Citations

8509 Background: Venetoclax (Ven) is a selective, potent, oral BCL-2 inhibitor. In the Phase 3 BELLINI trial, addition of Ven to bortezomib (B) + dexamethasone (d) significantly improved response rates and progression-free survival (PFS) vs placebo (Pbo) and showed significant efficacy in patients (pts) with either t(11;14) or BCL2high gene expression. Here we present updated safety and efficacy data from the prespecified second interim overall survival (OS) analysis. Methods: In this multicenter, randomized, double-blind study (NCT02755597), pts with relapsed/refractory multiple myeloma (RRMM) with 1-3 prior lines of therapy were randomized 2:1 to Ven (800 mg) or Pbo in combination with B (1.3 mg/m2) and d (20 mg). The primary endpoint was PFS; key secondary endpoints included overall response and overall survival (OS). Results: 291 pts were randomized; 194 to Ven, 97 to Pbo. Pt characteristics were well balanced among arms. In the Ven arm, median age was 66, 17% had high-risk cytogenetics, 11% had t(11;14), and 34% had BCL2high gene expression. As of 13 Sept 2019, 59 pts were still on study, 45 (23%) Ven vs 14 (14%) Pbo. At a median follow-up of 28.6 months, there were 64 (33%) deaths in the Ven arm vs 24 (25%) in Pbo. At the initial data cutoff (26 Nov 2018), PFS HR was 0.63 (0.44,0.90) and OS HR was 2.03 (1.04,3.95). Table shows updated PFS and OS. Most common treatment-emergent adverse events (TEAEs) with Ven were diarrhea (59%), nausea (37%), and constipation (35%). Most common grade 3/4 AEs (Ven/Pbo) were neutropenia (21%/8%), thrombocytopenia (15%/30%), anemia (16%/15%), diarrhea (15%/12%), and pneumonia (18%/13%). Serious AEs occurred in 54% Ven and 52% Pbo pts. 24% discontinued Ven due to AEs vs 12% Pbo. There were 14 treatment-emergent deaths in the Ven arm and 1 in Pbo. Conclusions: The addition of Ven to Bd significantly improves PFS but resulted in increased mortality vs Pbo in the total population. Greatest PFS improvement with Ven was observed in pts with t(11;14) or BCL2high gene expression, where Ven shows a favorable benefit-risk profile. The study continues for final OS analysis. Clinical trial information: NCT02755597 . [Table: see text]

e19136 Background: Patient reported side effect bother is needed to understand tolerability of cancer drugs. We examined whether increase in side effect bother from baseline to cycle 7 as measured by a single item (GP5) from the FACT-G, “I am bothered by side effects of treatment”, was associated with early treatment discontinuation (ETD) in a multiple myeloma (MM) trial. Methods: Data were drawn from the induction phase of ECOG ACRIN E1A06, a two arm, phase 3 trial conducted in patients with untreated MM. The induction phase occurred over twelve, 28-day cycles. GP5 was assessed at registration and cycle 7. ETD was defined as completion of less than 12 cycles of treatment. We tested whether increase in side effect bother on the GP5 from baseline to cycle 7 was associated with months to ETD in two ways. At each timepoint, GP5 was rated with these response options: “Not at all”, “A little bit”, “Somewhat”, “Quite a bit”, “Very Much”. First, we stratified Kaplan Meier curves by patients with versus without substantially increased side effect burden from registration to cycle 7 on the GP5, defined as an increase of > 2 response categories; Cox regression was used to calculate a hazard ratio. Second, we fit a joint model of the GP5 change trajectory on months to ETD that substituted the estimated slope of a longitudinal logistic regression model into the hazard function of a Cox model. In this model, GP5 was dichotomized as 0 = “Not at all/”A little bit”; 1 = “Somewhat”/ “Quite a bit”/ “Very Much”. Results: 159 patients were followed during induction for a median of 11 months (range: 0.2-16.0). 10 patients (6%) reported a substantial increase on GP5 from registration to cycle 7. After 16 months, these patients had a significantly higher hazard of ETD as estimated by Kaplan Meier methods: 40% experienced ETD vs. 24% of patients without substantial GP5 increase [hazard ratio (HR): 3.08 (95% CI: 1.18-8.02)]. In the joint model, the effect of GP5 on hazard of ETD was larger [HR: 9.56 (95% CI: 2.41-37.82)]. Conclusions: This study found initial evidence that increase in side effect bother as measured by the GP5 predicts ETD and may therefore reflect treatment intolerability in cancer drug trials. The effects found in this study will be tested for replication in additional ECOG-ACRIN trials with diverse designs, treatments, and cancer types. Clinical trial information: NCT00602641 .

