Completion of Pembrolizumab in Advanced Non-Small Cell Lung Cancer-Real World Outcomes After Two Years of Therapy (COPILOT).

BACKGROUND: Seminal trials with first-line pembrolizumab for metastatic non-small cell lung cancer (NSCLC) mandated a maximum two-years treatment. We describe real-world outcomes of a multi-site Australian cohort of patients who completed two-years of pembrolizumab. METHODS: Retrospective data were collected from the national AUstralian Registry and biObank of thoRacic cAncers (AURORA). Primary endpoints were progression rate post pembrolizumab discontinuation; and progression free survival (PFS). Local treatment of oligoprogressive disease during pembrolizumab was allowed. RESULTS: A total of 71 patients from six centers, median age 66.0 years, 49% male and 90% ECOG ≤ 1 were identified. Patients were Caucasian (82%) or Asian (16%); past (66%) or current (24%) smokers with mean 37 pack-years. Histology comprised 73% adenocarcinoma and 16% squamous. 18 patients (25%) had brain metastases at diagnosis. Median PD-L1 tumor proportion score (TPS) was 68%; 12 patients (17%) TPS < 1% and 43 (61%) TPS ≥ 50%. No patients had EGFR/ALK/ROS1 alterations; 29/49 tested (60%) had KRAS mutations. Median follow up was 38.7 months. Objective response rate 78.6%. Median PFS 46.1 months (95% CI 39.5-NR), not reached (46.1-NR) in PD-L1 TPS ≥ 1% versus 28.1 months (16.3-NR) in TPS < 1% (P = .013). 17 patients (24%) received additional local therapy for oligoprogression. Post pembrolizumab discontinuation, 20 patients (28%) had disease progression. Higher rates of progression occurred with TPS < 1% (OR 3.46, P = .06), without complete response (OR 5.06, P = .04), and with treated oligoprogression (OR 3.11, P = .05). 36-month landmark survival was 98.2%. CONCLUSION: Patients completing two-years of pembrolizumab for NSCLC in an Australian cohort had high rates of KRAS mutation and PD-L1 expression; a proportion had brain metastases and treated oligoprogression. Progression post pembrolizumab was higher in PD-L1 TPS < 1% and in those without complete response.

Phase 1a dose escalation study of ivonescimab (AK112/SMT112), an anti-PD-1/VEGF-A bispecific antibody, in patients with advanced solid tumors.

BACKGROUND: Studies showed that vascular endothelial growth factor (VEGF) inhibitors could improve therapeutic efficacy of PD-1/PD-L1 antibodies by transforming the immunosuppressive tumor microenvironment (TME) into an immunoresponsive TME. Ivonescimab is a first-in-class, humanized tetravalent bispecific antibody targeting PD-1 and VEGF-A simultaneously. Here, we report the first-in-human, phase 1a study of ivonescimab in patients with advanced solid tumors. METHODS: Patients with advanced solid tumors were treated with ivonescimab 0.3, 1, 3, 10, 20 or 30 mg/kg intravenously every 2 weeks using a 3+3+3 dose escalation design. Dose expansion occurred at 10 and 20 mg/kg in selected tumor types. The primary objective was to assess the safety and tolerability, and to determine the maximum tolerated dose (MTD). The secondary objectives included pharmacokinetics, pharmacodynamics and preliminary antitumor activity based on Response Evaluation Criteria in Solid Tumors V.1.1. RESULTS: Between October 2, 2019 and January 14, 2021, a total of 51 patients were enrolled and received ivonescimab. Two dose-limiting toxicities were reported at 30 mg/kg. The MTD of ivonescimab was 20 mg/kg every 2 weeks. Grade≥3 treatment-related adverse events (TRAEs) occurred in 14 patients (27.5%). The most common TRAEs of any grade were rash (29.4%), arthralgia (19.6%), hypertension (19.6%), fatigue (17.6%), diarrhea (15.7%) and pruritus (11.8%). The most common grade≥3 TRAEs were hypertension (7/51, 13.7%), alanine aminotransferase increased (3/51, 5.2%), aspartate aminotransferase increased (2/51, 3.9%) and colitis (2/51, 3.9%). Of 47 patients who had at least one postbaseline assessment, the confirmed objective response rate was 25.5% (12/47) and disease control rate was 63.8% (30/47). Among 19 patients with platinum-resistant ovarian cancer, 5 patients (26.3%) achieved partial response (PR). Efficacy signals were also observed in patients with mismatch repair proficient (pMMR) colorectal cancer, non-small cell lung cancer, and both MMR deficient and pMMR endometrial cancer. CONCLUSIONS: Ivonescimab demonstrated manageable safety profiles and promising efficacy signals in multiple solid tumors. Exploration of alternative dosing regimens of ivonescimab monotherapy and combination therapies is warranted. TRIAL REGISTRATION NUMBER: NCT04047290.

