Platinum-based Therapy Research Articles

MP29-07 APC MUTATION CONTRIBUTES TO NEUROENDOCRINE DIFFERENTIATION AND POOR OVERALL SURVIVAL IN METASTATIC PROSTATE CANCER PATIENTS

You have accessJournal of UrologyCME1 Apr 2023MP29-07 APC MUTATION CONTRIBUTES TO NEUROENDOCRINE DIFFERENTIATION AND POOR OVERALL SURVIVAL IN METASTATIC PROSTATE CANCER PATIENTS Yuto Baba, Takeo Kosaka, Kohei Nakamura, Yota Yasumizu, Nobuyuki Tanaka, Toshikazu Takeda, Kazuhiro Matsumoto, Shinya Morita, Ryuichi Mizuno, Hiroshi Nishihara, and Mototsugu Oya Yuto BabaYuto Baba More articles by this author , Takeo KosakaTakeo Kosaka More articles by this author , Kohei NakamuraKohei Nakamura More articles by this author , Yota YasumizuYota Yasumizu More articles by this author , Nobuyuki TanakaNobuyuki Tanaka More articles by this author , Toshikazu TakedaToshikazu Takeda More articles by this author , Kazuhiro MatsumotoKazuhiro Matsumoto More articles by this author , Shinya MoritaShinya Morita More articles by this author , Ryuichi MizunoRyuichi Mizuno More articles by this author , Hiroshi NishiharaHiroshi Nishihara More articles by this author , and Mototsugu OyaMototsugu Oya More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003257.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Although therapeutic strategies for metastatic prostate cancer (PCa) have expanded, some patients still suffer rapid progression. We investigated if their genomic characteristics correlated with treatment resistance and their clinical outcomes. METHODS: We identified 70 metastatic prostate cancer patients who underwent gene-panel tests since 2018. The correlation between the profiles of genomic mutation and the oncological outcomes including overall survival, time to treatment-related neuroendocrine prostate cancer (tNEPC), and the efficacy of each sequential treatment such as androgen receptor pathway inhibitors (ARPI), docetaxel (DTX), cabazitaxel (CBZ), and platinum-based chemotherapies were evaluated. RESULTS: Among the 70 patients, 27 (38.6%) patients developed metastases after definitive therapies while 43 (61.4%) already had metastases at the initial diagnosis. The most common genomic mutations were TP53 (35.7%), BRCA2 (22.9%), PTEN (21.4%), RB1 (18.6%), MYC (14.3%), APC (11.4%), and CDK12 (10.0%). As for treatment profiles, all the patients received androgen-deprivation therapy (ADT), 53 (75.7%) patients received ARPI, 48 (68.6%) patients received DTX, 32 (45.7%) patients received CBZ, and 37 (52.9%) patients received platinum-based therapy. Second biopsy of prostate or metastatic lesion revealed the pathological transformation from adenocarcinoma to tNEPC in 25 (35.7%) patients. Univariate and Multivariate analysis also indicated that that patients with APC and MYC mutations had shorter overall survival (HR=17.9, p=0.006 and HR=3.98, p=0.018, respectively). Focusing on the 8 APC-mutated patients, while their 30% PSA response rare after ARAT or DTX were not statistically low (p=0.74 and p=0.23), five out of them (62.5%) showed NEPC in the second biopsy samples and shorter time to NEPC development compared with those without APC mutations (p=0.05). In our cohort, APC mutation did not exist alone but coincided with either RB1 (5 patients, 62.5%) or TP53 (4 patients, 50%), major tumor suppressor genes. CONCLUSIONS: APC mutation, associated with other genomic alteration of tumor suppressor and NED, can be an important prognostic indicator in PCa patients. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e383 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yuto Baba More articles by this author Takeo Kosaka More articles by this author Kohei Nakamura More articles by this author Yota Yasumizu More articles by this author Nobuyuki Tanaka More articles by this author Toshikazu Takeda More articles by this author Kazuhiro Matsumoto More articles by this author Shinya Morita More articles by this author Ryuichi Mizuno More articles by this author Hiroshi Nishihara More articles by this author Mototsugu Oya More articles by this author Expand All Advertisement PDF downloadLoading ...

Efficacy and outcomes of ramucirumab and docetaxel in patients with metastatic non-small cell lung cancer after disease progression on immune checkpoint inhibitor therapy: Results of a monocentric, retrospective analysis.

Current first-line standard therapy for metastatic non-small cell lung cancer without driver mutations involves chemotherapy and immunotherapy combination. Prior to the advent of immune checkpoint inhibition, REVEL, a randomized phase III trial demonstrated improved progression-free and overall survival with ramucirumab and docetaxel (ram+doc) in patients who failed platinum-based first-line therapy. Long-term outcomes related to second-line ramucirumab and docetaxel after first-line immunotherapy exposure remain unknown. We analyzed outcomes for 35 patients from our center whom received ramucirumab and docetaxel following disease progression on chemotherapy and immunotherapy combination. Median progression-free survival among patients who received ram+doc after exposure to immunotherapy was 6.6 months (95% CI = 5.5 to 14.9 months; p<0.0001), and median overall survival was 20.9 months (95% CI = 13.4 months to infinity; p<0.0001). These outcomes suggest that there may a synergistic benefit to combining chemotherapy with anti-angiogenic therapy after immunotherapy exposure. Future analyses should be evaluated prospectively and among a larger patient subset.

Abstract P5-02-45: An HRD scoring system based on long-focal copy number alterations predictive of PARP inhibitor response

