Supplementary Figure from Telaglenastat plus Everolimus in Advanced Renal Cell Carcinoma: A Randomized, Double-Blinded, Placebo-Controlled, Phase II ENTRATA Trial
Abstract Background POLARIS is an ongoing, prospective, real-world (RW) study of palbociclib (PAL) in patients (pts) with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (HR+/HER2- ABC). A biomarker goal of this study was to evaluate serial changes in circulating tumor DNA (ctDNA) dynamics among pts with long-term clinical response to PAL plus endocrine therapy (ie, received ≥18 cycles). Methods The data set included pts who received PAL combination therapy, gave consent for blood collection to obtain ctDNA, and had long-term clinical response. The Guardant360 Next-Generation Sequencing platform, which analyzed approximately 73 genes, was used to sequence ctDNA for somatic single-nucleotide variants, including copy number variants. Longitudinal ctDNA changes (at baseline and various time points) and the RW clinical response to PAL are described. Results As of December 17, 2020, 35 pts of 1280 enrolled received ≥18 cycles of PAL combination therapy, with blood samples collected over a minimum of a 24-month period. Pts received PAL plus an aromatase inhibitor (n=16) or fulvestrant (n=19). Median age was 64 years. Thirty pts (85.7%) were white, 29 (82.9%) were postmenopausal, 31 (88.6%) had an Eastern Cooperative Oncology Group score of 0 or 1, 12 (34.3%) had visceral disease, 9 (25.7%) had de novo disease, and 24 (68.6%) had recurrent disease. Six pts (17.1%) had a RW best overall response (BOR) of complete response (CR), 9 (25.7%) had partial response (PR), and 20 (57.1%) had stable disease (SD). Two pts had disease progression resulting in change of therapy at cycles 25 and 38, respectively. Biomarker samples were collected from a median (range) total number of 9 (3-12) visits. The median (range) number of somatic variants detected was 4 (0-11) and included the most prevalent somatic mutations (eg, PIK3CA, TP53, BRCA1/2, FGFR2, GATA3). No ctDNA mutations were detected in 6 pts (17%) post baseline up to 24 months. Among 15 pts who achieved CR/PR, 12 (80%) either had no detectable or sustained very low ctDNA burden or had corresponding ctDNA decrease. Among 16 pts who remained with SD, 12 (75%) either had no detectable or sustained very low ctDNA burden or had ctDNA decrease. Among 8 pts whose disease progressed, 5 (63%) had an increasing trend in ctDNA mutation frequency. Conclusions This study is among the first to provide serial blood-based tumor genotyping data from routine clinical practice. Interim data indicate that even pts with ongoing detectable ctDNA have a BOR of CR, PR, or SD with PAL for HR+/HER2- ABC, suggesting certain mutations might not be drivers of PAL resistance. Dynamic changes of ctDNA mutations may be predictive for treatment response, and may have clinical utility in disease surveillance monitoring. Additional longitudinal data will be presented. Pfizer; NCT03280303 Citation Format: Joanne L. Blum, Aditya Bardia, Sharon Wilks, Steven L. McCune, Carrie L. Dul, John J. Migas, Derrick W. Spell, Zhe Zhang, Yuan Liu, Yao Wang, Debu Tripathy. Longitudinal ctDNA changes in patients with long-term response to palbociclib combination therapy for advanced breast cancer: A preliminary analysis from the real-world POLARIS study [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 LB033.
Retroviral and adeno-associated viral sequences can dramatically silence transgene expression in mice. We now report that this repression also occurs in stably infected HeLa cells when the cells are grown without selection. Expression of a transduced lac Z gene (rAAV/CMV lac Z) is silenced in greater than 90% of cells after 60 days in culture. Surprisingly, high-level expression can be reactivated by treating the cells with sodium butyrate or trichostatin A but not with 5-azacytidine. When cell clones with integrated copies of rAAV/CMV lac Z were isolated, lac Z expression was silenced in 80% of the clones; however, lac Z expression was reactivated in all of the silenced clones by treatment with butyrate or trichostatin A. The two drugs also reactivated a silenced globin gene construct (rAAV/HS2αβ AS3 ) in stably infected K562 cells. Trichostatin A is a specific inhibitor of histone deacetylase; therefore, we propose that hyperacetylation of histones after drug treatment changes the structure of chromatin on integrated viral sequences and relieves repression of transduced genes. The reactivation of silenced, transduced genes has implications for gene therapy. Efficient viral gene transfer followed by drug treatment to relieve suppression may provide a powerful combination for treatment of various genetic and infectious diseases.
