bluuebunny/crossref_metadata_2025 huggingface dataset:
Palbociclib (P) in patients (pts) with non-small cell lung cancer (NSCLC) with CDKN2A alterations: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.
Authors: Ahn Eugene R , Mangat Pam K. , Garrett-Mayer Elizabeth , Halabi Susan , Dib Elie G. , Haggstrom Daniel Ernest , Alguire Kathryn B. , Alvarez Ricardo H. , Calfa Carmen Julia , Cannon Timothy Lewis , Crilley Pamela A. , Gaba Anu G. , Marr Alissa S. , Sangal Ashish , Thota Ramya , Antonelli Kaitlyn R. , Islam Samiha , Rygiel Andrew Lawrence , Bruinooge Suanna S. , Schilsky Richard L.
Published: March 2020

9041

Background: TAPUR is a phase II basket study evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of NSCLC pts with CDKN2A loss or mutation treated with P are reported. Methods: Eligible pts had advanced NSCLC, no standard treatment options, measurable disease, ECOG PS 0-2 and adequate organ function. Genomic testing was performed using commercially available tests. Pts matched to P had NSCLC with CDKN2A loss or mutation and no RB mutations. A Simon two-stage design was used to test a null rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have disease control (DC) (objective response (OR) or stable disease at 16 weeks (wks) (SD16+)), an additional 18 pts are enrolled. If ≥7 of 28 pts have DC, the drug is considered worthy of further study. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: Twenty-nine pts were enrolled from January 2017 to June 2018; 1 pt was unevaluable for response but is included in safety analyses. Pts received P at 125 mg orally once daily for 21 days, followed by 7 days off. Demographics and outcomes are summarized in Table (N = 28). One PR and 6 SD16+ were observed for a DC rate of 29% (90% CI, 15% to 37%). 10 pts had at least one grade 3 or 4 AE or SAE at least possibly related to P with the most common being cytopenias. Other grade 3-4 AEs or SAEs at least possibly related to P included fatigue, anorexia, febrile neutropenia, myocardial infarction, sepsis, vomiting, and hypophosphatemia. Conclusions: Monotherapy with P demonstrated evidence of anti-tumor activity in heavily pre-treated NSCLC pts with CDKN2A loss or mutation . Additional study is warranted to confirm the efficacy of P in pts with NSCLC with CDKN2A loss or mutation. Clinical trial information: NCT02693535. [Table: see text]
Osimertinib induced cardio-toxicity: A retrospective review of FDA adverse events reporting system (FAERS).
Authors: Anand Kartik , Ensor Joe , Trachtenberg Barry , Bernicker Eric
Published: March 2020

9044

Background: Osimertinib is an oral third generation irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). In the FLAURA trial (a Phase III randomized-control trial) Osimertinib arm had higher rate of cardio-toxicity compared to standard EGFR-TKIs. We queried FAERS database to find out rate of cardio-toxicity caused by Osimertinib compared to other EGFR-TKIs. Methods: We queried FAERS for “Cardiac failure”, “Electrogram QT-prolonged”, “Atrial Fibrillation(A.fib)”, “Myocardial Infarction(MI)”, “Cardiac failure congestive(CFC)” and “Pericardial Effusion(PE)” secondary to “Osimetinib”, “Erlotonib”, “Afatinib” and “Gefitinib” from 2016-2018. Disproportionality signal analysis was done by calculating Reporting Odds Ratio (ROR) with 95% confidence interval (CI). ROR was considered significant when lower limit of 95% CI was > 1. Results: Total AEs from all drugs were 5,138,230. Total AEs from all 4 TKIs were 8450, 2454 due to Osimertinib, 5836 due to other TKIs and 160 due to combination of both Osimertinib plus any of other 3 TKIs. ROR for Cardiac failure, A.fib, QT prolongation, MI, PE and CFC due to Osimertinib was 6.4(4.7-8.7), 4(2.8-5.8), 11.2(7.9-15.8), 1.6(0.9-2.6), 8.2(4.8-14) and 3.9(2.4-6.3) respectively. ROR for Cardiac failure, A.fib, QT prolongation, MI, PE and CFC on comparing Osimertinib vs other TKIs was 2.1(1.3-3.2), 2.1(1.3-3.5), 6.6(3.4-12.8), 1.2(0.6-2.3), 1.6(0.8-3.3) and 2.3(1.2-4.6) respectively. Findings are summarized in Table. Conclusions: Rate of QT prolongation, cardiac failure, CFC and A.fib were found to be higher due to Osimertinib compared to other TKIs. EKG monitoring for QT prolongation and monitoring for signs/symptoms of heart failure should be considered while using Osimertinib. [Table: see text]
Brigatinib in pretreated patients with ALK-positive advanced NSCLC.
Authors: Descourt Renaud , Perol Maurice , Rousseau-Bussac Gaelle , Planchard David , Mennecier Bertrand , Wislez Marie , Cortot Alexis B. , Guisier Florian , Gervais Radj , Galland Loick , Schott Roland , Dansin Eric , ARRONDEAU Jennifer , Auliac Jean-Bernard , Chouaid Christos
Published: March 2020

9045

Background: Brigatinib is a next-generation ALK inhibitor initially developed in pre-treated ALK+ NSCLC. Data on the efficacy of brigatinib in real world remain rare. Methods: This retrospective multicentric study analyzed ALK-+ advanced NSCLC patients pretreated with at least two tyrosine-kinase inhibitors, including crizotinib, and enrolled in the brigatinib French early access program. The primary endpoint was investigator-assessed progression-free survival (PFS). Results: 104 patients were included (mean age, 56.6 years; never smokers, 61.5%; adenocarcinoma, 98.1%). Patients had received a median of 3 previous treatment lines, including at least 2 ALK inhibitors, mainly crizotinib then ceritinib in 93% patients. At brigatinib initiation, 59.1% had performance status 0-1, 51.9% had ≥ 3 metastatic sites, 74.5% had central nervous system metastases (CNS) and 8.8% had carcinomatous meningitis. Median duration of brigatinib treatment was 6.7 (0.06–20.7) months. Median PFS was 6.6 (95% CI, 4.8–9.9) months for the entire population. In the 91 evaluable patients, disease control rate was 78.2% (stable, 28.2%; partial response, 45.7%; complete response, 4.3%). From brigatinib start, median overall survival was 17.2 (95% CI:11.0–not reached) months. Among the 68 patients with progressive disease after brigatinib, CNS was involved in 29.4% of cases. Ten (9.6%) patients had treatment discontinuation due to intolerance or patient request. Median OS from the diagnostic of NSCLC was 75,3 (95% CI, 38,2-174,6) months. Conclusions: This study confirms the efficacy of brigatinib in a cohort of patients heavily pretreated for ALK-+advanced NSCLC. These real-world results are consistent with clinical data reported in clinical trials.
First-in-human phase 1 study of DS-1062a in patients with advanced solid tumors.
Authors: Sands Jacob M. , Shimizu Toshio , Garon Edward B. , Greenberg Jonathan , Guevara Ferdinand M. , Heist Rebecca Suk , Kobayashi Fumiaki , Noguchi Yutaka , Okajima Daisuke , Tajima Naoyuki , Spira Alexander I. , Yamamoto Noboru , Lisberg Aaron Elliott
Published: March 2020