Abstract Homologous recombination deficiency (HRD) is characterized by a defective double-stranded DNA repair mechanism due to alterations in the homologous recombination (HR) pathway. Deleterious mutations in HR pathway genes can help identify potential responders to platinum-based chemotherapies and PARP inhibitors (PARPi), which promote apoptosis in HRD cells. Until recently, the use of PARPi in breast cancer (BC) was limited to advanced or metastatic disease with pathogenic or likely pathogenic germline BRCA (gBRCA) mutations. However, the use of PARPi has expanded to treat early-stage HER2-negative BC with a high risk of recurrence and gBRCA mutations, HER2-negative BC with somatic BRCA mutations, and triple-negative BC. To date, no universal method for HRD scoring is accepted; therefore, biomarkers are needed to stratify patients into PARPi responders and nonresponders more effectively. Because PARPi are used to treat HRD-driven cancers, we aimed to identify genomic consequences of HRD. For HRD-specific features, we calculated the proportion of long-focal total copy number alterations (LF-tCNA), which estimates amplification events for long-focal segments. Aneuploidy is especially prevalent in medullary, metaplastic, and invasive micropapillary BCs. These copy number variations are not necessarily consequences of HRD but can influence HRD scores. Genome-wide loss of heterozygosity (gwLOH) can be a result of HRD and used as a biomarker for HRD. We developed several scoring methods based on LF-tCNA, gwLOH, and aneuploidy scores. These scores were tested as predictors of HRD, defined as known loss-of-function germline mutations in BRCA1, BRCA2, PALB2, or BARD1 (TCGA-BRCA cohort, n = 1,032). To calculate the optimal HRD score, we used multivariate logistic regression analysis with HRD as an outcome and LF-tCNA, LOH, and ploidy as predictors. Based on the results of logistic regression, LF-tCNA and ploidy were selected to calculate HRD status. The positive and negative predictive values (PPV, NPV) were used to set the upper and lower thresholds, respectively. Samples with HRD scores above 7 (PPV) have the greatest potential for PARPi and platinum-based therapy response, while scores below -1 (NPV) were considered HRD wild type (WT). To validate the developed HRD score, we tested the score by combining BC cohorts (MSK_NCI and MET500 cohorts, n = 164) and used gBRCA1/2 pathogenic mutations as an outcome. Our HRD scoring system distinguished HRD WT from HRD-positive samples (AUC = 0.81) more effectively than a previously reported score based on LOH, telomeric-allelic imbalance (TAI), and large-scale state transitions (LST) (AUC = 0.72). We tested our HRD scoring system across tumor microenvironment molecular subtypes. The median HRD score in the basal-like subtype was increased compared to other subtypes, supporting the prevalence of gBRCA1/2 pathogenic mutations in this subtype. Moreover, the number of HRD-positive patients and the percent positive agreement, defined as the proportion of positive test results from our HRD also positive for HR mutations, were calculated for each BC subtype. Only 22% of basal-like HRD-positive samples also carried germline HR pathway mutations, which indicates 78% of HRD-positive patients who might benefit from PARPi or platinum treatment would have been missed by germline HR gene panels. This BC HRD scoring method is a promising tool for identifying HRD patients who may respond to PAPRi and platinum-based therapies, but additional studies are required for clinical validation. Citation Format: Maria Gurileva, Nikita Kotlov, Anna Love, Alexandra Melnikova, Krystle Nomie, Nathan Fowler, Alexander Bagaev. An HRD scoring system based on long-focal copy number alterations predictive of PARP inhibitor response [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-45.

Abstract PD5-01: PD5-01 Genomic and epigenomic BRCA alterations predict adaptive resistance and response to platinum-based therapy in triple negative breast cancer and ovarian carcinoma

Abstract Background. Homologous recombination deficiency (HRD), induced by germline and somatic BRCA1 or BRCA2 gene mutations (BRCAmut) and by BRCA1 promoter methylation (BRCA1meth), has been associated with better response to platinum agents in both triple negative breast cancer (TNBC) and ovarian carcinoma (OvCa). A major conundrum arising from recent studies is why patients with BRCA1meth cancers do more poorly compared to those with BRCAmut cancers given the biologically equivalent HRD in both states. Here, we address this question by performing detailed genomic analyses of primary TNBC and OvCa cohorts and through patient-derived xenografts (PDXs) and their derivative cell lines. Methods. Both new and publicly available cohorts of primary TNBC and OvCa encompassing 499 individuals treated with a combination of platinum and taxane chemotherapy were analyzed by whole genome and transcriptome sequencing as well as limited epigenetic analyses. A cohort of 43 PDX models of TNBC was genomically characterized and responses to both single agent platinum and docetaxel were evaluated in vivo. PDX longitudinal studies were performed to assess the dynamics of BRCA1 methylation following treatment. Results. Genomic analyses revealed that BRCA1mut and BRCA1meth cancers share the same pattern of BRCA1-linked genomic rearrangements. Nonetheless, in all four primary cancer cohorts examined we found that patients with BRCAmut cancers, but not those with BRCA1meth cancers, had significantly better response outcomes compared to those with BRCA proficient cancers. A separate analysis of PDX TNBCs with BRCA1 promoter methylation showed that PDXs derived from treatment naïve cancers had complete methylation of the BRCA1 promoter, whereas those derived from post-treatment cancers invariably had only partial methylation. Compared to PDXs with complete methylation, those with partial methylation had a lower response rate to in vivo platinum-based therapy, but not to docetaxel. Using single cell clonal expansions from BRCA1meth PDX models, we confirmed that partial methylation was the result of demethylation of one of the BRCA1 promoter alleles and not of the outgrowth of a non-methylated clone. Exposure of TNBC PDXs with complete methylation to a single course of platinum therapy resulted in the emergence of an unmethylated BRCA1 promoter allele, which associated with an increase in BRCA1 expression. We confirmed that platinum treatment results in progressive loss of BRCA1 methylation and restoration of BRCA1 expression in the clinical setting, by studying the BRCA1 status of a longitudinal series of four TNBC PDX models established from the same patient at different stages of her clinical history. Differential gene expression analysis revealed an increased immune transcriptional signal, especially an elevated M1 macrophage signature, associated with enhanced response to platinum therapy only in patients with BRCA proficient cancers, in both TNBC and OvCa. Integrating both the strength of this cancer immune signature and the presence of BRCA mutations resulted in more accurate predictions of response when compared to either HRD or BRCA status alone. Conclusions. These results suggest that unlike BRCAmut cancers, where BRCA deficiency is more genetically stable, BRCA1meth cancers are highly adaptive to genotoxin exposure resulting in demethylation of one allele, recovery of BRCA1 expression and acquired insensitivity to platinum. On the other end, a high immune transcriptional signature identifies patients with BRCA proficient cancers that are more likely to benefit from platinum therapy. Taken together, our study underscores the importance of characterizing molecular heterogeneity to optimize predictive precision in assigning response probabilities in TNBC and OvCa. Citation Format: Francesca Menghi, Kalyan Banda, Pooja Kumar, Robert Straub, Lacey E. Dobrolecki, Isabel Rodriguez, Susan E. Yost, Harshpreet Chandok, Marc Radke, George Somlo, Yuan Yuan, Michael T. Lewis, Elizabeth Swisher, Edison Liu. PD5-01 Genomic and epigenomic BRCA alterations predict adaptive resistance and response to platinum-based therapy in triple negative breast cancer and ovarian carcinoma [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD5-01.

