Citations

1020 Background: Trastuzumab-containing regimes have dramatically improved outcome of patients with HER2+ breast cancer. Efforts to improve efficacy and tolerability of combination regimens with this monoclonal antibody are important for patient care. Thus, we conducted a multi-institutional phase II study of a triplet combination in patients eligible to receive either first- or second-line treatment for HER2+ metastatic breast cancer (MBC). Methods: A phase II study designed to test that the true confirmed response rate (CRR) was at most 45% versus a true CRR of at least 65% was done (March 2005-June 2008). This design required that at least 25/45 confirmed responses in evaluable patients for the treatment to be considered promising. Patients received capecitabine 825 mg/m2 po (days 1–14), vinorelbine intravenously (IV) 25 mg/m2 days 1 and 8 every 3 weeks and trastuzumab IV 8mg/kg day 1, week 1, and then 6 mg/kg q 3 weeks. Tissue and blood have been collected for future studies on biomarkers. Results: 47 women were accrued, one patient cancelled participation prior to receiving any study drug, and another had a major protocol violation. 45 patients were evaluable and 30 (67%) achieved a confirmed response, (26 patients, 58% had a confirmed partial response and 4 patients, 9% had a confrimed complete response). Median progression free survival was 11.3 months (95% CI 8.4–23.2 months), median overall survival was 27.2 months (95% CI: 26.6-NA months), and among the 30 responders, the median duration of response time was 15.5 months (95% 7.7–26.1 months). The most common grade 3 events include neutropenia 61%, fatigue 13%, skin reaction-hand-foot 11%, and leukopenia 11%. Alopecia was not noted with this regimen. Conclusions: This triplet combination is effective, safe, and is promising in patients with HER2+ MBC. A phase III study should be conducted to compare the best doublet with this triplet combination whether this would lead to better clinical outcomes. [Table: see text]

623 Background: Neoadjuvant therapy plays an important role in breast cancer treatment. Unlike patients who undergo surgery followed by adjuvant therapy,there are no established guidelines for surgical management following neoadjuvant therapy. Methods: Surgical practice patterns from 50 patients in N0338 “Phase II trial of Docetaxel and Carboplatin administered every two weeks as induction therapy for Stage II and Stage III breast cancer” were reviewed. The protocol did not mandate surgical therapy leaving the decision to the treating surgeon and patient. Results: 66% of patients underwent mastectomy (M) and 33% underwent breast conservation therapy (BCT). Three (9%) had immediate reconstruction. Eight (24%) underwent contralateral prophylactic M. Residual tumor size did not always impact primary surgical therapy. In the M group 4 (12%) had no residual disease, 15 (45%) < 2cm and 14 (42%) > 2cm; whereas, in the BCT group 1 (6%) had no residual disease, 12 (70%) < 2cm and 4 (24%) > 2cm. Axillary lymph node (ALN) staging varied tremendously. Three (6%) patients presented with palpable lymphadenopathy and proceeded to complete axillary lymph node dissection (ALND) after chemotherapy (CT). Fine needle aspiration (8) or core needle biopsy (7) of the axilla was performed in 15 (30%) patients before CT; 1 was negative and went on to have sentinel lymph node biopsy (SLNB) after CT; 14 (94%) were positive with 13 (86%) going on to ALND and 1 SLNB after CT. Five (10%) underwent SLNB prior to CT. One (20%) was positive and went on to have ALND after CT; 4 (8%) were negative and had no further ALN staging. A total of 19 (39%) had SLNB after neoadjuvant therapy; 13 (68%) were positive and underwent ALND; 1 SLNB failed; 2 of 5 that were negative underwent ALND with 1 having a positive lymph node. Ten (20%) underwent ALND with no pre-operative staging with 8 being positive for ALN metastases. Conclusions: Review of study data from multiple institutions revealed no consistent criteria in selection of surgical intervention for the breast tumor or ALN staging. There remains a need for further research in this area to establish standard practice guidelines. Support from NIH, sanofi-aventis, Amgen, Breast Cancer Research Foundation. No significant financial relationships to disclose.

