Faculty Bibliography

The ongoing pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Here, using multidimensional epigenetic, transcriptional, in vitro and in vivo analyses, we report that Topoisomerase 1 (Top1) inhibition suppresses lethal inflammation induced by SARS-CoV-2. Therapeutic treatment with two doses of Topotecan (TPT), a FDA-approved Top1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as four days post-infection reduces morbidity and rescues mortality in a transgenic mouse model. These results support the potential of Top1 inhibition as an effective host-directed therapy against severe SARS-CoV-2 infection. TPT and its derivatives are inexpensive clinical-grade inhibitors available in most countries. Clinical trials are needed to evaluate the efficacy of repurposing Top1 inhibitors for COVID-19 in humans.

Background XmAb20717 is a humanized bispecific monoclonal antibody that simultaneously targets PD-1 and CTLA-4. We report preliminary data from an ongoing, multicenter, Phase 1 study investigating the safety/tolerability, pharmacokinetics/ pharmacodynamics, and clinical activity (RECIST 1.1) of XmAb20717 in patients with selected advanced solid tumors. Methods A 3+3 dose-escalation design was used to establish a maximum tolerated (MTD)/recommended dose for evaluation in parallel expansion cohorts, including melanoma, renal cell carcinoma, non-small cell lung cancer (NSCLC), prostate cancer, and a basket of tumor types without an FDA-approved checkpoint inhibitor (CI; n20 each). XmAb20717 was administered as an infusion on Days 1 and 15 of each 28-day cycle. Results As of 08Jul2020, 109 patients had been treated (table 1), and 30 were continuing treatment. In escalation, 6 dose levels (0.15-10.0 mg/kg) were evaluated (n=34); an MTD was not established. Expansion cohorts were initiated at 10 mg/kg (n=72), and a 15 mg/kg escalation cohort was added (n=3). T-cell proliferation was noted in peripheral blood at doses as low as 3 mg/kg and was highest at 10 mg/kg. At this dose, consistent proliferation of CD8+ and CD4+ T cells was observed, indicative of dual PD-1 and CTLA-4 checkpoint blockade (figure 1). Paired pre- and post-dosing biopsies showed increased intratumoral T-cell infiltration and IFNresponse signatures following treatment. Grade 3/4 treatmentrelated adverse events (TRAEs) reported for >=3 patients included rash (13%), transaminase elevations (7%), lipase increased (4% [2% with amylase increased]), and acute kidney injury (3%), all considered immune-related. There were 2 Grade 5 TRAEs: immune-mediated pancreatitis (in the pres- ence of pancreatic metastases) and immune-mediated myocarditis (Grade 4) that contributed to respiratory failure. A complete response was reported as the best overall response for 1 patient (melanoma); partial responses were reported for 5 patients (2 melanoma, 2 NSCLC, 1 ovarian). The objective response rate was 13% overall and 21% at 10 mg/kg (6/46 and 6/29 evaluable patients, respectively). All responders had prior CI exposure. Responses were observed only at 10 mg/kg and, within the 10 mg/kg group, appeared to correlate with higher peak serum concentration and area under the curve. Conclusions XmAb20717 induced T-cell proliferation in peripheral blood consistent with dual-checkpoint blockade. Preliminary data indicate XmAb20717 was generally well-tolerated and associated with evidence of antitumor activity in CIpretreated patients with various types of advanced solid tumors

PURPOSE/OBJECTIVE:next-generation sequencing based comprehensive genomic profiling (CGP) is becoming common practice. Although numerous studies have shown its feasibility to identify actionable genomic alterations in most patients, its clinical impact as part of routine management across all cancers in the community remains unknown. METHODS:for colorectal cancer). RESULTS:349 tests were sent for CGP from 333 patients and 95% had at least one actionable genomic alteration reported. According to the reported results, 23.2% had a Food and Drug Administration (FDA) approved therapy available, 61.3% had an off-label therapy available and 77.9% were potentially eligible for a clinical trial. Treatment recommendations were also reviewed within the OncoKB database and 47% of them were not clinically validated therapies. The CGP results led to treatment change in only 35 patients (10%), most commonly in NSCLC. Nineteen of these patients (54% of those treated and 5% of total) had documented clinical benefit with targeted therapy. CONCLUSION/CONCLUSIONS:we demonstrate that routine use of CGP in the community across all cancer types detects potentially actionable genomic alterations in a majority of patients, however has modest clinical impact enriched in the NSCLC subset.

INTRODUCTION: It remains challenging to treat squamous cell lung cancer (SCC) with limited therapeutic options. However, recent breakthroughs in targeted therapies and immunotherapies have shed some light on the management of this deadly disease. Areas covered: The article first reviews the current treatment options for advanced SCC, especially recent FDA approved molecular agents (afatinib, ramucirumab and necitumumab) and immunotherapies (nivolumab, pembrolizumab and atezolimumab). We then provide an overview on investigational therapies with data ranging from preclinical to phase II studies, focusing on new cytotoxic agents, emerging molecularly targeted agents (including a PARP inhibitor for Homologous Recombinant Deficiency positive SCC) and novel immunotherapeutic strategies. Expert opinion summary: Identification of potential therapeutic targets, development of novel clinical trials and the rapid approvals of immune checkpoint inhibitors have shifted the management paradigm for squamous cell lung cancer. On the other hand, continued efforts are needed to identify the predictive biomarkers and to investigate novel mechanistically-driven mono- and combination therapies. We need to learn more about the biology behind immune checkpoint blockade and tumor genomics in SCC for better patient selection and future trial design.

Pulmonary sarcomatoid carcinoma (PSC) is a unique and biologically fascinating group of poorly differentiated non-small cell lung cancer (NSCLC), however it is highly aggressive with poor overall survival compared to other types of NSCLC. Radical surgery remains the standard of care for early localized disease but this has shown to result in high recurrence rates. Traditional palliative chemotherapy is associated with poor response in advanced/metastatic PSC. Recent comprehensive genetic studies and clinical observations are starting to elucidate the key oncogenic underpinnings of PSC. In particular, the recent identification of frequent genetic alterations of the MET gene leading to exon 14 skipping have yielded actionable targets for intervention with available MET inhibitors for a subset of PSC patients. Immunotherapy against immune checkpoints, such as anti-PD1/PD-L1 agents, have also raised great interest for the management of PSC. A growing understanding of the molecular pathogenesis of PSC is rapidly yielding novel approaches for the treatment of this deadly malignancy.

While the wide belief is that monoclonal antibodies, due to their large size, would not be able to penetrate the blood-brain barrier, we present a rare case of aseptic meningitis induced by intravenous cetuximab administration. A 58-year-old man with tonsillar squamous cell cancer presented with headache and fever, which started approximately 1 h after his first dose of cetuximab (loading dose of 400 mg/m(2) equalling 800 mg). CT scan of the head was non-revealing and laboratory tests including complete blood count, serum comprehensive metabolic panel and coagulation profile were within normal limits. Aseptic meningitis in the setting of cetuximab therapy has been reported on 6 previous occasions. Consistent with these prior reports, it is interesting to note that this case also occurred after administration of the initial higher loading dose of Cetuximab. This is of interest as Cetuximab is more frequently being dosed at 500 mg/m(2) (higher dose) every 2 weeks in colorectal cancer.