Are exercise and sitting time during chemotherapy for ovarian cancer associated with treatment-related side-effects, chemotherapy completion and survival?

OBJECTIVE: To evaluate if exercise and sitting time during chemotherapy were associated with chemotherapy side-effects, completion of planned chemotherapy and survival. METHODS: We used data from the Ovarian cancer Prognosis And Lifestyle (OPAL) Study, a national prospective cohort of adults with newly-diagnosed epithelial ovarian cancer. At 3-monthly questionnaires we asked about exercise and sitting time in the past week, and treatment-related side-effects. Details about treatment, toxicities, progression and death were abstracted from medical records. We used linear, logistic and Cox regression, respectively, to assess associations between both exercise and sitting time, and chemotherapy side-effects and completion (≥85% relative dose intensity) and survival. RESULTS: 503 eligible participants were included in one or more analyses. Patients participating in higher-intensity exercise (≥30 min of moderate-vigorous exercise/week; 24%) reported significantly better Functional Assessment of Chronic Illness/Cancer Therapy (FACIT)-Fatigue (32.2 vs. 26.7) and FACT-Trial Outcome Index (69.4 vs. 61.7) scores, and were less likely to have clinician-reported moderate-severe neurotoxicity (odds ratio [OR]:0.50; 95% confidence interval [95%CI]:0.29-0.88), than minimal exercisers (<30 min moderate-vigorous exercise/week & <120 min walking/week; 52%). Participating in higher-intensity exercise was also possibly associated with greater chemotherapy completion (OR:1.70; 95%CI:0.90-3.20), particularly for paclitaxel. Sitting time was not associated with chemotherapy completion. For patients with advanced disease who underwent cytoreduction and received first-line carboplatin and paclitaxel, there was a suggestion higher-intensity exercise during chemotherapy may improve survival (HR:0.68; 95%CI:0.47-1.01). CONCLUSIONS: Patients with ovarian cancer who carry out moderate-vigorous exercise during chemotherapy have fewer side-effects and potentially better completion of planned chemotherapy and overall survival.

Innovations in Rare Gynecologic Cancer: Melanoma, Neuroendocrine, and Low-Grade Serous Ovarian.

In the field of gynecologic cancer, low-grade serous ovarian cancer (LGSOC) has been poorly understood and underinvestigated until recently. Similarly, understanding of the distinct properties and therapeutic sensitivities of gynecologic melanoma and cervical neuroendocrine tumors has recently accelerated. For each of these rare cancers, we explore the epidemiology and natural history, discuss the prognosis, diagnostic testing, and contemporary molecular classification, and then deliberate existing and emerging therapeutic strategies. In LGSOC, we focus on the clinical relevance of recent molecular studies that shed light on the importance of mitogen-activated protein kinase (MAPK) pathway gene mutation and chromosome 1 copy-number change on prognosis and MEK inhibitor sensitivity. We also discuss the relative chemoresistance of this disease and the fact that attention is shifting to combinations of molecular therapies such as endocrine agents plus cyclin-dependent kinase 4/6 inhibitors or MEK inhibitors plus FAK inhibitors. Gynecologic tract melanomas harbor a lower frequency of canonical BRAF mutations, and have lower tumor mutational burden and immune cell infiltration than cutaneous melanomas (CMs). As a result, patients with this disease are less likely to respond to BRAF/MEK or immune checkpoint inhibition than patients with CM. Emerging strategies include the combination of antiangiogenic agents with immune checkpoint inhibitors and the use of adoptive cellular therapies. In cervical neuroendocrine cancer, we discuss the use of surgery in early-stage disease, and the uncertainties regarding the role of radiotherapy. We also explore the evidence for chemotherapy and emerging investigational strategies including the use of poly (ADP-ribose) polymerase inhibitors. For all situations, we explore the shared decision-making process with the patient.

Neoadjuvant pembrolizumab, dabrafenib and trametinib in BRAFV600-mutant resectable melanoma: the randomized phase 2 NeoTrio trial.