First-line chemoimmunotherapy and immunotherapy in patients with non-small cell lung cancer and brain metastases: a registry study.

Introduction: Brain metastases commonly occur in patients with non-small cell lung cancer (NSCLC). Standard first-line treatment for NSCLC, without an EGFR, ALK or ROS1 mutation, is either chemoimmunotherapy or anti-PD-1 monotherapy. Traditionally, patients with symptomatic or untreated brain metastases were excluded from the pivotal clinical trials that established first-line treatment recommendations. The intracranial effectiveness of these treatment protocols has only recently been elucidated in small-scale prospective trials. Methods: Patients with NSCLC and brain metastases, treated with first-line chemoimmunotherapy or anti-PD-1 monotherapy were selected from the Australian Registry and biObank of thoracic cancers (AURORA) clinical database covering seven institutions. The primary outcome was a composite time-to-event (TTE) outcome, including extracranial and intracranial progression, death, or need for local intracranial therapy, which served as a surrogate for disease progression. The secondary outcome included overall survival (OS), intracranial objective response rate (iORR) and objective response rate (ORR). Results: 116 patients were included. 63% received combination chemoimmunotherapy and 37% received anti-PD-1 monotherapy. 69% of patients received upfront local therapy either with surgery, radiotherapy or both. The median TTE was 7.1 months (95% CI 5 - 9) with extracranial progression being the most common progression event. Neither type of systemic therapy or upfront local therapy were predictive of TTE in a multivariate analysis. The median OS was 17 months (95% CI 13-27). Treatment with chemoimmunotherapy was predictive of longer OS in multivariate analysis (HR 0.35; 95% CI 0.14 - 0.86; p=0.01). The iORR was 46.6%. The iORR was higher in patients treated with chemoimmunotherapy compared to immunotherapy (58% versus 31%, p=0.01). The use of chemoimmunotherapy being predictive of iORR in a multivariate analysis (OR 2.88; 95% CI 1.68 - 9.98; p=0.04). Conclusion: The results of this study of real-world data demonstrate the promising intracranial efficacy of chemoimmunotherapy in the first-line setting, potentially surpassing that of immunotherapy alone. No demonstrable difference in survival or TTE was seen between receipt of upfront local therapy. Prospective studies are required to assist clinical decision making regarding optimal sequencing of local and systemic therapies.

Systematic Review of Preoperative Prognostic Biomarkers in Perihilar Cholangiocarcinoma.

Perihilar cholangiocarcinoma (pCCA) is an uncommon malignancy with generally poor prognosis. Surgery is the primary curative treatment; however, the perioperative mortality and morbidity rates are high, with a low 5-year survival rate. Use of preoperative prognostic biomarkers to predict survival outcomes after surgery for pCCA are not well-established currently. This systematic review aimed to identify and summarise preoperative biomarkers associated with survival in pCCA, thereby potentially improving treatment decision-making. The Embase, Medline, and Cochrane databases were searched, and a systematic review was performed using the PRISMA guidelines. English-language studies examining the association between serum and/or tissue-derived biomarkers in pCCA and overall and/or disease-free survival were included. Our systematic review identified 64 biomarkers across 48 relevant studies. Raised serum CA19-9, bilirubin, CEA, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and tumour MMP9, and low serum albumin were most associated with poorer survival; however, the cutoff values used widely varied. Several promising molecular markers with prognostic significance were also identified, including tumour HMGA2, MUC5AC/6, IDH1, PIWIL2, and DNA index. In conclusion, several biomarkers have been identified in serum and tumour specimens that prognosticate overall and disease-free survival after pCCA resection. These, however, require external validation in large cohort studies and/or in preoperatively obtained specimens, especially tissue biopsy, to recommend their use.

Real world efficacy and toxicity of consolidation durvalumab following chemoradiotherapy in older Australian patients with unresectable stage III non-small cell lung cancer.

