AIM:Merkel Cell Carcinoma (MCC) is a rare skin cancer with a rising incidence worldwide. Anti-programmed death-1/ligand-1 (anti-PD-(L)1) therapies are effective for the treatment of advanced MCC. This study examines patterns of response / progression of advanced MCC to anti-PD-(L)1 therapies and describes subsequent management. METHOD:This is a multi-centre international retrospective cohort study with data collected up to May 2023 from 17 centres across 6 countries. Outcomes included objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) for anti-PD-(L)1 and subsequent therapy. RESULTS:One-hundred and eighty-five advanced MCC patients received anti-PD-(L)1 therapy. At median follow-up of 28.7 months (95 % CI: 21.4-38.3), ORR was 57.3 %, median DOR was 42.8 months (95 % CI, 25.8 - not reached (NR)), median PFS was 14 months (95 % CI, 8.1- 19.8), and median OS was 42.8 months (95 % CI, 30.3 - NR). One-hundred and eight patients (59 %) experienced progressive disease; 50 % (n = 54/108) with primary resistance and 26 % (n = 28/108) with secondary resistance. Fifty patients (27 %; n = 50/185) received subsequent systemic therapies (+/- local therapy) with response data; 18 (36 %; n = 18/50) received doublet platinum chemotherapy (ORR 67 %, DOR 5.0 months [95 % CI; 3.7 - NR]) and 16 (32 %; n = 16/50) were rechallenged with anti-PD-(L)1 (ORR 56 %, DOR 20.2 months [95 % CI; 8.3 - NR]). CONCLUSION:The most common subsequent treatment for patients with primary resistance was chemotherapy, while those with secondary resistance most frequently underwent further anti-PD-(L)1 therapy in combination with other therapies. Despite both therapies demonstrating promising ORR, doublet platinum chemotherapy had a poorer DOR compared to anti-PD-(L)1 rechallenge.

BACKGROUND:Australia has one of the highest rates of asbestos-associated diseases. Mesothelioma remains an area of unmet need with a 5-year overall survival of 10%. First-line immunotherapy with ipilimumab and nivolumab is now a standard of care for unresectable pleural mesothelioma following the CheckMate 743 trial, with supportive data from the later line single-arm MAPS2 trial. RIOMeso evaluates survival and toxicity of this regimen in real-world practice. METHODS:Demographic and clinicopathologic data of Australian patients treated with ipilimumab and nivolumab in first- and subsequent-line settings for pleural mesothelioma were collected retrospectively. Survival was reported using the Kaplan-Meier method and compared between subgroups with the log-rank test. Toxicity was investigator assessed using Common Terminology Criteria for Adverse Events version 5.0. RESULTS:A total of 119 patients were identified from 11 centers. The median age was 72 years, 83% were male, 92% had Eastern Cooperative Oncology Group less than or equal to 1, 50% were past or current smokers, and 78% had known asbestos exposure. In addition, 50% were epithelioid, 19% sarcomatoid, 14% biphasic, and 17% unavailable. Ipilimumab and nivolumab were used first line in 75% of patients. Median overall survival (mOS) was 14.5 months (95% confidence interval [CI]: 13.0-not reached [NR]) for the entire cohort. For patients treated first line, mOS was 14.5 months (95% CI: 12.5-NR) and in second- or later-line patients was 15.4 months (95% CI: 11.2-NR). There was no statistically significant difference in mOS for epithelioid patients compared with nonepithelioid (19.1 mo [95% CI: 15.4-NR] versus 13.0 mo [95% CI: 9.7-NR], respectively, p = 0.064). Furthermore, 24% of the patients had a Common Terminology Criteria for Adverse Events grade greater than or equal to 3 adverse events, including three treatment-related deaths. Colitis was the most frequent adverse event. CONCLUSIONS:Combination immunotherapy in real-world practice has poorer survival outcomes and seems more toxic compared with clinical trial data. This is the first detailed report of real-world survival and toxicity outcomes using ipilimumab and nivolumab treatment of pleural mesothelioma.

Australia historically has one of the highest rates of asbestos use and asbestos-associated diseases. Mesothelioma remains an area of unmet need with a 5-yr overall survival (OS) of 10%. First line combination immunotherapy with nivolumab and ipilimumab is now standard of care for unresectable pleural mesothelioma based on outcomes of the front line CheckMate743 trial, with supportive data from the later line single arm MAPS2 trial. The RIOMeso study examines survival and toxicity of this regimen in real-world practice.

