Rationale for targeting VEGF, FGF, and PDGF for the treatment of NSCLC

Lung cancer remains a leading cause of death globally, with the most frequent type, nonsmall cell lung cancer (NSCLC), having a 5-year survival rate of less than 20%. While platinum-based doublet chemotherapy is currently first-line therapy for advanced disease, it is associated with only modest clinical benefits at the cost of significant toxicities. In an effort to overcome these limitations, recent research has focused on targeted therapies, with recently approved agents targeting the epidermal growth factor receptor and vascular endothelial growth factor (VEGF) signaling pathways. However, these agents (gefitinib, erlotinib, and bevacizumab) provide antitumor activity for only a small proportion of patients, and patients whose tumors respond inevitably develop resistance to treatment. As angiogenesis is a crucial step in tumor growth and metastasis, antiangiogenic treatments might be expected to have antitumor activity. Important targets for the development of novel antiangiogenic therapies include VEGF, fibroblast growth factor, platelet-derived growth factor, and their receptors. It is hypothesized that targeting multiple angiogenic pathways may not only improve antitumor activity but also reduce the risk of resistance. Several novel agents, such as BIBF 1120, sorafenib, sunitinib, and cediranib have shown promising preliminary activity and tolerability in Phase II studies, and results of ongoing Phase III randomized studies will be necessary to establish the potential place of these new therapies in the management of individual patients with NSCLC

A phase I/II study of pemetrexed with sirolimus in advanced, previously treated non-small cell lung cancer

Background: Single-agent pemetrexed is a treatment for recurrent non-squamous non-small cell lung cancer (NSCLC) that provides limited benefit. Preclinical studies showed promising synergistic effects when the mammalian target of rapamycin (mTOR) inhibitor sirolimus was added to pemetrexed. Methods: This was a single-institution phase I/II study of pemetrexed in combination with sirolimus. The primary endpoint for the phase I was to determine the maximum tolerated dose (MTD) and safety of the combination. The primary endpoint for the phase II portion was to determine the overall response rate at the MTD. Key eligibility criteria included recurrent, metastatic NSCLC, ECOG performance status of 0–2, and adequate organ function. Sirolimus was administered orally daily after an initial loading dose, and pemetrexed was given intravenously on day 1 of every 21-day cycle. Results: Forty-two patients with recurrent, metastatic NSCLC were enrolled, 22 in phase I and 20 in phase II. The MTD was pemetrexed 500 mg/m2 every 3 weeks, and sirolimus 10 mg on day 1, and 3 mg daily thereafter. Treatment-related adverse events (AEs) occurred in 38 (90.5%) patients. The most common grade 3–4 treatment-related AEs were lymphopenia (31%) and hypophosphatemia (19%). Two treatment-related deaths occurred due to febrile neutropenia and infection, respectively. Among 27 total patients treated at the MTD, 6 (22.2%) had a partial response (PR), 12 (44.4%) had stable disease (SD) and 5 (18.5%) had progressive disease. Median progression-free survival (PFS) was 18.4 weeks (95% CI: 7.0–29.4). Conclusions: The combination of pemetrexed and sirolimus is active in heavily-pretreated NSCLC (ClinicalTrials.gov Identifier: NCT00923273)

A phase II, open-label study of ramucirumab in combination with paclitaxel and carboplatin as first-line therapy in patients with stage IIIB/IV non-small-cell lung cancer

IntroductionThe objective of this study was to determine whether the addition of ramucirumab to first-line paclitaxel–carboplatin chemotherapy in patients with advanced non–small-cell lung cancer (NSCLC) resulted in a 6-month progression-free survival (PFS) rate that compares favorably with the historic rate for bevacizumab combined with paclitaxel–carboplatin in this patient population.MethodsIn this phase II, single-arm, open-label, multicenter study, 40 patients with advanced NSCLC received ramucirumab (10 mg/kg intravenous [IV]) followed by paclitaxel (200 mg/m2 IV) and carboplatin area under the curve = 6 on day 1 every 21 days as first-line therapy. Therapy continued for up to six cycles. Patients not experiencing withdrawal criteria may have continued ramucirumab monotherapy every 3 weeks. The primary endpoint was PFS at 6 months, with 80% power to detect a 6-month PFS rate of at least 55%.ResultsThe 6-month PFS rate was 59.0% and the objective response rate was 55.0%. The most common treatment-related adverse events were fatigue, peripheral neuropathy, nausea, epistaxis, and myalgia. Single-nucleotide polymorphism (SNP) rs2981582 on the FGFR-2gene had significant associations with improved overall survival, PFS, and best overall response (p values without multiplicity adjustment were 0.0059, 0.0429, and 0.0392, respectively).ConclusionRamucirumab in combination with paclitaxel–carboplatin resulted in a 6-month PFS rate and safety profile that compared favorably with the historical control. In addition, no deaths were associated with this treatment. Furthermore, we describe an association of SNP on FGFR-2 gene with survival and response. These findings warrant further clinical investigation in patients with NSCLC

