CCP. Most patients responded well to NSAIDs or low dose prednisone (59%) and remained on immunotherapy (77%). Majority (76%) of the patients experienced concomitant irAE in other organ systems. Sixty-five percent of patients had complete response of their malignancy to immunotherapy.

Conclusion: Rheumatic irAEs are heterogenous clinical entities which require further evaluation into classification, patient susceptibility and response. From our study, there was no clear clinical pattern. Our case series supports that rheumatic irAE may be associated with tumour response. However, there is still limited experience in rheumatic irAEs management and outcomes. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/imj.15123DOI Listing
November 2020

Melanoma recurrence patterns and management after adjuvant targeted therapy: a multicentre analysis.

Br J Cancer 2021 02 22;124(3):574-580. Epub 2020 Oct 22.

Department of Medical Oncology, Alfred Hospital, Melbourne, VIC, Australia.

Background: Adjuvant targeted therapy (TT) improves relapse free survival in patients with resected BRAF mutant stage III melanoma. The outcomes and optimal management of patients who relapse after adjuvant TT is unknown.

Methods: Patients from twenty-one centres with recurrent melanoma after adjuvant TT were included. Disease characteristics, adjuvant therapy, recurrence, treatment at relapse and outcomes were examined.

Results: Eighty-five patients developed recurrent melanoma; nineteen (22%) during adjuvant TT. Median time to first recurrence was 18 months and median follow-up from first recurrence was 31 months. Fifty-eight (68%) patients received immunotherapy (IT) or TT as 1st line systemic therapy at either first or subsequent recurrence and had disease that was assessable for response. Response to anti-PD-1 (±trial agent), combination ipilimumab-nivolumab, TT rechallenge and ipilimumab monotherapy was 63%, 62% 25% and 10% respectively. Twenty-eight (33%) patients had died at census, all from melanoma. Two-year OS was 84% for anti-PD-1 therapy (±trial agent), 92% for combination ipilimumab and nivolumab, 49% for TT and 45% for ipilimumab monotherapy (p = 0.028).

Conclusions: Patients who relapse after adjuvant TT respond well to subsequent anti-PD-1 based therapy and have outcomes similar to those seen when first line anti-PD-1 therapy is used in stage IV melanoma.
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http://dx.doi.org/10.1038/s41416-020-01121-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851118PMC
February 2021

Circulating Tumor DNA Predicts Outcome from First-, but not Second-line Treatment and Identifies Melanoma Patients Who May Benefit from Combination Immunotherapy.

Clin Cancer Res 2020 11 16;26(22):5926-5933. Epub 2020 Oct 16.

School of Medical and Health Sciences, Edith Cowan University, Perth, Australia.

Purpose: We evaluated the predictive value of pretreatment ctDNA to inform therapeutic outcomes in patients with metastatic melanoma relative to type and line of treatment.

Experimental Design: Plasma circulating tumor DNA (ctDNA) was quantified in 125 samples collected from 110 patients prior to commencing treatment with immune checkpoint inhibitors (ICIs), as first- ( = 32) or second-line ( = 27) regimens, or prior to commencing first-line BRAF/MEK inhibitor therapy ( = 66). An external validation cohort included 128 patients commencing ICI therapies in the first- ( = 77) or second-line ( = 51) settings.

Results: In the discovery cohort, low ctDNA (≤20 copies/mL) prior to commencing therapy predicted longer progression-free survival (PFS) in patients treated with first-line ICIs [HR, 0.20; 95% confidence interval (CI) 0.07-0.53; < 0.0001], but not in the second-line setting. An independent cohort validated that ctDNA is predictive of PFS in the first-line setting (HR, 0.42; 95% CI, 0.22-0.83; = 0.006), but not in the second-line ICI setting. Moreover, ctDNA prior to commencing ICI treatment was not predictive of PFS for patients pretreated with BRAF/MEK inhibitors in either the discovery or validation cohorts. Reduced PFS and overall survival were observed in patients with high ctDNA receiving anti-PD-1 monotherapy, relative to those treated with combination anti-CTLA-4/anti-PD-1 inhibitors.

