bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of a fully human T cell engaging bispecific antibody for the treatment of multiple myeloma.
Authors: Buelow Ben , Pham Duy , Clarke Starlynn , Force Aldred Shelley , Dang Kevin , Pratap Payal , Ugamraj Harshad , Harris Katherine , Trinklein Nathan , Schellenberger Ute , Wiita Arun , Van Schooten Wim , Buelow Ben
Published: September 2018

8017

Background: Although BCMA is a plasma cell specific surface molecule attractive as an antibody target in multiple myeloma, its scarcity on the cell surface may limit the efficacy of a conventional antibody. T-cell engaging bispecific antibody approaches are highly efficacious and are particularly well suited for a membrane target with limited expression, such as BCMA. Teneobio has developed a multivalent antibody platform based on modular human VH domains, which allowed us to build T cell engaging bispecific antibodies with low and high T cell agonistic activities. Methods: UniRats were immunized with either CD3 or BCMA antigens and antigen-specific UniAbs were identified by antibody repertoire sequencing and high-throughput gene assembly, expression, and screening. High affinity binding VH sequences were selected using recombinant proteins and cells. In vitro efficacy studies included T-cell activation by cytokine- and tumor cell kill by calcein-release assays. In vivo efficacy of the molecules was evaluated in NSG mice harboring myeloma cells and human PBMCs. Results: BCMA-specific UniAbs bound plasma cells with high affinities (100-700pM) and cross-reacted with cynomolgus plasma cells. Strong and weak T cell agonists were identified that bound human T cells with high and low affinities respectively and cross-reacted with cynomolgus T cells. T cell engaging bispecifics with a strong (H929 cytotoxicity:EC50=27pM) and a weak T cell activating arm (H929 cytotoxicity: EC50=1170pM) demonstrated T-cell activation and tumor-cell cytotoxicity in vitro; bispecifics with a weak CD3 engaging arm showed markedly reduced cytokine production even at doses saturating for cytotoxicity. In viv o, BCMAxCD3 bispecific antibodies reduced tumor load and increased survival when co-administered with human PBMCs as compared to controls. Conclusions: Our results suggest that T cell engaging bispecifics with low-affinity anti-CD3 arms could be preferred for the treatment of Multiple Myeloma.
Carfilzomib-associated cardiovascular adverse events: A systematic review and meta-analysis.
Authors: Waxman Adam Justin , Chandra Clasen Suparna , Garfall Alfred L. , Carver Joseph R. , Vogl Dan T. , O'Quinn Rupal , Cohen Adam D. , Stadtmauer Edward Allen , Ky Bonnie , Weiss Brendan M.
Published: September 2018

8018

Background: The incidence and nature of cardiovascular adverse events (CVAEs) with carfilzomib (CFZ) in multiple myeloma (MM) remain incompletely defined. We performed the first systematic review and meta-analysis of CFZ CVAEs. Methods: PubMed was queried for the keywords “carfilzomib,” “Kyprolis,” and “PX-171.” Phase 1-3 clinical trials of carfilzomib in MM with evaluable toxicity data were included. CVAEs were defined as heart failure, hypertension, ischemia, and arrhythmia. All-grade and grade ≥3 CVAEs and study characteristics were recorded. Summary incidence rates and relative risks (for randomized trials) with 95% confidence intervals were calculated using the logistic-normal random-effects model. Subgroup analyses were performed using study level covariates. Results: 514 studies were reviewed. 2623 MM patients from 25 eligible studies were included. Incidence rates are summarized in the table. All grade and grade ≥3 CVAEs were seen in 16.8% and 7.6 %, respectively. Phase 2 or 3 studies, carfilzomib doses ≥45mg/m2, and longer infusion length were study characteristics associated with high-grade cardiac AEs (p<0.05). Median age >65, prior MM therapies, and concurrent MM therapies were not associated with CVAEs (p>.05). For the three randomized trials, the relative risk of all-grade and grade ≥3 CVAEs were 1.75 and 2.25, respectively (p<0.001). Conclusions: CFZ is associated with a significant incidence of CVAEs, including heart failure, hypertension, ischemia, and arrhythmia. Phase I studies may be underdetecting CVAEs. Future studies are needed to: identify patients at high-risk for CVAEs, develop optimal monitoring strategies, and explore therapies to mitigate these risks. [Table: see text]
Prognostic impact of kinetics of circulating plasma cells before and after induction therapy in newly diagnosed multiple myeloma patients undergoing early transplantation.
Authors: Chakraborty Rajshekhar , Muchtar Eli , Dispenzieri Angela , Lacy Martha , Buadi Francis , Dingli David , Hogan William J. , Kumar Shaji , Jevremovic Dragan , Hayman Suzanne R. , Kapoor Prashant , Leung Nelson , Gertz Morie A.
Published: September 2018