e19132 Background: The Functional Assessment of Cancer Therapy–General has an item about patient tolerability of treatment: “I am bothered by side effects of treatment” (GP5). We examined the predictive value of this single item for early treatment discontinuation in clinical trials. Methods: GP5 level prior to protocol therapy (rated using a 5-point Likert scale) and treatment start/end dates and off treatment reason data at each treatment phase were drawn from five phase III clinical trials conducted by ECOG-ACRIN. In the present analysis, GP5 was dichotomized as 0 = “Not at all”/“A little bit” and 1 = “Somewhat”/“Quite a bit”/“Very Much”. Early treatment discontinuation was defined either as receiving less than protocol specified cycles of treatment when maximum cycles specified in the protocol (E1A06 induction, E1912 induction, E1609 induction, E1105 induction, E5103 adjuvant), analyzed using logistic regression via odds ratio [OR]), or treatment cessation for reasons other than progressive disease or death when treatment continued until progression or intolerability (E1A06 maintenance, E1912 maintenance, E1609 maintenance, E1105 maintenance), analyzed using Cox proportional hazard model via hazard ratio [HR]. Results: GP5 prior to treatment was significantly associated with early discontinuation of E1A06 maintenance, E1609 maintenance, E1912 maintenance, and E1912 induction. No significant association was found for other therapies examined in the study. Conclusions: High GP5 level prior to treatment is associated with higher likelihood of early treatment discontinuation in patients who have received previous treatment. The limited predictive value of GP5 for treatment naïve patients is more limited, serial on-treatment assessment should be considered in this setting. Clinical trial information: NCT00602641 . [Table: see text]

4500 Background: Trastuzumab is a monoclonal antibody against human epidermal growth factor receptor 2 (HER2). The primary objective of RTOG 1010 was to determine if trastuzumab increases disease-free survival (DFS) when combined with trimodality treatment for patients with HER2 overexpressing esophageal adenocarcinoma. Methods: This open label, randomized phase III trial included patients with newly diagnosed stage T1N1-2, T2-3N0-2 adenocarcinoma of the esophagus involving the mid, distal, or esophagogastric junction and up to 5cm of the stomach. All patients received chemotherapy (C) of paclitaxel, 50mg/m2 and carboplatin AUC = 2, weekly for 6 weeks, with radiation (XRT: 3D-CRT or IMRT, 50.4 Gy in 28 fractions) followed by surgery. Patients were randomized 1:1 to receive weekly trastuzumab 4mg/kg week 1 then 2mg/kg/weekly x 5 during CXRT then 6 mg/kg for 1 dose prior to surgery and 6mg/kg every 3 weeks for 13 treatments after surgery. HER2 status was determined by IHC and gene amplification by FISH. With a 2-sided alpha of 0.05, 162 DFS events provide 90% power to detect a signal for an increase in median DFS from 15 to 25 months. DFS and overall survival (OS) were estimated by the Kaplan-Meier method. and arms were compared using the log rank test. The Cox proportional hazards model was used to analyze treatment effect. Results: 571 patients were entered for assessment of HER2 expression, 203 HER2+ patients randomized. The median follow-up for alive patients is 5.0 years. The estimated 2, 3, and 4-year DFS (95% CI) for the CXRT +trastuzumab arm were 41.8% (31.8%, 51.7%), 34.3% (24.7%, 43.9%), and 33.1% (23.6%, 42.7%), respectively, and for the CXRT arm were 40.0% (30.0%, 49.9%), 33.4% (23.8%, 43.0%), and 30.1% (20.7%, 39.4%), respectively; log-rank p = 0.85. The median DFS time is 19.6 months (13.5-26.2) for the CXRT +trastuzumab arm compared to 14.2 months (10.5-23.0) for the CXRT arm. The hazard ratio (95% CI) comparing the DFS of CXRT+trastuzumab arm to the CXRT arm was 0.97 (0.69, 1.36). The median OS time was 38.5 months (26.2-70.4) for the CXRT+trastuzumab arm compared to 38.9 months (29.0-64.5) for the CXRT arm, hazard ratio (95% CI): 1.01 (0.69, 1.47). There was no statistically significant increase in treatment-related toxicities with the addition of trastuzumab including no increase in cardiac events. Conclusions: The addition of trastuzumab to trimodality treatment did not improve DFS for patients with HER2 overexpressing esophageal adenocarcinoma. Supported by NCI grants U10CA180868, UG1CA189867, U10CA180822 and Genentech. Clinical trial information: NCT01196390 .