9051

Background: DS-1062a is a trophoblast cell-surface antigen 2 (TROP2)-targeting antibody drug conjugate. TROP2 is highly expressed in epithelial cancers, including non-small cell lung cancer (NSCLC). Overexpression of TROP2 may be associated with poor survival in some solid tumors. Preclinical studies showed promising antitumor activity of DS-1062a in mouse models with TROP2-positive tumors. Preliminary results are reported in the dose escalation part of this phase 1 study. Methods: This is an ongoing phase 1 study of DS-1062a in patients (pts) with advanced solid tumors in the US and Japan (NCT03401385). Adult (age ≥20 years in Japan or ≥18 years in US) pts with measurable disease per RECIST v1.1 and sufficient tumor tissue sample for TROP2 measurement were eligible. Pts were excluded if they had multiple primary malignancies or untreated brain metastases. Endpoints included safety, pharmacokinetics, and efficacy. Results: As of November 16, 2018, 22 pts with advanced NSCLC were treated with DS-1062a at doses of 0.27-mg/kg (n = 4), 0.5-mg/kg (n = 5), 1.0-mg/kg (n = 7), and 2.0-mg/kg (n = 6). Overall, mean (standard deviation) treatment duration and cumulative dose were 7.8 (4.1) weeks and 181.8 (141.4) mg, respectively, with a median of 2 (range 1–6) cycles initiated. The majority (n = 18; 81.8%) of pts had ≥1 treatment-emergent adverse event (TEAE). The most common TEAE, fatigue (n = 9), was the only grade ≥3 treatment-related TEAE (n = 1; 2.0-mg/kg). Serious TEAEs, reported in 5 pts in the 0.27-mg/kg (n = 2), 0.5-mg/kg (n = 2), and 2.0-mg/kg (n = 1) cohorts, were not treatment-related. TEAEs leading to discontinuation occurred in 1 pt in the 0.27-mg/kg cohort (pleural effusion; not treatment-related). One pt died due to progressive disease. Peak concentration (Cmax) and area under the curve from time 0 to last measurable concentration (AUClast) increases were generally dose proportional. Of 18 tumor evaluable pts, 1 had a partial response (PR; 1.0-mg/kg), and 8 had stable disease (SD). Conclusions: DS-1062a was well tolerated at doses up to 2.0-mg/kg. An observable PR and multiple pts with SD warrant further evaluation of DS-1062a. The maximum tolerated dose has not been reached, and this study is ongoing. Clinical trial information: NCT03401385.
Characterization of 648 non-small cell lung cancer (NSCLC) cases with 28 unique HER2 exon 20 insertions.
Authors: Ou Sai-Hong Ignatius , Madison Russell , Robichaux Jacqulyne Ponville , Ross Jeffrey S. , Miller Vincent A. , Ali Siraj Mahamed , Schrock Alexa Betzig , Heymach John
Published: March 2020

9063

Background: EGFR and HER2 ( ERBB2) exon 20 insertion (ex20ins) mutations represent a subset of driver alterations in NSCLC, which historically have largely not responded to available targeted therapies. Recently, inhibitors specifically targeting ex20ins have shown efficacy in the clinic. Previous studies have described the landscape of EGFR ex20ins in NSCLC (PMID: 29981927), but similar descriptions of HER2 ex20ins are lacking. Methods: Hybrid capture-based comprehensive genomic profiling (CGP) was performed on 39,644 tissue and 4,062 blood-based circulating tumor DNA (ctDNA) samples from 43,706 unique patients with advanced NSCLC. Tumor mutational burden (TMB) was determined on 0.8-1.1 Mbp of sequenced DNA for tissue samples and reported as mutations/Mb. Results: HER2 ex20ins were detected in 1.5% (648/43,706) of NSCLC cases (614 tissue and 34 ctDNA). HER2 ex20ins represented 35% (648/1,845) of HER2-altered NSCLCs overall, while 46% (843/1,845) of cases had HER2 amplification (≥5 copies), 17% (320/1,845) had a non-ex20ins HER2 short variant (SV; most commonly S310F in 84 cases and V659E in 29 cases), and 1.8% (34/1,845) had HER2 amplification + SV. There were 28 unique ex20ins including most commonly A775_G776insYVMA (69%, 450/648), G776 > VC (12%, 76/648) and P780_Y781insGSP (8.6%, 56/648). Cases with HER2 ex20ins were significantly enriched for adenocarcinoma histology (89% vs 66%), female gender (64% vs 51%) and low TMB (95% vs 65% TMB < 10 mut/Mb) compared to HER2 wild-type cases (all p < 0.0001). HER2 amplification (7 median copies, range 5-39) co-occurred in 16% (103/648) of HER2 ex20ins cases. Co-occurrence of other known NSCLC drivers in HER2 ex20ins cases was rare (0.8%, 5/648). In contrast, non- HER2ex20ins cases with HER2 amplification or other HER2 SVs each had co-occurring known driver alterations in ~30% of cases. There was no significant difference in histology, gender, age, HER2 co-amplification or TMB in cases with YVMA vs non-YVMA ex20ins. Conclusions: HER2 ex20ins are found in 1.5% of NSCLCs and are generally mutually exclusive of other known drivers. Detection of these alterations may be critical to identify matched targeted therapy options for this subset of patients.
Phase II study of ABBV-399 (Process II) in patients with C-MET positive stage IV/recurrent lung squamous cell cancer (SCC): LUNG-MAP sub-study S1400K (NCT03574753).
Authors: Waqar Saiama Naheed , Redman Mary Weber , Arnold Susanne M. , Hirsch Fred R. , Mack Philip C. , Schwartz Lawrence Howard , Gandara David R. , Stinchcombe Tom , Leighl Natasha B. , Ramalingam Suresh S. , Tanna Saloni H. , Raddin Ryan S. , Minichiello Katherine , Kelly Karen , Bradley Jeffrey D. , Herbst Roy S. , Papadimitrakopoulou Vassiliki
Published: March 2020