8020

Background: Circulating plasma cells (CPCs) at diagnosis, prior to transplant and at relapse have a negative prognostic impact on survival in multiple myeloma (MM). However, the impact of changes in CPCs along the course of illness has not been defined. Methods: We evaluated 247 patients with newly diagnosed MM (NDMM) undergoing early autologous stem cell transplantation (ASCT) in the era of novel agents (2007 to 2015), who had serial evaluation of CPCs at diagnosis and pre-ASCT by 6-color flow cytometry. Results: The median age at transplant was 62 years.A total of 117 (47%) patients had no detectable CPCs at both time points (CPC-/-), 82 (33%) had CPCs at diagnosis followed by complete eradication after induction therapy (CPC+/-) and 48 (19%) had detectable clonal CPCs at transplant, with persistence of cells (CPC+/+; n=45) or emergence of new CPCs (CPC-/+; n=3) after induction. The incidence of t(11;14) by iFISH was lower in the CPC-/- group (19%) compared to CPC+/- (29%) and CPC +/+ or -/+ (39%) groups ( p=0.033). Conversely, the incidence of hyperdiploidy was significantly higher in patients with CPC-/-, compared to those with CPC+/- and CPC+/+ or -/+ (64%, 44% and 39% respectively; p=0.005). The rate of post-ASCT stringent complete response was 32% in the CPC-/- group, 30% in CPC+/- group and 12% in CPC+/+ or -/+ group ( p=0.018). At a median follow-up of 58 months from ASCT, the median progression-free survival (PFS) from transplant in the 3 respective groups was 30, 24 and 14 months and the 5-year overall survival (OS) rates were 83%, 70% and 43% ( p<0.001 for both comparisons). On a multivariate analysis, using CPC-/- group as the comparator, PFS and OS was significantly inferior in CPC+/- (RR 1.6; p=0.020 and RR 2.7; p=0.008 for PFS and OS respectively) and CPC +/+ or -/+ groups (RR 2.9; p<0.001 and RR 5.8; p<0.001 for PFS and OS respectively). Conclusions: Clonal CPCs are detectable in more than 50% of newly diagnosed MM patients undergoing upfront ASCT. Monitoring for CPCs before initiation of induction therapy and before ASCT by 6-color flow cytometry is highly predictive of outcome in NDMM and should be incorporated into prospective clinical trials.
Daratumumab, lenalidomide, and dexamethasone (DRd) vs lenalidomide and dexamethasone (Rd) in relapsed or refractory multiple myeloma (RRMM): Efficacy and safety update (POLLUX).
Authors: Bahlis Nizar J. , Moreau Philippe , Nahi Hareth , Plesner Torben , Goldschmidt Hartmut , Suzuki Kenshi , Orlowski Robert Z. , Rabin Neil , Leiba Merav , Oriol Albert , Chari Ajai , San Miguel Jesus , Richardson Paul G. , Usmani Saad Zafar , O'Rourke Lisa Marie , Wu Kaida , Casneuf Tineke , Chiu Christopher , Qin Xiang , Dimopoulos Meletios A.
Published: September 2018