11564 Background: Epithelioid sarcoma (ES) is a rare, aggressive soft tissue sarcoma characterized by loss of inhibitor of integrase 1 (INI1), allowing enhancer of zeste homologue 2 (EZH2) to repress cell differentiation and promote tumorigenesis. Tazemetostat (TAZ) is a selective inhibitor of EZH2 approved by the FDA for treatment of patients (pts) aged ≥16 years with metastatic or locally advanced ES ineligible for complete resection. Methods: This open-label, multicenter, multi-cohort phase 2 study (NCT02601950) evaluated safety and efficacy of TAZ in pts with INI1-negative tumors. ES pts were enrolled in Cohorts 5 and 6; pts in Cohort 6 underwent mandatory pre-dose (at screening) and post-dose biopsies (at Day 1 of cycle 2). Herein, we report the interim efficacy and safety data from Cohort 6. Results: As of July 31 2019, 44 pts were enrolled into Cohort 6 and treated with TAZ 800 mg BID. The objective response rate (ORR) was 11.4%; 4 pts (9.1%) had a partial response and 1 pt (2.3%) had a complete response (Table). Another 17 pts (38.6%) had stable disease (SD). 18 pts had progressive disease; 13 of these pts remained on study beyond progression. Progression-free survival (PFS) and overall survival (OS) at 56 weeks were 19.4% and 59.4%, respectively. In a pooled posthoc analysis of 106 ES pts from Cohorts 5 (n = 62), and 6, ORR was 13.2%. Grade 3–4 adverse events (AEs) were reported in 16 pts (36.4%), most commonly anemia (6.8%; n = 3) and tumor pain (6.8%; n = 3). 3 pts (6.8%) experienced grade 3–4 treatment-related AEs. One pt discontinued study drug and there were no treatment-emergent dose reductions or treatment-related deaths. These safety data from Cohort 6 are consistent with previously reported data from Cohort 5. 19 paired biopsies were included for translational endpoint analyses. Preliminary RNA seq and pathway analyses are currently ongoing and updated data, including additional biomarker data will be presented. Conclusions: Consistent with previously reported data from the completed Cohort 5, TAZ demonstrated clinically meaningful, durable, single agent activity in ES pts. Efficacy data from Cohort 6 continue to mature with 8 patients still on treatment. TAZ was well tolerated with a low incidence of treatment related AEs. Clinical trial information: NCT02601950 . [Table: see text]

TPS9082 Background: Limited stage small cell lung cancer (LS-SCLC) is treated with standard of care platinum/etoposide (EP) and thoracic radiation therapy (TRT) with curative intent, however the majority of patients are not cured and median overall survival is approximately 30 months. Addition of atezolizumab to chemotherapy in extensive stage SCLC has improved progression free and overall survival in a non-curative setting leading to hope that addition of an immune checkpoint inhibitor to standard chemoradiotherapy could benefit LS-SCLC patients. LU005 is a randomized phase II/III trial of standard concurrent chemoradiation with or without atezolizumab for patients with LS-SCLC. Methods: Patients are randomly assigned in a 1:1 ratio to standard EP chemotherapy with concurrent TRT (45 Gy BID or 66 Gy QD) with or without atezolizumab beginning concurrently with TRT, and continued every 3 weeks for up to 12 months. Eligible patients have LS-SCLC, PS 0-2, adequate organ function, no concerning comorbidities (including no active autoimmune disease) and are eligible for TRT. Patients are randomized prior to their second cycle of EP and thoracic radiation begins with the second overall cycle of chemotherapy (first cycle of study therapy) in both treatment arms. Prophylactic cranial radiation (PCI) is recommended for patients who respond to treatment. The phase II/III primary endpoints are progression free (PFS) and overall survival (OS) respectively. Secondary endpoints include objective response rates, local and distant disease control, and quality of life/patient reported outcomes assessment. Translational science component includes blood and tissue based immune related assays. This study activated in May 2019. 50 of 506 planned patients have been accrued as of 2/1/2020. Supported by grants U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), U23CA180803 (IROC) from the National Cancer Institute (NCI) and Genentech. *Authors Ross and Higgins are co-first authors and contributed equally to this work. Clinical trial information: NCT03811002.