9075

Background: Lung-MAP is a platform trial to assess targeted therapies in SCC. S1400K was designed to evaluate the response to ABBV-399, an antibody-drug conjugate targeting C-MET, in patients with C-Met positive SCC. Methods: Patients with previously treated SCC with c-MET positive tumors (H score ≥150, Ventana SP44 assay), PS≤1, adequate organ function, peripheral neuropathy ≤ grade (G) 2, edema ≤ G2, albumin ≥3 g/dL, hepatic involvement by tumor < 50%. Patients were enrolled into 2 cohorts: Cohort 1 (immune checkpoint inhibitor (ICI) naïve) and cohort 2 (ICI refractory). ABBV-399 2.7 mg/kg was administered intravenously over 30 minutes every 3 weeks until disease progression or unacceptable toxicity. Response assessments were performed every 6 weeks. The primary endpoint was response by RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), response within cohort, duration of response (DoR), and toxicities associated with ABBV-399. Interim analysis was planned after 20 evaluable patients, with ≥ 3 responses needed to continue enrollment. Results: Between 2/15/18 and 10/16/2018, 50 patients (17% of patients screened) were assigned to S1400K, 28 patients enrolled (15 in cohort 1 and 13 in cohort 2), 25 were determined eligible, of whom 23 received ABBV-399 and were assessed for adverse events. There were 3 G5 events (2 pneumonitis, both in cohort 2 and 1 bronchopulmonary hemorrhage) and 4 G3 events. S1400K was temporarily closed on 10/16/2018 for interim analysis and safety concerns, and formally closed on 12/21/2018. Two responses were reported, both in cohort 1 (1 complete and 1 unconfirmed partial response, CR and UPR) for a response rate of 9% (95% CI: 0-20%). The CR remains on treatment at 4 months and DoR for the UPR was 2.3 months. Ten patients had stable disease and disease control rate was 52% (3-73%). The median OS and PFS were 4.7 and 2.4 months. Conclusions: ABBV-399 failed to meet the pre-specified response needed to justify continuing enrollment. Pneumonitis was an unanticipated toxicity observed in patients with SCC with previous immunotherapy exposure. Clinical trial information: NCT03574753.
Clinicopathologic profile and treatment outcomes of non-sensitizing EGFR and HER2 (ERBB2) activating mutations in NSCLC: Results from a single-center retrospective study.
Authors: Patil Tejas , Mushtaq Rao Rashid , Marsh Sydney , Azelby Christine , Pujara Miheer , Aisner Dara , Purcell William T. , Schenk Erin Lynn , Bunn Paul A. , Pacheco Jose Maria , Camidge D. Ross , Doebele Robert Charles
Published: March 2020

9090

Background: The clinicopathologic characteristics and optimal treatment strategies for non-sensitizing EGFR ( ns- EGFR) and HER2 activating mutations in NSCLC remain unclear. Methods: Single-center retrospective study of patients seen at University of Colorado from 2008 – 2018 with stage IV NSCLC was performed. Clinicopathologic features and treatment outcomes of patients with ns-EGFR (Exon 18, Exon 20, L861Q) and HER2 mutations were collected. Best response to TKI was determined (RECIST v1.1). PFS was calculated using Kaplan-Meier method. Results: Among 359 patients, we identified 49 ns-EGFR (36 Exon 20, 10 Exon 18, 3 L861Q) and 28 HER2 mutations (27 Exon 20, 1 gene amplification) detected via NGS (65/77), real-time PCR (9/77), FISH (1/77) and undocumented (2/77). PDL1 > 50% was seen in 44% ns- EGFR and 57% HER2. Adenocarcinoma was the most common histology (97%). Most patients were female (62%), never smokers (63%), and presented with metastatic disease (stage: I 5%, II 4%, III 6%, IV 85%). HER2+ NSCLC demonstrated a tropism for lung metastases (64%) that was significant when compared to EGFR Exon 19, EGFR L858R, ALK, ROS1, and KRAS cohorts (p < 0.001). No differences were found when other metastatic sites were compared. Among evaluable patients, response rates to TKI therapy is shown. Aggregate median PFS on TKI for ns-EGFR and HER2+ NSCLC was 6 months compared to EGFR Exon 19 (15 months; p < 0.01; HR 0.4; CI 0.24 – 0.67) and EGFR L858R (22 months; p < 0.01; HR 0.27 and 0.8; CI 0.14 – 0.54). Aggregate median OS for ns-EGFR and HER2+ NSCLC was 28 months with no differences when compared to EGFR Exon 19 and L858R subgroups. Conclusions: HER2+ NSCLC appears to have a predisposition for lung metastases. Higher DCR was observed with newer generation TKIs, but novel targeted therapeutic approaches are needed as overall outcomes remain poor. [Table: see text]
Final PFS analysis and safety data from the phase III J-ALEX study of alectinib (ALC) vs. crizotinib (CRZ) in ALK-inhibitor naïve ALK-positive non-small cell lung cancer (ALK+ NSCLC).
Authors: Seto Takashi , Nishio Makoto , Hida Toyoaki , Nokihara Hiroshi , Morise Masahiro , Kim Young Hak , Azuma Koichi , Takiguchi Yuichi , Yoshioka Hiroshige , Kumagai Toru , Hotta Katsuyuki , Watanabe Satoshi , Goto Koichi , Satouchi Miyako , Kozuki Toshiyuki , Nakagawa Kazuhiko , Mitsudomi Tetsuya , Yamamoto Nobuyuki , Asakawa Takashi , Tamura Tomohide
Published: March 2020