Abstract OT3-23-01: VELA: A first-in-human phase 1/2 study of BLU-222, a potent, selective cyclin-dependent kinase (CDK) 2 inhibitor in patients with cyclin E1 gene (CCNE1)-amplified or CDK4/6 inhibitor-resistant advanced solid tumors

Abstract Background The regulation of cell growth and proliferation is dependent on cyclins and CDKs. The formation of the cyclin D-CDK4/6 complex increases the expression of cyclin E1 and E2. Cyclin E1 and E2 bind to and activate CDK2; this results in a cyclin E/CDK2 complex that assists with downstream expression of DNA synthesis machinery. The use of CDK4/6 inhibitors such as palbociclib or ribociclib is an effective treatment in patients with hormone receptor-positive (HR+), human epithelial growth factor receptor-2 negative (HER2-) breast cancer; however, resistance to treatment eventually occurs. Aberrant cyclin E/CDK2 activity has been identified as a potential resistance mechanism by which tumors can evade CDK4/6 inhibitors. BLU-222 is an oral, investigational, potent, and selective CDK2 inhibitor. In preclinical studies, BLU-222 treatment in combination with ribociclib led to durable tumor regression in both CDK4/6-resistant and sensitive models of HR+HER2- breast cancer. Trial design VELA (NCT05252416) is an international, open-label, first-in-human phase 1/2 study evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of BLU-222 in adult patients with CCNE1-amplified tumors or with HR+HER2- breast cancer with disease progression on CDK4/6 inhibitors. In phase 1 and 2, patients aged ≥18 years with an Eastern Cooperative Oncology Group performance status 0–2 are eligible. In phase 2, all patients must have ≥1 measurable target lesion per Response Evaluation Criteria in Solid Tumors version 1.1. Primary endpoints include assessing the safety of BLU-222 as a single agent or BLU-222 in combination with either carboplatin or ribociclib and/or fulvestrant (phase 1 and 2), identifying the maximum tolerated dose and/or recommended phase 2 dose (phase 1), and determining the objective response rate (phase 2). In the phase 1 dose-escalation part, patients with any advanced solid tumor with progression on standard of care (SOC) will receive BLU-222; patients with gastric or endometrial cancer (EC) with progression on ≥2 prior therapies (including ≥1 platinum-based therapy) or with CCNE1-amplified platinum-resistant/refractory ovarian cancer (OC) will receive BLU-222 and carboplatin; patients with HR+HER- breast cancer with progression on CDK4/6 inhibitors will receive BLU-222, ribociclib, and fulvestrant. In the phase 2 dose-expansion part, patients with CCNE1-amplified tumors including EC (progression on ≥2 prior therapies), platinum-resistant/refractory OC, or other advanced solid tumors (progression after SOC) will receive BLU-222 monotherapy; patients with CCNE1-amplified platinum-resistant/refractory OC will receive BLU-222 and carboplatin; and patients with CDK4/6 inhibitor-resistant HR+HER2- breast cancer will receive BLU-222 and fulvestrant with/without ribociclib. Pharmacokinetic parameters will be calculated using standard non-compartmental methods from the plasma concentration–time data. Tissue biopsies will be collected during cycle 1 to assess the phosphorylation of retinoblastoma 1 (Rb1) protein which will be used as a pharmacodynamic marker to assess target inhibition. Dose escalation is ongoing and approximately 50 sites are anticipated to enroll patients across North America, Europe, and the Asia/Pacific region. Citation Format: Manish R Patel, Dejan Juric, Brian S Henick, Kathleen N Moore, Doreen Do, Joshua Chapman, Hui Zhang, Maria Roche, Kate J Newberry, Mikael Rinne, Timothy A Yap. VELA: A first-in-human phase 1/2 study of BLU-222, a potent, selective cyclin-dependent kinase (CDK) 2 inhibitor in patients with cyclin E1 gene (CCNE1)-amplified or CDK4/6 inhibitor-resistant advanced solid tumors [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-23-01.

Abstract P4-01-08: Efficacy of PARP Inhibitors in Patients With BRCA1/2-related Breast Cancer with Prior Platinum Exposure: A Systematic Review and Meta-Analysis

Abstract Background: Approximately 5% of breast cancer patients carry a deleterious germline BRCA1/2 mutation, which leads malignant cells to be deficient in the repair of DNA double-strand breaks via homologous recombination. The poly(adenosine diphosphate–ribose) polymerase (PARP) enzymes are important on DNA single-strand break repair and PARP inhibitors (PARPi) cause an accumulation of unresolved DNA damage in tumors with BRCA1/2 mutations, resulting in cell death. However, because platinum salts also ultimately cause double-strand DNA breaks and may have overlapping mechanisms of resistance with PARPi, the efficacy of PARPi in patients with prior platinum therapy is unknown. We sought to evaluate the efficacy of PARPi in patients with BRCA1/2-related breast cancer and previous platinum exposure. Methods: We performed a systematic review and meta-analysis of studies that evaluated the efficacy of PARPi in patients with advanced or metastatic breast cancer and germline BRCA1/2 mutations. Two independent investigators identified double-blind, randomized controlled trials (RCTs) that included the subgroup of previous exposure to platinum. PubMed, Embase, and Cochrane databases were searched for papers up to June 26, 2022. Data extraction from published reports and quality assessment were performed under Cochrane recommendations. Hazard ratios (HRs) with a 95% confidence interval (CI) were pooled, and a p-value of &amp;lt; 0.05 was considered statistically significant. The software Review Manager 5.3 was selected for conducting the statistical analysis. The primary endpoint of interest was progression-free survival (PFS). Results: Out of 2069 database results (487 on PubMed; 1376 on Embase; and 206 on Cochrane), 42 studies were selected for full review, and 4 RCTs, with a total of 249 patients, were included in the final investigation. The PARPi included were Olaparib, Talazoparib, Niraparib, and Veliparib. Pooled analysis showed that PARPi improved PFS in breast cancer patients with prior treatment with platinum-based therapy compared to the control group [HR = 0.72; 95% CI, 0.53-0.97; p = 0.03]. In comparison, the population without previous platinum exposure had a similar but slightly greater benefit from PARPi [HR = 0.68; 95% CI, 0.52-0.89; p = 0.005]. A subgroup analysis containing only the three randomized trials with PARPi monotherapy confirmed the central tendency favoring PARPi over physicians’ choice of single-agent chemotherapy in patients with prior platinum-therapy; however, because of small numbers and wide confidence interval it was not statistically significant [HR = 0.72; 95% CI, 0.51-1.01; p = 0.06]. Conclusions: Our findings suggest that PARPi are associated with longer PFS in patients with advanced breast cancer and previous exposure to platinum therapy, decreasing the concerns about cross-resistance between the drug classes. Nonetheless, more extensive studies are still necessary to investigate the efficacy of PARPi in patients with prior platinum exposure and truly platinum-resistant disease. Progression-free survival of included studies Citation Format: Alice D. Marinho, Beatriz Mella S. Pessoa, Gabriela R. Brandao, Caroliny H. Da Silva, Pedro A. Reis, Ana Carolina M. Comini, Felipe Batalini. Efficacy of PARP Inhibitors in Patients With BRCA1/2-related Breast Cancer with Prior Platinum Exposure: A Systematic Review and Meta-Analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-08.