TPS9077 Background: ALCHEMIST (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial) is a clinical trial platform of the National Cancer Institute that offers biomarker analysis for high-risk resected non-small cell lung cancer (NSCLC) to support randomized trials of novel adjuvant therapies within the National Clinical Trials Network (NCTN). EA5142, a trial of adjuvant nivolumab for patients (pts) without EGFR / ALK alterations, has completed enrollment. Given the survival benefit seen with 1st-line chemo-immunotherapy (chemo-IO) for advanced NSCLC without EGFR / ALK alterations, there was compelling rationale for the launch of a trial offering concurrent immunotherapy with adjuvant chemo. Here we report updated enrollment to ALCHEMIST as of Jan 14, 2020. Methods: ALCHEMIST includes a screening trial (A151216, 5362 registered) that enrolls pts with completely resected clinical stage IB (≥4 cm)–IIIA (per AJCC 7) NSCLC. Tissue and blood are collected, biomarker testing includes EGFR sequencing, ALK FISH and PD-L1 IHC. 733 active sites are enrolling across the NCTN. Pts with EGFR mutations may enroll to adjuvant erlotinib vs observation (A081105, 352 randomized); those with ALK fusions may enroll to adjuvant crizotinib vs observation (E4512, 99 randomized). A trial offering adjuvant nivolumab vs observation regardless of PD-L1 status (EA5142, 935 randomized) recently completed enrollment. To support ongoing investigation of adjuvant immunotherapy, ALCHEMIST is adding A081801 (opens spring 2020). Pts will be randomized to one of 3 arms: chemo-IO with pembrolizumab during and after chemo vs sequential chemo followed by pembrolizumab vs chemo alone. Pts with pathological N2 nodes are eligible and can undergo postoperative radiotherapy after completing chemo. Pts are eligible if enrolled to A151216, negative for EGFR and ALK alterations, and with PD-L1 testing completed (required for stratification). Local testing for EGFR, ALK and PD-L1 will be accepted for enrollment; central testing will not delay randomization. Pts may not have received any therapy except surgery for the lung cancer and must be age >18, Eastern Cooperative Oncology Group performance status 0-1, have no active autoimmune disease requiring systemic treatment within 2 years, must not be pregnant or nursing, have no active second malignancy within 3 years and meet standard organ function values. By building off the ongoing ALCHEMIST platform, we hope to facilitate rapid enrollment to A081801 across participating NCTN sites. Clinical trial information: NCT02194738.

9045 Background: A minority of the > 40,000 patients (pts) diagnosed with stage III NSCLC annually in the US are cured by CRT, more recently followed by adjuvant immune checkpoint inhibitors (ICI). PD-L1 blockade with CRT may attenuate tumor-related immunosuppression via depletion of regulatory T cells and clonal expansion of effector T cells. Further, CRT may expose otherwise hidden antigens that present additional targets to the reconstituting immune system. Adjuvant ICI has improved survival. Whether ICI before CRT will further improve outcomes is unknown. Methods: This Alliance Foundation Trials (AFT) study evaluated safety and efficacy of atezolizumab before and after CRT. 4 cycles of atezolizumab 1200 mg IV q 21 days with restaging after cycles 2 and 4 were followed by carboplatin and paclitaxel (C/P) weekly with 60 Gy radiation and C/P consolidation followed by atezolizumab for 1 year of therapy. Primary endpoint is disease control rate (DCR) (complete response + partial response (PR) + stable disease (SD)) at 12 weeks (wks). Secondary endpoints include overall response rate, progression-free survival, overall survival, safety and quality of life assessed by EORTC QLQ-30. Correlatives include PD-L1 and tumor mutation burden as predictive biomarkers. Tumor tissue was obtained at study entry; plasma and immune cells were isolated at multiple timepoints. Results: 64 pts with stage III NSCLC, performance status (PS) 0-1, no active autoimmune disease or significant organ dysfunction enrolled at 13 Alliance sites from 11/2017 to 7/2019. 62 pts received ≥ 1 dose of atezolizumab and are included in the primary analysis; median age 63.9 years (38.1-86.5), 51.6% female, 77.4% white, 61.3% former smokers, 56.5% PS 0. DCR at 12 wks was 77.4% (80% confidence interval 69.2-84.3%) (30.7% PR, 46.8% SD). 54 pts reported adverse events (AEs) during induction, mostly grade (gr) 1. There were 13 serious AEs, most unrelated to study treatment; 1 gr 3 anaphylactic reaction, 1 gr 3 colitis, and 1 gr 4 Guillain-Barre syndrome were attributable to atezolizumab. Baseline PD-L1 status was available for 49 pts. DCR was 82.4% for pts with PD-L1 negative and 90.9% for pts with PD-L1 positive tumors. Conclusions: Atezolizumab prior to and following CRT for stage III unresectable NSCLC was well tolerated with an encouraging 12-wk DCR. Analysis of secondary endpoints is ongoing. Further study of induction ICI therapy is warranted in patients with unresectable stage III NSCLC. Support: AFT, Genentech; Clinical trial information: NCT03102242.