Phase I, open-label, dose-escalation study of the safety, pharmacokinetics, pharmacodynamics, and efficacy of GSK2879552 in relapsed/refractory SCLC

INTRODUCTION: This first-time-in-humans study assessed the safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of GSK2879552 in patients with relapsed or refractory SCLC. METHODS: This phase I, multicenter, open-label study (NCT02034123) enrolled patients (≥18 years old) with relapsed or refractory SCLC (after ≥1 platinum-containing chemotherapy or refusal of standard therapy). Part 1 was a dose-escalation study; Part 2 was a dose-expansion study. Dose escalations were based on safety, PK, and PD. The primary end point (Part 1) was to determine the safety, tolerability, and recommended dose and regimen of GSK2879552. Secondary end points were to characterize PK and PD parameters and measure disease control rate at week 16. Part 2 was not conducted. RESULTS: Between February 4, 2014, and April 18, 2017, a total of 29 patients were allocated to one of nine dose cohorts (0.25 mg-3 mg once daily and 3-mg or 4-mg intermittent dosing). In all, 22 patients completed the study; 7 withdrew, primarily owing to adverse events (AEs). Most patients (24 of 29 [83%]) had at least one treatment-related AE, most commonly thrombocytopenia (12 of 29 [41%]). Twelve serious AEs (SAEs) were reported by nine patients; six were considered treatment related, the most common of which was encephalopathy (four SAEs). Three patients died; one death was related to SAEs. PK was characterized by rapid absorption, slow elimination, and a dose-proportional increase in exposure. CONCLUSIONS: GSK2879552 is a potent, selective inhibitor of lysine demethylase 1A and has demonstrated favorable PK properties but provided poor disease control and a high AE rate in patients with SCLC. The study was terminated, as the risk-benefit profile did not favor continuation

INDUCE-3: A randomized, double-blind study of GSK3359609 (GSK609), an inducible T-cell co-stimulatory (ICOS) agonist antibody, plus pembrolizumab (PE) versus placebo (PL) plus PE for first-line treatment of PD-L1-positive recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC).

TPS6591 Background: Pembrolizumab as part of first-line treatment for patients (pts) with R/M HNSCC has improved survival. However, in order to further improve outcomes in this population investigation of rational combinations targeting different mechanisms that cancers exploit to evade the immune system is required. ICOS, a member of the CD28/B7 immunoglobulin receptor superfamily, provides a co-stimulatory signal augmenting T-cell proliferation, cytokine production, cytotoxic function and survival. GSK609 is a humanized IgG4 antibody selected for its potent agonist activity and non-depleting properties. The rationale for targeting ICOS with GSK609 plus PD-1 blockade with PE is supported by preclinical and clinical evidence (Rischin, et al. Annals of Oncol 2019;30[Supplement_5]:v454–5). INDUCE-3 trial (NCT04128696) will explore if the addition of GSK609 to PE improves outcomes of pts with R/M HNSCC. Methods: INDUCE-3 uses a 2-in-1 adaptive design that has the option to seamlessly expand from an initial Phase 2 to a Phase 3 study. Pts (n = 600) will be stratified by PD-L1 status and HPV status (oropharynx only) then randomly assigned in a 1:1 ratio to receive GSK609 plus PE or PL plus PE, every 3 weeks until progression, unacceptable toxicity, or up to 35 cycles. GSK609 plus PE will be assessed for superiority versus PL plus PE in overall survival (OS) and progression-free survival (PFS) per RECISTv1.1 as dual primary endpoints; secondary endpoints include PFS per immune-based RECIST; milestone OS; safety and tolerability; time to deterioration in patient-reported physical function and pain. Efficacy and patient-reported outcome endpoints will be assessed in the PD-L1 combined positive score (CPS) ≥1 and ≥20 populations. Key eligibility criteria are aged ≥18 years; locally incurable R/M HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx; no prior systemic therapy in the R/M setting; PD-L1 CPS ≥1 by central testing; measurable disease per RECIST v1.1 and ECOG PS 0/1. Recruitment is ongoing in countries across the globe. Funding: Study is funded by GlaxoSmithKline and in collaboration with Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Clinical trial information: NCT04128696