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9000 Background: Immune checkpoint inhibition is now given in combination with chemotherapy for first line (1L) therapy of extensive stage small cell lung cancer (ES-SCLC). We conducted a randomized phase II study of nivolumab (anti-PD1) in combination with platinum-etoposide (CE) as 1L treatment for patients with ES-SCLC (EA5161, NCT03382561). Methods: Patients with measurable (RECIST v1.1) ES-SCLC, ECOG performance status 0 or 1, who had not received prior systemic treatment for ES-SCLC were enrolled. Patients were randomized 1:1 to nivolumab 360 mg + CE every 21 days for 4 cycles followed by maintenance nivolumab 240 mg every 2 weeks until progression or up to 2 years (arm A) or CE every 21 days for 4 cycles followed by observation (arm B). Prophylactic cranial irradiation (PCI) was permitted at the investigator’s discretion. Investigator’s choice of cisplatin or carboplatin was allowed across both arms. The primary endpoint was PFS in eligible and treated patients. Secondary endpoints included OS, ORR, and safety. Adverse events (AEs) were graded per NCI-CTCAE v4.0. Results: This study was activated in May 2018 and completed accrual in December 2018. 160 patients were enrolled. Baseline characteristics were well balanced between arms. In the ITT population (n = 160), nivolumab + CE significantly improved the PFS compared to CE with HR 0.65 (95% CI, 0.46, 0.91; p = 0.012); mPFS 5.5 versus 4.6 months, respectively. Secondary endpoint of OS was also improved with nivolumab + CE versus CE with HR 0.67 (95% CI, 0.46, 0.98; p = 0.038); mOS 11.3 versus 8.5 months. Among patients who initiated study therapy, nivolumab + CE significantly improved the PFS compared to CE with HR 0.68 (95% CI, 0.48, 1.00; p = 0.047); mPFS 5.5 versus 4.7 months, respectively; in this population, OS was also improved with nivolumab + CE versus CE with HR 0.73 (95% CI, 0.49, 1.11; p = 0.14); mOS 11.3 versus 9.3 months. The ORR was 52.29% versus 47.71%. The incidence of treatment-related grade 3/4 AEs was 77% versus 62% and AEs leading to discontinuation 6.21% versus 2.07%. Ten patients remain on maintenance nivolumab. Lethal adverse events independent of treatment were similar between the two arms (9 in arm A; 7 in arm B). Conclusions: The addition of nivolumab to CE as 1L treatment for ES-SCLC significantly improved PFS and OS. No new safety signals were observed. Clinical trial information: NCT03382561.

Successful chemotherapeutic intervention for management of lung cancer requires an efficient drug delivery system. Gold nanoparticles (GNPs) can incorporate various therapeutics; however, GNPs have limitations as drug carriers. Nano-sized cellular vesicles like exosomes (Exo) can ferry GNP-therapeutic complexes without causing any particle aggregation or immune response. In the present study, we describe the development and testing of a novel Exo-GNP-based therapeutic delivery system -‘nanosomes’- for lung cancer therapy. This system consists of GNPs conjugated to anticancer drug doxorubicin (Dox) by a pH-cleavable bond that is physically loaded onto the exosomes (Exo-GNP-Dox). The therapeutic efficacy of Dox in nanosomes was assessed in H1299 and A549 non-small cell lung cancer cells, normal MRC9 lung fibroblasts, and Dox-sensitive human coronary artery smooth muscle cells (HCASM). The enhanced rate of drug release under acidic conditions, successful uptake of the nanosomes by the recipient cells and the cell viability assays demonstrated that nanosomes exhibit preferential cytotoxicity towards cancer cells and have minimal activity on non-cancerous cells. Finally, the underlying mechanism of cytotoxicity involved ROS-mediated DNA damage. Results from this study mark the establishment of an amenable drug delivery vehicle and highlight the advantages of a natural drug carrier that demonstrates reduced cellular toxicity and efficient delivery of therapeutics to cancer cells.

Background: Recurrent head and neck squamous cell carcinoma (rHNSCC) represents a significant global health burden with an unmet medical need. In this study we determined the safety and efficacy of RM-1929 photoimmunotherapy in patients with heavily pretreated rHNSCC.

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