TPS496
Background: Complete response (CR) is still a rare event in patients with advanced clear cell renal cell carcinoma (ccRCC). The combination of nivolumab plus cabozantinib was recently approved ...for the first-line treatment of ccRCC based on the CheckMate 9ER phase 3 study demonstrating improved progression-free survival (PFS) & objective response rate (ORR) in comparison to sunitinib. However, the CR rate was only 9%. Since the anti-tumor effects of immune checkpoint inhibitors are dependent on the presence of activated tumor-infiltrating T cells, drugs that could synergize with T cells' anti-tumor activity can allow us to improve CR rates. Activation of the cGAS-STING pathway which is induced by radiation-induced DNA damage, is one promising mechanism that has been investigated. Many studies have shown that radiation treatment augments immune checkpoint inhibition. However, it is not always possible to radiate all metastatic lesions. Therefore, targeted peptide receptor radionuclide therapies, have been developed by conjugating radioisotopes to receptor binding analogs targeting specific cancer cell surface proteins, thereby delivering targeted radiation to cancer cells in the body with minimal damage to surrounding healthy cells.
177
Lu girentuximab is the first antibody-radioisotope designed for ccRCC, targeting carbonic anhydrase 9-expressing cells, which includes > 90% of ccRCC. It has been tested in metastatic ccRCC as a single agent & shown to be safe and effective in stabilizing disease in 57% of pts. In this study, we hypothesize
177
Lu girentuximab-induced DNA damage will potentiate the STING pathway, and this activation will synergize with nivolumab and cabozantinib to promote trafficking and infiltration of activated T cells to tumors and achieve higher CR rates. Methods: Up to 100 patients with treatment na'i"ve, biopsy-proven ccRCC with adequate organ/marrow function with 1 evaluable lesion by RECIST 1.1 will be enrolled. A 5-patient safety lead-in will evaluate myelosuppression. Ongoing safety, & futility monitoring will employ a Bayesian approach. The sample size was chosen for reasonable operating characteristics to distinguish a CR rate (primary endpoint) of 18% as better than 9% using a beta(0.09, 0.91) prior. Secondary endpoints are ORR, PFS by RECIST 1.1, and overall survival.
177
Lu-girentuximab 1480 MBq/m
2
(61% of single agent MTD) will be administered every 12 weeks for up to 3 cycles. Starting with the 2
nd
cycle, nivolumab & cabozantinib will be added at standard dose. To explore the effects of the treatment on inducing activated T cell infiltration, patients will undergo pre/post-treatment PET scan with 18FF-AraG radiotracer as well as biopsies for single cell, spatial transcriptomics and proteomics studies. Clinical trial information: NCT05239533 .
TPS4605
Background: Complete response (CR) is still a rare event in patients with advanced clear cell renal cell carcinoma (ccRCC). The combination of nivolumab plus cabozantinib was recently ...approved for the first-line treatment of ccRCC based on the CheckMate 9ER phase III study demonstrating improved progression-free survival (PFS) and objective response rate (ORR) in comparison to sunitinib. However, the CR rate was only 9%. Since the anti-tumor effects of immune checkpoint inhibitors are dependent on the presence of activated tumor-infiltrating T cells, drugs that could synergize with T cells’ anti-tumor activity can allow us to improve CR rates. Activation of the cGAS-STING pathway, the master regulator of anti-tumor immunity which is induced by radiation-induced DNA damage, is one promising mechanism that has been investigated. Many studies have shown that radiation treatment augments immune checkpoint inhibition. However, it is not always possible to radiate all metastatic lesions. Therefore, targeted peptide receptor radionuclide therapies (PRRT), have been developed by conjugating radioisotopes to receptor binding analogs targeting specific cancer cell surface proteins, thereby delivering targeted radiation to cancer cells in the body with minimal damage to surrounding healthy cells.