Abstract PD5-04: PD5-04 Characterizing the HER2-/Immune-/DNA repair (DRD-) response predictive breast cancer subtype: the hunt for new protein targets in a high-needs population with low response to all I-SPY2 agents

Abstract Background: In previous work we leveraged the I-SPY2 trial to create treatment response predictive subtypes (RPS) incorporating tumor biology beyond clinical HR/HER2, to better predict drug responses in an expanded treatment landscape that includes platinum agents, dual HER2-targeting regimens and immunotherapy [1]. We showed that best performing schemas incorporate Immune, DRD and HER2/Luminal phenotypes, and that treatment allocation based on these would increase the overall pCR rate to 63% from 51% using HR/HER2-based treatment selection. The RPS schema has been selected for prospective evaluation in I-SPY2. Using the RPS, one would prioritize platinum-based therapy for HER2-/Immune-/DRD+, immunotherapy for HER2-/Immune+, and dual-anti-HER2 for HER2+ that are not luminal. HER2+/Luminal patients have low response rates to dual-anti-HER2 therapy but may respond better to anti-AKT. However, there is still a considerable ‘biomarker-negative’ group of resistant cancers (HER2-/Immune-/DRD-) with very low pCR rates to all tested agents, that require a new therapeutic approach. Here we characterize the protein signaling architecture of these tumors to identify new target candidates. Methods: 987 I-SPY 2 patients from 10 arms of the trial were considered for this analysis. All have gene expression, pCR and RPS; 944 have distant recurrence free survival (DRFS) data; and 736 have reverse phase protein array (RPPA) data from laser capture microdissected tumor epithelium. These data – known collectively as the I-SPY2-990 mRNA/RPPA Data Resource - were recently made public on NCBI’s Gene Expression Omnibus [GEO: GSE196096]. We focus on HER2-/Immune-/DRD- tumors, applying Wilcoxon and t-tests to identify phosphoproteins that differ between HR+HER2-/Immune-/DRD- and other HR+HER2- tumors; and between TN/Immune-/DRD- and other TNs. The Benjamini-Hochberg (BH) method is used to adjust p-values for multiple hypothesis testing. In addition, the Kaplan-Meier method is used to estimate DRFS. Results: 201/736 I-SPY 2 patients with RPPA data are classified HER2-/Immune-/DRD- (HR+HER2-: n=138; TN: n=63). Of these, 8.5% (17/201) achieved pCR. Non-responding HER2-/Immune-DRD- had worse outcomes than responders (~75% vs. ~95% DRFS at 5 years). 60/139 phospho-proteins differ significantly between HR+HER2-/Immune-/DRD- and other HR+HER2- tumors (n=122). These tumors are relatively ‘cold’, in that 90% (54/60) of the phosphoprotein activities characterizing this group are at lower levels than in the overall HR+HER2- population; including immune (e.g. pPDL1, pJAK/STAT) and proliferation (e.g., Ki67, CyclinB1, pAURK) endpoints. Phosphoproteins showing higher levels in this subset include ERBB2 (BH p=1.7E-06), Cyclin D1 (BH p=1.4E-05), pAR (BH p=1.4E-05), and ER (BH p=3E-04). Within the TN subset, only 3/139 phospho-proteins differed significantly between TN/Immune-/DRD- and other TN tumors (n=189). These were all immune-related (pPDL1, pSTAT1, and HLA DR), with lower expression in the TN/Immune-/DRD- group. Conclusion: HR+HER2- and TN patients who are Immune-Low and DRD-Low have very low pCR rates to all tested therapeutics in I-SPY2 including standard chemotherapy, platinum, and immunotherapy. Senolytics (possibly targeting Cyclin D1), HER2low agents, and AR modulators may overcome resistance in HR+HER2-/Immune-/DRD-, whereas an immune activator beyond checkpoint inhibition is suggested for TN/Immune-/DRD- patients. [1] Wolf et. al., Redefining Breast Cancer Subtypes to Guide Treatment Prioritization and Maximize Response: Predictive Biomarkers across 10 Cancer Therapies. Cancer Cell 2022 Citation Format: Denise M. Wolf, Christina Yau, Julia Wulfkuhle, Rosa I. Gallagher, Lamorna A. Brown Swigart, Gillian L. Hirst, Jean-Philippe Coppe, Mark Jesus M. Magbanua, Rosalyn Sayaman, I-SPY2 Investigators, Laura Sit, Nola M. Hylton, Angela DeMichele, Donald A. Berry, Lajos Pusztai, Douglas Yee, Laura J. Esserman, Emanuel F. Petricoin, Laura Van ’t Veer. PD5-04 Characterizing the HER2-/Immune-/DNA repair (DRD-) response predictive breast cancer subtype: the hunt for new protein targets in a high-needs population with low response to all I-SPY2 agents [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD5-04.

A phase II single-arm trial of niraparib in platinum-sensitive metastatic castration-resistant prostate cancer with DNA repair defects (PLATPARP).