INTRODUCTION: Consolidation durvalumab following platinum-based chemoradiotherapy (CRT) significantly improved overall survival for patients with unresectable stage III non-small cell lung cancer (NSCLC) in the PACIFIC trial. However, older patients were underrepresented in PACIFIC, and subsequent analyses suggested trends toward poorer survival and increased toxicity in patients aged ≥70 years old. We assessed the effectiveness and safety of consolidation durvalumab following CRT in older Australian patients with unresectable stage III NSCLC. MATERIALS AND METHODS: This retrospective observational study was conducted across seven sites in Sydney, Australia between January 2018 and September 2021. All adult patients with unresectable stage III NSCLC who received platinum-based chemoradiotherapy followed by at least one cycle of consolidation durvalumab were included. Older patients were defined as being ≥70 years old. RESULTS: Of 152 patients included in the analysis, 42.8% (n = 67) patients were 70 years or older. Median follow-up was 26.1 months. The two-year overall survival and median PFS was similar between older and younger patients. At two years, 74.8% (95% confidence interval [CI]: 65.4-84.2%) of patients <70 years old and 65.2% (95% CI: 53.4-77.0%) of older patients were alive (p = 0.07; hazard ratio [HR] 1.64, 95% CI: 0.95-2.81). Median progression-free survival (PFS) in patients <70 years was 30.3 months (95% CI: 22.2-38.4 months) compared with 26.7 months (95% CI: 12.8-40.6 months) in older patients (p = 0.22; HR 1.46, 95% CI: 0.80-2.65). Toxicity was also similar, with 11.5% of patients <70 years old and 18.5% of older patients experiencing grade 3-4 adverse events (AEs; p = 0.23); 16.1% and 24.6% of the patients, respectively, discontinued treatment due to toxicity (p = 0.19). Grade 3-4 AEs and treatment discontinuation were associated with Charlson Comorbidity Index >5 (p = 0.011) and chronic obstructive pulmonary disease diagnosis at presentation (p = 0.002), respectively. DISCUSSION: Older Australian patients receiving consolidation durvalumab following CRT experienced comparable outcomes to their younger peers. Comorbidity burden may be more important determinants of treatment tolerance than chronological age.

Influence of EGFR mutation status and PD-L1 expression in stage III unresectable non-small cell lung cancer treated with chemoradiation and consolidation durvalumab.

BACKGROUND: Consolidation durvalumab after concurrent chemoradiation is the standard of care for unresectable stage III non-small cell lung cancer (NSCLC) based on the PACIFIC trial. However, there have been reports in the literature suggesting the efficacy of the treatment differs in patients whose tumors harbor epidermal growth factor receptor (EGFR) mutations and in those with low programed death ligand-1 (PD-L1) expression. This study describes the survival outcomes for patients with unresectable stage III NSCLC treated with chemoradiation followed by durvalumab with a specific focus on EGFR mutation status and PD-L1 expression. METHODS: This retrospective observational study was conducted across six sites in Greater Sydney, Australia. It included all patients diagnosed with unresectable stage III NSCLC treated with chemoradiation and who received at least one cycle of durvalumab between January 2018 and September 2021. Patients were stratified according to EGFR mutation status and PD-L1 tumor proportion score (TPS) of 1%. RESULTS: Of the 145 patients included in the analysis, 15/145 (10%) patients harbored an EGFR mutation and 61/145 (42%) patients had PD-L1 TPS of <1%. At a median follow-up of 15.1 months from the start of durvalumab, median progression-free survival (PFS) in EGFR mutant versus wild-type patients was 7.5 and 33.9 months, respectively (hazard ratio [HR]: 2.7; 95% confidence intervals [95% CI] 1.2-5.7; p = .01). Overall survival (OS) was not different between EGFR mutant and wild-type patients. There was no statistically significant difference in PFS (HR .7, 95% CI .4-1.7, p = .43) or OS (HR .5, 95% CI .4-4.7, p = .16) between patients with PD-L1 TPS of <1% versus PD-L1 TPS of ≥1%. CONCLUSIONS: Our data adds to the growing evidence that suggests consolidation durvalumab after definitive chemoradiation may not be as efficacious in patients with EGFR-mutant tumors compared with EGFR wild-type NSCLC.

Brief Report: Real-World Toxicity and Survival of Combination Immunotherapy in Pleural Mesothelioma-RIOMeso.

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.

A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer.

