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Clinical benefit through Siglec-15 targeting with NC318 antibody in subjects with Siglec-15 positive advanced solid tumors [Meeting Abstract]
Shum, E; Myint, H; Shaik, J; Zhou, Q; Barbu, E; Morawski, A; Abukharma, H; Liu, L; Nelson, M; Zeidan, S; Cusumano, Z; Tolcher, A; Langermann, S; Gutierrez, M; Hamid, O
Background Siglec-15 (S15) is a member of the Siglec family of immunoglobulin superfamily proteins involved in immune regulation. NC318 is a first-in-class humanized IgG1k monoclonal antibody that blocks S15-mediated immune suppression. Methods The Phase 1 dose-escalation study was a classical 3 +3 design in 15 tumor types (n=49). Phase 2 (n=47) was conducted at 400 mg q2w in 4 tumor types. Inclusion criteria included subjects with advanced/metastatic solid tumors refractory or resistant to currently available therapies with a TPS PD-L1 score <50%. The median number of previous therapies was >=3, including checkpoint inhibitors (figure 1). Results NC318 was well tolerated with no novel immunologic or safety signals observed. Disease control rate amongst evaluable population (n=83) is 38% {1 CR, 3 PR and 28 SD (stable disease)}. Median duration of disease control is 24 weeks (16-48 weeks) amongst 20 subjects achieving a minimal 16- week duration of stable disease. Two NSCLC subjects (1CR and 1PR) are still on therapy over 2 years. We observed an increase in a soluble form of Siglec-15 (sS15) in all patients receiving NC318 treatment that was dose-dependent. sS15 serves as a pharmacodynamic marker for NC318 activity. PK/ PD modeling of NC318 from this Phase1/2 study using sS15 as a PD marker suggested increasing the dose of NC318 to 800 mg q1w to enhance overall exposure of NC318. Development of an S15 specific IHC assay allowed us to do posthoc analysis by immuno-histochemistry (IHC) from screening biopsies amongst subjects who showed disease control (CR, PR and SD) compared to subjects with progressive disease. S15 expression on tumor cell membrane was a predictor for stable disease, longer duration on therapy when compared to progressive disease {H score >= 1 (p=0.046), including NSCLC subjects}, as well as for progression-free survival (PFS) (figures 2 and 3). There was no correlation with the outcome whether PD-L1 was positive or negative. Together, development of a predictive indicator of S15 staining coupled with the NC318 PK/PD data, resulted in a protocol amendment to prospectively enroll subjects with Siglec-15+ adenocarcinoma lung, squamous H&N, and breast cancers at 800 mg q1w. Soluble S15, immunophenotyping, cytokine and chemokine levels and neutrophil-lymphocyte ratio will be presented at the meeting. Conclusions NC318 shows promising early evidence of disease control in subjects with Siglec-15 positive advanced or metastatic solid tumors in phase 1 & 2 studies, prompting evaluation of S15 expression as a predictive biomarker in the prospective study at 800mg q1w dosing
EMBASE:636986061
ISSN: 2051-1426
CID: 5138542
Preliminary clinical experience with XMAB20717, a PD-1 X CTLA-4 bispecific antibody, in patients with advanced solid tumors [Meeting Abstract]
Shum, E; Reilley, M; Najjar, Y; Daud, A; Thompson, J; Baranda, J; Harvey, R D; Shields, A; Cohen, E; Pant, S; Leidner, R; Mita, A; Cohen, R; Chmielowski, B; Stein, M; Hu-Lieskovan, S; Fleener, C; Ding, Y; Bao, L; Chollate, S; Shorr, J; Clynes, R; Hickingbottom, B
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
EMBASE:636985411
ISSN: 2051-1426
CID: 5134952
TOP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation
Ho, Jessica Sook Yuin; Mok, Bobo Wing-Yee; Campisi, Laura; Jordan, Tristan; Yildiz, Soner; Parameswaran, Sreeja; Wayman, Joseph A; Gaudreault, Natasha N; Meekins, David A; Indran, Sabarish V; Morozov, Igor; Trujillo, Jessie D; Fstkchyan, Yesai S; Rathnasinghe, Raveen; Zhu, Zeyu; Zheng, Simin; Zhao, Nan; White, Kris; Ray-Jones, Helen; Malysheva, Valeriya; Thiecke, Michiel J; Lau, Siu-Ying; Liu, Honglian; Zhang, Anna Junxia; Lee, Andrew Chak-Yiu; Liu, Wen-Chun; Jangra, Sonia; Escalera, Alba; Aydillo, Teresa; Melo, Betsaida Salom; Guccione, Ernesto; Sebra, Robert; Shum, Elaine; Bakker, Jan; Kaufman, David A; Moreira, Andre L; Carossino, Mariano; Balasuriya, Udeni B R; Byun, Minji; Albrecht, Randy A; Schotsaert, Michael; Garcia-Sastre, Adolfo; Chanda, Sumit K; Miraldi, Emily R; Jeyasekharan, Anand D; TenOever, Benjamin R; Spivakov, Mikhail; Weirauch, Matthew T; Heinz, Sven; Chen, Honglin; Benner, Christopher; Richt, Juergen A; Marazzi, Ivan
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.