Immune checkpoint inhibitors and BRAF-targeted therapy each improve survival in melanoma. Immune changes early during targeted therapy suggest the mechanisms of each drug class could work synergistically. In the non-comparative, randomized, phase 2 NeoTrio trial, we investigated whether targeted therapy could boost the proportion of patients achieving long-term recurrence-free survival with neoadjuvant immunotherapy in resectable stage III BRAFV600-mutant melanoma. Sixty patients (42% females) were randomized to pembrolizumab alone (n = 20), sequential therapy (dabrafenib plus trametinib followed by pembrolizumab; n = 20) or concurrent (triple) therapy (n = 20), followed by surgery and adjuvant therapy. The primary outcome was pathological response; secondary outcomes included radiographic response, recurrence-free survival, overall survival, surgical outcomes, peripheral blood and tumor analyses and safety. The pathological response rate was 55% (11/20; including six pathological complete responses (pCRs)) with pembrolizumab, 50% (10/20; three pCRs) with sequential therapy and 80% (16/20; ten pCRs) with concurrent therapy, which met the primary outcome in each arm. Treatment-related adverse events affected 75-100% of patients during neoadjuvant treatment, with seven early discontinuations (all in the concurrent arm). At 2 years, event-free survival was 60% with pembrolizumab, 80% with sequential therapy and 71% with concurrent therapy. Recurrences after major pathological response were more common in the targeted therapy arms, suggesting a reduction in response 'quality' when targeted therapy is added to neoadjuvant immunotherapy. Risking the curative potential of immunotherapy in melanoma cannot be justified. Pending longer follow-up, we suggest that immunotherapy and targeted therapy should not be combined in the neoadjuvant setting for melanoma. ClinicalTrials.gov registration: NCT02858921 .

Homologous recombination proficient subtypes of high-grade serous ovarian cancer: treatment options for a poor prognosis group.

Approximately 50% of tubo-ovarian high-grade serous carcinomas (HGSCs) have functional homologous recombination-mediated (HR) DNA repair, so-called HR-proficient tumors, which are often associated with primary platinum resistance (relapse within six months after completion of first-line therapy), minimal benefit from poly(ADP-ribose) polymerase (PARP) inhibitors, and shorter survival. HR-proficient tumors comprise multiple molecular subtypes including cases with CCNE1 amplification, AKT2 amplification or CDK12 alteration, and are often characterized as "cold" tumors with fewer infiltrating lymphocytes and decreased expression of PD-1/PD-L1. Several new treatment approaches aim to manipulate these negative prognostic features and render HR-proficient tumors more susceptible to treatment. Alterations in multiple different molecules and pathways in the DNA damage response are driving new drug development to target HR-proficient cancer cells, such as inhibitors of the CDK or P13K/AKT pathways, as well as ATR inhibitors. Treatment combinations with chemotherapy or PARP inhibitors and agents targeting DNA replication stress have shown promising preclinical and clinical results. New approaches in immunotherapy are also being explored, including vaccines or antibody drug conjugates. Many approaches are still in the early stages of development and further clinical trials will determine their clinical relevance. There is a need to include HR-proficient tumors in ovarian cancer trials and to analyze them in a more targeted manner to provide further evidence for their specific therapy, as this will be crucial in improving the overall prognosis of HGSC and ovarian cancer in general.

Phase 1, first-in-human study of TYRP1-TCB (RO7293583), a novel TYRP1-targeting CD3 T-cell engager, in metastatic melanoma: active drug monitoring to assess the impact of immune response on drug exposure.