The lysyl oxidase family represents a promising target in stromal targeting of solid tumors due to the importance of this family in crosslinking and stabilizing fibrillar collagens and its known role in tumor desmoplasia. Using small-molecule drug-design approaches, we generated and validated PXS-5505, a first-in-class highly selective and potent pan-lysyl oxidase inhibitor. We demonstrate in vitro and in vivo that pan-lysyl oxidase inhibition decreases chemotherapy-induced pancreatic tumor desmoplasia and stiffness, reduces cancer cell invasion and metastasis, improves tumor perfusion and enhances the efficacy of chemotherapy in the autochthonous genetically engineered KPC model, while also demonstrating antifibrotic effects in human patient-derived xenograft models of pancreatic cancer. PXS-5505 is orally bioavailable, safe and effective at inhibiting lysyl oxidase activity in tissues. Our findings present the rationale for progression of a pan-lysyl oxidase inhibitor aimed at eliciting a reduction in stromal matrix to potentiate chemotherapy in pancreatic ductal adenocarcinoma.

Feasibility of Microlearning for Improving the Self-Efficacy of Cancer Patients Managing Side Effects of Chemotherapy.

Lung cancer patients have a high symptom burden that negatively affects their quality of life. Increasing patient self-efficacy to deal with treatment side effects can ameliorate their symptom burden. Education programs can help enhance patient self-efficacy by giving patients more control over their condition through increased disease literacy. This study aimed to evaluate the feasibility of microlearning for delivering lung cancer patients' information on side effects of chemotherapy. Secondary objectives of the program are to understand the acceptability of microlearning for delivery this type of education to lung cancer patients and the potential impact of microlearning on patient self-efficacy, knowledge and confidence managing side effects of chemotherapy. A mixed-methods prepost test (or quasi-experimental) study design was used to better enable patients to identify and manage the side effects of their condition and chemotherapy. Participants were patients diagnosed with stage II to stage IV lung cancer, who had a life expectancy of greater than 3 months and were aged 18 years or older. Multiple validated scales were used to assess patient self-efficacy pre- and post-intervention. The online program was evaluated using quantitative data of completion rates extracted from the online platform. Semi-structured interviews were used to explore the impact of the online program on perceived self-efficacy and quality of life. Twenty-three participants agreed to participate in the study and five agreed to complete a semi-structured interview. Participants found the content comprehensive, relevant and engaging. The program improved perceived disease literacy and helped participants develop coping strategies to manage side effects. Participants also found the platform easy to use and navigate. Additional courses and features were requested. Patients with a diagnosis of cancer receive a large amount of information about the side effects of chemotherapy and how to manage them. This information is often provided soon after diagnosis or upon commencement of therapy, which can be overwhelming for some patients. Microlearning, a method of online learning that spaces distributing of content over several weeks, may be a useful tool for supporting delivering of health information to this group of patients.

Systematic Review of Single-Agent vs. Multi-Agent Chemotherapy for Advanced Pancreatic Adenocarcinoma in Elderly vs. Younger Patients.

PURPOSE: To systematically review all studies comparing multi-agent to single-agent chemotherapy in the first and second-line setting for unresectable pancreatic adenocarcinoma, so as to compare the outcomes of young and elderly patients. METHODS: This review searched three databases for relevant studies. The inclusion criteria were diagnosis of locally advanced or metastatic pancreatic adenocarcinoma, comparison of an elderly versus young population, comparison of single-agent versus multi-agent chemotherapy, data on survival outcomes, and randomised controlled trials. The exclusion criteria were phase I trials, incomplete studies, retrospective analyses, systematic reviews, and case reports. A meta-analysis was performed on second-line chemotherapy in elderly patients. RESULTS: Six articles were included in this systematic review. Three of these studies explored first-line treatment and three explored second-line treatment. In the subgroup analysis, the meta-analysis showed statistically improved overall survival for elderly patients receiving single-agent second-line treatment. CONCLUSIONS: This systematic review confirmed that combination chemotherapy improved survival in the first-line treatment of advanced pancreatic adenocarcinoma, regardless of age. The benefit of combination chemotherapy in second-line studies for elderly patients with advanced pancreas cancer was less clear.

Small-Cell Lung Cancer-An Update on Targeted and Immunotherapies.

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.

Identification and Characterisation of Infiltrating Immune Cells in Malignant Pleural Mesothelioma Using Spatial Transcriptomics.