TPS291 Background: Platinum-based chemotherapy, either as monotherapy or in combination with taxanes, is increasingly used for patients with metastatic castration-resistant prostate cancer (mCRPC) harboring germline and/or somatic homologous recombination repair gene mutations (HRRm). However, clinical responses with platinum-based therapy are often of limited duration and limited by cumulative toxicities. The PARP inhibitor (PARPi) olaparib is approved for the treatment of mCRPC patients with pathogenic HRRm after progression on enzalutamide or abiraterone. Importantly, sensitivity to platinum-based chemotherapy may predict improved clinical outcomes with PARPi, and ‘maintenance’ PARPi strategies are routinely used in patients with advanced ovarian and pancreatic malignancies with HRRm with initial clinical response to platinum chemotherapy. We hypothesize that maintenance niraparib, a PARPi with demonstrated activity in mCRPC with HRRm, will prolong clinical responses to platinum-based chemotherapy with acceptable toxicity in mCRPC patients harboring germline and/or somatic HRRm. Methods: We are conducting an open-label, single-arm, phase II study to evaluate the clinical benefit of maintenance niraparib in biomarker-defined, platinum-sensitive mCRPC patients. Eligible subjects harbor a pathogenic germline and/or somatic mutation in BRCA1/2, ATM, FANCA, CDK12, RAD51B, RAD54L, PALB2, CHEK2, HDAC2, or BRIP1 and have received at least 3 cycles (or minimum 9 weeks) of platinum-based chemotherapy for the treatment of mCRPC per investigator discretion. Following ³4 weeks since completion of chemotherapy, subjects without evidence of clinical or radiographic disease progression receive investigational treatment with maintenance niraparib (starting dose 200 mg daily). The primary objective is an improvement in 6 month PFS rate (PFS6) (H0: PFS6 rate 25%; H1: PFS6 rate 50%; power 0.77 with one-sided α = 0.05). Serial plasma samples are obtained for correlative analyses of markers of response and/or resistance to maintenance niraparib. Eight of a planned total of 18 subjects have enrolled (N=3 germline BRCA2; N=2 somatic BRCA2; N=1 germline PALB2; N=1 germline ATM; N=1 germline CHEK2). This study incorporates a novel, combined genetic and clinical patient-selection approach for PARPi therapy to optimize clinical outcomes. Clinical trial information: NCT04288687 .

TROPHY-U-01 cohort 6: Sacituzumab govitecan (SG), SG plus zimberelimab (ZIM), SG plus ZIM plus domvanalimab (DOM), or carboplatin (CARBO) + gemcitabine (GEM) in cisplatin-ineligible patients (pts) with treatment-naive metastatic urothelial cancer (mUC).

TPS592 Background: SG is an antibody-drug conjugate composed of an anti-trophoblast cell-surface antigen-2 (Trop-2) antibody coupled to SN-38 via a proprietary hydrolyzable linker. In Cohort 1 of the phase 2 TROPHY-U-01 trial, SG monotherapy resulted in a 27% objective response rate (ORR) and median overall survival (OS) of 10.9 months with an overall manageable toxicity profile in pts with locally advanced or mUC who previously received platinum-based therapy and a checkpoint inhibitor (CPI; Tagawa S, et al. J Clin Oncol. 2021). The results led to accelerated FDA approval of SG for this population. ZIM (anti-PD-1) and DOM (anti-TIGIT) are CPIs under clinical investigation for anti-tumor activity. Cohort 6 of TROPHY-U-01 trial (C6) will assess SG monotherapy vs SG plus CPI combinations (SG + ZIM; SG + ZIM + DOM) vs CARBO/GEM followed by avelumab maintenance in treatment naive cis-ineligible pts with locally advanced or mUC. Methods: TROPHY-U-01 (NCT03547973) is a multicohort, open-label, global, phase 2 trial. C6 includes pts with cis-ineligible unresectable locally advanced or mUC who are ≥18 y; have an ECOG performance status 0-1; have available tissue for biomarker testing; have no prior mUC therapy, except (neo)adjuvant chemotherapy with recurrence &gt;12 mo from completion; are CPI-naive or &gt;12 mo from completion; have adequate hematologic and hepatic function; and have creatinine clearance ≥30 mL/min. A safety lead-in will occur where 6-8 pts will be treated with SG 10 mg/kg on D1 and D8 of a 21-D cycle + ZIM 360 mg q3wk. A second safety lead-in will occur where 6-8 pts will be treated with SG 10 mg/kg on D1 and D8 of a 21-D cycle + ZIM 360 mg q3wk + DOM 1200 mg q3wk. After the safety lead-in, pts will be randomized 1:2:2:2 to: Arm 1: SG 10 mg/kg on D1 and D8 of a 21-D cycle; Arm 2: SG 10 mg/kg on D1 and D8 of a 21-D cycle and ZIM 360 mg q3wk; Arm 3: SG 10 mg/kg on D1 and D8 of a 21-D cycle and ZIM 360 mg q3wk and DOM 1200 mg q3wk; and Arm 4: CARBO (AUC 4.5-5) on D1 of each 21-D cycle + GEM 1000 mg/m2 on D1 and D8 of each 21-D cycle for the first 4-6 cycles followed by switch maintenance avelumab 800 mg q2wk in the absence of progression. All pts will continue treatment until progression, unacceptable toxicity, or loss of clinical benefit. Primary endpoint is ORR per central review based on RECIST 1.1. Secondary endpoints include progression-free survival, duration of response, and clinical benefit rate by central review and investigator review, as well as ORR by investigator review, and OS, and safety and tolerability (Arms 1-3). C6 aims to enroll an estimated 226 pts. With 60 subjects each in Arms 2-4, a comparison of Arm 2 or 3 vs Arm 4 will have ~88% power at one-sided α of 0.05 to demonstrate an improvement in ORR, with a null hypothesis of ORR 40% for Arms 2-3 and an alternative hypothesis of ORR at 65% for Arms 2-4. Clinical trial information: NCT03547973 .

TROPHU-U-01 cohort 5: Evaluation of maintenance sacituzumab govitecan (SG) plus zimberelimab (ZIM), ZIM, or avelumab in cisplatin-eligible patients (pts) with unresectable or metastatic urothelial cancer (mUC).