Introduction: Although checkpoint inhibitors (CPIs) have improved outcomes for patients with metastatic melanoma, those progressing on CPIs have limited therapeutic options. To address this unmet need and overcome CPI resistance mechanisms, novel immunotherapies, such as T-cell engaging agents, are being developed. The use of these agents has sometimes been limited by the immune response mounted against them in the form of anti-drug antibodies (ADAs), which is challenging to predict preclinically and can lead to neutralization of the drug and loss of efficacy. Methods: TYRP1-TCB (RO7293583; RG6232) is a T-cell engaging bispecific (TCB) antibody that targets tyrosinase-related protein 1 (TYRP1), which is expressed in many melanomas, thereby directing T cells to kill TYRP1-expressing tumor cells. Preclinical studies show TYRP1-TCB to have potent anti-tumor activity. This first-in-human (FIH) phase 1 dose-escalation study characterized the safety, tolerability, maximum tolerated dose/optimal biological dose, and pharmacokinetics (PK) of TYRP1-TCB in patients with metastatic melanoma (NCT04551352). Results: Twenty participants with cutaneous, uveal, or mucosal TYRP1-positive melanoma received TYRP1-TCB in escalating doses (0.045 to 0.4 mg). All participants experienced ≥1 treatment-related adverse event (TRAE); two participants experienced grade 3 TRAEs. The most common toxicities were grade 1-2 cytokine release syndrome (CRS) and rash. Fractionated dosing mitigated CRS and was associated with lower levels of interleukin-6 and tumor necrosis factor-alpha. Measurement of active drug (dual TYPR1- and CD3-binding) PK rapidly identified loss of active drug exposure in all participants treated with 0.4 mg in a flat dosing schedule for ≥3 cycles. Loss of exposure was associated with development of ADAs towards both the TYRP1 and CD3 domains. A total drug PK assay, measuring free and ADA-bound forms, demonstrated that TYRP1-TCB-ADA immune complexes were present in participant samples, but showed no drug activity in vitro. Discussion: This study provides important insights into how the use of active drug PK assays, coupled with mechanistic follow-up, can inform and enable ongoing benefit/risk assessment for individuals participating in FIH dose-escalation trials. Translational studies that lead to a better understanding of the underlying biology of cognate T- and B-cell interactions, ultimately resulting in ADA development to novel biotherapeutics, are needed.

Imaging for assessment of cancer treatment response to immune checkpoint inhibitors can be complementary in identifying hypophysitis.

Introduction: Hypophysitis is reported in 8.5%-14% of patients receiving combination immune checkpoint inhibition (cICI) but can be a diagnostic challenge. This study aimed to assess the role of routine diagnostic imaging performed during therapeutic monitoring of combination anti-CTLA-4/anti-PD-1 treatment in the identification of hypophysitis and the relationship of imaging findings to clinical diagnostic criteria. Methods: This retrospective cohort study identified patients treated with cICI between January 2016 and January 2019 at a quaternary melanoma service. Medical records were reviewed to identify patients with a documented diagnosis of hypophysitis based on clinical criteria. Available structural brain imaging with magnetic resonance imaging (MRI) or computed tomography (CT) of the brain and 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography with computed tomography (FDG-PET/CT) were assessed retrospectively. The main radiological outcome measures were a relative change in pituitary size or FDG uptake temporally attributed to cICI. Results: There were 162 patients (median age 60 years, 30% female) included. A total of 100 and 134 had serial CT/MRI of the brain and FDG-PET/CT, respectively. There were 31 patients who had a documented diagnosis of hypophysitis and an additional 20 who had isolated pituitary imaging findings. The pituitary gland enlargement was mild, and the largest absolute gland size was 13 mm, with a relative increase of 7 mm from baseline. There were no cases of optic chiasm compression. Pituitary enlargement and increased FDG uptake were universally transient. High-dose glucocorticoid treatment for concurrent irAEs prevented assessment of the pituitary-adrenal axis in 90% of patients with isolated imaging findings. Conclusion: Careful review of changes in pituitary characteristics on imaging performed for assessment of therapeutic response to iICI may lead to increased identification and more prompt management of cICI-induced hypophysitis.

Protocol for a randomized controlled trial comparing a very low-carbohydrate diet or moderate-carbohydrate plate-method diet for type 2 diabetes: the LEGEND (Lifestyle Education about Nutrition for Diabetes) trial.

BACKGROUND: Optimal carbohydrate intake is an important and controversial area in the nutritional management of type 2 diabetes. Some evidence indicates that reducing overall carbohydrate intake with a low- or very low-carbohydrate eating plan can improve glycemic control compared to following eating plans that involve greater carbohydrate intake. However, critical knowledge gaps currently prevent clear recommendations about carbohydrate intake levels. METHODS: The LEGEND (Lifestyle Education about Nutrition for Diabetes) Trial aims to compare a very low-carbohydrate diet to a moderate-carbohydrate plate-method diet for glycemic control in adults with type 2 diabetes. This two-site trial plans to recruit 180 adults with type 2 diabetes. We will randomize participants to either a 20-session group-based diet and lifestyle intervention that teaches either a very low-carbohydrate diet or a moderate-carbohydrate plate-method diet. We will assess participants at study entry and 4 and 12 months later. The primary outcome is HbA1c, and secondary outcomes include inflammation (high sensitivity C-reactive protein), body weight, changes in diabetes medications, lipids (small particle LDL, HDL, triglycerides), skeletal metabolism (bone mineral density from dual-energy x-ray absorptiometry and bone turnover markers serum procollagen type I N propeptide and serum C-terminal telopeptide of type I collagen), and body composition (percent body fat, percent lean body mass). DISCUSSION: The LEGEND trial is a randomized controlled trial to assess optimal carbohydrate intake in type 2 diabetes by evaluating the effects of a very low-carbohydrate diet vs. a moderate-carbohydrate plate-method diet over a year-long period. The research addresses important gaps in the evidence base for the nutritional management of type 2 diabetes by providing data on potential benefits and adverse effects of different levels of carbohydrate intake. TRIAL REGISTRATION: ClinicalTrials.gov NCT05237128. Registered on February 11, 2022.

