Purpose: Pancreatic ductal adenocarcinoma upregulates CD73, potentially contributing to immune surveillance evasion. Combining oleclumab (CD73 inhibitor) and durvalumab with chemotherapy may identify an effective treatment option. Patients and Methods: We describe a multicenter phase Ib/II randomized clinical trial in patients with metastatic pancreatic ductal adenocarcinoma, untreated (cohort A) or previously received gemcitabine-based chemotherapy (cohort B; NCT03611556). During escalation, patients received oleclumab 1,500 or 3,000 mg, durvalumab 1,500 mg, and gemcitabine plus nab-paclitaxel (GnP; cohort A; n = 14) or modified FOLFOX (cohort B; n = 11). During expansion, cohort A patients (n = 170) were randomized to GnP (arm A1), oleclumab [recommended phase II dose (RP2D)] with GnP (arm A2), or oleclumab (RP2D) with durvalumab plus GnP (arm A3). Primary objectives were safety (escalation) and objective response rate (expansion). Secondary objectives included progression-free survival (PFS) and overall survival (OS). Results: During escalation, 1/11 patients from cohort B (oleclumab 3,000 mg) experienced two dose-limiting toxicities. Oleclumab’s RP2D was 3,000 mg. During expansion, grade ≥3 treatment-related adverse events occurred in 67.7% (42/62) of patients in A1, 73.7% (28/38) in A2, and 77.1% (54/70) in A3. The objective response rate was 29.0%, 21.1%, and 32.9% in A1, A2, and A3, respectively (A1 vs. A3; P = 0.650). PFS [HR = 0.72; 95% confidence interval (CI), 0.47, 1.11] and OS (HR = 0.75; 95% CI, 0.50–1.13) were similar for A3 versus A1. Patients with high CD73 expression had improved PFS and OS in A3 versus A1, although this should be interpreted with caution. Conclusions: Although the safety profile was acceptable, this study did not meet its primary efficacy endpoint.

Purpose: Camrelizumab inhibits PD-1 in non-clinical models and showed typical non-clinical pharmacokinetic (PK) and safety profiles for an IgG4 monoclonal antibody. We report results from the First-in-Human Phase 1 trial of camrelizumab in Australian population. Methods: Camrelizumab was administered to patients with advanced solid tumors who had failed standard therapies. In the dose-escalation phase (n=23), camrelizumab was administered intravenously at 1 mg/kg, 3 mg/kg, 6 mg/kg, and 10 mg/kg every 2 weeks. In dose expansion (n=26), camrelizumab was given at 200 mg or 600 mg every 4 weeks. Results: Two dose-limiting toxicities were observed during dose escalation: transaminase elevation and diarrhea (both grade 3). Overall, treatment-related adverse events were consistent with the expected toxicity profile of immune checkpoint inhibition, with the striking exception of the dose-related development of angiomatous skin lesions characterized as reactive cutaneous capillary endothelial proliferation. The PK profile showed a dose-progressive increase in half-life from 3 days at 1 mg/kg to 7 days at 10 mg/kg. Moreover, receptor occupancy assays showed a PD-1 occupancy of > 50% in most patients out to 28 days post-dose. The objective response rate was 15.2% (95% CI 6.3– 28.9). Conclusion: Camrelizumab has manageable toxicity and encouraging preliminary antitumor activity in advanced solid tumors in Australia. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT02492789.

Background. Colorectal cancer (CRC) is the fourth most deadly cancer worldwide. Unfortunately, a quarter of the patients are diagnosed at late stages, when surgical options are limited. Targeted therapies, particularly immune-checkpoint inhibitors (ICIs), are the latest addition and have been studied herein regarding their efficacy outcomes. Methods. Clinical studies were identified through the PubMed, Scopus and Cochrane databases. Any trial that evaluated ICIs in patients with metastatic CRC (mCRC) and reported the objective response rate was deemed eligible. Data analysis was performed by employing the random-effects model in STATA v.17. Results. A total of 461 articles were identified; 13 clinical trials were included, encompassing a total cohort of 1209 patients. Our study determined that a single PD-1/PD-L1 checkpoint blockade provides durable clinical response in mCRC patients with high microsatellite instability (MSI-H). The combinatorial therapy of CTLA-4 + PD-1 inhibitors also showed high response rates in pre-treated MSI-H patients. The single-arm REGONIVO trial reported durable clinical response in patients with microsatellite stable (MSS) status. Conclusions. Our study surmises that PD-1/PD-L1 inhibitors as well as combination therapy with CTLA-4 and PD-1 inhibitors show encouraging response rates in mCRC patients, albeit exclusively in patients with cancer that are of MSI-H status. A single study suggests that nivolumab + regorafenib can reach a durable response rate in MSS patients; however, further studies in larger randomized settings are required.

