tbuckley/cabot-search huggingface dataset:
IMbrave150: Exploratory analysis to examine the association between treatment response and overall survival (OS) in patients (pts) with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor).
Authors: Michel Ducreux, Andrew X. Zhu, Ann-Lii Cheng, Peter R. Galle, Masafumi Ikeda, Alan Nicholas, Wendy Verret, Lindong Li, Vincent E. Gaillard, Riccardo Lencioni, Richard S. Finn
Journal: Journal of Clinical Oncology (2021)

4071 Background: Based on IMbrave150 (NCT03434379) results, atezo + bev has been approved in &gt; 60 countries for pts with unresectable HCC who have not received prior systemic therapy (Finn RS, NEJM 2020). OS and objective response rate (ORR) improvements with atezo + bev vs sor were maintained with an additional 12 mo of follow up since primary analysis. Updated median OS was 19.2 mo with atezo + bev vs 13.4 mo with sor (stratified HR, 0.66; 95% CI: 0.52, 0.85). Updated ORR was 30% with atezo + bev vs 11% with sor by independently-assessed (IRF) RECIST 1.1 (Finn RS, ASCO GI 2021). Here, we report an exploratory analysis examining the association of response by RECIST 1.1 with OS and independent predictors of survival. Methods: Pts in this Ph III study were systemic treatment–naive with unresectable HCC, ≥1 measurable untreated lesion (RECIST 1.1), Child-Pugh class A liver function and ECOG PS 0/1. Pts were randomized 2:1 to atezo 1200 mg IV q3w + bev 15 mg/kg IV q3w or sor 400 mg bid until unacceptable toxicity or loss of clinical benefit per investigator. ORR was determined by IRF RECIST 1.1. Kaplan-Meier analyses of OS by response status were conducted without landmark and with 4- and 6-mo landmarks. Multivariate analysis was conducted using Cox modeling with time-dependent covariate (responder [yes/no]) with backwards elimination. These analyses only included pts treated with atezo + bev. Results: IMbrave150 enrolled 501 pts, including 336 treated with atezo + bev. Median follow-up was 15.6 mo. OS was longer in pts with confirmed response per RECIST 1.1 (responders, CR + PR) vs non-responders by Kaplan-Meier analyses without landmark and with 4- and 6-mo landmarks (Table). By multivariate analysis, in addition to responder (yes/no), 5 of the 10 initially included predictors of OS remained in the final Cox model ( P&lt; 0.10): ECOG PS (0/1), geographic region (Asia excluding Japan/rest of the world), etiology (hepatitis B/hepatitis C/non-viral), macrovascular invasion and/or extrahepatic spread (yes/no), and baseline alpha-fetoprotein ( &lt; 400 ng/mL/≥400 ng/mL). Conclusions: Atezo + bev is the new standard of care for pts with previously untreated, unresectable HCC. Here we showed that in IMbrave150 pts treated with atezo + bev, response by RECIST 1.1 was associated with OS, suggesting that confirmed response is an independent predictor of OS in these pts. Clinical trial information: NCT03434379. [Table: see text]
POLR2A/TPR mutations as potential biomarker for better efficacy of immunoterpy in non-small cell lung cancer (NSCLC).