BRCA1 and BRCA2 carriers with breast, ovarian and prostate cancer demonstrate a different pattern of metastatic disease compared with non-carriers: results from a rapid autopsy programme.

AIM: To catalogue and compare the pattern of metastatic disease in germline BRCA1/2 pathogenic mutation carriers and non-carriers with breast, ovarian and prostate cancer from a rapid autopsy programme. METHODS AND RESULTS: The number of metastases in the major body systems and the proportion of participants with metastases were documented in 50 participants (19 germline mutation carriers). Analysis was conducted on the participants' pattern of disease for the different cancers and mutation subgroups. The four commonly affected organ systems were the digestive (liver only) (82%), respiratory (76%), gastrointestinal (65%) and reticuloendothelial (42%). There were significant differences in the pattern of metastatic breast cancer in BRCA1/2 germline carriers compared with non-carriers. Breast cancer carriers had significantly fewer organ systems involved (median n = 3, range = 1-3) compared with non-carriers (median n = 9, range = 1-7) (P = 0.03). BRCA1/2 carriers with ovarian carcinomas had significantly more organ systems with metastatic carcinoma (median n = 10, range = 3-8) than non-carriers (median n = 5, range = 3-5) (P < 0.001). There were no significant differences in the number of involved systems in BRCA2 carriers compared with non-carriers with prostate cancer (P = 1.0). There was an absence of locoregional disease (6.5%) compared with distant disease (93.5%) among the three cancer subtypes (P < 0.001). The majority of metastatic deposits (97%) collected during the autopsy were identified by recent diagnostic imaging. CONCLUSION: Even though a major limitation of this study is that our numbers are small, especially in the breast cancer carrier group, the metastatic patterns of breast and ovarian cancers may be impacted by BRCA1/2 carrier status, suggesting that tumours derived from patients with these mutations use different mechanisms of dissemination. The findings may focus clinical diagnostic imaging for monitoring metastases where whole-body imaging resources are scant.

Multiomic analysis of homologous recombination-deficient end-stage high-grade serous ovarian cancer.

High-grade serous ovarian cancer (HGSC) is frequently characterized by homologous recombination (HR) DNA repair deficiency and, while most such tumors are sensitive to initial treatment, acquired resistance is common. We undertook a multiomics approach to interrogate molecular diversity in end-stage disease, using multiple autopsy samples collected from 15 women with HR-deficient HGSC. Patients had polyclonal disease, and several resistance mechanisms were identified within most patients, including reversion mutations and HR restoration by other means. We also observed frequent whole-genome duplication and global changes in immune composition with evidence of immune escape. This analysis highlights diverse evolutionary changes within HGSC that evade therapy and ultimately overwhelm individual patients.

The genomic and immune landscape of long-term survivors of high-grade serous ovarian cancer.

Fewer than half of all patients with advanced-stage high-grade serous ovarian cancers (HGSCs) survive more than five years after diagnosis, but those who have an exceptionally long survival could provide insights into tumor biology and therapeutic approaches. We analyzed 60 patients with advanced-stage HGSC who survived more than 10 years after diagnosis using whole-genome sequencing, transcriptome and methylome profiling of their primary tumor samples, comparing this data to 66 short- or moderate-term survivors. Tumors of long-term survivors were more likely to have multiple alterations in genes associated with DNA repair and more frequent somatic variants resulting in an increased predicted neoantigen load. Patients clustered into survival groups based on genomic and immune cell signatures, including three subsets of patients with BRCA1 alterations with distinctly different outcomes. Specific combinations of germline and somatic gene alterations, tumor cell phenotypes and differential immune responses appear to contribute to long-term survival in HGSC.