177
Lu girentuximab is the first antibody-radioisotope designed for ccRCC, targeting carbonic anhydrase IX-expressing cells, which includes > 90% of ccRCC. It has been tested in metastatic ccRCC as a single agent and shown to be safe and effective in stabilizing disease in 57% of pts. In this study, we hypothesize that
177
Lu girentuximab-induced DNA damage will potentiate the STING pathway, and this activation will synergize with nivolumab and cabozantinib to promote trafficking and infiltration of activated T cells to tumors and achieve higher CR rates. Methods: Up to 100 patients with treatment naïve, biopsy-proven ccRCC with adequate organ/marrow function with ≥1 evaluable lesion by RECIST 1.1 will be enrolled. A 5-patient safety lead-in will evaluate myelosuppression. Ongoing safety, and futility monitoring will employ a Bayesian approach. The sample size was chosen for reasonable operating characteristics to distinguish a CR rate of 18% as better than 9% using a beta(0.09, 0.91) prior. Secondary endpoints are objective response, PFS by RECIST 1.1, and overall survival.
177
Lu-girentuximab 1480 MBq/m
2
(61% of single agent MTD) will be administered every 12 weeks for up to 3 treatment cycles. After the first cycle, nivolumab and cabozantinib will be added starting with the second cycle at standard dose. To explore the effects of the combination therapy on inducing activated T cell infiltration, patients will undergo pre/post-treatment PET scan with 18FF-AraG radiotracer as well as biopsies for single cell, spatial transcriptomics and proteomics studies.
TPS749
Background: Complete response (CR) is still a rare event in patients with advanced clear cell renal cell carcinoma (ccRCC). The combination of nivolumab plus cabozantinib was recently approved ...for the first-line treatment of ccRCC based on the CheckMate 9ER phase 3 study demonstrating improved progression-free survival (PFS) and objective response rate (ORR) in comparison to sunitinib. However, the CR rate was only 9%. Since the anti-tumor effects of immune checkpoint inhibitors are dependent on the presence of activated tumor-infiltrating T cells, drugs that could synergize with T cells’ anti-tumor activity can allow us to improve CR rates. Activation of the cGAS-STING pathway which is induced by radiation-induced DNA damage, is one promising mechanism that has been investigated. Many studies have shown that radiation treatment augments immune checkpoint inhibition. However, it is not always possible to radiate all metastatic lesions. Therefore, targeted peptide receptor radionuclide therapies, have been developed by conjugating radioisotopes to receptor binding analogs targeting specific cancer cell surface proteins, thereby delivering targeted radiation to cancer cells in the body with minimal damage to surrounding healthy cells.
177
Lu girentuximab is the first antibody-radioisotope designed for ccRCC, targeting carbonic anhydrase 9-expressing cells, which includes >90% of ccRCC. It has been tested in metastatic ccRCC as a single agent and shown to be safe and effective in stabilizing disease in 57% of pts. In this study, we hypothesize that
177
Lu girentuximab-induced DNA damage will potentiate the STING pathway, and this activation will synergize with nivolumab and cabozantinib to promote trafficking and infiltration of activated T cells to tumors and achieve higher CR rates. Methods: Up to 100 patients with treatment naïve, biopsy-proven ccRCC with adequate organ/marrow function with ≥1 evaluable lesion by RECIST 1.1 will be enrolled. A 5-patient safety lead-in will evaluate myelosuppression. Ongoing safety, and futility monitoring will employ a Bayesian approach. The sample size was chosen for reasonable operating characteristics to distinguish a CR rate (primary endpoint) of 18% as better than 9% using a beta(0.09, 0.91) prior. Secondary endpoints are ORR, PFS by RECIST 1.1, and overall survival.
177
Lu-girentuximab 1480 MBq/m
2
(61% of single agent MTD) will be administered every 12 weeks for up to 3 cycles. Starting with the second cycle, nivolumab and cabozantinib will be added at standard dose. To explore the effects of the treatment on inducing activated T cell infiltration, patients will undergo pre/post-treatment PET scan with 18FF-AraG radiotracer as well as biopsies for single cell, spatial transcriptomics and proteomics studies. This investigator initiated trial is supported by Telix Pharmaceuticals and DOD grant W81XWH-22-1-0456.