Increasing evidence strongly supports the key role of the tumour microenvironment in response to systemic therapy, particularly immune checkpoint inhibitors (ICIs). The tumour microenvironment is a complex tapestry of immune cells, some of which can suppress T-cell immunity to negatively impact ICI therapy. The immune component of the tumour microenvironment, although poorly understood, has the potential to reveal novel insights that can impact the efficacy and safety of ICI therapy. Successful identification and validation of these factors using cutting-edge spatial and single-cell technologies may enable the development of broad acting adjunct therapies as well as personalised cancer immunotherapies in the near future. In this paper we describe a protocol built upon Visium (10x Genomics) spatial transcriptomics to map and characterise the tumour-infiltrating immune microenvironment in malignant pleural mesothelioma. Using ImSig tumour-specific immune cell gene signatures and BayesSpace Bayesian statistical methodology, we were able to significantly improve immune cell identification and spatial resolution, respectively, improving our ability to analyse immune cell interactions within the tumour microenvironment.

LOREALAUS: LOrlatinib REAL-World AUStralian Experience in Advanced ALK-Rearranged NSCLC.

Introduction: Over the past decade, ALK tyrosine kinase inhibitors have delivered unprecedented survival for individuals with ALK-positive (ALK+) lung cancers. Real-world data enhance the understanding of optimal drug sequencing and expectations for survival. Methods: Multicenter real-world study of individuals with pretreated advanced ALK+ lung cancers managed on a lorlatinib access program between 2016 and 2020. Key outcomes were lorlatinib efficacy, tolerability, and treatment sequencing. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method among all individuals (PFSa and OSa), with at least 30 days (one-cycle) lorlatinib exposure (PFSb and OSb), and with good performance status (PFSc and OSc). Subgroups of interest were analyzed to assess signals of potential clinical applicability. Two OS index dates were analyzed, from lorlatinib initiation and advanced ALK+ diagnosis. Results: The population (N = 38, 10 sites) was heavily pretreated (23 had ≥2 previous treatment lines) with a high disease burden (26 had 2-4 sites and 11 had >4 sites of metastatic disease, 19 had brain metastases). The overall response rate was 44% and the disease control rate was 81%. Lorlatinib dose reduction (18%), interruption (16%), and discontinuation (3%) were consistent with the trial experience. From advanced ALK+ diagnosis, the median OS for populations a, b, and c was 45.0 months, 69.9 months and 61.2 months respectively. From lorlatinib initiation, the median PFSa, PFSb and PFSc was 7.3 months, 13.2 months and 27.7 months and the median OSa, OSb and OSc was 19.9 months, 25.1 months and 27.7 months. The median PFSa with versus without brain metastases was 34.6 months versus 5.8 months (p = 0.09). The intracranial median PFS was 14.2 months. Previous good response versus poor response to the first ALK-directed therapy median PFSa was 27.7 months versus 4.7 months with a hazard ratio of 0.3 (p = 0.01). Conclusions: Lorlatinib is a potent, highly active brain-penetrant third-generation ALK tyrosine kinase inhibitors with benefits for most individuals in the later-line setting in a real-world evaluation, consistent with clinical trial data.

Use of durvalumab in stage III non-small-cell lung cancer based on eligibility for the PACIFIC study.

BACKGROUND: Durvalumab following concurrent chemoradiotherapy is standard treatment for unresectable stage III non-small-cell lung cancer based on the results of the PACIFIC trial. Based on trial criteria, not all patients are eligible for durvalumab in routine clinical practice. METHODS: We evaluated eligibility for durvalumab in a real-world clinical setting and the impact of eligibility on outcomes. Consecutive patients treated with concurrent chemoradiotherapy at two tertiary centers between January 2015 and June 2022 were assessed. Clinical characteristics and outcomes were evaluated based on eligibility criteria for the PACIFIC trial. RESULTS: A total of 126 patients were included. Seventy patients (56%) were eligible for durvalumab. Ineligibility was associated with shorter progression-free survival of 9.7 months versus 18.4 months (hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.39-0.95, p = 0.029) and overall survival of 26.4 months versus 58.7 months (HR 0.47, 95% CI 0.28-0.80, p = 0.005). Common reasons for ineligibility were history of previous malignancy (32%) and progressive disease or death during chemoradiotherapy (25%). Ineligible patients who received durvalumab had similar outcomes to eligible patients who received durvalumab. CONCLUSIONS: In a real-world cohort, adjuvant durvalumab is safe and beneficial in a substantial proportion of patients who would not have been eligible for the PACIFIC trial.