Authors: Xiaoyuan Zeng, Fei Zhao, Yaoxu Chen
Journal: Journal of Clinical Oncology (2021)

e21011 Background: Immunotherapy represents promising treatment in patients with non-small cell lung cancer (NSCLC).However, response rates for immunotherapy remain limited. There is a need to identify potential biomarkers to distinguish patients who respond to immunotherapy. POLR2A has been reported to be a potential target gene for immunotherapy of HER2-low breast cancer with 17p loss, together with TPR, responsible for RNA binding that is essential for cell survival. It is unclear whether POLR2A/TPR mutations could predict the efficacy of immunotherapy in NSCLC. Methods: WES (Whole Exome Sequencing) and survival data of NSCLC patients treated with anti–PD-1/PD-L1 or anti–CTLA-4 antibodies (Rizvi2015; Miao2018) were analyzed. WES, survival data of 1144 patients with NSCLC was obtained from The Cancer Genome Atlas (TCGA). In addition, the tumor-infiltrating immune cells present in NSCLC were analyzed by CIBERSORT, utilizing data from 515 patients by lung adenocarcinoma (LUAD) in TCGA pan-cancer cohort. Results: POLR2A/TPR mutations were significantly associated with better PFS in Rizvi2015 cohort (HR = 0.3; 95% CI, 0.09-1.02; P = 0.041), MIAO2018 cohort (HR = 0; 95% CI, 0-INF; P = 0.01). In TCGA, no association between POLR2A/TPR mutations and OS was observed (P = 0.67), suggesting that POLR2A/TPR mutations were not prognostic factor. POLR2A/TPR mutations were associated with higher TMB and TNB (p = 0.00018 and p = 0.00016 in Rizvi2015 cohort, p = 0.0042 and 0 = 0.0038 in Miao2018 cohort). In addition, POLR2A or TPR mutations was positively correlated with infiltrating levels of T cells CD4+ memory activated( p = 0.011), T cells CD8+(p = 0.017), and Macrophages M1(p = 0.0055). Conclusions: Our finding suggests that POLR2A/TPR mutations were associated with better PFS in NSCLC patients treated with Immunotherapy, with significantly higher TMB and TNB. The role of PTPRD/PTPRT in immunotherapy could be related with better immune cell infiltration.
Antitumor efficiency of combination of bortezomib and themosolomide on subcutaneous PDX-model of human glioblastoma.
Authors: A. V. Volkova, Rostorguev Eduard Evgenievich, Anna S. Goncharova, M. V. Mindar, Ekaterina V. Zaikina, D. V. Khodakova, Ekaterina A. Lukbanova, L. Z. Kurbanova, Vladislav E. Khatyushin, Sergey E. Kavitskiy
Journal: Journal of Clinical Oncology (2021)

e15011 Background: Poor clinical effects of standard treatment for glioblastoma determine the need for the development of new therapeutic strategies. Aberrant functioning of the proteasome system, as well as activation of the HIF-1α signaling pathway, are characteristic of glial tumor cells; they can be considered as potential therapeutic targets in the treatment of malignant brain tumors. One of the possible options for improving the results of glioblastoma treatment may involve strategies for inhibiting the HIF-1α pathway. Bortezomib, a proteasome inhibitor, can block the biological effects of HIF-1α. Bortezomib showed a pronounced antitumor effect in in vitro testing on various models of solid malignant tumors, giving grounds for further studies of its effectiveness in vivo. Patient-derived xenograft (PDX) models are characterized by a variety of cell subclones and are therefore considered the most reliable tool for predicting therapeutic responses. Methods: A PDX model of glioblastoma was created in 20 Balb/c Nude mice implanted with a subcutaneously inoculated human glioblastoma. Temozolomide (0.5 mg/kg), bortezomib (0.25 mg/kg), or a combination of temozolomide and bortezomib were administered intraperitoneally daily for 21 days. The tumor histotype was confirmed by histological analysis (staining with hematoxylin and eosin). The antitumor effect was determined by the inhibition of tumor growth (ITG%), the volume of tumor nodes, and the index of tumor growth. Results: The highest value of the inhibition of tumor growth (ITG%) was registered in the group of animals receiving a combination of temozolomide and bortezomib – 85.38%. The values in the groups receiving temozolomide or bortezomib monotherapy were 57.32% and 63.11%, respectively. Conclusions: An analysis of the antitumor efficacy of bortezomib combined with temozolomide in human subcutaneous PDX-glioblastomas demonstrated their synergistic effect.
Real-world neo-adjuvant with or without adjuvant treatment patterns among pancreatic ductal adenocarcinoma patients in the U.S.