Tissue-resident memory T cells from a metastatic vaginal melanoma patient are tumor-responsive T cells and increase after anti-PD-1 treatment.

BACKGROUND: Vaginal melanoma (VM) is a rare cancer and has a poor response to immune checkpoint blockade (ICB). CD8+Tissue Resident Memory (TRM) T cells proliferate in response to ICB and correlate with longer survival in metastatic cutaneous melanoma. However, their capacity to respond to VM and their neoantigens is not known. METHODS: Using longitudinal samples, we explored the evolution of VM mutations by whole-exome sequencing and RNAseq, we also defined the immune context using multiplex immunohistochemistry and nanostring pan cancer immune profile. Then using fresh single cell suspensions of the metastatic samples, we explored VM T cells via mass cytometry and single cell RNAseq and T cell receptor sequencing (TCRseq). Finally, we investigated TRM, pre-TRM and exhausted T cell function against melanoma neo-antigens and melanoma differentiation antigens in vitro. RESULTS: Primary VM was non-inflamed and devoid of CD8+ TRM cells. In contrast, both metastases showed proliferating CD8+ TRM were clustered at the tumor margin, with increased numbers in the second ICB-refractory metastasis. The first metastasis showed dense infiltration of CD8+ T cells, the second showed immune exclusion with loss of melanoma cell Major histocompatibility complex (MHC)-I expression associated with downregulation of antigen presentation pathway gene expression. CD8+ TRM from both metastases responded to autologous melanoma cells more robustly than all other CD8+ T cell subsets. In addition, CD8+ TRM shared TCR clones across metastases, suggesting a response to common antigens, which was supported by recognition of the same neoantigen by expanded tumor infiltrating lymphocytes. CONCLUSIONS: In this study, we identified TRM clusters in VM metastases from a patient, but not primary disease. We showed TRM location at the tumor margin, and their superior functional response to autologous tumor cells, predicted neoantigens and melanoma differentiation antigens. These CD8+ TRM exhibited the highest tumor-responsive potential and shared their TCR with tumor-infiltrating effector memory T cells. This suggests VM metastases from this patient retain strong antitumor T cell functional responses; however, this response is suppressed in vivo. The loss of VG MHC-I expression is a common immune escape mechanism which was not addressed by anti-PD-1 monotherapy; rather an additional targeted approach to upregulate MHC-I expression is required.

Characterization of the treatment-naive immune microenvironment in melanoma with BRAF mutation.

BACKGROUND: Patients with BRAF-mutant and wild-type melanoma have different response rates to immune checkpoint blockade therapy. However, the reasons for this remain unknown. To address this issue, we investigated the precise immune composition resulting from BRAF mutation in treatment-naive melanoma to determine whether this may be a driver for different response to immunotherapy. METHODS: In this study, we characterized the treatment-naive immune context in patients with BRAF-mutant and BRAF wild-type (BRAF-wt) melanoma using data from single-cell RNA sequencing, bulk RNA sequencing, flow cytometry and immunohistochemistry (IHC). RESULTS: In single-cell data, BRAF-mutant melanoma displayed a significantly reduced infiltration of CD8+ T cells and macrophages but also increased B cells, natural killer (NK) cells and NKT cells. We then validated this finding using bulk RNA-seq data from the skin cutaneous melanoma cohort in The Cancer Genome Atlas and deconvoluted the data using seven different algorithms. Interestingly, BRAF-mutant tumors had more CD4+ T cells than BRAF-wt samples in both primary and metastatic cohorts. In the metastatic cohort, BRAF-mutant melanoma demonstrated more B cells but less CD8+ T cell infiltration when compared with BRAF-wt samples. In addition, we further investigated the immune cell infiltrate using flow cytometry and multiplex IHC techniques. We confirmed that BRAF-mutant melanoma metastases were enriched for CD4+ T cells and B cells and had a co-existing decrease in CD8+ T cells. Furthermore, we then identified B cells were associated with a trend for improved survival (p=0.078) in the BRAF-mutant samples and Th2 cells were associated with prolonged survival in the BRAF-wt samples. CONCLUSIONS: In conclusion, treatment-naive BRAF-mutant melanoma has a distinct immune context compared with BRAF-wt melanoma, with significantly decreased CD8+ T cells and increased B cells and CD4+ T cells in the tumor microenvironment. These findings indicate that further mechanistic studies are warranted to reveal how this difference in immune context leads to improved outcome to combination immune checkpoint blockade in BRAF-mutant melanoma.