Abstract
Background
Complete response (CR) is still a rare event in patients with advanced clear cell renal cell carcinoma (ccRCC). The combination of nivolumab plus cabozantinib was recently ...approved for the first-line treatment of ccRCC based on the CheckMate 9ER phase 3 study demonstrating improved progression-free survival (PFS) and objective response rate (ORR) in comparison to sunitinib. However, the CR rate was only 9%. Since the anti-tumor effects of immune checkpoint inhibitors are dependent on the presence of activated tumor-infiltrating T cells, drugs that could synergize with T cells’ anti-tumor activity can allow us to improve CR rates. Activation of the cGAS-STING pathway, the master regulator of anti-tumor immunity which is induced by radiation-induced DNA damage, is one promising mechanism that has been investigated. Many studies have shown that radiation treatment augments immune checkpoint inhibition. However, it is not always possible to radiate all metastatic lesions. Therefore, targeted peptide receptor radionuclide therapies (PRRT), have been developed by conjugating radioisotopes to receptor binding analogs targeting specific cancer cell surface proteins, thereby delivering targeted radiation to cancer cells in the body with minimal damage to surrounding healthy cells. 177Lu girentuximab is the first antibody-radioisotope designed for ccRCC, targeting carbonic anhydrase IX-expressing cells, which includes >90% of ccRCC. It has been tested in metastatic ccRCC as a single agent and shown to be safe and effective in stabilizing disease in 57% of pts. In this study, we hypothesize that 177Lu girentuximab-induced DNA damage will potentiate the STING pathway, and this activation will synergize with nivolumab and cabozantinib to promote trafficking and infiltration of activated T cells to tumors and achieve higher CR rates.
Methods
Up to 100 patients with treatment naïve, biopsy-proven ccRCC with adequate organ/marrow function with ≥1 evaluable lesion by RECIST 1.1 will be enrolled. A 5-patient safety lead-in will evaluate myelosuppression. Ongoing safety, and futility monitoring will employ a Bayesian approach. The sample size was chosen for reasonable operating characteristics to distinguish a CR rate (primary endpoint) of 18% as better than 9% using a beta(0.09, 0.91) prior. Secondary endpoints are objective response, PFS by RECIST 1.1, and overall survival. 177Lu-girentuximab 1480 MBq/m2 (61% of single agent MTD) will be administered every 12 weeks for up to 3 treatment cycles. Starting with the second cycle, nivolumab and cabozantinib will be added at standard dose. To explore the effects of the combination therapy on inducing activated T cell infiltration, patients will undergo pre/post-treatment PET scan with 18FF-AraG radiotracer as well as biopsies for single cell, spatial transcriptomics and proteomics studies. This is an investigator initiated trial. Telix Pharmaceuticals provided drug and funding support. Also supported by DOD grant W81XWH-22-1-0456
CDMRP DOD Funding: yes
Abstract
Breast cancer (BrCa) is the most common invasive cancer in Hispanic women. Although at decreased risk, Hispanic women are diagnosed at younger ages and with more aggressive disease than ...non-Hispanic Whites. Early detection is key in BrCa survival; however, there are no pre-diagnostic circulating biomarkers for early detection. This pilot nested case-control study based on our Mexican-American Cohort (MAC) study evaluates the role of global metabolic expression in predicting BrCa risk. MAC includes ∼23,000 participants in the Houston area with baseline blood specimens and epidemiological data. Using mass spectrometry-based global protein expression, 435 plasma metabolites were analyzed by Metabolon in 30 invasive BrCa cases (14 pre- (preM) and 16 post-menopausal (postM)) diagnosed 1-5 years after enrollment and 40 healthy controls (matched to cases on age, menopausal status) and length of follow-up). Mean age of preM women was 37.6 years (range 32-43) compared to 63.4 for postM (range 50-81). Using principal component analysis, we evaluated differences by disease and menopausal status. We found 76 metabolites that differed significantly (P<0.05) between cases and controls among postM women compared to only 13 metabolites in preM women. Using a pathway-based approach, we found that the majority of case-control differences were in metabolites related to hormone, lipid and energy metabolism. The specific metabolites differed by menopausal status. In postM cases, levels of