Authors: Prakash Navaratnam, Monica Chase, Howard Steven Friedman, Seongjung Joo, Michael J. Pishvaian
Journal: Journal of Clinical Oncology (2021)

e16217 Background: The vast majority of pancreatic ductal adenocarcinoma (PDAC) patients have unresectable disease at diagnosis, with only about 20% presenting with either resectable or borderline resectable tumors and who may receive adjuvant with or without neo-adjuvant treatment with surgery. This study seeks to characterize these treatment patterns in the real-world setting. Methods: This was a retrospective observational study to evaluate adjuvant treatment of PDAC patients, with or without neo-adjuvant treatment in the U.S. Patients with at least two medical claims with a primary diagnosis for PDAC between 2016 to 2019 were identified in the Truven MarketScan administrative claims database. A surgical resection within 3 months of any primary PDAC coded medical encounter was the index event, with patients required to be continuously enrolled for at least 3 months before and 6 months after the surgery. Patient demographics and treatment patterns (chemotherapy, radiotherapy, and chemoradiation) were evaluated over the pre-index (3 months) and post-index (3 and 6 months) observation windows. Neo-adjuvant and adjuvant treatment patterns were reported for the overall population and also stratified by age and sex. Results: 737 patients met the selection criteria with a majority (n=520, 71%) being &lt;65 years old and 53% females (n=387). 65% (n=478) of patients received adjuvant chemotherapy during the 6-month post-index compared with 28% (n=207) receiving neo-adjuvant treatment. In the neo-adjuvant setting, patients were likely to receive leucovorin+fluorouracil+irinotecan+oxaliplatin (FOLFIRINOX; 43%, n=88) followed by gemcitabine+pacitaxel (18%, n=37), across all patients, as well as stratified by age or sex. Among patients that received adjuvant but did not receive neo-adjuvant treatment, patients were likely to receive gemcitabine monotherapy (35%, n=112) followed by gemcitabine+capecitabine (GEMCAP; 23%, n=72). Among adjuvant patients that had received neo-adjuvant treatment, the most common chemotherapy regimens were gemcitabine monotherapy (22%, n=35), GEMCAP (18%, n=29) and FOLFIRINOX (16%, n=26). For patients ≥ 65 years old, the most common adjuvant regimen was gemcitabine monotherapy (n=62, 29%) whereas for patients &lt;65, the most common regimens were GEMCAP (25%, n=90) and gemcitabine monotherapy (16%, n=85). Gemcitabine monotherapy (41%; n=118 of 453) was the main adjuvant regimen for patients with index dates of 2016-2017 but for those with index dates of 2018-2019 the most common was FOLFIRINOX (34%; n=64 of 284) followed by GEMCAP (18%; n=35 of 284). Conclusions: The majority (70%) of patients that underwent PDAC resection surgery did not receive neo-adjuvant treatment and about a third of patients did not receive any adjuvant treatment. These results suggest an unmet need in the management of PDAC.
Real-world effectiveness of lenvatinib monotherapy among previously treated unresectable hepatocellular carcinoma patients in United States clinical practices.
Authors: Amit G. Singal, Saurabh P Nagar, Abigail Hitchens, Shrividya Iyer
Journal: Journal of Clinical Oncology (2021)

e16129 Background: In the United States (U.S.), lenvatinib monotherapy was approved in August 2018 for first-line treatment of patients with unresectable hepatocellular carcinoma (uHCC) based on the pivotal trial, REFLECT. Treatment patterns in uHCC are evolving with recent approvals. The main objective of our real-world data (RWD) study was to assess treatment patterns and clinical effectiveness of lenvatinib among previously treated uHCC patients in U.S. clinical practices. Methods: A retrospective patient chart review study was conducted among U.S. adult patients (≥18 years) with uHCC and ECOG status of 0 or 1, who initiated lenvatinib monotherapy as second- or later-line systemic therapy between Aug 2018 and Sept 2019. Data were extracted from individual patients’ electronic health records and captured in electronic case report forms. Clinical outcomes assessed include provider-reported best response, progression-free survival (PFS) and overall survival (OS). PFS and OS were estimated using Kaplan-Meier methods. For PFS, patients were censored at end of treatment or end of follow-up in case of ongoing treatment, while censoring occurred at end of follow-up for OS. Results: Of 164 patients, median age was 62 years, majority were male (72%), and most were Caucasian (56%) followed by African American (23%). The most common liver disease etiologies were alcohol-related (32%), hepatitis C (26%), non-alcoholic steatohepatitis (21%) and hepatitis B (15%). Only one-third (31%) had Child Pugh A cirrhosis, with nearly half (49%) having Child Pugh B cirrhosis. Most patients had Barcelona Clinic Liver Cancer Stage B (24%) or C (38%) disease. Median body weight was 77 kg, and the median starting dose of lenvatinib was 12 mg daily. Median duration of lenvatinib treatment was 6.9 months, with 43% of patients remaining on lenvatinib at end of follow-up. RECIST v1.1 was reported as the criteria used to assess response in 60% of patients. Provider-reported best response was complete response (CR):9%, partial response (PR):45% and stable disease (SD): 26%. Median PFS and median OS were estimated to be 12.5 months and 14.0 months respectively. At 6 and 12 months, landmark PFS was 71% and 52%, respectively and landmark OS was 84% and 58%, respectively. PFS and OS estimates were consistent in subgroup analyses among those who had received lenvatinib in the second-line (81%, n=133) or treated with lenvatinib post immunotherapy (66%, n=109) (Table). Conclusions: Results from this retrospective real-world study affirm the clinical effectiveness of lenvatinib monotherapy among previously treated uHCC patients, including those with prior immunotherapy.[Table: see text]
A phase II, open-label, single-arm trial of pembrolizumab for refractory atypical and anaplastic meningioma and hemangiopericytoma.