8025

Background: Daratumumab (D) is a human CD38-targeting mAb that significantly prolongs progression-free survival (PFS) when added to standard-of-care regimens in patients (pts) with RRMM. We examined updated efficacy and safety data from POLLUX (NCT02076009), a randomized phase 3 study of DRd vs Rd in RRMM. Methods: Pts with ≥1 prior line of therapy (LOT) received Rd (25 mg PO lenalidomide on days 1-21 of each q4w cycle; 40 mg dexamethasone weekly) ± D (16 mg/kg IV qw for cycles 1 and 2, q2w for cycles 3-6, then q4w until disease progression). Pts refractory to lenalidomide were ineligible. Minimal residual disease (MRD) was assessed on bone marrow samples at time of suspected complete response (CR) and at 3 and 6 months post-suspected CR at sensitivities of 10–4, 10–5, and 10–6 via next-generation sequencing (Adaptive Biotechnologies, Seattle, WA). Results: Pts received a median (range) of 1 (1-11) prior LOT. 55% received prior IMiDs (18% lenalidomide). Based on previous median follow-up of 17.3 months, DRd significantly prolonged PFS (median: not reached vs 17.5 months; HR, 0.37; 95% CI, 0.28-0.50; P< 0.0001) and significantly improved overall response rate (ORR; 93% vs 76%, P< 0.0001) vs Rd. DRd induced higher rates of deep responses vs Rd (≥very good partial response [VGPR]: 78% vs 45%; ≥CR: 46% vs 20%; all P< 0.0001) and included MRD negativity, which was > 3-fold higher across all 3 sensitivity thresholds for DRd vs Rd (25% vs 6% at the 10–5 threshold). MRD-negative pts demonstrated longer PFS vs MRD-positive pts. Follow up for overall survival (OS) is ongoing (OS events: 40 [14%] in DRd and 56 [20%] in Rd). No new safety signals were identified with longer follow up. Updated efficacy and safety data based on approximately 25-months follow up will be presented at the meeting. Conclusions: DRd provided significant benefits vs Rd in terms of PFS, ORR, and MRD negativity, and the favorable safety profile of DRd was maintained with longer follow up. These data further validate the use of DRd in RRMM pts who received ≥1 prior therapy. Clinical trial information: NCT02076009.
Impact of metformin use in the outcomes of multiple myeloma patients post stem cell transplant.
Authors: Duma Narjust , Vera Aguilera Jesus , Paludo Jonas , Wang Yucai , Anagnostou Theodora , Fonder Amie L. , Buadi Francis , Kumar Shaji , Lacy Martha , Hayman Suzanne R. , Dispenzieri Angela , Gertz Morie A. , Dingli David
Published: September 2018

8034

Background: Multiple myeloma (MM), a monoclonal plasma cell disorder, is one of the most common hematologic malignancies in the US. In preclinical studies, metformin demonstrated plasma cells cytotoxicity. However, there is lack of studies translating the effect of metformin into the clinical setting. Therefore, we assessed the clinical effect of metformin in patients (pts) with MM. Methods: All MM pts who underwent stem cell transplant (SCT) at the Mayo Clinic Rochester from 2007 to 2012 were reviewed. Patients were grouped based on metformin use. Initial diagnosis at our institution and ≥12 months of follow up were required. Kaplan-Meier method and Cox regression were used for time-to-event and multivariate analysis. Results: Out of 687 pts, 78 (11.4%) were using metformin at the time of MM diagnosis. Baseline characteristics in the metformin (Mt) and no-metformin (NMt) groups were similar (Table). Median (M) metformin dose was 2000 mg daily and m duration of metformin use from MM diagnosis was 22 months. Pts on the Mt group achieved higher rates of CR after SCT (41% vs. 29%, p<0.02). Median PFS after SCT was longer in the Mt group, 31.3 months (95% CI: 10.4-52.2) vs. 16.6 months in the NMt group (95%CI: 14.5-18.7) p<0.04. There was a trend towards longer OS in the Mt group, but it was not statistically significant (170 vs. 106 months, p<0.10). In a multivariate analysis of metformin use, age, ISS, LDH, and cytogenetics/FISH, the former was an independent predictor of PFS after SCT (OR: 0.38, 95%CI: 0.20-0.68, p<0.001). Conclusions: Metformin use was associated with a better PFS and higher CR after SCT in our MM cohort. A trend towards better OS was also noted in the Mt group. Larger studies are needed to enhance our understanding of the clinic effect of metformin on MM. [Table: see text]
Impact of post-autologous stem cell transplant (ASCT) maintenance therapy on outcomes in patients (Pts) with newly diagnosed multiple myeloma (NDMM) using the large prospective community-based Connect MM registry.
Authors: Jagannath Sundar , Abonour Rafat , Durie Brian G. , Shah Jatin J. , Narang Mohit , Terebelo Howard R. , Gasparetto Cristina , Toomey Kathleen , Hardin James W. , Wagner Lynne I. , Agarwal Amit , Srinivasan Shankar , Kitali Amani , Zafar Faiza , Sturniolo Michael , Rifkin Robert M.
Published: September 2018