Background:POLARIS is a prospective, real-world (RW) study of palbociclib (PAL) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC) in the US and Canada. Analyses include evaluating the association between circulating tumor DNA (ctDNA) and clinical response to PAL.Methods: All pts provided informed consent. Blood samples are collected on day 1 of each 4-wk cycle for 6 cycles, at day 1 of every 2-3 cycles, and end of treatment. ctDNA is sequenced using the Guardant360 platform for somatic single-nucleotide variants in complete or critical exons of 73 genes. Analyses include association between clinical outcomes and ctDNA mutation frequencies at baseline and change from baseline to cycle 2, day 1 (C2D1), stratified by line of prior therapy.Results: As of July 2018, 127 pts had ≥1 evaluable ctDNA measurement. Of these, 104 had baseline and C2D1 results; 96 had tumor response assessed. The most common mutations at baseline were PIK3CA (41%), TP53 (33%), and ESR1 (20%). PAL was associated with a decline in mutation frequency of PIK3CA, TP53, and ESR1alleles but not all genes, highlighting differential response based on genomic profile and clonal heterogeneity (Table). Overall, fast progressors (progression <6 mo, n=19) tended to have higher baseline ctDNA values and displayed smaller decreases in ctDNA at C2D1 than slow progressors (progression ≥6 mo, n=4).Conclusions: This study is among the first to provide RW data on blood-based genotyping. Interim data indicate that genomic architecture and longitudinal changes may be predictive and prognostic in pts with HR+/HER2– ABC receiving PAL. Updated data from 239 pts will be presented, including association between individual ctDNA mutation dynamics, clonal heterogeneity, and clinical outcomes (therapeutic response and progression-free survival). Pfizer; NCT03280303Change from baseline in ctDNA mutation frequencyMutationOverall (n=104)*First Line (n=70)Second Line and Later (n=34)Baseline, n (%)†C2D1, n (%)†Baseline, n (%)†C2D1, n (%)†Baseline, n (%)†C2D1, n (%)†PIK3CA43 (41)26 (25)27 (39)14 (20)16 (47)12 (35)TP5334 (33)27 (26)23 (33)17 (24)11(32)10 (29)ESR121 (20)11 (11)9 (13)3 (4)12 (35)8 (24)ARID1A19 (18)14 (13)13 (19)7 (10)6 (18)7 (21)NF111 (11)11 (11)7 (10)6 (9)4 (12)5 (15)BRCA210 (10)10 (10)8 (11)7 (10)2 (6)3 (9)GATA310 (10)5 (5)8 (11)5 (7)2 (6)O (O)None detected13 (13)24 (23)7 (10)20 (29)6 (18)4 (12)ctDNA=circulating tumor DNA; C2D1=cycle 2, day 1. *Patients with both baseline and C2D1 ctDNA data available. †Percentages are relative to the corresponding number of patients (n).Citation Format: Aditya Bardia, Joanne L. Blum, Steven L. McCune, Kamal Patel, Richard C. Frank, Kailash Mosalpuria, Meghan S. Karuturi, Lloyd A. Shabazz, Gabrielle B. Rocque, Yuan Liu, Zhe Zhang, Jian Wang, Yao Wang, Debu Tripathy. Blood-based genotyping and clinical outcomes in patients with advanced breast cancer receiving the CDK4/6 inhibitor palbociclib in real-world settings: Results from POLARIS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 443.