3552 Background: Delta-like 3 (DLL3) is highly and specifically expressed in solid tumors, such as neuroendocrine carcinomas (NECs), malignant melanoma (MM), and medullary thyroid carcinoma (MTC). Rovalpituzumab tesirine (Rova-T) is a DLL3-targeting antibody-drug conjugate. Methods: This Phase 1/2 study (NCT02709889) enrolled patients with relapsed/refractory DLL3+ (>1% by IHC) advanced solid tumors and ECOG performance status of 0-1. Rova-T was given IV at 0.2, 0.3, or 0.4 mg/kg on d 1 of each 6-wk cycle (q6wk) for dose escalation (3+3 design) in disease-specific cohorts in Phase I. The recommended Phase 2 dose (RP2D) was tested in Phase II. Safety and dose-limiting toxicities (DLTs) were primary endpoints; efficacy outcomes were secondary endpoints. Results: The study enrolled 200 patients; 101 had NECs (large cell NEC [n=13], neuroendocrine prostate cancer [n=21], high-grade gastroenteropancreatic NEC [n=36], other [n=31]) and 99 had other solid tumors (MM [n=20], MTC [n=13], glioblastoma [GBM; n=23], other [n=43]). The median age was 61 y (range, 28-84); 63% were male. The RP2D was 0.3 mg/kg q6wk for 2 cycles in all cohorts. There were 7 DLTs in 5 patients: 2 with 0.2 mg/kg (Grade [Gr] 3 photosensitivity reaction, Gr 3 dyspnea), 2 with 0.3 mg/kg (1 with Gr 2 effusion, Gr 3 tumor lysis syndrome, and Gr 3 rhabdomyolysis; 1 with Gr 4 kidney injury), and 1 with 0.4 mg/kg (Gr 4 thrombocytopenia). Despite only 1 DLT identified with 0.4 mg/kg, the totality of the safety data suggested that this dose is not well tolerated. Common adverse events (AEs) in patients given 0.3 mg/kg (n=145) are shown (Table). Serious AEs occurred in 77/145 patients (53%), most commonly (≥3%) malignant neoplasm progression (n=18; 12%), pleural effusion (n=7; 5%), pericardial effusion (n=6; 4%), and dyspnea (n=5; 3%). The objective response rate (ORR) was 11% (21/200): 14 had NEC, 2 had MM, 2 had MTC, 2 had small cell carcinoma (SCC) not of lung origin (all partial responses), and 1 had GBM (complete response). In patients with NECs given 0.3 mg/kg, ORR, clinical benefit rate, and progression-free survival trended in favor of those with high DLL3-expressing tumors (≥50% by IHC) which represented 51% of NECs. Conclusions: Rova-T was tolerable in patients with advanced solid tumors at 0.3 mg/kg q6wk for 2 cycles. Antitumor activity was observed in patients with NEC, MM, MTC, SCC, and GBM. Clinical trial information: NCT02709889 . [Table: see text]