9092

Background: The primary analysis of the J-ALEX (JapicCTI-132316) study for the ALK-inhibitor naïve ALK+ NSCLC demonstrated superior progression-free survival (PFS) of ALC compared with CRZ (HR 0.34, 99.7% CI 0.17–0.71, stratified log-rank p < 0·0001) by the Independent Review Facility (IRF) (data cutoff, December 3 2015, Hida et al., Lancet 2017) . Here, we report the final PFS and OS 2nd interim data (data cutoff, June 30 2018). Methods: ALK+ NSCLC (by IHC and FISH or RT-PCR) patients were randomized 1:1 either to receive ALC (300 mg BID, n = 103) or CRZ (250 mg BID, n = 104). Stratification factors included ECOG PS, treatment line, and clinical stage. Primary endpoint was PFS according to the blinded IRF. Secondary endpoints included OS, objective response rate, and safety. Results: After a median follow-up of 42.2 months in the ALC arm and 42.4 months in the CRZ arm, an event of disease progression or death occurred in 54% and 86% in the ALC arm and the CRZ arm, respectively. The final PFS HR was 0.37 (95%CI 0.26-0.52): median IRF-PFS was 34.1 months (95%CI 22.1– not estimated) in the ALC arm and 10.2 months (95%CI 8.3–12.0) in the CRZ arm. HRs for the time to CNS progression or death was 0.33 (95%CI 0.11–0.93) and 0.20 (95%CI 0.08–0.49) with or without CNS metastases at baseline, respectively. The 2nd interim analysis of OS was still immature (events 30.1% in the ALC arm, 31.7% in the CRZ arm; stratified HR 0.80, 95%CI 0.35–1.82). Most of patients (77.9%) in the CRZ arm received ALC as a subsequent therapy whereas only 10.7% of patients in the ALC arm received CRZ. Proportion of patients with grade 3–4 AEs (37% vs 61%), AEs leading to interruption (40% vs 82%) or discontinuation (12% vs 23%) were lower in the ALC arm than the CRZ arm. There were no treatment-related deaths in either arm. Conclusions: In the final PFS analysis, ALC continued to demonstrate the superiority in IRF-PFS in ALK-inhibitor naïve ALK+ NSCLC regardless of baseline CNS metastases with a favorable safety profile. The updated result of OS will be presented in the future congress. Clinical trial information: JapicCTI-132316.
Project Switch: Docetaxel as a potential synthetic control in metastatic non-small cell lung cancer (mNSCLC) trials.
Authors: Menefee Michael E. , Gong Yutao , Mishra-Kalyani Pallavi Shruti , Sridhara Rajeshwari , Kanapuru Bindu , Blumenthal Gideon Michael , Pazdur Richard
Published: March 2020

9105

Background: Docetaxel is a common comparator arm to test novel therapies in post-platinum mNSCLC trials. The advent of Real World Evidence (RWE) has renewed interest in the use of synthetic control arms (control arms from previously conducted randomized trials) to improve accrual to trials and increase patient access of promising experimental agents. We reviewed legacy second-line (2L) mNSCLC trials to assess the impact of switching docetaxel control arms from one trial to another and compare to an experimental regimen. Methods: We identified 5 contemporary 2L trials that enrolled 2013 patients receiving an experimental therapy vs. docetaxel: 5 immunoncology head-to-head trials (one with 2 arms) and one anti-VEGF add-on trial. Kaplan-Meier curves of overall survival (OS) and progression-free survival (PFS) were produced for docetaxel controls. We calculated OS and PFS hazard ratios and 95% confidence intervals for each synthetic trial. A pooled doc arm was also compared with each experimental agent. Results: See Table. Conclusions: Both individual and pooled docetaxel switching of control arms approximated the original OS HR and 95% CI. Methods such as bootstrapped sampling and propensity score matching will be performed in an effort to more closely approximate the original trial characteristics. [Table: see text]
Non-small cell lung cancer (NSCLC) case study examining whether results in a randomized control arm are replicated by a synthetic control arm (SCA).
Authors: Davi Ruthie , Chandler Mark , Elashoff Barbara , Ferris Andrea Stern , Howland Andrew , Lee David , Majumdar Antara , Stewart Mark , Strianese Larry , Stuart Elizabeth , Yin Xiang , Yver Antoine
Published: March 2020

9108

Background: The FDA’s accelerated approval (AA) pathway provides conditional approval for an investigational product (IP) after positive effect on a surrogate endpoint has been provided, allowing patients earlier access to the therapy. Confirmation of a positive effect on the clinical endpoint after conditional approval is required and usually includes a randomized trial. However, such a trial is challenged by availability of the IP outside the trial. Recruitment becomes more difficult, and patients assigned to control are more likely to drop-out and use the non-assigned IP, which may bias the observed treatment effect. In AA settings we propose a SCA composed of patient level data from previous clinical trials to augment or replace the randomized control. Validity of this approach in one case study is assessed by examining if a SCA can replicate the outcomes of a target randomized control (TRC) from a recent NSCLC trial. Methods: The patients for the NSCLC SCA were required to have satisfied the key eligibility criteria of the target trial and were further selected using a propensity score-based approach to balance the baseline characteristics in the SCA and TRC. All patient selections were made without knowledge of patient outcomes. Results: The results show comparable balance in observed baseline characteristics of the SCA and TRC was achieved. Overall survival (OS) in TRC was replicated by SCA. The Kaplan Meier curves for OS in the SCA and TRC visually overlap. In addition, the log rank test (p = 0.65) and hazard ratio of 1.04 (95% CI: (0.88, 1.23)) were not statistically significant. Conclusions: If the SCA had been in place of the randomized control in this study, conclusions about the treatment effect would have been the same. While this may not hold when it is not possible to balance the groups on all confounders, this suggests that in some settings, SCA could augment or replace the randomized control in future trials easing recruitment, retention, and crossover challenges without compromising the understanding of the treatment effect. Future work should examine in what settings SCA is appropriate and consider the implications of potential unobserved confounders.
Efficacy of PD-1 monoclonal antibody SHR-1210 plus apatinib in patients with advanced nonsquamous NSCLC with wild‐type EGFR and ALK.
Authors: Zhou Caicun , Gao Guanghui , Wang Yi Na , Zhao Jun , Chen Gongyan , Liu Zhihua , Gu Kangsheng , Huang Meijuan , He Jianxing , Chen Jianhua , Ma Zhiyong , Feng Ji Feng , Shi Jianhua , Wang Quanren , Yang Ying , Yu Xinmin , Cheng Ying , Yao Yu , Ren Shengxiang
Published: March 2020