TPS598 Background: SG is an antibody-drug conjugate composed of an anti-trophoblast cell-surface antigen-2 (Trop-2) antibody coupled to a topoisomerase-I inhibitor, SN-38, via a hydrolyzable linker. In Cohort 1 of the phase 2 TROPHY-U-01 trial, SG monotherapy resulted in a 27% objective response rate (ORR) and median overall survival (OS) of 10.9 months with an overall manageable toxicity profile in pts with locally advanced or mUC who previously received platinum-based therapy and a checkpoint inhibitor (CPI; Tagawa S, et al. J Clin Oncol. 2021). These results led to accelerated FDA approval of SG in this population. The CPI ZIM is a fully human IgG4 monoclonal antibody targeting PD-1. CPIs are active in mUC, including avelumab that is FDA-approved as switch maintenance therapy for locally advanced or mUC that has not progressed with first-line platinum-based chemotherapy. Cohort 5 of the TROPHY-U-01 trial will evaluate the safety, tolerability, and efficacy of SG + ZIM vs ZIM alone vs avelumab as switch maintenance in pts with mUC who have received gemcitabine (GEM)/cisplatin without progressive disease (PD). Methods: TROPHY-U-01 (NCT03547973) is a multicohort, open-label, global, phase 2 trial. Cohort 5 includes pts who have not progressed after completion of 4-6 cycles of GEM/cisplatin. Key eligibility requirements include ≥18 y; ECOG PS 0-1; available tissue for biomarker testing; adequate blood counts without transfusion or growth factor within 2 weeks of study drug initiation; creatinine clearance ≥30 mL/min. A safety lead-in of 6-8 pts will be conducted, where pts will be treated with SG 10 mg/kg IV on D1 and D8 of a 21-D cycle plus ZIM 360 mg IV q3wk on a 21-D cycle. On safety lead-in, if SG + ZIM is deemed safe, pts will be randomized 1:1:1. Those in Arm 1 will receive SG 10 mg/kg IV on D1 and D8 of a 21-D cycle followed by ZIM 360 mg IV, q3wk (D1 of a 21-D cycle). Pts in Arm 2 will receive avelumab 800 mg IV q2wk (D1 of a 14-D cycle). Pts in Arm 3 will receive ZIM 360 mg IV q3wk. All pts will continue treatment until PD, unacceptable toxicity, or loss of clinical benefit. The primary endpoint is progression-free survival based on central review by RECIST 1.1 criteria. Secondary endpoints include OS (all arms), safety/tolerability of SG in combination with ZIM (Arm 1). Cohort 5 aims to enroll an estimated 158 pts. A sample size of 50 pts per randomized arm is determined based on clinical consideration for exploring the activity of anticancer agents. Clinical trial information: NCT03547973 .

Impact of age on the therapy-related characteristics and outcomes of testicular germ cell tumors at a tertiary care center in India.

415 Background: Testicular germ cell tumors (t-GCTs) commonly present in age group 20-40 years (yrs). Older patients (pts) in many cancers have worse tolerance to therapy and outcomes. We examine herein the effect of older age in t-GCT pts. Methods: We conducted a chart-review-based retrospective analysis of pts of t-GCTs diagnosed and treated at our urogenital clinic from 2015-2021. Pts were divided into two groups: Age ≤40 years (Group A) and &gt;40 years (Group B). Multivariable Cox regression models were constructed to analyze the prognostic value of older age while adjusting for measured confounders. Results: A total of 298 patients of t-GCT were identified; the median age was 30 yrs (interquartile range 24-37), 43.0% with intermediate or poor risk, 64.8% patients with non-seminomatous GCT (NSGCT), 250 pts in gp A and 48 in gp B. Baseline characteristics in both gps differed significantly with respect to the risk category, and seminoma histology, while there was no difference for performance status (ECOG ≥2), see table. Bleomycin, cisplatin, and etoposide (BEP) was the most common chemotherapy (226/262 pts), and use of BEP was not different in 2 gps (p=0.249). Grade III/IV adverse effect burden was greater in gp B vs gp A for febrile neutropenia, nausea/vomiting, and diarrhea, while infertility was more in gp A (Table). Outcomes in terms of markers normalization (163 vs 33, p=0.408) and radiological response (complete remission, 93 vs 20, p=0.205) did not differ. Median overall survival was not reached in both gps, and the hazard ratio for age &gt;40 yrs was 1.91 (95% confidence interval 0.91-3.99, p =0.086), after adjusting for risk category, performance status, and response to therapy. Conclusions: Age does not deter the use of platinum-based therapy, which, although more toxic, has similar efficacy to younger pts of t-GCT. [Table: see text]

Study EV-104: Phase 1 study of intravesical enfortumab vedotin for treatment of patients with non-muscle invasive bladder cancer (NMIBC)—Trial in progress.

TPS582 Background: The majority of patients with bladder cancer present with non-muscle invasive disease (Chang 2016; Woldu 2017; Kates 2020; Li 2020). The standard of care for treatment of high risk NMIBC involves transurethral resection of the bladder tumor (TURBT) followed by intravesical Bacillus Calmette-Guerin (BCG) or chemotherapy. Although the response rate to BCG therapy is high, many patients recur within 1–5 years (Matulay JU 2021). For patients who have BCG unresponsive disease after adequate course of BCG, there are limited options. While radical cystectomy (RC) is still considered the standard of care, most patients are reluctant to undergo RC and their options are limited to intravesical chemotherapy or pembrolizumab. Enfortumab vedotin (EV) is an antibody-drug conjugate directed to Nectin-4, which is highly expressed in bladder tumors. In EV-301, a phase 3 study, EV showed an OS benefit vs chemotherapy in patients with locally advanced or metastatic urothelial carcinoma (la/mUC) who had previously received platinum-based therapy and a PD-1 or PD-L1 inhibitor (Powles NEJM 2021). Based on its demonstrated benefit in la/mUC, EV is currently being evaluated in earlier UC settings. The purpose of this study is to investigate the intravesical administration of EV for patients with NMIBC. Methods: EV-104 (NCT05014139) is a phase 1, open-label, multicenter, dose-escalation and dose-expansion study designed to evaluate the safety, tolerability, PK, and antitumor activity of intravesical EV in adults with high-risk BCG-unresponsive NMIBC (carcinoma in situ with or without papillary disease) who are ineligible for or refuse RC. The dose escalation part of the trial aims to identify the maximum tolerated dose (MTD) and/or recommended dose of intravesical EV. The dose expansion part will evaluate patients at the MTD or recommended dose and further characterize safety and antitumor activity of intravesical EV. The study treatment regimen will include an induction phase, where patients will receive intravesical EV weekly for 6 weeks followed by monthly maintenance for a total of 9 additional EV doses. Patients will be assessed for response every 3 months by cystoscopy and urine cytology, while on study. Safety and antitumor activity endpoints will be summarized using descriptive statistics. The study is currently enrolling in the US with additional sites planned in Canada and the EU. Clinical trial information: NCT05014139 .