PMID: 33836156
ISSN: 1097-4172
CID: 4840702
Entinostat plus pembrolizumab in patients with metastatic NSCLC previously treated with anti-PD-(L)1 therapy
Hellmann, Matthew D; Janne, Pasi A; Opyrchal, Mateusz; Hafez, Navid; Raez, Luis E; Gabrilovich, Dmitry I; Wang, Fang; Trepel, Jane B; Lee, Min-Jung; Yuno, Akira; Lee, Sunmin; Brouwer, Susan; Sankoh, Serap; Wang, Lei; Tamang, David; Schmidt, Emmett V; Meyers, Michael L; Ramalingam, Suresh S; Shum, Elaine; Ordentlich, Peter
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.
PMID: 33203644
ISSN: 1078-0432
CID: 4681412
Comparing Lung Cancer in Never Smokers and Ever Smokers in Asian or Asian American Patients Treated at a Tertiary Urban Public Hospital in New York [Meeting Abstract]
Kroening, G.; Sabari, J.; Velcheti, V.; Chachoua, A.; Wong, K.; Shum, E.
ISI:000709606500313
ISSN: 1556-0864
CID: 5074192
Topoisomerase 1 inhibition therapy protects against SARS-CoV-2-induced inflammation and death in animal models [PrePrint]
Yuin Ho, Jessica Sook; Wing-Yee Mok, Bobo; Campisi, Laura; Jordan, Tristan; Yildiz, Soner; Parameswaran, Sreeja; Wayman, Joseph A; Gaudreault, Natasha N; Meekins, David A; Indran, Sabarish V; Morozov, Igor; Trujillo, Jessie D; Fstkchyan, Yesai S; Rathnasinghe, Raveen; Zhu, Zeyu; Zheng, Simin; Zhao, Nan; White, Kris; Ray-Jones, Helen; Malysheva, Valeriya; Thiecke, Michiel J; Lau, Siu-Ying; Liu, Honglian; Junxia Zhang, Anna; Chak-Yiu Lee, Andrew; Liu, Wen-Chun; Aydillo, Teresa; Salom Melo, Betsaida; Guccione, Ernesto; Sebra, Robert; Shum, Elaine; Bakker, Jan; Kaufman, David A; Moreira, Andre L; Carossino, Mariano; Balasuriya, Udeni B R; Byun, Minji; Miraldi, Emily R; Albrecht, Randy A; Schotsaert, Michael; Garcia-Sastre, Adolfo; Chanda, Sumit K; Jeyasekharan, Anand D; TenOever, Benjamin R; Spivakov, Mikhail; Weirauch, Matthew T; Heinz, Sven; Chen, Honglin; Benner, Christopher; Richt, Juergen A; Marazzi, Ivan
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.
PMID: 33299999
ISSN: 2692-8205
CID: 4843582
Expanding the Role of Immunotherapy to Limited-Stage SCLC [Editorial]
Punekar, Salman R; Shum, Elaine
PMID: 33246593
ISSN: 1556-1380
CID: 4716352
Preliminary safety, pharmacokinetics/ pharmacodynamics, and antitumor activity of XMAB20717, a PD-1 x CTLA-4 bispecific antibody, in patients with advanced solid tumors [Meeting Abstract]
Shum, E; Daud, A; Reilley, M; Najjar, Y; Thompson, J; Baranda, J; Donald, Harvey R; Leidner, R; Shields, A; Cohen, E; Cohen, R; Mita, A; Pant, S; Stein, M; Chmielowski, B; Hu-Lieskovan, S; Fleener, C; Ding, Y; Chollate, S; Avina, H; Shorr, J; Clynes, R; Hickingbottom, B
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
EMBASE:635024108
ISSN: 2051-1426
CID: 4885092
Impact and Diagnostic Gaps of Comprehensive Genomic Profiling in Real-World Clinical Practice
Singh, Aditi P; Shum, Elaine; Rajdev, Lakshmi; Cheng, Haiying; Goel, Sanjay; Perez-Soler, Roman; Halmos, Balazs
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.
PMID: 32375398
ISSN: 2072-6694
CID: 4430322
Finding a place for ceritinib in the landscape of ALK-positive non-small cell lung cancer [Editorial]
Shum, Elaine; Gandhi, Leena
ISI:000413569400024
ISSN: 2219-6803
CID: 2767412