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.

Unresectable locally advanced pancreatic cancer (LAPC) is generally managed with chemotherapy or chemoradiotherapy, but prognosis is poor with a median survival of ∼13 months (or up to 19 months in some studies). We assessed a novel brachytherapy device, using phosphorous-32 (³²P) microparticles, combined with standard-of-care chemotherapy. In this international, multicentre, single-arm, open-label pilot study, adult patients with histologically or cytologically proven unresectable LAPC received ³²P microparticles, via endoscopic ultrasound-guided fine-needle implantation, planned for week 4 of 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) or gemcitabine/nab-paclitaxel chemotherapy, per investigator’s choice. The primary endpoint was safety and tolerability measured using Common Terminology Criteria for Adverse Events version 4.0. The lead efficacy endpoint was local disease control rate at 16 weeks. Fifty patients were enrolled and received chemotherapy [intention-to-treat (ITT) population]. Forty-two patients received ³²P microparticle implantation [per protocol (PP) population]. A total of 1102 treatment-emergent adverse events (TEAEs) were reported in the ITT/safety population (956 PP), of which 167 (139 PP) were grade ≥3. In the PP population, 41 TEAEs in 16 (38.1%) patients were possibly or probably related to ³²P microparticles or implantation procedure, including 8 grade ≥3 in 3 (7.1%) patients, compared with 609 TEAEs in 42 (100%) patients attributed to chemotherapy, including 67 grade ≥3 in 28 patients (66.7%). The local disease control rate at 16 weeks was 82.0% (95% confidence interval: 68.6% to 90.9%) (ITT) and 90.5% (95% confidence interval: 77.4% to 97.3%) (PP). Tumour volume, carbohydrate antigen 19-9 levels, and metabolic tumour response at week 12 improved significantly. Ten patients (20.0% ITT; 23.8% PP) had surgical resection and median overall survival was 15.2 and 15.5 months for ITT and PP populations, respectively. Endoscopic ultrasound-guided ³²P microparticle implantation has an acceptable safety profile. This study also suggests clinically relevant benefits of combining ³²P microparticles with standard-of-care systemic chemotherapy for patients with unresectable LAPC.

Artificial intelligence applications in biomedicine face major challenges from data privacy requirements. To address this issue for clinically annotated tissue proteomic data, we developed a federated deep learning approach (ProCanFDL), training local models on simulated sites containing data from a pan-cancer cohort (n = 1,260) and 29 cohorts held behind private firewalls (n = 6,265), representing 19,930 replicate data-independent acquisition mass spectrometry runs. Local parameter updates were aggregated to build the global model, achieving a 43% performance gain on the hold-out test set (n = 625) in 14 cancer subtyping tasks compared with local models and matching centralized model performance. The approach’s generalizability was demonstrated by retraining the global model with data from two external, data-independent acquisition mass spectrometry cohorts (n = 55) and eight acquired by tandem mass tag proteomics (n = 832). ProCanFDL presents a solution for internationally collaborative machine learning initiatives using proteomic data, for example, for discovering predictive biomarkers or treatment targets while maintaining data privacy. Significance: A federated deep learning approach applied to human proteomic data, acquired using two distinct proteomic technologies from 40 tumor cohorts across eight countries, enabled accurate cancer histopathologic subtyping while preserving data privacy. This approach will enable the privacy-compliant development of large-scale proteomic artificial intelligence models, including foundation models, across institutions globally.