steroid hormones epiandrosterone sulfate, androsterone sulfate, and 5-alpha-androstan-3beta,17beta-diol disulfate were higher than in controls; among preM cases, steroid hormones 5-alpha-pregnan-3beta,20alpha-diol disulfate and 5-alpha-pregnan-3alpha,20beta-diol disulfate 1 levels were higher. PostM cases had significantly (P<0.05) lower levels in fatty acids valerylcarnitine and butyrylcarnitine and higher levels of monoacylglycerols and glycerol 3-phosphate (G3P) than controls; there were no significant differences in these metabolites in preM cases and controls. The statistically significant (P<0.05) decreases in 3-phosphoglycerate, pyruvate, sarcosine (N-methylglycine), citrate, and malate which are all associated with glycolysis and the tricarboxylic acid cycle found in cases compared to controls irrespective of menopausal status, suggest energy metabolism may be associated with BrCa risk. In summary, our findings suggest: (1) case-control differences in plasma levels of specific metabolites associated with key functional pathways; (2) the specific metabolites and number of relevant metabolites differs by menopausal status; and (3) these differences are detectable years prior to diagnosis. Future studies exploring these associations with tumor hormone receptor status, dietary intake and anthropometric measurements will aid in further identifying key pre-diagnostic plasma markers for BrCa.
Citation Format: Sara S. Strom, Hua Zhao, Abenaa Brewster, Yuko Yamamura. Prediagnostic breast cancer metabolites in Mexican Americans: a nested case control study. abstract. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-193. doi:10.1158/1538-7445.AM2015-LB-193
Abstract only
2521
Background: LVGN6051, a monoclonal antibody against CD137 (also known as 4-1BB or TNFRSF9) with an engineered Fc capable of selectively binding to the Fcγ receptor IIB, acts as a ...conditional CD137 agonist, resulting in immune activation optimally in tumor microenvironment ( Qi, Nat. Commun. 2019 ). In preclinical models, LVGN6051 demonstrated robust anti-tumor efficacy and safety as a single agent and in combination with anti-PD-1 antibodies. Therefore, we have initiated this first-in-human study of LVGN6051 alone or in combination with pembrolizumab for the treatment of advanced or metastatic malignancy. Methods: This study includes accelerated dose escalation monotherapy up to 2 mg/kg of LVGN6051, and traditional 3 + 3 design for higher doses of LVGN6051 alone or in combination with pembrolizumab. Then, this study will enroll patients with specific types of malignancies following Simon’s two-stage design. Both agents are administered once every 3 weeks. Primary objectives of this study were to define the safety profile and to establish the recommended phase 2 dose (RP2D) of LVGN6051 alone or in combination with pembrolizumab. Pharmacokinetics, immunogenicity, pharmacodynamics and clinical efficacy will be also evaluated. Results: At the cut-off date on January 18, 2021, 16 subjects have been enrolled into the monotherapy cohorts (n=12, no DLT observed up to 7 mg/kg), and the combination cohort (n=4, ongoing at LVGN6051 2 mg/kg and pembrolizumab 200 mg, one DLT observed). No treatment-related adverse event (TRAE) was observed in monotherapy. Treatment-emergent adverse events (TEAE) in combination included increased ALT/AST, thrombocytopenia, and fatigue. In the combination cohort, one patient with predominant hepatic metastases and history of intermittent grade 2 hepatic impairment experienced grade 3 increased ALT/AST (DLT) on cycle 1 day 15 that were resolved to her baseline without corticosteroids on cycle 1 day 18. TRAE included increased ALT/AST, thrombocytopenia, neutropenia, nausea and fatigue. Seven of 10 evaluable patients in the monotherapy cohorts demonstrated stable disease with the longest treatment being 8+ months. Tumor reductions by >10% were observed in melanoma and neuroendocrine tumor on monotherapy. One patient with metastatic head and neck squamous cell carcinoma who had progressed on an anti-PD-L1 based therapy showed an immune partial response (iPR) for 6+ months to the combination therapy. Conclusions: Preliminary evidence showed that LVGN6051 was well tolerated and tumor shrinkages were observed. While we continue assessing its safety profile, antitumor activity was observed in the LVGN6051 and pembrolizumab cohort. The favorable safety profile and preliminary antitumor activity warrant further evaluation in patients with advanced malignancies. Clinical trial information: NCT04130542.