8040

Background: Maintenance therapy (MT) improved progression-free survival (PFS) and overall survival (OS) in MM clinical trials. The observational Connect MM registry, which is largely community based, was used to assess impact of MT on outcomes in ASCT-eligible NDMM pts. Methods: Adult NDMM pts ≤60 days from diagnosis were eligible for enrollment. Pts receiving induction and ASCT were included and analyzed by 4 MT regimens: No MT, lenalidomide-based (LEN), bortezomib-based (BORT), and LEN+BORT MT. Duration was from 100 days post-ASCT (no MT group) or start of MT until progressive disease, death, discontinuation, or data cutoff. End points were PFS, 2nd PFS, OS, and safety. An exploratory analysis of the impact of baseline characteristics was performed. Results: Of 1493 enrolled pts (Cohort 1; Sep 2009 – Dec 2011), 1450 were treated; 81% (n=1173) were in a community setting. A total of 432 (29%) met analysis criteria. Data cutoff was Jan 7, 2016 (median follow-up of 39.3 mo). Median age was 60 y (range, 24-78 y); 60%, men; and 86%, white. 165 pts did not receive MT. Of 267 pts receiving MT, 213 (80%) received LEN; 30 (11%), BORT; and 16 (6%), LEN+BORT. Only LEN MT is presented, as interpretation of other MT data was limited by small sample sizes. Median treatment duration for LEN MT vs No MT was 35.2 vs 26.1 mo, respectively. PFS and OS significantly increased with LEN MT vs No MT (Table); 2nd PFS was similar for both. Exploratory analyses showed generally similar PFS and OS improvements across subgroups (age, ECOG status, ISS stage, risk group, and induction regimen). No new safety signals were observed. Conclusions: In ASCT-eligible NDMM pts, PFS and OS improved with LEN MT vs No MT and appeared to be independent of induction regimen. Preliminary analysis of 2nd PFS suggests no impact on the efficacy of 2nd line therapy. These data from a largely community-based setting confirm results from randomized phase III trials. Clinical trial information: NCT01081028. [Table: see text]
Outcomes of secondary cancers among myeloma survivors.
Authors: Castillo Jorge J. , Olszewski Adam J.
Published: September 2018

8043

Background: With increasing survival, myeloma patients (pts) experience second cancers. We analyzed receipt of surgery and cancer-specific survival (CSS) among myeloma survivors with common solid tumors, in comparison with pts without myeloma. Methods: We extracted Surveillance, Epidemiology, and End Results (SEER) data on pts diagnosed with common cancers in 2004-2013. Among them, we identified myeloma survivors, and we matched each to 50 randomly sampled controls with the same cancer by age, sex, race, and year of diagnosis. We then compared CSS, cumulative incidence function (CIF) for death from the index cancer (but not from myeloma), and receipt of surgery (for non-metastastic, stage-matched tumors only) using a Cox (for hazard ratio, HR), Fine-Gray (for subhazard ratio, SHR), and conditional logistic models, respectively. Results: Myeloma survivors were significantly older ( P<.001), and more often black (except in bladder cancer) than pts with respective cancers from the general population. In the case-control analysis, breast ( P=.002) and lung cancers ( P=.003) were more often diagnosed at an early stage among myeloma survivors. Receipt of surgery did not significantly differ, except for lower use of prostatectomy in myeloma survivors (odds ratio, 0.59, 95%CI, 0.44-0.81). CSS significantly differed only in lung cancer, and was better among myeloma survivors even when stratified by stage. CIF of cancer death was significantly lower for myeloma cases with lung and colorectal cancer. Conclusions: Despite additional competing mortality from recurrent myeloma, myeloma survivors have similar CSS and CIF of death after common cancers compared with other pts. This highlights the need to treat them similarly to other pts, without assuming a poor prognosis. Better outcomes in lung cancer are not fully explained by earlier detection, suggesting a biological difference. [Table: see text]
AFM26 is a novel, highly potent BCMA/CD16A-directed bispecific antibody for high affinity NK-cell engagement in multiple myeloma.
Authors: Gantke Thorsten , Reusch Uwe , Kellner Christian , Ellwanger Kristina , Fucek Ivica , Weichel Michael , Kerber Anne , Peipp Matthias , Treder Martin
Published: September 2018