9112

Background: Our preclinical study suggested combination of PD-1 monoclonal antibody SHR-1210 and VEGFR 2 inhibitor apatinib significantly improved antitumor effects. This was an open-label, multi-center, phase 1/2 study of intravenous SHR-1210 plus oral apatinib in patients with advanced NSCLC. Here, we reported preliminary efficacy and safety outcomes of SHR-1210 plus apatinib in patients with wild‐type EGFR and ALK. Methods: In dose-escalation phase, advanced non-squamous NSCLC patients (pts) previously treated with at least 2nd line chemotherapy were enrolled to explore 2 dose levels of apatinib (250, 375mg/d) + SHR-1210 (200mg, q2w). 250mg/d of apatinib was selected to be combined with SHR-1210 in phase II trial. Pts previously treated with 1st line platinum-based chemotherapy were enrolled. Primary endpoint was ORR per RECIST 1.1. Archived or fresh tumor tissues and blood samples were taken before the treatment, PD-L1 expression and tumor mutation burden (TMB) were tested and correlated with efficacy. TMB was detected by Oseq-pan cancer panel (including 636 genes and 1.95Mb), and then calculated by in-house algorithm developed by BGI Genomics Co., Ltd. Results: 96 pts with advanced non-squamous NSCLC harboring wild‐type EGFR and ALK were recruited . 23 had ≥2 prior lines of systemic treatment, and 73 had 1 prior line of treatment. Median age was 57, male 79.8%, adenocarcinoma 93.9%, ex-smokers 56.7%. ORR and DCR in 91evaluable pts were 29.7% and 81.3%, respectively. Blood TMB (bTMB) test was available in 80/91 evaluable patients and the cut-point was 1.54 muts/Mb as determined by receiver operating characteristic curve. ORR in pts with high bTMB was 50% (19/38). At data cutoff of 20 Jan 2019, 20/27 responders were still on treatment (table). Across all 96pts, 54(56.2%) grade ≥3 TRAEs. AEs of grade ≥3 occurring in 2 or more pts included hypertension, hand-foot syndrome, gamma-glutamyl transferase increase, proteinuria, abnormal hepatic function and alkaline phosphatase increase. Conclusions: SHR-1210 plus apatinib demonstrated promising anti-tumor activity with acceptable safety in patients with non-squamous NSCLC, especially in those with high bTMB. Prospective study is needed to validate the clinical outcome and bTMB as a predictor of efficacy. Clinical trial information: NCT03083041. [Table: see text]
A phase II study (NCI9775) of sapanisertib (MLN0128/TAK-228) in relapsed and/or refractory acute lymphoblastic leukemia (ALL): Interim analysis.
Authors: Al-Kali Aref , Aldoss Ibrahim , Strand Carrie , Shah Bijal D. , Webster Jonathan Allen , Bhatnagar Bhavana , Akhtari Mojtaba , Doyle L. Austin , Kaufmann Scott H.
Published: March 2020

e18506

Background: Sapanisertib (SAP) is an oral small molecule dual mTOR complex 1 and 2 (TORC1/2) inhibitor that showed activity in lymphoid neoplasms. It blocks a feedback loop involving mTORC2 activation when TORC1 is selectively inhibited (Yun S et al, Blood 2016). SAP induces apoptosis of malignant lymphoid cells in vitro and in xenografts, with greatest effects in ALL cell lines. We aim to assess potential efficacy of SAP when used as a single agent in relapsed/refractory ALL. Methods: Adults (age ≥18) with ECOG performance status 0-2 and normal organ function (creatinine/total bilirubin <1.5 upper limit of normal) with relapsed and/or refractory ALL (B- or T-cell) were enrolled. Newly diagnosed patients (pts) unfit for aggressive treatments and BCR-ABL+ ALL were allowed if there was no suitable standard treatment. SAP was given at 3 mg orally daily for 21 days every 28 days. Dose escalation was allowed after 2 cycles. Hydroxyurea and corticosteroids were not allowed after starting SAP. The primary end point was complete remission (CR) or CR with incomplete count recovery (CRi). This is a one stage Simon design study with interim analysis after 11 pts completed treatment. Enrollment was continued until interim analysis was done. Results: A total of 16 pts were enrolled on the study with a median age of 46 years old, 56% being males. 1/16 (6%) was treatment naïve. Median number of prior therapies is 3 (range, 1-9). The mean duration on SAP was 14.7 days (range 1-22). Three pts were able to start cycle 2. Safety was evaluable in 14 pts. All 14 pts had at least one G3 AE, while 10 pts had at least one G4 AE. G3/4 related non-hematological adverse events (AE) included 3 mucositis, 1 hepatic failure, 1 sepsis, 3 hyperglycemia, 1 anorexia, 1 seizure, 1 confusion, and 1 pneumonitis. One pt had G5 AE with malignancy. G3/4 hematological AEs included 2 with lymphopenia, 1 thrombocytopenia, 3 with leukopenia, and 1 with neutropenia. No pt achieved a CR/CRi. Best response was stable disease in 2 (12.5%) pts. Five pts had progressive disease while 9 were not evaluable because of early removal. Conclusions: SAP exhibited the expected safety profile. Although several pts developed cytopenias on drug, there was no evidence of clinically meaningful single-agent activity against ALL. Analysis of paired bone marrow aspirates from this trial is being performed to assess whether mTOR was substantially inhibited at therapeutically achievable drug concentrations. Clinical trial information: NCT02484430.
A novel thrombopoietin mimetic RWJ-800088 increases megakaryopoiesis without causing malignant proliferation in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).
Authors: Adrianzen Herrera Diego Andres , Choudhary Gaurav , Bhagat Tushar , Gordon-Mitchell Shanisha , Zhang Hui , Steidl Ulrich , Will Britta , Eichenbaum Gary , Guha Chandan , Verma Amit
Published: March 2020