Introduction: Treatment of oesophageal (OC), gastro-oesophageal junction (GOJ), and gastric cancer (GC) includes either neoadjuvant Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) for OC or GOJ or perioperative 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) for OC, GOJ, and GC adenocarcinomas. This study aims to describe the real-world outcomes of patients with GC, GOJ, and OC treated with FLOT or CROSS and identify variables associated with efficacy through exploratory analysis. We also aimed to evaluate the comparison of FLOT and CROSS for the treatment of OC and GOJ adenocarcinomas. Methods: This is a retrospective observational study of patients with locally advanced OC, GOJ, or GC treated with FLOT or CROSS between January 2015 and June 2021 in 5 cancer centres across Sydney, Australia. Long-rank test was used to compare survival estimated between subgroups. Hazard ratios for univariate and multivariate analyses were estimated with Cox proportional regression. Results: The study included 168 patients. The 24-month relapse-free survival (RFS) and overall survival (OS) for FLOT were 59% and 69%, respectively. The median RFS was 29.6 months and median OS was not reached. For CROSS, the 24-month RFS and OS were 55% and 63% with a median RFS and OS of 28.5 and 40.2 months, respectively. There was no difference in OS and RFS between the treatments. FLOT was less tolerable than CROSS with more dose reductions, treatment discontinuation, and clinically relevant grade 3 and 4 toxicity. Neutrophil lymphocyte ratio was associated with survival for both treatments. Conclusion: Similar efficacy outcomes were seen in this real-world population compared to the clinical trials for FLOT and CROSS.

Abstract BACKGROUND Astrocytomas display molecular heterogeneity with prognostic implications for genomic alterations, including IDH, EGFR, TERT promoter and CDKN2A/B. Increasing access to comprehensive genomic profiling (CGP) provides an opportunity to characterize the genomic landscape of these tumors and their clinical implications. METHODS Patients with astrocytomas undergoing CGP through the Australian Molecular Screening and Therapeutics (MoST) precision oncology program between March 2017 and January 2022 were identified; the frequencies of genomic alterations were assessed. Associations between overall survival (OS) and alterations in EGFR, TERT promoter and/or CDKN2A/B were estimated using Kaplan-Meier methods. RESULTS 214 patients with astrocytomas were included. Median age was 49 years; majority were ECOG performance status 0-1 at screening (N=200/214, 93%) and histologically grade 4 (N=184/214, 86%). The median OS (mOS) for the cohort was 26.2mo (95%CI 24.0-31.5). For histologically grade 2/3 IDH-mutant tumors, mOS was 31.3mo (N=1) and 122.6mo (N=11, 95%CI 110-NA) for those with or without alterations in EGFR, TERT promoter and/or CDKN2A/B, respectively. For histologically grade 2/3 IDH-wildtype tumors, mOS was 19.9mo (N=7, 95%CI 15.8-NA) and 118.5mo (N=10, 95%CI 77.3-NA), respectively. For histologically grade 4 IDH-mutant tumors, mOS was 81.3mo (N=4, 95%CI 32.7-NA) and 82.8mo (N=15, 95%CI 71.0-NA), respectively. For histologically grade 4 IDH-wildtype tumors, mOS was 19.6mo (N=120 [56% TERT promoter, 42% EGFR, 14% CDKN2A/B], 95%CI 18.0-24.8) compared to 32.1mo (N=45, 95%CI 22.0-58.6; logrank P=0.0015), respectively. In grade 4 IDH-wildtype tumors additional co-occurring alterations involved PTEN (39%), TP53 (33%), NF1 (21%), RB1 (13%), CDK4 (13%) and PIK3CA (5%) genes. For the overall cohort, potentially actionable variants were seen in BRAF (5%), KIT (5%), MSH2 (2%), FGFR1 (1%) and FGFR3 (4%). Tumor mutational burden was ≥5 mutations/ megabase in 14%, without significant OS impact. CONCLUSION CGP provides additional prognostic information that complements histological grading. This demonstrates an emerging role in understanding the molecular heterogeneity of astrocytomas.