Treatment patterns after poly-ADP ribose polymerase (PARP) inhibitors in epithelial ovarian cancer patients.

OBJECTIVES: The primary objective of this study was to describe treatment patterns after poly-ADP ribose polymerase (PARP) inhibitor in patients with epithelial ovarian cancer. Secondary objectives were to evaluate duration of response, time to first subsequent therapy, progression-free survival and overall survival. METHODS: This was a retrospective analysis of patients with epithelial ovarian cancer treated with PARP inhibitor therapy at six Australian gynecological oncology centers. Eligible patients were identified via clinics, trial databases and pharmacy dispensing logs between January 2005 and September 2019. Information regarding clinico-pathological characteristics and treatment outcomes were collated from medical records. RESULTS: A total of 85 patients with epithelial ovarian cancer were identified. Of these, 61% had germline BRCA1/2 mutations, 9% had somatic BRCA1/2 mutations, 5% had confirmed homologous recombination deficiency and 25% were BRCA1/2 wildtype mutations. A total of seventy-seven (91%) patients received chemotherapy after PARP inhibitor, with fifty-six (72.7%) of these patients receiving platinum-based chemotherapy. Four patients (5%) had a complete response, 15 (20%) a partial response, 15 (20%) stable disease and 41 (55%) progressive disease. Median duration of response to chemotherapy was 7.0 months (range 0.2-20.4). Median time to first subsequent therapy was 17.6 and 15.1 months in patients who received a PARP inhibitor as maintenance therapy and treatment, respectively. Median progression-free survival of first line treatment after PARP inhibitor was 9.6, 3.5 and 4.6 months for platinum doublet, single agent platinum and non-platinum chemotherapy, respectively. Adjusting for age and FIGO (Federation of Gynecological Oncologists classification) stage progression-free survival did not differ between treatment groups (p=0.14). Median overall survival for the cohort was 69 months, and patients with platinum sensitive ovarian cancer had improved survival compared with those with platinum refractory or resistant disease. CONCLUSION: Platinum doublet chemotherapy resulted in non-significant improved progression-free survival compared with other regimens, suggesting potential independent mechanisms of resistance between PARP inhibitor and platinum compounds.

Clinical, FDG-PET and molecular markers of immune checkpoint inhibitor response in patients with metastatic Merkel cell carcinoma.

BACKGROUND: Metastatic Merkel cell carcinoma (mMCC) is an aggressive neuroendocrine malignancy of the skin with a poor prognosis. Immune checkpoint inhibitors (ICIs) have shown substantial efficacy and favorable safety in clinical trials. METHODS: Medical records of patients (pts) with mMCC treated with ICIs from August 2015 to December 2018 at Peter MacCallum Cancer Centre in Australia were analyzed. Response was assessed with serial imaging, the majority with FDG-PET/CT scans. RNA sequencing and immunohistochemistry for PD-L1, CD3 and Merkel cell polyomavirus (MCPyV) on tumor samples was performed. RESULTS: 23 pts with mMCC were treated with ICIs. A median of 8 cycles (range 1 to 47) were administered, with treatment ongoing in 6 pts. Objective responses (OR) were observed in 14 pts (61%): 10 (44%) complete responses (CR) and 4 (17%) partial responses (PR). Median time to response was 8 weeks (range 6 to 12) and 12-month progression-free survival rate was 39%. Increased OR were seen in pts aged less than 75 (OR 80% vs 46%), no prior history of chemotherapy (OR 64% vs 50%), patients with an immune-related adverse event (OR 100% vs 43%) and in MCPyV-negative tumors (OR 69% vs 43%). Pts with a CR had lower mean metabolic tumor volume on baseline FDG-PET/CT scan (CR: 35.7 mL, no CR: 187.8 mL, p=0.05). There was no correlation between PD-L1 positivity and MCPyV status (p=0.764) or OR (p=0.245). 10 pts received radiation therapy (RT) during ICI: 4 pts started RT concurrently (OR 75%, CR 50%), 3 pts had isolated ICI-resistant lesions successfully treated with RT and 3 pts with multisite progression continued to progress despite RT. Overall, 6 pts (26%) had grade 1-2 immune-related adverse events. CONCLUSION: ICIs showed efficacy and safety in mMCC consistent with trial data. Clinical and imaging predictors of response were identified.