3519 Background: An understanding of the mechanisms of acquired resistance to CDK4 & 6 inhibitors, either alone or with endocrine therapy (ET), is an unmet need. Abemaciclib is a CDK4 & 6 inhibitor approved for treatment of HR+, HER2- advanced breast cancer (ABC). Here we evaluated acquired genomic alterations detected in circulating tumor DNA (ctDNA) from patients (pts) treated with abemaciclib + nonsteroidal aromatase inhibitor (AI) or placebo + AI in MONARCH 3 or abemaciclib monotherapy in nextMONARCH 1. Methods: MONARCH 3 randomized postmenopausal women with HR+, HER2- ABC with no prior systemic therapy in the advanced setting to abemaciclib (150 mg Q12H) or placebo + AI. nextMONARCH 1 randomized women with HR+, HER2- metastatic breast cancer who had progressed on or after prior ET and CT to abemaciclib (150 mg Q12H) + tamoxifen, abemaciclib (150 mg Q12H), or abemaciclib (200 mg Q12H) + loperamide. Plasma from pts in the abemaciclib or placebo + AI arms (MONARCH 3) or abemaciclib monotherapy arms (nextMONARCH 1) was analyzed by the Guardant360 assay to identify potential tumor-related genomic alterations including point mutations, indels, amplifications, and fusions acquired at EOT in comparison with baseline. Results: For MONARCH 3, commonly acquired alterations at EOT included ESR1 (17%), TP53 (10%), EGFR (8%), FGFR1 (7%), and PDGFRA (7%) in the abemaciclib + AI arm, and ESR1 (31%), TP53 (10%), and BRCA1 (7%) in the placebo + AI arm. Acquired alterations more frequent for abemaciclib + AI pts included RB1 (6%), MYC (5%), and AR (5%), compared to 0% in the placebo + AI arm (p = 0.008 RB1; p = 0.015 MYC or AR). In contrast, acquired ESR1 alterations were less frequent with abemaciclib + AI vs placebo + AI (17% vs 31%, p = 0.038). In nextMONARCH 1, the most commonly acquired alterations with abemaciclib monotherapy were in TP53 (10%), EGFR (9%), RB1 (9%), MYC (9%), and MET (8%). In addition, acquired alterations in ESR1 (6%) and AR (3%) were also found. PIK3CA alterations were not frequently acquired (abemaciclib + AI 1%, placebo + AI 6%, abemaciclib monotherapy 5%). Conclusions: Acquired genomic alterations potentially associated with emerging mechanisms of resistance to abemaciclib alone or in combination with AI may include RB1, MYC, or AR alterations, while the acquisition of ESR1 alterations was less common in pts treated with abemaciclib + AI compared to placebo + AI. These findings are hypothesis-generating and provide insight into mechanisms of resistance to abemaciclib vs ET. Clinical trial information: NCT02246621, NCT02747004 .

Dyn2 and α-actinin 4 interact directly to regulate invasive cell migration and the stabilization of invadopodia. Intriguingly, this is specific for α-actinin 4, and not the highly related protein α-actinin 1. These findings elucidate a novel mechanism of regulating cell migration, with important implications for invasive tumor cells.

Abstract Genetic variants that define two distinct haplotypes at the TMEM106B locus have been implicated in multiple neurodegenerative diseases and in healthy brain ageing. In frontotemporal dementia (FTD), the high expressing TMEM106B risk haplotype was shown to increase susceptibility for FTD with TDP-43 inclusions (FTD-TDP) and to modify disease penetrance in progranulin mutation carriers (FTD-GRN). To elucidate the biological function of TMEM106B and determine whether lowering TMEM106B may be a viable therapeutic strategy, we performed brain transcriptomic analyses in 8-month-old animals from our recently developed Tmem106b−/− mouse model. We included 10 Tmem106b+/+ (wild-type), 10 Tmem106b+/− and 10 Tmem106−/− mice. The most differentially expressed genes (153 downregulated and 60 upregulated) were identified between Tmem106b−/− and wild-type animals, with an enrichment for genes implicated in myelination-related cellular processes including axon ensheathment and oligodendrocyte differentiation. Co-expression analysis also revealed that the most downregulated group of correlated genes was enriched for myelination-related processes. We further detected a significant loss of OLIG2-positive cells in the corpus callosum of Tmem106b−/− mice, which was present already in young animals (21 days) and persisted until old age (23 months), without worsening. Quantitative polymerase chain reaction revealed a reduction of differentiated but not undifferentiated oligodendrocytes cellular markers. While no obvious changes in myelin were observed at the ultrastructure levels in unchallenged animals, treatment with cuprizone revealed that Tmem106b−/− mice are more susceptible to cuprizone-induced demyelination and have a reduced capacity to remyelinate, a finding which we were able to replicate in a newly generated Tmem106b CRISPR/cas9 knock-out mouse model. Finally, using a TMEM106B HeLa knock-out cell line and primary cultured oligodendrocytes, we determined that loss of TMEM106B leads to abnormalities in the distribution of lysosomes and PLP1. Together these findings reveal an important function for TMEM106B in myelination with possible consequences for therapeutic strategies aimed at lowering TMEM106B levels.