Abstract
Background: Wee1 kinase, which prevents premature mitotic entry by inhibiting cyclin-dependent kinases (CDKs), may be essential when cyclin E1 is overexpressed in order to prevent DNA damage ...and cell death. In preclinical studies, cancer models harboring CCNE1 amplification are highly sensitive to treatment with adavosertib, a Wee1 kinase inhibitor. A multicenter phase 2 study was conducted to assess the antitumor activity of adavosertib in patients with CCNE1 amplified advanced refractory solid tumors.
Methods: Patients with advanced refractory solid tumors harboring CCNE1 amplification pre-identified in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory were eligible. They had refractory disease, on standard options available, or they declined standard-of-care therapy. Eligible patients must be aged ≥ 18 years and had measurable disease per RECIST (Response Evaluation Criteria in Solid Tumors) 1.1, ECOG (Eastern Cooperative Oncology Group) performance status of 0-1, and adequate organ functions. After informed consent, patients received adavosertib 300 mg daily on days 1 to 5 and 8 to 12 of a 21-day cycle. The primary endpoint was objective response rate (ORR). The trial employed Simon's two-stage design.
Results: Between January 22, 2019 and May 20, 2020, 29 patients with 12 tumor types were enrolled on study: ovarian = 14, breast = 3, endometrial = 2; and carcinosarcoma, cholangiocarcinoma, esophageal, gallbladder, germ cell tumor, melanoma, prostate, sarcoma, sarcomatoid and urothelial = 10 (1 each tumor). Median follow-up was 11.7 months. The median line of prior systemic therapy was 4 (range 1-8). Twenty-seven patients were evaluable for response. In these patients, 7 confirmed partial responses (PR) were observed, for an ORR of 25.9% (95% CI 15.1-47.5%). The median progression-free survival was 4.0 months and one-year overall survival was 55%. In 13 patients with measurable high-grade serous ovarian cancer, 5 achieved PR (38.5%) and 8 had stable disease ≥6 months/PR (61.5%). Other PRs were seen in 1 urothelial carcinoma and 1 melanoma. Fifteen patients experienced grade 3 or higher treatment-related adverse events: neutropenia (24%), thrombocytopenia (17%), anemia (14%), nausea (17%), diarrhea (17%) and fatigue (17%). Sixteen patients required dose duction of adavosertib to 250 mg, and 7 further to 200 mg. Biomarker analysis is ongoing to investigate potential biomarkers of response.
Conclusions: Adavosertib monotherapy demonstrates promising clinical activity in patients with refractory solid tumors harboring CCNE1 amplification, especially in high-grade serous ovarian cancer. Further exploration of adavosertib in CCNE1 amplified high grade serous ovarian cancer is warranted.
Citation Format: Siqing Fu, Shuyang Yao, Yuan Yuan, Rebecca A. Previs, Anthony D. Elias, Richard Carvajal, Thomas J. George, Ying Yuan, Yuko Yamamura, Shannon Westin, Yan Xing, Ecaterina E. Ileana Dumbrava, Daniel D. Karp, Sarina A. Piha-Paul, Apostolia M. Tsimberidou, Jordi Rodon, Naoko Takebe, Charles Kunos, Karen Lu, Khanda Keyomarsi, Funda Meric-Bernstam. Phase II trial of the Wee1 inhibitor adavosertib in advanced refractory solid tumors with CCNE1 amplification abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 974.