Noncanonical IL6 Signaling-Mediated Activation of YAP Regulates Cell Migration and Invasion in Ovarian Clear Cell Cancer.

Ovarian clear cell adenocarcinoma (OCCA) is characterized by a particularly poor response to conventional chemotherapy and a short overall survival time in women with established disease. The development of targeted treatments for OCCA relies on a better understanding of its molecular characteristics. IL6 is strongly expressed in OCCA and may therefore provide a novel therapeutic target. Here we use CRISPR/Cas9 and conditional short hairpin interfering RNA to perform loss-of-function studies in human OCCA cell lines to explore the requirement for IL6 in vitro and in vivo. While reduction of IL6 expression exerted limited effects in vitro, its attenuation significantly impaired tumor growth and neovascularization in vivo. In contrast to typical signaling via STAT3, IL6 in OCCA signaled via a noncanonical pathway involving gp130, Src, and the Hippo pathway protein YAP. A high-throughput combination drug screen identified agents that enhanced cell killing following reduction of IL6 signaling. Intersection of screen hits obtained from two cell lines and orthogonal approaches to attenuation of IL6 yielded AKT and EGFR inhibitors as enhancers of the inhibitory monoclonal IL6 receptor antibody tocilizumab. This study defines for the first time the requirements for, and mechanisms of, signaling by IL6 in human OCCA cell lines and identifies potential combinatory therapeutic approaches. Given the molecular diversity of OCCA, further in vitro and in vivo studies are warranted to determine whether such approaches will overcome the limited efficacy of tocilizumab observed in ovarian cancer to date. SIGNIFICANCE: This study defines the requirements for and mechanisms of noncanonical signaling by IL6 in human ovarian clear cell adenocarcinoma cell lines and identifies combinatory therapeutic approaches to be explored clinically.

Efficacy of immune checkpoint inhibitors for in-transit melanoma.

BACKGROUND: The efficacy of immune checkpoint inhibitors (ICI) in metastatic melanoma is well established. However, there are limited data regarding their efficacy in in-transit melanoma (ITM). This study assessed the efficacy of ICI in patients with ITM. METHODS: A retrospective review of patients with ITM commenced on an ICI between March 2013 and February 2018 at three tertiary centers in Australia. Patients were excluded if they had previous or synchronous distant metastases. Overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) were based on a composite of radiological and clinical assessments. RESULTS: Fifty-four patients were included: 27 (50%) female; median age 75 (range 26-94); 12 (22%) stage IIIB, 40 (74%) stage IIIC and 2 (4%) stage IIID; 10 (19%) BRAF mutant. Forty (74%) received single-agent anti-PD-1 (pembrolizumab or nivolumab), 8 (15%) single agent anti-CTLA-4 (ipilimumab), 5 (9%) combination anti-PD-1/anti-CTLA-4 (ipilimumab and nivolumab or pembrolizumab) and 1 (2%) combination anti-PD-L1 (atezolizumab) and MEK inhibitor (cobimetinib). The median follow-up was 15 months (2-46).ORR to ICI was 54%: 14 (26%) complete responses; 15 (28%) partial responses; 9 (17%) stable disease; 16 (30%) progressive disease. Thirteen (46%) responders had only one ITM lesion. ORR was 58% for single-agent anti-PD-1, 38% for single-agent anti-CTLA4 and 40% for anti-PD-1/anti-CTLA-4. The median PFS was 11.7 months (6.6-not reached). 1-year and 2-year PFS were 48% and 39%, respectively,. Fourteen progressed locoregionally and 11 progressed distantly. The median OS was not reached. 1-year and 2-year OS were 85% and 63%, respectively. No clinicopathological features were associated with ORR. CONCLUSIONS AND RELEVANCE: ICI produce objective responses in ITM and should be considered in patients with unresectable ITM or disease recurrence.

FDG PET/CT for tumoral and systemic immune response monitoring of advanced melanoma during first-line combination ipilimumab and nivolumab treatment.