Effect of Radio-Chemotherapy on PD-L1 Immunohistochemical Expression in Head and Neck Squamous Cell Carcinoma

Programmed death-ligand 1 (PD-L1) checkpoint inhibitors represent a mainstay of therapy in head and neck squamous cell cancer (HNSCC). However, little is known about the influence of combined therapy on PD-L1 expression. The study aims to gather evidence on this topic. A systematic search was carried out in electronic databases Pubmed-MEDLINE and Embase to retrieve studies on the comparison of PD-L1 expression before and after conventional therapy. Data were extracted and a quantitative analysis with pooled odds ratios (ORs) was performed when applicable. Of 5688 items, 15 were finally included. Only a minority of studies assessed PD-L1 with the recommended combined positive score (CPS). The results are highly heterogeneous, with some studies reporting an increase in PD-L1 expression and others reporting a decrease. Three studies allowed for quantitative analysis and showed a pooled OR of 0.49 (CI 0.27-0.90). From the present evidence, a clear conclusion towards an increase or decrease in PD-L1 expression after combined therapy cannot be drawn, but even with few studies available, a trend towards an increase in expression in tumor cells at a cutoff of 1% can be noted in patients undergoing platinum-based therapy. Future studies will provide more robust data on the effect of combined therapy on PD-L1 expression.

Copy number footprints of platinum-based anticancer therapies.

Recently, distinct mutational footprints observed in metastatic tumors, secondary malignancies and normal human tissues have been demonstrated to be caused by the exposure to several chemotherapeutic drugs. These characteristic mutations originate from specific lesions caused by these chemicals to the DNA of exposed cells. However, it is unknown whether the exposure to these chemotherapies leads to a specific footprint of larger chromosomal aberrations. Here, we address this question exploiting whole genome sequencing data of metastatic tumors obtained from patients exposed to different chemotherapeutic drugs. As a result, we discovered a specific copy number footprint across tumors from patients previously exposed to platinum-based therapies. This footprint is characterized by a significant increase in the number of chromosomal fragments of copy number 1-4 and size smaller than 10 Mb in exposed tumors with respect to their unexposed counterparts (median 14-387% greater across tumor types). The number of chromosomal fragments characteristic of the platinum-associated CN footprint increases significantly with the activity of the well known platinum-related footprint of single nucleotide variants across exposed tumors.

Feasibility of omitting the clinical target volume under PET-CT guidance in unresectable stage III non-small-cell lung cancer: A phase II clinical trial

BackgroundThis clinical trial aims at investigate the feasibility of CTV-omitted, positron-emission tomography computed tomography (PET-CT) combined with intensity-modulated radiation therapy (IMRT) for unresectable stage III NSCLC. Methods and MaterialsThis was a single-center, phase II clinical trial initiated in July 2016. Patients with unresectable stage III NSCLC undergoing routine IMRT were randomly enrolled into the study group (CTV-omitted under PET-CT guidance) and the control group (CTV-delineated). Patients received platinum-based dual-drug concurrent chemoradio therapy. In the study group, the PGTV dose was 60 Gy given in 30 daily 2 Gy fractions; in the control group, the PCTV dose was 54 Gy given in 30 daily 1.8 Gy fractions, and the PGTV dose was 60 Gy given in 30 daily 2 Gy fractions. The primary endpoint was the incidence of radiation respiratory events or esophagitis with grade 3 or higher. The secondary endpoints included objective response rate (ORR), locate control rate, progression-free survival (PFS), failure pattern and overall survival (OS). ResultsA total of 90 patients were enrolled between July 2016 and March 2019. The incidence of radiation respiratory events or esophagitis with grade 3 or higher was 11.1 % in the study group, significantly lower than the rate of 28.9 % in the control group (P = 0.035), basically due to the reduced irradiated volumes of the lungs and esophagus in the study group. The median PFS was 9.0 months versus 10.0 months (P = 0.597), and the median OS 31.0 months versus 26.0 months (P = 0.489) in the study group and the control group, respectively. The failure pattern was not significantly different between the two groups (P = 0.826). ConclusionOmitting the CTV under PET-CT guidance has high feasibility to reduce severe radiation associated toxicity in IMRT for unresectable stage III NSCLC, without compromising the efficacy.

Homologous recombination deficiency prediction using low-pass whole genome sequencing in breast cancer

Homologous recombination repair deficiency (HRD) results in a defect in DNA repair and is a frequent driver of tumorigenesis. Poly(ADP-ribose) polymerase inhibitors (PARPi) or platinum-based therapies have increased theraputic effectiveness when treating HRD positive cancers. For breast cancer and ovairan cancer HRD companion diagnostic tests are commonly used. However, the currently used HRD tests are based on high-depth genome sequencing or hybridization-based capture sequencing, which are technically complex and costly. In this study, we modified an existing method named shallowHRD, which uses low-pass whole genome sequencing (WGS) for HRD detection, and estimated the performance of the modified shallowHRD pipeline. Our shallowHRD pipeline achieved an AUC of 0.997 in simulated low-pass WGS data, with a sensitivity of 0.981 and a specificity of 0.964; and achieved a higher HRD risk score in clinical BRCA-deficient breast cancer samples (p = 5.5 × 10−5, compared with BRCA-intact breast cancer samples). We also estimated the limit of detection the shallowHRD pipeline could accurately predict HRD status with a minimum sequencing depth of 0.1 ×, a tumor purity of > 20%, and an input DNA amount of 1 ng. Our study demostrates using low-pass sequencing, HRD status can be determined with high accuracy using a simple approach with greatly reduced cost.

Retrospective analysis of drug intake affecting the intestinal microbiota and the therapeutic effects of chemotherapy on gastric cancer.