Use and outcomes from neoadjuvant chemotherapy in borderline resectable pancreatic ductal adenocarcinoma in an Australasian population.

BACKGROUND: Use of neoadjuvant (NA) chemotherapy is recommended when pancreatic ductal adenocarcinoma (PDAC) is borderline resectable METHOD: A retrospective analysis of consecutive patients with localized PDAC between January 2016 and March 2019 within the Australasian Pancreatic Cancer Registry (PURPLE, Pancreatic cancer: Understanding Routine Practice and Lifting End results) was performed. Clinicopathological characteristics, treatment, and outcome were analyzed. Overall survival (OS) comparison was performed using log-rank model and Kaplan-Meier analysis. RESULTS: The PURPLE database included 754 cases with localised PDAC, including 148 (20%) cases with borderline resectable pancreatic cancer (BRPC). Of the 148 BRPC patients, 44 (30%) underwent immediate surgery, 80 (54%) received NA chemotherapy, and 24 (16%) were inoperable. The median age of NA therapy patients was 63 years and FOLFIRINOX (53%) was more often used as NA therapy than gemcitabine/nab-paclitaxel (31%). Patients who received FOLFIRINOX were younger than those who received gemcitabine/nab-paclitaxel (60 years vs. 67 years, p = .01). Surgery was performed in 54% (43 of 80) of BRPC patients receiving NA chemotherapy, with 53% (16 of 30) achieving R0 resections. BRPC patients undergoing surgery had a median OS of 30 months, and 38% (9 of 24) achieved R0 resection. NA chemotherapy patients had a median OS of 20 months, improving to 24 months versus 10 months for patients receiving FOLFIRINOX compared to gemcitabine/nab-paclitaxel (Hazard Ratio (HR) .3, p < .0001). CONCLUSIONS: NA chemotherapy use in BRPC is increasing in Australia. One half of patients receiving NA chemotherapy proceed to curative resection, with 53% achieving R0 resections. Patients receiving Infusional 5-flurouracil, Irinotecan and Oxaliplatin (FOLIRINOX) had increased survival than gemcitabine/nab-paclitaxel. Treatment strategies are being explored in the MASTERPLAN and DYNAMIC-Pancreas trials.

Five-year survival and clinical correlates among patients with advanced non-small cell lung cancer, melanoma and renal cell carcinoma treated with immune check-point inhibitors in Australian tertiary oncology centres.

AIMS: There is robust trial evidence for improved overall survival (OS) with immunotherapy in advanced solid organ malignancies. The real-world long-term survival data and the predictive variables are not yet known. Our aim was to evaluate factors associated with 3-year and 5-year OS for patients treated with immune checkpoint inhibitors (ICIs). METHODS: We performed a retrospective study of patients who received ICIs as management of advanced solid organ malignancies in two tertiary Australian oncology centres from 2012-2017. Data pertaining to clinical characteristics, metastatic disease burden, immune-related adverse events (IRAEs) and tumour responses were collected and their relationship to survival examined. RESULTS: In this analysis of 264 patients, 202 (76.5%) had melanoma, 46 (17.4%) had non-small cell lung cancer (NSCLC), 12 (4.5%) had renal cell carcinoma (RCC) and 4 (1.5%) had mesothelioma. The 5-year OS rates were 42.1% in patients with melanoma, 19.6% with NSCLC, 75% with RCC, and none of the mesothelioma patients were alive at 5 years. In multivariate analysis, an ECOG score of 0 (Hazard ratio [HR] 0.39; 95% confidence interval [CI] 0.23-0.66; p < 0.001) and the occurrence of IRAE's of any grade (HR 0.61; 95% CI 0.37-0.95; p = 0.05) were associated with better 5-year survival. The presence of bone metastases (HR 1.62; 95% CI 1.03-2.82; p = 0.05) and liver metastases (HR 1.76; 95% CI 1.07-2.89; p = 0.03) were associated with worse 5-year survival. CONCLUSIONS: These results support the long-term benefits of immunotherapy that in some patients, extend to at least 5 years. ECOG performance status of 0 and the occurrence of irAEs are associated with better long-term survival. Survival is significantly influenced by metastatic site and cancer type. These predictive clinical correlates aid discussions and planning in the delivery of ICIs to patients.