Conclusions: Pretreatment ctDNA is a reliable indicator of patient outcome in the first-line ICI treatment setting, but not in the second-line ICI setting, especially in patients pretreated with BRAF/MEK inhibitors. Preliminary evidence indicated that treatment-naïve patients with high ctDNA may preferentially benefit from combined ICIs.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2251DOI Listing
November 2020

Longer Follow-Up Confirms Recurrence-Free Survival Benefit of Adjuvant Pembrolizumab in High-Risk Stage III Melanoma: Updated Results From the EORTC 1325-MG/KEYNOTE-054 Trial.

J Clin Oncol 2020 11 18;38(33):3925-3936. Epub 2020 Sep 18.

European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium.

Purpose: We conducted the phase III double-blind European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial to evaluate pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. On the basis of 351 recurrence-free survival (RFS) events at a 1.25-year median follow-up, pembrolizumab prolonged RFS (hazard ratio [HR], 0.57; < .0001) compared with placebo. This led to the approval of pembrolizumab adjuvant treatment by the European Medicines Agency and US Food and Drug Administration. Here, we report an updated RFS analysis at the 3.05-year median follow-up.

Patients And Methods: A total of 1,019 patients with complete lymph node dissection of American Joint Committee on Cancer Staging Manual (seventh edition; AJCC-7), stage IIIA (at least one lymph node metastasis > 1 mm), IIIB, or IIIC (without in-transit metastasis) cutaneous melanoma were randomly assigned to receive pembrolizumab at a flat dose of 200 mg (n = 514) or placebo (n = 505) every 3 weeks for 1 year or until disease recurrence or unacceptable toxicity. The two coprimary end points were RFS in the overall population and in those with programmed death-ligand 1 (PD-L1)-positive tumors.

Results: Pembrolizumab (190 RFS events) compared with placebo (283 RFS events) resulted in prolonged RFS in the overall population (3-year RFS rate, 63.7% 44.1% for pembrolizumab placebo, respectively; HR, 0.56; 95% CI, 0.47 to 0.68) and in the PD-L1-positive tumor subgroup (HR, 0.57; 99% CI, 0.43 to 0.74). The impact of pembrolizumab on RFS was similar in subgroups, in particular according to AJCC-7 and AJCC-8 staging, and mutation status (HR, 0.51 [99% CI, 0.36 to 0.73] 0.66 [99% CI, 0.46 to 0.95] for V600 wild type).

Conclusion: In resected high-risk stage III melanoma, pembrolizumab adjuvant therapy provided a sustained and clinically meaningful improvement in RFS at 3-year median follow-up. This improvement was consistent across subgroups.
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http://dx.doi.org/10.1200/JCO.20.02110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676886PMC
November 2020

Design and Testing of a Custom Melanoma Next Generation Sequencing Panel for Analysis of Circulating Tumor DNA.

Cancers (Basel) 2020 Aug 10;12(8). Epub 2020 Aug 10.

Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia.

Detection of melanoma-associated mutations using circulating tumor DNA (ctDNA) from plasma is a potential alternative to using genomic DNA from invasive tissue biopsies. In this study, we developed a custom melanoma next-generation sequencing (NGS) panel which includes 123 amplicons in 30 genes covering driver and targetable mutations and alterations associated with treatment resistance. Analysis of a cohort of 74 stage III and IV treatment-naïve melanoma patients revealed that sensitivity of ctDNA detection was influenced by the amount of circulating-free DNA (cfDNA) input and stage of melanoma. At the recommended cfDNA input quantity of 20 ng (available in 28/74 patients), at least one cancer-associated mutation was detected in the ctDNA of 84% of stage IV patients and 47% of stage III patients with a limit of detection for mutant allele frequency (MAF) of 0.2%. This custom melanoma panel showed significant correlation with droplet digital PCR (ddPCR) and provided a more comprehensive melanoma mutation profile. Our custom panel could be further optimized by replacing amplicons spanning the promoter, which did not perform well due to the high GC content. To increase the detection rate to 90% of stage IV melanoma and decrease the sensitivity to 0.1% MAF, we recommend increasing the volume of plasma to 8 mL to achieve minimal recommended cfDNA input and the refinement of poorly performing amplicons. Our panel can also be expanded to include new targetable and treatment resistance mutations to improve the tracking of treatment response and resistance in melanoma patients treated with systemic drug therapies.
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http://dx.doi.org/10.3390/cancers12082228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465941PMC
August 2020

Evaluation of Combination Nivolumab and Ipilimumab Immunotherapy in Patients With Advanced Biliary Tract Cancers: Subgroup Analysis of a Phase 2 Nonrandomized Clinical Trial.