8045

Background: Despite recent advances in the treatment of multiple myeloma (MM), novel therapies are needed to achieve long-lasting remissions in a greater number of patients. Natural killer (NK) cells play a key role in the immune response to MM and have been implicated in the clinical efficacy of current standard of care interventions, including IMiDs, proteasome inhibitors, recently approved immunotherapies and autologous stem cell transplantation (ASCT). Numerous strategies are being developed to enhance the natural NK-cell cytotoxicity against myeloma cells, which is frequently dysregulated in MM. Approaches include modulation of activity, through cytokine stimulation or immune checkpoint targeting, and adoptive transfer of culture expanded NK-cells in ASCT-eligible MM. While highly attractive, these approaches are non-targeted, as they rely on the natural cytotoxicity of NK-cells, and may benefit from antigen-specific retargeting and effector activation. AFM26 is a novel tetravalent, bispecific antibody designed to specifically enhance NK-cell anti-MM activity by redirecting NK-cell lysis to BCMA, an antigen expressed on MM cells. Methods: NK-cell engagement and cytotoxicity of AFM26 towards MM cell lines and freshly isolated tumor cells from MM patients was characterized in vitro and compared with classical antibody formats. Results: AFM26 engages NK-cells with superior avidity ( KD: 1-2nM) through bivalent interaction with CD16A (FcγRIIIa) and demonstrates extended cell surface retention that is not affected by high level IgG, as is particularly relevant in MM. Importantly, AFM26 does not induce NK-cell depletion but selectively induces potent and efficacious lysis of MM cells in vitro. Conclusions: In summary, AFM26 is a promising candidate to enhance NK-cell activity and confer tumor-specificity to NK-cells in MM. Differentiation of AFM26 from classical antibody formats and its potential for combination with cellular NK-cell therapies is highlighted.
Risk stratification by detection of clonal circulating plasma cells (CPCs) by multi-parametric flow cytometry (MFC) in light chain amyloidosis (AL).
Authors: Sidana Surbhi , Tandon Nidhi , Dispenzieri Angela , Gertz Morie A. , Buadi Francis , Lacy Martha , Dingli David , Fonder Amie L. , Hayman Suzanne R. , Hobbs Miriam A. , Hwa Yi Lisa , Kapoor Prashant , Kyle Robert A. , Leung Nelson , Go Ronald S. , Lust John Anthony , Russell Stephen J. , Rajkumar S. Vincent , Kumar Shaji , Gonsalves Wilson I.
Published: September 2018

8047

Background: Presence of CPCs by six color MFC is associated with worse outcomes in multiple myeloma (MM). Using a slide based immunofluorescence assay, CPCs are associated with worse prognosis in AL, but outcomes with MFC are not known. Methods: We retrospectively analyzed 154 patients (pts) from Jan 2008 – Dec 2015 with AL who had CPCs analyzed by MFC at diagnosis. Results: CPCs were present in 42% pts (n = 64, median = 88 per 150,000 events, range 6-17844). Table 1 lists baseline characteristics, treatment and response. In univariate analysis, bone marrow (BM) plasma cells > 15% (p<0.0001), dFLC > 60 mg/dL (p=0.02) and presence of active MM (p=0.0004) were associated with detectable CPCs. In multivariate (MV) model, only BM plasma cells > 15% predicted for presence of CPCs (p=0.02). There was no difference in hematologic or organ response in the 2 groups. Median follow up was 43 months (m). Pts with detectable CPCs had worse survival than those without detectable CPCs (90 m vs. 98 m, p=0.0004). In MV analysis model with Mayo Stage and detectable CPCs, presence of CPCs at diagnosis was independently associated with poor survival (CPCs p= 0.02, Mayo Stage p < 0.0001). Conclusions: Presence of detectable CPCs is an independent adverse prognostic factor for survival in AL. Comparatively fewer pts with detectable CPCs underwent early ASCT, which may reflect a more aggressive disease presentation. [Table: see text]
Outcomes according to involved free light chain (FLC) levels in patients with normal FLC ratio after initial therapy in light chain amyloidosis (AL).
Authors: Tandon Nidhi , Sidana Surbhi , Dispenzieri Angela , Gertz Morie A. , Lacy Martha , Dingli David , Buadi Francis , Fonder Amie L. , Hayman Suzanne R. , Hwa Yi Lisa , Hobbs Miriam A. , Kapoor Prashant , Gonsalves Wilson I. , Leung Nelson , Go Ronald S. , Lust John Anthony , Russell Stephen J. , Kyle Robert A. , Rajkumar S.Vincent , Kumar Shaji
Published: September 2018