Elevated neutrophil-to-lymphocyte ratio (NLR) is associated with poorer progression-free survival in unresectable stage III NSCLC treated with consolidation durvalumab.

Sustained elevation in neutrophil-to-lymphocyte ratio (NLR) after initial chemoradiotherapy (CRT) has been shown to correlate with worse prognosis in a number of solid organ malignancies. Here, we conducted a retrospective observational cohort study involving six sites across Sydney, Australia, including all patients with unresectable stage III NSCLC treated with CRT and consolidation durvalumab between January 2018 and September 2021. Patients had NLR collected prior to CRT and prior to cycle one of durvalumab. We used an NLR value of 3 to stratify patients into high and low groups. Patients with sustained NLR were defined as those with values ≥3 at both timepoints. A total of 145 patients were included in the study. The median age of patients was 66 years with median follow-up of 15.1 months. The median PFS was 17.6 months in the pre-CRT NLR high cohort and not reached (NR) in the pre-CRT NLR low cohort (HR 1.99; p = 0.01). The median OS was 35.5 months in the high pre-CRT NLR cohort compared with 42.0 months in the low pre-CRT NLR cohort (HR 2.62; 95% CI: 1.23-5.56, p < 0.01). Median PFS for sustained NLR elevation was 17.1 months versus NR (HR 1.5; p < 0.01). Pre-CRT NLR and sustained NLR remained independently prognostic for PFS on multivariate analysis (p = 0.04, p = 0.01) respectively. Pre-CRT NLR and sustained NLR is associated with worse PFS outcomes in unresectable stage III NSCLC treated with CRT and durvalumab. Pre-CRT NLR is also associated with worse OS.

Activin-A, Growth Differentiation Factor-11 and Transforming Growth Factor-ß as predictive biomarkers for platinum chemotherapy in advanced non-small cell lung cancer.

BACKGROUND: Despite advances in immunotherapy and targeted therapy, platinum-based chemotherapy remains crucial for many patients with advanced non-small cell lung cancer (NSCLC). Resistance to platinum chemotherapy is common, and predictive biomarkers are needed to tailor treatment to patients likely to respond. In vitro evidence implicates the transforming growth factor-ß (TGF-ß) superfamily ligands activin-A and growth differentiation factor 11 (GDF-11) in innate platinum resistance. We performed a validation study to assess their utility as predictive biomarkers of platinum chemotherapy response in advanced NSCLC. PATIENTS AND METHODS: Our study included 123 adult patients with advanced NSCLC without a driver mutation treated with platinum chemotherapy. 98 patients were from a retrospective cohort and 25 from a prospective cohort. We performed immunohistochemistry staining for Activin-A, GDF-11 and TGF-ß on tumour samples for each patient and analysed IHC expression with objective radiological response and overall survival. RESULTS: The overall median survival was 14.8 months. We performed statistical analysis around a cytoplasmic score of 8/18 for Activin-A and GDF-11 based on previously published work, and 110/30 for TGF-ß based on a calculated cutpoint for significance. No survival difference was detected between these groups for Activin-A (p=0.35), GDF-11 (p=0.57) or TGF-ß (p=0.34). There was no association between rates of progressive disease and high Activin-A expression (p=0.43), high GDF-11 expression (p=1.0) or high TGF-ß expression p=0.89). CONCLUSION: Within the confines of our study, Activin-A, GDF-11 and TGF-ß expression was not a predictor of objective radiological response to chemotherapy or overall survival.

The Management of Unresectable, Advanced Gastrointestinal Stromal Tumours.

Gastrointestinal stromal tumours (GISTs) are the most common gastrointestinal tract mesenchymal tumours. Tyrosine kinase inhibitors (TKIs) have transformed the management of advanced GIST. Imatinib was the first TKI to gain approval as management for patients with advanced GIST, establishing a new standard of care. Since then, as a result of several trials including the GRID and INVICTUS studies, we now have five lines of approved targeted therapy, including imatinib, sunitinib, regorafenib, ripretinib and avapritinib for the treatment of unresectable, advanced GISTs. In this review, the Australasian Gastrointestinal Trials Group (AGITG) provide an overview of the key trials that have changed clinical practice, discuss the molecular drivers of GISTs, the importance of molecular testing and directing therapy according to molecular targets, as well as future strategies in the management of advanced GISTs.