379 Background: Administration of some medications, such as antibiotics, antacids, and probiotic supplementation, may affects the treatment outcomes of immune checkpoint inhibitors (ICIs), through the change of gut microbiota in cancer patients. Even when ICIs are combined with cytotoxic chemotherapy (Chemo), a use of such medications is expected to be a potential biomarker. However, the impacts of medications that affect gut microbiota on the efficacy of Chemo alone is unclear. Methods: We retrospectively analyzed patients who received fluoropyrimidines and platinum-based therapy for advanced gastric cancer in our institutions between January 2010 and December 2019. Progression-free survival (PFS) and overall survival (OS) by history of antibiotic/antacid/probiotic supplementation, were analysed. Results: A total of 101 pts were analyzed. Median age was 66 years (range, 30-81), female/male; 36/65, 1st-line regimen SP/XP/SOX/XELOX/FOLFOX; 52/2/39/1/7. In all patients, The median PFS for first-line treatment was 5.8 months (95% CI: 5.0-7.3) and the median OS was 15.5 months (95% CI: 12.5-18.6).Univariate analysis for PFS of first-line treatment did not show a significant difference in antibiotic use (median 7.6 vs 5.5 months, HR: 0.79 [95%CI: 0.50-1.24], p=0.31), oral antacids (median 6.6 vs 5.8 months, HR: 0.96 [95%CI: 0.61-1.54], p=0.89) and probiotic supplementation (median 9.1 vs 5.5 months, HR: 0.7 [95%CI: 0.38-1.26], p=0.24). Similarly in OS, the use of antibiotics (median 18.4 versus 13.4 months, HR: 0.85 [95%CI: 0.53-1.37], p=0.49), oral antacids (median 16.3 vs 13.8 months, HR: 1.15 [95%CI: 0.70-1.88], p=0.58), and oral probiotic supplementation (median 20.2 vs 13.8 months, HR: 0.77 [95%CI: 0.42-1.40], p=0.40), with no statistically significant differences. Conclusions: In this study, there were no significant differences in PFS and OS between patients administered with or without antibiotics, antacids, or probiotic supplementation. Future studies are expected to investigate the impacts of these medications on the treatment outcomes of ICIs+Chemo combination.

Clinical outcomes for IDH1 mutant biliary tract cancer (BTC) treated with contemporary systemic therapy.

513 Background: Isocitrate dehydrogenase 1 and 2 (IDH1/2) play a key role in cellular metabolism and epigenetic regulation. Conserved missense IDH1 mutations lead to an accumulation of the onco-metabolite 2-hydroxygluterate, which drives oncogenesis and inhibits cellular differentiation. Ivosidenib is now approved for IDH1 mutant BTC following the results of the phase III ClarIDHy trial. It remains unclear what are the long-term outcomes for patients (pts) with IDH1 mutant BTC treated with chemotherapy, targeted therapy, and immunotherapy. Methods: This was a retrospective analysis of BTC pts who underwent prospective, clinical grade, next generation sequencing by MSK-IMPACT 341, 410, 468 or 505. The primary objective was to define the clinical outcomes of systemic treatment for those pts with IDH1 mutant BTC. Secondary objectives included description of co-occurring genomic alterations. Progression-free survival (PFS) was calculated from the start date of treatment to the date of progression or death. Overall survival (OS) was calculated from the date of unresectable/metastatic disease. This study was approved by the MSKCC Institutional Review Board (NCT01775072). Results: 1124 pts with BTC underwent somatic genomic sequencing with MSK-IMPACT, 143 (12.7%) of which had IDH1 mutations. 78 (55%) were female and median age at diagnosis was 54 (range 32-94). Almost all were intrahepatic cholangiocarcinoma (139; 97%), with 2 (1.5%) gallbladder, and 2 (1.5%) perihilar. The most common co-occurring alterations were in ARID1A (33; 21.7%), PBRM1 (29;20.3%) and BAP1 (19;13.3%). Median TMB was 2.6 mut/Mb (0.8-68.5). 2 pts had microsatellite instability and 1 had a co-occurring IDH2 mutation. 112 (78%) had unresectable/metastatic disease at diagnosis. The median number of lines of therapy was 2 (0-9). With a median follow up time of 18.4 months (mos) (range 1.5 - 184.2), median OS was 23.8 mos (95% CI 20.4-29.1) for those with unresectable and metastatic disease. When only accounting for pts with distant metastatic disease, median OS was 20.7 mos (95% CI 17.6-28). In those who had first line platinum-based therapy (86/133, 65%), median PFS (mPFS) was 8.3 mos (95% CI 6.4-11.2). 49 (37%) pts were treated with an IDH1 inhibitor, with 46/49 (94%) receiving ivosidenib, 29/49 (59%) in the second line. mPFS for those treated with ivosidenib in second line was 4.6 mos (95% CI 3.6-10.0) vs. 2.6 mos (95% CI 1.8-6.7) for 5-fu based chemotherapy (p=0.032). There was no difference in OS for those treated with IDH1 inhibitors compared to those that were not (25.7 vs. 20.7 mos; p=0.5). 11 (8%) pts received immunotherapy-based treatments with a mPFS of 2.7 mos (95% CI 2.2-NR). Conclusions: Our retrospective data indicate that IDH1 mutant BTC appears to exhibit similar PFS to first-line cytotoxic chemotherapy compared to historic unselected populations with favorable outcomes to second line IDH1 inhibition.

Mint3‐targeted therapy: A novel therapeutic strategy for urothelial carcinoma

Mint3‐targeted therapy: A novel therapeutic strategy for urothelial carcinoma

Results of TRIO-15, a multicenter, open-label, phase II study of the efficacy and safety of ganitumab in patients with recurrent platinum-sensitive ovarian cancer

BackgroundIGF signaling has been implicated in the pathogenesis and progression of ovarian carcinoma (OC). Single agent activity and safety of ganitumab (AMG 479), a fully human monoclonal antibody against IGF1R that blocks binding of IGF1 and IGF2, were evaluated in patients with platinum-sensitive recurrent OC. MethodsPatients with CA125 progression (GCIG criteria) or measurable disease per RECIST following primary platinum-based therapy received 18 mg/kg of ganitumab q3w. The primary endpoint was objective response rate (ORR) assessed per RECIST 1.1 by an independent radiology review committee (IRC) and/or GCIG CA125 criteria. Secondary endpoints included clinical benefit rate (CBR), progression free survival (PFS) and overall survival (OS). Results61 pts. were accrued. Objective responses were seen in 5/61 patients (ORR 8.2%, 95% CI, 3.1–18.8) with 1 partial response (PR) by RECIST and 2 complete responses (CR) as well as 2 PR by CA125 criteria. CBR was 80.3% (95% CI, 67.8–89.0%). The median PFS according to RECIST by IRC was 2.1 months (95% CI, 2.0–3.1). The median PFS per RECIST IRC and/or CA125 was 2.0 months (95% CI, 1.8–2.2). The median OS was 21 months (95% CI, 19.5-NA). The most common overall adverse events were fatigue (36.1%) and hypertension (34.4%). Grade 1/2 hyperglycemia occurred in 30.4% of patients. Hypertension (11.5%) and hypersensitivity (8.2%) were the most frequent grade 3 adverse events. ConclusionsIGF1R inhibition with ganitumab was well-tolerated, however, our results do not support further study of ganitumab as a single agent in unselected OC patients.