e20567 Background: Limited 2L therapy options and no established 3L standard of care make treating relapsed ED-SCLC challenging. This study explores current treatment and outcomes in patients receiving 2L and 3L therapy in community practice. Methods: CA209-118, a prospective observational study of adult lung cancer patients in 70 US community practices, enrolled ED-SCLC patients on or before initiating 2L therapy from April 2014 to September 2017; they were followed until death, end of follow-up, or study withdrawal. Study sites reported therapy start and end dates and reasons for discontinuation. Platinum-refractory (PT-ref) was defined as a gap of ≤90 days between the end of 1L and start of 2L; platinum sensitive (PT-sen) was a > 90-day gap. Results: 165 ED-SCLC patients were enrolled prior to initiating 2L. The most common 2L therapies were topotecan (TOP, n = 89), PT + etoposide or irinotecan (ETOP or IRI, n = 30), paclitaxel monotherapy (PAC, n = 12), or nivolumab (n = 9). Mean age was 65 years, 53% were male, 96% were white, 94% were current or former smokers, and 17% had ECOG scores ≥2. At database (DB) lock, 26 (16%) completed 2L, 26 (16%) were still receiving 2L therapy, 78 (47%) discontinued 2L due to progression or death, 18 (11%) due to adverse events, and 17 (10%) for other reasons. In 2L, median OS was 5.1 months (95% CI: 4.6, 6.3) overall, 4.4 months (95% CI: 3.7, 5.8) for PT-ref patients (n = 69) and 6.3 months (95% CI: 5.1,7.8) for PT-sen patients (n = 96). Median time to discontinuation or death was 1.9 months (95% CI: 1.6, 2.3). The 91 3L patients most commonly received PAC (n = 24), TOP (n = 18), and PT + ETOP or IRI (n = 10). At DB lock, 13 (14%) completed 3L, 11 (12%) were still receiving 3L therapy, 45 (49%) discontinued due to progression or death and 22 (24%) due to AEs or other reasons. In 3L, median OS was 5.8 months (95% CI: 4.3, 7.1) and time to discontinuation was 2.1 months (95% CI: 1.4, 2.8). Conclusions: Treatment patterns in community practice for 2L and 3L appear largely limited to historical agents. Median survival and duration of therapy were short, highlighting the need for more effective and tolerable treatments in ED-SCLC.
CheckMate 9KD (NCT03338790) is a non-randomized, multicohort, phase 2 trial of nivolumab plus other anticancer treatments for metastatic castration-resistant prostate cancer (mCRPC). We report results from cohorts A1 and A2 of CheckMate 9KD, specifically evaluating nivolumab plus rucaparib.
<div>AbstractPurpose:<p>No standard treatment exists for platinum-refractory, recurrent/metastatic nasopharyngeal cancer (NPC). This phase II study (NCT02605967) evaluated progression-free survival (PFS) of spartalizumab, an antiprogrammed cell death protein-1 (PD-1) monoclonal antibody, versus chemotherapy, in NPC.</p>Patients and Methods:<p>Patients with nonkeratinizing recurrent/metastatic NPC who progressed on/after platinum-based chemotherapy were enrolled. Spartalizumab was dosed 400 mg once every 4 weeks, and chemotherapy was received per investigator's choice.</p>Results:<p>Patients were randomized to receive either spartalizumab (82 patients) or chemotherapy (40 patients). The most common spartalizumab treatment-related adverse events were fatigue (10.3%) and pruritus (9.3%). Median PFS in the spartalizumab arm was 1.9 months versus 6.6 months in the chemotherapy arm (<i>P</i> = 0.915). The overall response rate in the spartalizumab arm was 17.1% versus 35.0% in the chemotherapy arm. Median duration of response was 10.2 versus 5.7 months in the spartalizumab versus chemotherapy arms, respectively. Median overall survival was 25.2 and 15.5 months in the spartalizumab and chemotherapy arms, respectively. Tumor RNA sequencing showed a correlation between response to spartalizumab and <i>IFNγ, LAG-3</i>, and <i>TIM-3</i> gene expression.</p>Conclusions:<p>Spartalizumab demonstrated a safety profile consistent with other anti–PD-1 antibodies. The primary endpoint of median PFS was not met; however, median overall survival and median duration of response were longer with spartalizumab compared with chemotherapy.</p></div>
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