8049

Background: Complete response in AL is defined as normal FLC ratio with negative serum and urine immunofixation. It is not clear if high involved serum FLC (hIFLC) in a patient with normal ratio may contribute to ongoing amyloid formation and hence affect outcomes. Methods: Data of 1308 patients (pts) with systemic AL seen within 90 days of diagnosis, at Mayo Clinic between 2006-2015, was analyzed retrospectively. Among these, 369 pts had 2 consecutive normal FLC ratio values after 1st line treatment and form the study population. Log rank test was used to estimate survival differences. Results: Among these 369 pts, pts with hIFLC at 1streading of normal FLC ratio (hIFLC1; n=170; 46.1%) were compared to those who did not (n=199; 53.9%). At diagnosis, the median age [61.5 vs 60.8 years (y); p=0.2], proportion of males (62.4 vs 58.3%; p=0.4), percentage of pts with renal involvement (73.5 vs 64.8%; p=0.07), in mayo stage I / II / III / IV (32.9% / 23%/ 27.3% / 16.8% vs 43.6 %/ 22.9% / 18.1% / 15.4%; p=0.1), with bone marrow plasma cells >10% (24.2 vs 30%; p=0.2) and with presence of t(11; 14)(48.4 vs 60; p=0.08) was similar, while cardiac (67.5 vs 53.3%; p=0.006) and hepatic (18.2 vs 9.1%; p=0.01) involvement was higher in hIFLC1 group. The median follow-up from diagnosis was 6.1 y (95% CI; 5.6, 6.8). The median progression free survival (PFS) in pts who had hIFLC1 was lower than for those who did not; 2.6 y (95% CI; 1.9, 4.5) vs 5.2 y (95% CI; 4.6, 6.4), p<0.0001, as was the median overall survival [OS; 6.7 y (95% CI; 4.5, 8.3) vs not reached (NR), p<0.0001]. We performed a more stringent comparison for pts with 2 consecutive hIFLC values (hIFLC2; n=112; 30.4%) versus not (n=257; 69.6%). The median PFS (3.2 y; 95%CI; 2.2, 4.5 vs 5.6 y; 95% CI; 4.7, 7.1; p<0.0001) and OS (7.8 y; 95% CI; 6.4, NR vs NR; 95%CI; 9.5, NR; p<0.0001) were significantly reduced in pts with hIFLC2 versus not as well. A multivariate analysis confirmed an impact of hIFLC1 and hIFLC2 on PFS/OS independent of serum creatinine. Conclusions: In pts with systemic AL, persistent elevation of the involved FLC predicts for poor prognosis (independent of serum creatinine) even among those who achieved normal FLC ratio after 1st line treatment.
Ado-trastuzumab emtansine in patients with HER2 mutant lung cancers: Results from a phase II basket trial.
Authors: Li Bob T. , Shen Ronglai , Buonocore Darren , Olah Zachary T. , Ni Ai , Ginsberg Michelle S. , Ulaner Gary , Weber Wolfgang , Ladanyi Marc , Won Helen H. , Riely Gregory J. , Solit David B. , Hyman David Michael , Rudin Charles M. , Berger Michael F. , Scaltriti Maurizio , Baselga Jose , Kris Mark G. , Arcila Maria E.
Published: September 2018