e18527

Background: In patients (pts) with AML and MDS, thrombocytopenia is a source of morbidity/mortality and there is a need for safer treatment options. RWJ-800088 (RWJ) is a novel pegylated thrombopoietin (TPO) mimetic peptide that increases megakaryopoiesis preclinically and in humans. Before using a TPO mimetic agent in AML and MDS pts, it is important to evaluate if the agent has potential stimulatory effects on malignant myeloid cells. To assess whether RWJ is likely to stimulate malignant myeloid cells, we evaluated its effects in vitro on primary human samples from healthy controls and AML/MDS pts. Methods: We studied the effect of various RWJ doses on proliferation of AML/MDS cell lines; clonogenic capacity for leukemic colony forming units (CFU) and megakaryocytic CFU (CFU-Mk) of mononuclear cells (MNC) from controls and several MDS and AML pts; and expression of differentiation markers in MNC cultures. Results: RWJ treatment had no effect on proliferation of THP1, MOLM13, MV411 and MDSL cell lines at doses up to 1000 ng/ml. A slight increase in proliferation of CMK, a megakaryocytic cell line, was seen at doses > 5xEC50 (mean 12%, p = 0.03). Primary clonogenic assays from 18 AML/MDS pts did not show increased growth of leukemic CFU at RWJ concentrations up to 10 ng/ml and RWJ had a nonsignificant inhibitory effect in 4 pts. Notably, RWJ significantly increased normal CFU-Mk formation from MNC in 6 of 8 AML and all MDS pts (mean 2.6-fold, p = 0.02), as well as from healthy CD34+ stem cells and healthy MNC controls (mean 1.7-fold, p = 0.03). FACS analysis of primary cultures treated with RWJ showed no increase in the malignant blast compartment, no change in differentiation markers of granulocyte/monocyte or erythrocyte lineages but a significant increase in the number of CD41a+ megakaryocytic cells (mean 1.8-fold, p < 0.01). RWJ treatment increased phosphorylation of STAT5 but not STAT3, demonstrating on target stimulation of the TPO receptor in hematopoietic cells. Conclusions: Our results show that the novel TPO mimetic RWJ stimulates megakaryopoiesis without causing proliferation of the malignant myeloid clone in MDS and AML.
Characteristics and outcomes of Philadelphia chromosome-negative myeloproliferative neoplasm in a tertiary institute in India: An ambispective study.
Authors: Soti Kamal Raj , Kumar Lalit , Saxena Renu , Bakhshi Sameer , Gogia Ajay , Malik Prabhat Singh , Sahoo Ranjit , Sazawal Sudha
Published: March 2020

e18553

Background: Philadelphia chromosome (Ph) negative Myeloproliferative neoplasm (MPN) is a rare heterogeneous group of clonal hematological malignancy. We aim to describe the clinico-pathological features, treatment, outcomes and complications of this disorder. Methods: It is an ambispective study. All Ph negative MPN patients registered during 2001 to 31st December 2015 at our institute were reviewed for demographic data, diagnosis based on WHO 2008 criteria, treatment, complications and outcomes. SPSS software was used. Results: There were 55 patients registered with PMF (37), ET (9), PV (7), CNL (1) and MPN-U (1). PMF showed median age 51.2 years (23-70), male: female ratio of 1.46, symptomatic (36), splenomegaly (29), mean hemoglobin 9.7 gm/dl (3-16), JAK2 mutation positive (14), CALR mutation positive (1). Most of the patients were DIPSS intermediate-1 risk 22 (59.4%) grouping. They received hydroxyurea (13), steroids (9), ruxolitinib (6), immunomodulators/steroids (4), aspirin (3), allogeneic stem cell transplantation (2), interferon (1), radiation (1), danazol (1) and observation (1). Median OS was not reached. OS at 5 years is 84% (95% CI 70% to 98%). Survival probability at 36 months is significant for circulating blasts <1% and high bone marrow fibrosis but not significant on multivariate analysis. Progression probability at 36 months is significant for circulating blast <1% and high DIPSS score but not significant in multivariate analysis. PV showed median age 58 years (23-70), male: female ratio 6:1, symptomatic (7), splenomegaly (6), mean hemoglobin 18.4 gm/dl (16.6-21.5), JAK2 mutation positivity (5), low risk (2), high risk (5). They received hydroxyurea (6), phlebotomy (3) and aspirin (1). Five out of 7 patients are in stable condition. ET showed median age 39 years (24-72), male: female ratio 2:1, symptomatic (4), splenomegaly (2), mean hemoglobin 12.2 gm/dl (7.5-15.4), JAK2 mutation positivity (4), low risk (7) and high risk (2). They received aspirin (6), hydroxyurea (5), and observation (1). Three patients are in stable condition. CNL (1) developed pneumothorax and was lost to follow up. MPN-U (1) received hydroxyuea. Seven died due to pneumonia (5), transfusion hypersensitivity (1) and AML transformation (1). Conclusions: PMF is the most common Ph negative MPN in our institute with DIPSS intermediate-1 being the most common risk group. At a median follow up of 36 months overall survival at 5 years is 84%.
Expression and prognostic relevance of calcium calmodulin-dependent protein kinase kinase 2 (CaMKK2) in chronic lymphocytic leukemia (CLL).
Authors: Jauhari Shekeab , Volkheimer Alicia D. , Barak Ian , Guadalupe Eross , Weinberg J. Brice , Chao Nelson Jen An , Li Zhiguo , Racioppi Luigi
Published: March 2020