JAMA Oncol 2020 09;6(9):1405-1409

Department of Medical Oncology, Austin Health, Melbourne, Australia.

Importance: Biliary tract cancers represent a rare group of malignant conditions with very limited treatment options. Patients with advanced disease have a poor outcome with current therapies.

Objective: To evaluate the efficacy and safety of combination immunotherapy with nivolumab and ipilimumab in patients with advanced biliary tract cancers.

Design, Setting, And Participants: The CA209-538 prospective multicenter phase 2 nonrandomized clinical trial included patients with advanced rare cancers including patients with biliary tract cancers. This subgroup analysis evaluated 39 patients from CA209-538 with biliary tract cancers who were enrolled from December 2017 to December 2019. Most of the patients (n = 33) had experienced disease progression after 1 or more lines of therapy and had tumor tissue available for biomarker research.

Interventions: Patients received treatment with nivolumab at a dose of 3 mg/kg and ipilimumab at 1 mg/kg every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg every 2 weeks and continued for up to 96 weeks until disease progression or the development of unacceptable toxic events.

Main Outcomes And Measures: The primary end point was disease control rate (complete remission, partial remission, or stable disease) as assessed by RECIST 1.1.

Results: Among the 39 patients included in this subgroup analysis of a phase 2 clinical trial (20 men, 19 women; mean [range] age, 65 [37-81] years), the objective response rate was 23% (n = 9) with a disease control rate of 44% (n = 17); all responders had received prior chemotherapy, and none had a microsatellite unstable tumor. Responses were exclusively observed in patients with intrahepatic cholangiocarcinoma and gallbladder carcinoma. The median duration of response was not reached (range, 2.5 to ≥23 months). The median progression-free survival was 2.9 months (95% CI, 2.2-4.6 months), and overall survival was 5.7 months (95% CI, 2.7-11.9 months). Immune-related toxic events were reported in 49% of patients (n = 19), with 15% (n = 6) experiencing grade 3 or 4 events.

Conclusions And Relevance: This subgroup analysis of a phase 2 clinical trial found that combination immunotherapy with nivolumab and ipilimumab was associated with substantial positive outcomes patients with advanced biliary tract cancers. This treatment compares favorably to single-agent anti-programmed cell death protein 1 (anti-PD-1) therapy and warrants further investigation. Ongoing translational research is focused on identifying biomarkers that can predict treatment response.

Trial Registration: ClinicalTrials.gov Identifier: NCT02923934.
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http://dx.doi.org/10.1001/jamaoncol.2020.2814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393585PMC
September 2020

Association of BRAF V600E/K Mutation Status and Prior BRAF/MEK Inhibition With Pembrolizumab Outcomes in Advanced Melanoma: Pooled Analysis of 3 Clinical Trials.

JAMA Oncol 2020 08;6(8):1256-1264

The Angeles Clinic and Research Institute, Los Angeles, California.

Importance: The optimal sequencing of immune checkpoint inhibitors and targeted therapy for BRAF V600E/K-mutant melanoma is not well established.

Objective: To assess the association of BRAF wild-type (WT) or BRAF V600E/K-mutant status and BRAF inhibitor (BRAFi) with or without MEK inhibitor (MEKi) therapy with response to pembrolizumab.

Design, Setting, And Participants: This study is a post hoc subgroup analysis of pooled data from 3 multinational, multisite studies: KEYNOTE-001 (data cutoff September 1, 2017), KEYNOTE-002 (data cutoff May 30, 2018), and KEYNOTE-006 (data cutoff December 4, 2017). Patients included in this analysis were adults with advanced melanoma and known BRAF V600E/K tumor status who had received pembrolizumab.