Authors: Shlomit Yust-Katz, Alexandera Amiel, Tali Siegal, Dror Limon
Journal: Journal of Clinical Oncology (2021)

2064 Background: Grade II and III meningiomas are invasive tumors which tend to recur following initial treatment and are associated with shorter survival (relative to grade I). Hemangiopericytoma (HPC) is a dural based tumor that originates in the pericytes in the walls of capillaries. Treatment options for these tumors include surgical resection and radiation. There are no defined standard treatments after failure of these modalities, and efficient systemic treatments are lacking. This trial concept was formed following previous reports of high PD-L1 levels in anaplastic meningioma. We currently report our initial experience with pembrolizumab for refractory atypical/anaplastic meningioma (RAM) and HPC patients. Methods: This is a single arm, single institute, phase 2 trial. Inclusion criteria included patients with RAM or HPC whose all previous lines of treatment were exhausted. All patients were treated with pembrolizumab (200mg every 3 weeks) until disease progression. Primary endpoint was 6- and 12-months progression free survival (PFS). The study was planned for 25 patients and we report here preliminary results. Results: Through February 2021, 12 patients were enrolled to this study (two with HPC, 10 with RAM). After a median follow up of 18.5 months, the 6 and 12 months PFS were 25% and 16.7% respectively, with a median PFS of 2.75 months. Two patients had a partial response while all others progressed, making the overall response rate 16.7%. One of the responders had HPC and has been stable for 30 months, while the second had atypical meningioma and was stable for 13 months. Median survival has not been yet reached; 1 year survival rate was 82.5%. Grade 3 toxicities included hyperglycemia, elevated liver enzymes and fatigue (that did not cause treatment discontinuation), with no grade 4 or 5 toxicities. PD-L1, mutation burden, MSI and other genomic analyses are still pending. Conclusions: Pembrolizumab induced a low response rate for RAM and HPC. However, a subset of patients might benefit from this treatment with a prolonged response period. To define this subpopulation further molecular studies are needed. Clinical trial information: NCT03016091.
Retrospective analysis of HER2-low in young breast cancer patients.