e19002

Background: CaMKK2 has restricted tissue expression in humans, regulates diverse cell functions, and is overexpressed in several human malignancies. Blocking its function reduces cancer cell migration and survival in vitro and in vivo. The relevance of CaMKK2 signaling in lymphoma is uncertain, however. Here, we sought to characterize CaMKK2 expression in CLL, as well as its predictive variables and prognostic relevance. Methods: B cell samples from 39 CLL patients and 4 healthy donors were obtained from a biorepository at our institution through an active protocol. Commercially available kits were used for RNA isolation, cDNA generation, and RT-PCR. The Kolmogorov-Smirnov test was used to compare CaMKK2 expression between patients and donors. Regression analysis was used to identify independent predictors of CaMKK2 expression. Treatment-free survival was estimated using the Kaplan-Meier method. Results: CaMKK2 mRNA was standardized to actin and overexpressed in CLL cells v. healthy donor B cells (2.27 - 11.83 x 10-2 v. 0.93 - 1.67 x 10-2, p = 0.0014). Nine variables were evaluated for possible association, including age, gender, race, WBC and monocyte count, IGVH mutation status, FISH panel, Zap70 and CD38 status. By univariate analysis, unmutated IGVH and African-American race were associated with higher CaMKK2 expression (p = 0.0023 and 0.0238). Race was identified as a potential confounder for IGVH mutation status and vice versa. In a multivariate model, only IGVH mutation status predicted for CaMKK2 expression. Patients in the highest quartile of CaMKK2 expression had lower 2 year treatment-free survival compared with all others (10.7% v. 59.2%, p = 0.0054). Conclusions: CaMKK2 mRNA is over-expressed in CLL cells relative to normal B cells. Higher CaMKK2 expression in CLL may be associated with unmutated IGVH and African-American race and predict shorter time to treatment. Our analyses are limited by all unmutated IGVH patients receiving early treatment in our cohort. [Table: see text]
Impact of absolute lymphocyte count on prognosis of aggressive non-Hodgkin lymphoma.
Authors: Kaur Anahat , Grover Punita , Bulchandani Sheetal , Odeny Thomas A , Madhusudhana Sheshadri , Shrestha Anuj
Published: March 2020

e19034

Background: Multiple studies have attempted to identify parameters to predict prognosis and overall survival (OS) in Non-Hodgkin Lymphoma (NHL). Revised International Prognostic Index (R-IPI) is commonly used but does not capture all predictive risk factors in the Rituximab era. Low absolute lymphocyte count (ALC) on follow up after first line therapy has been reported to predict relapse. The prognostic value and exact cut off for low ALC at diagnosis is not known. We aimed to investigate whether ALC at time of diagnosis is an independent predictor for OS in aggressive NHL. Methods: We retrospectively evaluated patients with aggressive NHL treated at our center from 1/2000 to 12/2016 with at least 2 year longitudinal follow up after diagnosis. We retrieved data for baseline characteristics including age, sex, Ann Arbor stage, R-IPI score, HIV status, histopathological diagnosis (Diffuse Large B Cell Lymphoma (DLBCL), Burkitt′s lymphoma, Follicular Lymphoma Grade IIIB, high-grade B cell lymphoma), type of chemotherapy and clinical response. Patients were divided into four subgroups based on ALC at diagnosis: < 500, 501-1000, 1001-1500 and > 1500X109/L. Statistical analysis was done using REDCAP and Stata v13. Results: A total of 92 patients were identified. The average age at diagnosis was 53.4 years, 63% were male and 73.5% were diagnosed with DLBCL. Per R-IPI score, 16.3% were high risk, 31.3% were high intermediate risk, 22.5% low intermediate risk and 30% were low risk. The median OS for patients with ALC < 500 x109/L (5.4%) was 1.5 years, ALC 501-1000 (38%) was 2.3 years, ALC 1001-1500 (23.9%) was 4.25 years and ALC > 1500 (32.6%) was 5.2 years. On multivariate analysis this difference was not statistically significant due to small sample size. Conclusions: We found that low ALC at diagnosis trended towards worse OS in aggressive NHL but did not reach statistical significance on multivariate analysis. Our study is limited by retrospective nature and sample size. Multicenter studies need to be done to validate these results. Studies are also needed to know the exact cut off for low ALC. [Table: see text]
Comparison of salvage therapies for relapsed or refractory diffuse large B-cell lymphoma (DLBCL): Network meta-analysis.
Authors: Vosuri Venkata , Kaisreddy Ravi , Bandi Somasekhar
Published: March 2020

e19037

Background: Salvage chemotherapy followed by autologous stem cell transplantation(ASCT) is the standard second-line treatment for relapsed or refractory diffuse large b-cell lymphoma(DLBCL). Rituximab plus ifosfamide, carboplatin, and etoposide(R-ICE) and rituximab plus dexamethasone, high dose cytarabine, cisplatin(R-DHAP) are the two widely used regimens worldwide but quest for optimal regimen continues. Our objective is to compare currently available salvage therapies based on complete response and adverse events. Methods: Pubmed, EMBASE and Clinicaltrials.gov were queried for salvage therapies in relapsed or refractory DLBCL. Only randomized clinical trials including phase 2 and 3 trials involving salvage therapies for relapsed or refractory DLBCL were selected. Data was extracted based on meta-analysis guidelines by two independent reviewers. Network meta-analyses of treatment effects and adverse outcomes were calculated with a frequentist approach. Results: Overall, 5 studies(1480 patients) were included. The salvage therapies investigated were rituximab plus ifosfamide, carboplatin, and etoposide(R-ICE), rituximab plus dexamethasone, high dose cytarabine, cisplatin(R-DHAP), rituximab plus gemcitabine, dexamethasone, cisplatin(R-GDP), ofatumumab plus dexamethasone, cytarabine, and cisplatin(O-DHAP), ifosfamide plus ofatumunab, carboplatin, and etoposide(O-ICE), dacetuzumab plus rituximab, ifosfamide, carboplatin and etoposide(DR-ICE). Of the 6 regimens in the network, treatment with R-DHAP (OR:0.36,95%CI:0.24-0.54), R-GDP(OR:0.37,95%CI: 0.21-0.65), O-ICE(OR:0.16,95%CI: 0.05-0.53), O-DHAP(OR:0.30,95%CI:0.17-0.52), DR-ICE(OR:0.77,95%CI:0.40-1.49) were not superior against network placebo(R-ICE) in achieving complete response. Higher odds of occurring severe adverse events was observed in R-DHAP(OR:2.02,95%CI: 1.35-3.01) and O-DHAP(OR:2.15,95%CI: 1.24-3.72) salvage regimens when compared to R-ICE. Conclusions: R-DHAP, R-GDP, O-ICE and O-DHAP were found to have no difference in treatment effect in achieving complete response in comparison to R-ICE. R-DHAP and O-DHAP are associated with higher number of severe adverse events in comparison with R-ICE. Outcomes mentioned above should be interpreted in the context of drugs and other factors involved in the disease.
The efficacy of ibrutinib-based combination therapy for mantle cell lymphoma: A systematic review.
Authors: Thirunagari Prem , Siyahian Aida , Iftikhar Ahmad , Wahab Ahsan , Ashraf Afia , Majeed Ammara , Nunes Cavalcante Parr Nadia C , Russ Atlantis Dawn , Kumar Abhijeet , Anwer Faiz
Published: March 2020