Acute myeloid leukemia (AML) is comprised of several bone marrow-based cancers and is the most common type of leukemia in the United States. The etiology of AML is not well understood. A case-control ...study was conducted at The University of Texas M. D. Anderson Cancer Center to investigate associations between lifestyle characteristics and the risk of AML in Texas.
This study included 638 adult patients with de novo AML (cases) and a group of 636 matched controls. Interviewer-administered questionnaires were used to collect demographic and occupational data. The distribution of cases by World Health Organization (WHO) subtype was 71 patients (11%) with recurrent cytogenetic abnormalities (AML-RCA), 134 patients (21%) with multilineage dysplasia (AML-MD), and 389 patients (61%) with AML not otherwise categorized (AML-NOC). Multivariate logistic regression analyses were performed among all AML cases and among both sexes and each WHO subgroup.
Among men, heavy smoking (≥30 pack-years; odds ratio OR, 1.86) and occupational solvent exposure at low levels (OR, 2.87) or moderate/high levels (OR, 4.13) statistically significantly increased the risk of AML. Among women, obesity (OR, 1.62) and solvent exposure to low levels (OR, 2.73) or moderate/high levels (OR, 3.90) increased the risk of AML. Across WHO subtypes, obesity was associated with a statistically significantly increased risk of AML-RCA (OR, 3.15), whereas solvent exposure increased the risk in all subtypes at low levels (AML-RCA: OR, 4.11; AML-MD: OR, 2.54) and moderate/high levels (AML-RCA: OR, 5.13; AML-MD: OR, 3.02). A joint effect between smoking and solvent exposure was observed, and the highest risk was observed among smokers who had solvent exposure (OR, 4.51).
The current results suggested that several factors play a role in AML predisposition with possible joint effects. Risk profiles for AML differed by sex and WHO subtype.
To investigate the role of primary hypothyroidism (HYPT) on breast carcinogenesis, the authors evaluated 1) the association between HYPT and a diagnosis of invasive breast carcinoma and 2) the ...clinicopathologic characteristics of breast carcinoma in patients with HYPT.
For this retrospective chart review study, 1136 women with primary breast carcinoma (PBC) were identified from the authors' departmental data base. These women (cases) were frequency-matched for age (+/- 5 years) and ethnicity with 1088 healthy participants (controls) who attended a breast carcinona screening clinic. Women with HYPT who were receiving thyroid-replacement therapy before they were diagnosed with breast carcinoma or before the screening visit were identified.
The mean ages of cases and controls (51.6 years vs. 51.0 years, respectively; P = 0.30) and their menopausal status (65.4% premenopausal vs. 62% postmenopausal; P = 0.10) were comparable. Two hundred forty-two women in the case group (10.9%) with HYPT were identified. The prevalence of this condition was significantly greater the control group compared with the case group (14.9% vs. 7.0%, respectively; P < 0.001). PBC patients were 57% less likely to have HYPT compared with their healthy counterparts (odds ratio, 0.43l 95% confidence interval, 0.33-0.57). Seventy-eight white patients with PBC had HYPT and, compared with women who were euthyroid, they were older at the time of diagnosis (58.8 years vs. 51.1 years; P < 0.001), were more likely to have localized disease (95.0% vs. 85.9% clinical T1 or T2 disease, respectively; P = 0.025), and were more likely to have no pathologic lymph node involvement (62.8% vs. 54.4%; P = 0.15).
Primary HYPT was associated with a reduced risk for PBC and a more indolent invasive disease. These data suggest a possible biologic role for thyroid hormone in the etiology of breast carcinoma and indicate areas of research for the prevention and treatment of breast carcinoma.
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