Faculty Bibliography

Background XmAb20717 is a humanized bispecific monoclonal antibody that simultaneously targets PD-1 and CTLA-4. We report updated data on patients treated at the recommended expansion dose from an ongoing, multicenter, Phase 1, doseescalation and -expansion study of intravenous XmAb20717 in patients with selected advanced solid tumors that progressed after treatment with all standard therapies or with no standard therapeutic options. Methods A maximum tolerated dose was not reached in dose escalation. XmAb20717 10 mg/kg every 2 weeks (Q2W) was selected as the expansion dose, based on consistent T-cell proliferation in peripheral blood indicative of dual PD-1/CTLA-4 checkpoint blockade, and response to treatment (RECIST [1.1]).1 Parallel expansion cohorts included ~20 patients each with melanoma, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), castration-resistant prostate cancer (CRPC), and a basket of tumor types without an FDAapproved checkpoint inhibitor (CI). Patients treated with 10 mg/kg in dose escalation were pooled with expansion cohorts for analysis of clinical activity and safety. Results As of 9 June 2021, 110 patients, ranging in age from 39 to 89 years and 66.4% male, were treated, and 5 were continuing treatment. Patients had received a median of 4 prior systemic treatment regimens, including CI therapy for 64.5%. The objective response rate was 13.0% (10/77 patients evaluable for efficacy), including 1 complete response (melanoma [confirmed]) and 9 partial responses (confirmed: 1 melanoma, 2 RCC, 2 CRPC, 1 ovarian cancer; unconfirmed: 1 melanoma, 2 NSCLC). The CRPC responders (2/7 with RECIST-measurable disease) had confirmed PSA decreases >= 50% from baseline (to 0.02 and 0.3 ng/mL); neither had progression on bone scans. All responders had prior CI exposure, except those with CRPC. Robust CD4 and CD8 T-cell activation was seen. Low baseline tumoral expression of myeloid recruitment genes, including IL-8, was associated with clinical benefit. Grade >= 3 immunotherapy-related adverse events in >= 3 patients included rash (16.4%), transaminase elevations (9.1%), hyperglycemia (4.5%), acute kidney injury (3.6%), amylase and lipase increased (2.7%), and lipase increased (2.7%). Conclusions Preliminary data indicate 10 mg/kg XmAb20717 Q2W was associated with complete and partial responses in multiple tumor types and was generally well-tolerated in these heavily pretreated patients with advanced cancer. Changes in T-cell populations in the periphery and tumor are consistent with robust dual checkpoint blockade. These findings support further development of XmAb20717 in advanced solid tumors, including metastatic prostate cancer

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), an FDA-approved TOP1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as 4 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 severe coronavirus disease 2019 (COVID-19) in humans.

PURPOSE/OBJECTIVE:New therapies are needed to treat immune checkpoint inhibitor-resistant non-small cell lung cancer (NSCLC) and identify biomarkers to personalize treatment. Epigenetic therapies, including histone deacetylase inhibitors, may synergize with programmed cell death-1 (PD-1)blockade to overcome resistance. We report outcomes in patients with anti-PD-(L)1-resistant/refractory NSCLC treated with pembrolizumab plus entinostat in ENCORE 601. EXPERIMENTAL DESIGN/METHODS:The expansion cohort of ENCORE 601 included patients with NSCLC who previously experienced disease progression with immune checkpoint inhibitors. The primary endpoint for the phase 2 expansion cohort is overall response rate (ORR); safety, tolerability, and exploratory endpoints are described. RESULTS:Of 76 treated patients,71 were evaluable for efficacy. irRECIST-assessed ORRwas 9.2%(95% CI: 3.8-18.1), which did not meet the prespecified threshold for positivity. Median DOR was 10.1 months(95% CI: 3.9-NE),PFS at 6 months was 22%, median PFS was 2.8 months(95% CI: 1.5-4.1),and median OS was11.7 months (95% CI: 7.6-13.4). Benefit was enriched among patients with high levels of circulating classical monocytes at baseline. Baseline tumor PD-L1 expression and IFNγgene expression were not associated with benefit. Treatment-related Grade ≥3 adverse events occurred in 41% of patients. CONCLUSIONS:In anti-PD-(L)1-experienced NSCLC patients, entinostat plus pembrolizumab did not achieve the primary response rate endpoint but provided a clinically meaningful benefit with objective response in 9% of patients. No new toxicities, including immune-related adverse events, were seen for either drug. Future studies will continue to evaluate the association of monocyte levels and response.

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.