e19043

Background: Mantle Cell Lymphoma (MCL) is generally treated with rituximab (R) in combination with other drugs. However, treatment for relapsed or refractory (RR) MCL is challenging. For Ibrutinib (Ibr), we aim to determine the efficacy in combination therapy for newly diagnosed (ND) and RR MCL. Methods: Per PRISMA guidelines, a systematic review was performed using four databases. Results: Eleven studies with 363 patients were identified, most commonly studied regimens were ibrutinib in combination with R in 2 phase II studies and 2 studies on Ibr in combination with venetoclax. Ibr was also studied as part of the three-drug regimens in combination with bendamustine & R, lenalidomide & R, and obinutuzumab & venetoclax. Ibr was studied in combination with other drugs such as palbociclib, ublituximab, and bortezomib as part of the two-drug regimens. Results summarized in Table. Adverse events included cytopenia, atrial fibrillation, septic shock, tumor lysis syndrome, and GI toxicities. Conclusions: Ibr in combination with R demonstrated the highest overall ORR and CR in treatment of ND MCL, whereas combination with venetoclax and obinutuzumab demonstrated highest overall ORR and CR in treatment of RR MCL. Additional studies are needed to further assess and confirm its role in treatment. [Table: see text]
Survival outcomes in the elderly with limited stage diffuse large B-cell lymphoma treated with chemotherapy: SEER propensity-matched analysis.
Authors: Kaisreddy Ravi , Vosuri Venkata , Bandi Somasekhar
Published: March 2020

e19046

Background: Current data shows a median age of diffuse large b-cell lymphoma (DLBCL) diagnosis of 70 years. More than 50% of elderly DLBCL patients can be expected to be cured by modern immunochemotherapy. Survival outcomes in elderly patients with limited stage DLBCL treated with chemotherapy outside of clinical trials are poorly characterized. Our objective is to determine survival pattern and factors that influence survival in elderly patients with limited stage DLBCL treated with chemotherapy through analysis of data from a large nationwide cancer registry in modern treatment era. Methods: The Surveillance Epidemiology and End Results (SEER 18) treatment database (2001-2013) was used to detect limited stage (Ann Arbor lymphoma stage I and II) DLBCL (ICD-O-3 code: 9680/3) adult cases with ages between 60-80 years treated with chemotherapy. Patients were divided into two cohorts. Cohort 1 included patients aged ≥60 to 70 yrs and Cohort 2 included patients aged > 70 to 80 yrs. The variable "First Malignant Primary Indicator" was used to differentiate between primary DLBCL and secondary DLBCL cases. Overall survival (OS) was calculated using the Kaplan-Meier methods and multivariate cox regression model to determine the impact of race, gender, radiation use and primary malignant indicator on survival using 1:1 propensity score matching. Chi square test was applied to delineate for any significant difference between two cohorts. Results: Overall, 11138 patients were included with 5569 patients in each cohort. The relative incidence of limited stage secondary DLBCL was greater for cohort 2 when compared to cohort 1 (26% vs. 15%, p < 0.01). The odds of receiving radiation was 27% higher in cohort 1 compared to cohort 2 (p < 0.0001). Compared to cohort 1 (median OS-130 months), cohort 2 had worse median OS of 72 months (p < 0.0001). Female gender, not receiving radiation and secondary status have shown strong relationship with increased risk of death on multivariate cox regression analysis in the elderly limited stage DLBCL patients. Conclusions: Overall survival was worse in age group 70-80 yrs when compared to age group 60-70 yrs in limited stage DLBCL patients treated with chemotherapy. This may be due to differences in treatment approaches. Female gender, not receiving radiation and secondary status are poor prognostic factors of survival in above group of patients. Race has no impact on survival.
Efficacy and safety of PEG-rhG-CSF in primary and secondary prevention of chemotherapy-induced neutropenia.
Authors: Zhu Jun , Li Huiping , Fan Zhengfu , Gao Yunong , Tu Meifeng , Shao Bin , Gao Tian
Published: March 2020

e19051

Background: This study was to evaluate the efficacy and safety of PEG-rhG-CSF (brand name:jinyouli) in primary and secondary prevention of CIN(chemotherapy-induced neutropenia). Methods: This is a single-center,one-arm clinical study.Patients with non-myeloid malignant tumors were enrolled. PEG-rhG-CSF was given subcutaneously at 24-48h after chemotherapy. The indicator was febrile neutropenia(FN) and IV grade absolute neutrophil count. Results: From January 2016 until June 2018,217 patients were enrolled including 119 lymphoma patients, 50 breast cancer patients, 30 bone tumor patients,18 gynecologic oncology patients, and While146 with primary prevention and 71 with secondary prevention. The incidence of FN was 5.0% (35/692), which was 4.3% (21/478) in the primary prevention patients and 6.5% (14/214) in the secondary prevention patients ( p= 0.233).Logistic regression analysis showed that the longer the treatment cycle, the lower the incidence of FN. Comparison of the indicators of different chemotherapy cycles showed that the IV grade absolute neutrophil count (ANC) reduction was significantly lower in the primary prevention patients than in the secondary prevention patients in the first cycle of chemotherapy[17.1%(25/146) vs.46.5%(33/70),p = 0.000],the incidence of FN and IV grade ANC reduction were significantly lower in the second cycle of treatment than in the first cycle(p < 0.05).The adverse event were mainly bone pain, the incidence of 1/2 grade bone pain was 3.7% (8/217) and the incidence of grade 3/4 bone pain was 1.8% (4/217). Conclusions: The prevention of CIN with PEG-rhG-CSF after chemotherapy can effectively reduce the incidence of FN.For the first chemotherapy cycle, primary prevention is more effective than secondary prevention in preventing the incidence of IV grade ANC reduction. Clinical trial information: NCT02905916.