PURPOSE: We aimed to investigate the role of FDG-PET/CT in monitoring of response and immune-related adverse events (irAEs) following first-line combination-immune checkpoint inhibitor (combination-ICI) therapy for advanced melanoma. METHODS: We retrospectively reviewed outcomes in patients who had (1) first-line nivolumab plus ipilimumab; (2) pre- and post-treatment FDG-PET/CT scans (pre-FDG-PET/CT and post-FDG-PET/CT) within 2 and 4 months of starting ICI, respectively; and (3) at least one lesion assessable by PET response criteria in solid tumors (PERCIST). Extracranial response was monitored by 3 monthly FDG-PET/CT. Whole-body metabolic tumor volume (wbMTV) was measured pre- and post-treatment and correlated with outcome. FDG-PET/CT manifestations of irAE were defined as new increased non-tumoral uptake on post-FDG-PET/CT and were correlated with clinical presentation. RESULTS: Thirty-one consecutive patients, median age 60 years (range, 30-78), were identified from 2016 to 2018. The median number of combination-ICI cycles to the first post-FDG-PET/CT response assessment was 3 (interquartile range (IQR), 2-4). The best-overall responses were complete metabolic response (CMR) in 25 (80%), partial metabolic response (PMR) in 3 (10%), and progressive metabolic disease (PMD) in 3 (10%) patients. Patients with PMD had significantly higher pre-treatment wbMTV (p = 0.009). At a median follow-up of 21.5 months, 26 (84%) patients were alive with median progression-free and overall survival not reached. Secondary progression occurred in 9/31 (29%) patients at a median of 8.2 months (IQR, 6.9-15.5), of those majority (78%) was detected by FDG-PET/CT. Of 36 findings on post-FDG-PET/CT suggestive of irAE, 29 (80%) had clinical confirmation. In 3 (7%), the FDG-PET/CT findings preceded clinical presentation. The most common FDG-PET/CT detectable irAEs were endocrinopathies (36%) and enterocolitis (35%). CONCLUSION: FDG-PET/CT response evaluation predicts the long-term outcome of patients treated with first-line combination-ICIs. Long-term treatment response monitoring for detection of extracranial secondary progression is feasible by FDG-PET/CT. Beyond response assessment, FDG-PET/CT frequently detects clinically relevant irAEs, which may involve multiple systems contemporaneously or at various time-points and may precede clinical diagnosis.

i-Move, a personalised exercise intervention for patients with advanced melanoma receiving immunotherapy: a randomised feasibility trial protocol.

INTRODUCTION: There is increasing evidence demonstrating the benefits of exercise in counteracting cancer treatment-related fatigue. Immunotherapy is an established treatment for advanced melanoma, and is associated with fatigue in a third of patients. The safety and efficacy of exercise in counteracting treatment-related fatigue in patients with advanced melanoma receiving immunotherapy are yet to be determined. This study aims to assess the safety, adherence to and acceptability of a mixed-methods parallel-group, pilot randomised controlled trial of a personalised, 12-week semi-supervised exercise programme prescribed by an exercise physiologist (iMove) in 30 patients with stage IV melanoma scheduled to commence immunotherapy: single agent ipilimumab, nivolumab or pembrolizumab, or combination ipilimumab and nivolumab. The trial will be used to provide preliminary evidence of the potential efficacy of exercise for managing fatigue. METHODS AND ANALYSIS: Thirty participants will be recruited from a specialist cancer centre between May and September, 2019. Participants will be randomised 1:1 to receive iMove, or usual care (an information booklet about exercise for people with cancer). Feasibility data comprise: eligibility; recruitment and retention rates; adherence to and acceptability of exercise consultations, personalised exercise programme and study measures; and exercise-related adverse events. Patient-reported outcome measures assess potential impact of the exercise intervention on: fatigue, role functioning, symptoms and quality of life. Follow-up will comprise five time points over 24 weeks. Physical assessments measure physical fitness and functioning. ETHICS AND DISSEMINATION: This study was reviewed and approved by the Peter MacCallum Cancer Centre Human Research Ethics Committee (HREC/48927/PMCC-2019). The findings from this trial will be disseminated via conference presentations and publications in peer-reviewed journals, and by engagement with clinicians, media, government and consumers. In particular, we will promote the outcomes of this work among the oncology community should this pilot indicate benefit for patients. TRIAL REGISTRATION NUMBER: ACTRN12619000952145; Pre-results.