Interventions: Patients received pembrolizumab in dosages of 2 mg/kg every 3 weeks, 10 mg/kg every 2 weeks, or 10 mg/kg every 3 weeks.

Main Outcomes And Measures: End points were objective response rate (ORR) and progression-free survival (PFS) assessed by Response Evaluation Criteria in Solid Tumors, version 1.1, and overall survival (OS). Objective response rates, 4-year PFS, and OS rates were compared in the following patient subgroups: BRAF WT vs BRAF V600E/K-mutant melanoma and BRAF V600E/K-mutant melanoma with vs without previous treatment with BRAFi with or without MEKi therapy.

Results: The overall study population (N = 1558) included 944 men (60.6%) and 614 women (39.4%). The mean (SD) age was 60.0 years (14.0). The ORR was 38.3% (596/1558), 4-year PFS rate was 22.0%, and 4-year OS rate was 36.9%. For patients with BRAF WT (n = 1124) and BRAF V600E/K-mutant melanoma (n = 434), ORR was 39.8% (n = 447) and 34.3% (n = 149), 4-year PFS rate was 22.9% and 19.8%, and 4-year OS rate was 37.5% and 35.1%, respectively. Patients with BRAF V600E/K-mutant melanoma who had (n = 271) vs had not (n = 163) previously received BRAFi with or without MEKi therapy had baseline characteristics with worse prognosis; ORR was 28.4% (n = 77) and 44.2% (n = 72), 4-year PFS rate was 15.2% and 27.8%, and 4-year OS rate was 26.9% and 49.3%, respectively.

Conclusions And Relevance: Results of this subgroup analysis support the use of pembrolizumab for treatment of advanced melanoma regardless of BRAF V600E/K mutation status or receipt of prior BRAFi with or without MEKi therapy.
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http://dx.doi.org/10.1001/jamaoncol.2020.2288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366279PMC
August 2020

A Phase Ib/II Study of the BRAF Inhibitor Encorafenib Plus the MEK Inhibitor Binimetinib in Patients with -mutant Solid Tumors.

Clin Cancer Res 2020 10 15;26(19):5102-5112. Epub 2020 Jul 15.

Istituto Nazionale Tumori, IRCCS "Fondazione G. Pascale," Naples, Italy.

Purpose: This open-label, dose-finding phase Ib/II study reports the safety and activity of the first combination use with BRAF inhibitor (BRAFi) encorafenib plus MEK inhibitor (MEKi) binimetinib in patients with V600E-mutant solid tumors.

Patients And Methods: In phase I, the recommended phase 2 doses (RP2D) were established (primary objective). In phase II, the clinical activity of the combination at the RP2D was assessed (primary objective) in patients with -mutant metastatic colorectal cancer (mCRC), BRAFi-treated -mutant melanoma, and BRAFi-naïve BRAF-mutant melanoma.

Results: A total of 126 patients with mutant solid tumors were enrolled (phase I: 47 patients; phase II: 79 patients). The RP2D was encorafenib 450 mg once daily plus binimetinib 45 mg twice daily and pharmacokinetic data suggest that drug exposures of each agent were similar in combination compared with single-agent studies. In the phase II cohorts, confirmed responses were seen in two of 11 (18%) evaluable patients with mCRC, 11 of 26 (42%) evaluable patients with BRAFi-pretreated melanoma, and 28 of 42 (67%) BRAFi-naïve patients with melanoma. The most common grade 3/4 adverse event in phase II was increased alanine aminotransferase.

Conclusions: The combination of encorafenib (450 mg) plus binimetinib (45 mg) showed acceptable tolerability and encouraging activity in patients with V600-mutant tumors, which led to the dose selection for the melanoma COLUMBUS study. The safety profile of the combination was consistent with other approved BRAFi plus MEKi regimens, with several differences, including lower rates of dose-limiting pyrexia, arthralgia, and photosensitivity.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3550DOI Listing
October 2020