Abstract Splicing alterations are common in diseases such as cancer, where mutations in splicing factor genes are frequently responsible for aberrant splicing. Here we present an alternative mechanism for splicing regulation in T-cell acute lymphoblastic leukemia (T-ALL) that involves posttranslational stabilization of the splicing machinery via deubiquitination. We demonstrate there are extensive exon skipping changes in disease, affecting proteasomal subunits, cell-cycle regulators, and the RNA machinery. We present that the serine/arginine-rich splicing factors (SRSF), controlling exon skipping, are critical for leukemia cell survival. The ubiquitin-specific peptidase 7 (USP7) regulates SRSF6 protein levels via active deubiquitination, and USP7 inhibition alters the exon skipping pattern and blocks T-ALL growth. The splicing inhibitor H3B-8800 affects splicing of proteasomal transcripts and proteasome activity and acts synergistically with proteasome inhibitors in inhibiting T-ALL growth. Our study provides the proof-of-principle for regulation of splicing factors via deubiquitination and suggests new therapeutic modalities in T-ALL. Significance: Our study provides a new proof-of-principle for posttranslational regulation of splicing factors independently of mutations in aggressive T-cell leukemia. It further suggests a new drug combination of splicing and proteasomal inhibitors, a concept that might apply to other diseases with or without mutations affecting the splicing machinery. This article is highlighted in the In This Issue feature, p. 1241

Abstract Introduction: Brain tumors, including benign pituitary adenomas (PA), cause high levels of anxiety and distress. Patients with PA also report high unmet needs for information, a factor correlated with anxiety. Although many factors can contribute to anxiety, condition-specific education may alleviate anxiety for these patients. Aim: To explore the patients’ experience related to discovery of a pituitary adenoma and pilot a patient education intervention to address peri-diagnostic anxiety. Method: This mixed-methods pilot study evaluated the acceptability and effectiveness of an education intervention for adults diagnosed with PA (nonfunctioning PA or prolactinoma). At their first endocrine appointment, patients were given disease-specific information verbally, reinforced with printed material. Anxiety [Generalized Anxiety Disorder (GAD)-7 and Visual Analogue Scale for Anxiety (VAS-A)], patient satisfaction (Likert 1–5), patient knowledge of pituitary tumors [patient knowledge questionnaire (PKQ)] and need for information (Likert 1–5) was measured prior, immediately after, and 1 month following appointment. Patients participated in a semi-structured phone interview designed to explore patient diagnostic experiences pre-and post- intervention and to elicit patient evaluation of the intervention. Interviews were tape-recorded, transcribed, and analyzed using qualitative methods. Results: Seventeen patients participated in the study; 15 of these completed the interview. Baseline need for information was high (4.6± 0.6). Anxiety level by VAS-A [median (IQR) was 50 (35–71) prior, 47 (21–68) immediately after and 1 month later 31 (14–44)] and GAD-7 [median value before 9 (4–13), immediately after 7 (3–13) and 1 month later 5 (3–8)] improved significantly (P &lt; 0.01). PKQ was high at baseline (15 ± 0.4 /18) and increased (after 15.9 ± 0.4 and 1 month 15.8 ± 0.4, P=0.045). Patient satisfaction significantly improved (2.8 vs 4.6, P &lt; 0.01). Analysis of the semi-structured interviews identified 3 main themes: (1) Communication, (2) Need for information; and (3) Impact of the diagnosis on patient experience. Patient experience in relation to each theme was reported negatively prior to the intervention and positively post-intervention. Conclusion: The diagnostic experience is challenging for patients with newly diagnosed PA and is associated with high levels of anxiety despite most patients being notified of the benign diagnosis. Although patients desire more information, patients scored highly on the baseline PKQ. The delivery of information had a significant positive impact on patient satisfaction and led to a reduction in anxiety. While these observations are not controlled, the themes identified have important clinical implications. They suggest that patient experience can be improved by a timely, streamlined diagnostic process with readily accessible information.