Authors: Abeid Mohamed Athman Omar, Azza Mohamad Amin Darwish
Journal: Journal of Clinical Oncology (2021)

e12515 Background: Traditionally, breast cancer (BC) is considered human epidermal growth factor receptor-2 (HER2) positive based on HER2 overexpression or amplification (HER2 3+ or ISH positive HER2 2+). However, an emerging subgroup of HER2 negative (HER2 1+ or 2+ and ISH negative) known as HER2-Low is associated with poor prognosis than HER2-normal (HER2 0). Currently, there is an increased interest in developing new drugs targeting HER2-Low BC to improve survival. The fact that BC in young constitutes a significant minority outside the western world but is underrepresented in clinical trials, it is worth conducting a dedicated study of HER2-low in this population to determine whether it affects their outcome. Methods: Confirmed HER2 negative BC patients aged ≤40 diagnosed in 2012-2017 were retrospectively reviewed in two centers in Alexandria, Egypt. Patients were classified as HER2-low (1+, 2+) and HER2-normal. The clinicopathological characteristics and survival outcome were determined and compared. Results: There were five hundred HER2 negative BC patients; 82% were hormone receptor-positive (HR+) vs.18% triple-negative (TNBC). Among the HER2 negative, only 31% were HER2-Low (n = 155), of which 20% was HER2-Low 1+ while 11% was HER2-Low 2+. In comparison, HER2-Low was significantly more HR+ than HER2-normal (89% vs. 79% respectively, p = 0.009). Other tumor characteristics (T-size, nodal status, Ki-67, lymphovascular invasion - LVI, extracapsular extension - ECE) were similar in HER2-Low and HER2-normal. So were the disease-free survival (DFS) and overall survival (OS). Nevertheless, sub-grouping HER2-Low into 1+ and 2+ showed significant differences in tumor characteristics between HER2-normal, HER2-Low 1+, and HER2-Low 2+, in nodal status, tumor stage, ECE, and HR status. Moreover, DFS was significantly lower in HER2-Low 2+ (63.5%) compared to HER2-normal (70%) and HER2-Low 1+ (75%); p = 0.039. Also, the OS was also significantly lower in HER2-Low 2+ compared to HER2-normal, 90% vs 96% respectively, p = 0.023. Conclusions: Our results suggest no significant difference in DFS and OS between HER2-Low and HER2-normal in young BC patients. However, subdividing HER-low into HER2-low 1+ and HER2-Low 2+ better discriminates this group; HER2-Low 2+ had significantly poor DFS and OS and this should be considered in the clinical trials.
Assessment of predictive biomarker prevalence in molecularly defined adult-type ovarian granulosa cell tumors.
Authors: Robert Tyler Hillman, Douglas I. Lin, David Marc Gershenson
Journal: Journal of Clinical Oncology (2021)

5567 Background: The FDA has separately approved pembrolizumab for all advanced solid tumors with either microsatellite instability or high tumor mutational burden (≥10 mutations per megabase), and homologous recombination deficiency is an established biomarker for response to poly ADP ribose polymerase inhibitors in epithelial ovarian cancer. The detection of these predictive biomarkers in adult-type ovarian granulosa cell tumors could identify novel treatment strategies in this rare disease. The primary objective of this study was to determine the prevalence of established predictive biomarkers among molecularly defined adult-type ovarian granulosa cell tumors. Methods: With institutional review board approval, we performed a cross-sectional study examining de-identified FoundationOne companion diagnostic molecular profiles for 423 women with molecularly defined (FOXL2 c.C402G positive) adult type ovarian granulosa cell tumors. The dataset was comprised of coding variants for up to 406 genes as well as genomic signatures including microsatellite instability, tumor mutational burden, and genome wide loss of heterozygosity. PD-L1 expression by immunohistochemistry was also available for a subset of tumors. Descriptive statistics were used for comparison between groups and all statistical tests were two-sided. Results: Women in this cohort had a mean age of 57 years (range 24-87) at the time of sample submission for molecular profiling. The median tumor mutational burden was 1.3 mutations per megabase [mut/Mb] (range 0-8.8 mut/Mb). TP53-mutated aGCT had a higher tumor mutation burden than TP53 non-mutated tumors (median 2.4 mut/Mb, 95% CI 1.7-3.0 mut/Mb vs median 1.3 mut/Mb, 95% CI 1.5-1.9 mut/Mb; P=.02). All 384 tumors with available microsatellite instability testing were microsatellite stable. Sixty-seven tumors had PD-L1 expression measured and of these 94% (63/67) were negative with the remainder “low positive.” No tumors were positive for genome wide loss of heterozygosity. Apart from FOXL2 c.C402G, the most frequent short variants were TERT promoter mutations (-124C&gt;T: 190/423, 45.0%; -146C&gt;T: 39/423, 9.2%). Other frequently observed variants included truncating mutations in KMT2D/MLL2 (71/423, 16.8%), pathogenic TP53 mutations (35/423, 8.3%), CDKN2A/B deletions (43/423, 10.2%), and activating PIK3CA mutations (23/423, 5.4%). Conclusions: No women with molecularly defined adult-type ovarian granulosa cell tumors in this large cross-sectional study would be eligible for FDA-approved pembrolizumab based on either microsatellite instability or high tumor mutational burden. No tumors exhibited evidence of homologous recombination deficiency and molecularly targetable mutations were rare. The development of novel precision treatment options remains a critical unmet need for this rare disease.