Background Neoadjuvant carboplatin and paclitaxel with radiotherapy (CROSS) and perioperative docetaxel, oxaliplatin, calcium folinate and fluorouracil (FLOT) are widely used for gastric (GC), gastro-oesophageal junction (GOJ) and oesophageal cancers (OC). Prognostic and predictive markers for response and survival outcomes are lacking. This study evaluates dynamic neutrophil-lymphocyte ratios (NLR), platelet-lymphocyte ratios (PLR), albumin and body mass index (BMI) as predictors of survival, response and toxicity. Methods This multi-centre retrospective observational study across 5 Sydney hospitals included patients receiving CROSS or FLOT from 2015 to 2021. Haematological results and BMI were recorded at baseline and pre-operatively, and after adjuvant treatment for FLOT. Toxicities were also recorded. An NLR ≥2 and PLR ≥200 was used to stratify patients. Univariate and multivariate analyses were performed to determine predictors of overall survival (OS), disease free survival (DFS), rates of pathological complete response (pCR) and toxicity. Results One hundred sixty-eight patients were included (95 FLOT, 73 FLOT). A baseline NLR ≥2 was predictive for worse DFS (HR 2.78, 95% CI: 1.41–5.50, P<0.01) and OS (HR 2.90, 95% CI: 1.48–5.67, P<0.01). Sustained elevation in NLR was predictive for DFS (HR 1.54, 95% CI: 1.08–2.17, P=0.01) and OS (HR 1.65, 95% CI: 1.17–2.33, P<0.01). An NLR ≥2 correlated with worse pCR rates (16% for NLR ≥2, 48% for NLR <2, P=0.04). A baseline serum albumin <33 was predictive of worse DFS and OS with a HR of 6.17 (P=0.01) and 4.66 (P=0.01) respectively. Baseline PLR, BMI, and dynamic changes in these markers were not associated with DFS, OS or pCR rates. There was no association of the aforementioned variables with toxicity. Conclusions This demonstrates that a high inflammatory state represented by an NLR ≥2, both at baseline and sustained, is prognostic and predictive of response in patients receiving FLOT or CROSS. Baseline hypoalbuminaemia is predictive of poorer outcomes.

Small-cell lung cancer (SCLC) is an aggressive disease with distinct biological and clinical features. The clinical course of SCLC is generally characterised by initial sensitivity to DNA-damaging therapies, followed by early relapse and broad cross resistance to second line agents. Whilst there has been an enormous expansion of effective targeted and immune-based therapeutic options for non-small cell lung cancer (NSCLC) in the last decade, little improvement has been achieved in SCLC treatment and survival due, at least in part, to underappreciated inter- and intra-tumoral heterogeneity. Here we review the current treatment paradigm of SCLC including recent advances made in utilizing immunotherapy and the challenges of identifying a predictive biomarker for immunotherapy response. We examine emerging new targeted therapies, combination immunotherapy and future directions of SCLC treatment research.

Peri-operative 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) or neoadjuvant carboplatin, paclitaxel with radiation (CROSS) has become the standard of care for locally advanced gastro-oesophageal junction (GOJ) and oesophageal cancer (OC). Currently head to head comparisons of the 2 regimens are lacking. This study aims to evaluate, using real-world data, the efficacy and toxicity difference of FLOT and CROSS for the treatment of GOJ and OC adenocarcinomas. This is a retrospective multi-center observation study of patients from 5 centres in Western Sydney with locally advanced histological confirmed GOJ or OC adenocarcinoma treated with FLOT or CROSS between 2015 and 2021. Treatment recommendations were based on expert consensus from multidisciplinary team meetings. Overall survival (OS) was defined from time of diagnosis (TOD) to death from any cause. Relapse free Survival (RFS) was defined from TOD to first occurrence of disease progression, relapse, or death. Log-rank test was used to estimate a difference between OS/RFS. Hazard ratios for univariate and multivariate analysis was estimated using cox-proportional hazard. Toxicity was graded as per the Common Terminology Criteria for Adverse Events version 5.0. Of the 104 patients, 34 (33%) received FLOT and 70 (67%) had CROSS. There was no difference in OS or RFS between treatments. The hazard ratio for death for FLOT compared to CROSS on univariate and multivariate analysis was 0.97 (95% CI 0.49-1.95 p-value>0.9) and 1.33 (95% CI 1.33(0.39-4.49, p=0.649) respectively. No significant difference in complete pathological response (20% (CROSS), 30% (FLOT)) was seen. Recurrence occurred in 41% (79% distant) of CROSS treated patients compared to 32% (63% distant) in FLOT. 85% and 29% of FLOT treated patients completed 4 and 8 cycles of treatment, respectively(vs 75% completing CROSS treatment). Patients receiving FLOT had more statistically significant clinically relevant grade 2 and 3 toxicity than those with CROSS. CROSS and FLOT had similar efficacy outcomes in the treatment of GOJ and OC adenocarcinoma. However FLOT appeared to be less well tolerated with more discontinuations.

Background: Langerhans cell histiocytosis (LCH) is a rare neoplasm involving proliferation of langerin-positive (CD207+) histiocytes. LCH has a broad spectrum of presentations from indolent single organ disease to systemic multi-organ disease. Recent studies have reported BRAF V600E mutations occurring in 55% of cases of LCH.1