8510

Background: Human epidermal growth factor receptor 2 ( HER2, ERBB2) mutations occur in 2% of lung cancers, resulting in receptor dimerization and kinase activation with in vitro sensitivity to trastuzumab. Ado-trastuzumab emtansine is a HER2 targeted antibody drug conjugate linking trastuzumab with the anti-microtubule agent emtansine. Methods: Patients (pts) with HER2 mutant lung cancers were enrolled into a cohort of the basket trial of ado-trastuzumab emtansine in HER2amplified or mutant cancers, treated at 3.6mg/kg IV every 3 weeks. The primary endpoint was overall response rate (ORR) using RECIST v1.1. A Simon two stage optimal design was used with type I error rate under 2.7% (and a family wise error rate across baskets under 10%), power of 89%, H0 10%, H1 40%; the H0 will be rejected if 5 or more responses are observed in 18 pts. Other endpoints include duration of response (DOR), progression-free survival (PFS) and toxicity. HER2 testing was performed on tumor tissue by next generation sequencing (NGS), fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). Results: The cohort completed accrual with 18 pts treated. The median age was 63 (range 47-74 years), 72% were female, 39% were never smokers and all had adenocarcinomas. The median lines of prior systemic therapy was 2 (range 0-4). ORR was 33% (5/15 confirmed, 95% CI 12-62%) not including a partial response awaiting confirmation and 3 pts pending response evaluation. Median DOR was not reached (range 3 to 7+ mo), median PFS was 4mo (95% CI 3mo-not reached). Toxicities were mainly grade 1 or 2 including infusion reaction, thrombocytopenia and transaminitis, there were no dose reductions or treatment related deaths. There were 10 (56%) exon 20 insertions and 8 (44%) point mutations; responders were seen across mutation subtypes (A775_G776insYVMA, G776delinsVC, V659E, S310F). HER2amplification was negative for all pts by NGS and positive for 1 of 12 pts by FISH. There was no IHC3+ in 10 pts tested. Conclusions: Ado-trastuzumab emtansine is active and well tolerated in pts with HER2 mutant lung cancers. This study has met its primary endpoint. Further development in a multicenter study is warranted. Clinical trial information: NCT02675829.
Prevalence and clinical correlation of programmed cell death 1 ligand (PD-L1) expression in patients with resected non-small cell lung cancer (NSCLC): Results from the European Thoracic Oncology Platform (ETOP) Lungscape cohort.
Authors: Kerr Keith , Thunnissen Erik , Dafni Urania , Soltermann Alex , Finn Stephen P. , Bubendorf Lukas , Verbeken Eric , Biernat Wojciech , Warth Arne , Marchetti Antonio , Speel Ernst-Jan M. , Pokharel Saraswati , Quinn Anne Marie , Monkhorst Kim , Navarro Atilio , Madsen Line Bille , Polydoropoulou Varvara , Kammler Rosita , Peters Solange , Stahel Rolf A. ,   ETOP Lungscape Consortium
Published: September 2018

8516

Background: Conflicting data exists on the potential prognostic impact of PD-L1 expression in NSCLC. The Lungscape project, a fully annotated large biobank of resected stage I-III NSCLC, allows detailed analysis of this issue. Methods: Prevalence of PD-L1 positivity and its association with clinicopathological characteristics and patient outcome - Relapse-free Survival (RFS), Time-to-Relapse (TTR) and Overall Survival (OS) - was explored in the ETOP Lungscape cohort. PD-L1 expression was assessed on tissue microarrays (TMAs) using the DAKO 28-8 immunohistochemistry assay. Positivity cut-off points of ≥1%, 5% and 50% for neoplastic cell membrane staining were considered. Results: PD-L1 data were available for 2182 patients, from 15 ETOP centers, with median follow-up 4.8 years; 1191 patients still alive; median age 66 years; 64% male, 32/54/11% for current/former/never smokers; 49/29/22% for stages I/II/III; 51/42/4/3% adenocarcinomas (AC)/squamous cell (SCC) /large cell and sarcomatoid (LCS)/other. Median RFS/TTR/OS were 53/99/69 months (AC: 52/84/72, SCC: 54/not reached/64; and LSC 52/103/74). PD-L1 prevalence with 1% cut-off was, overall: 43%, 95% confidence interval (95%CI): 41-46; (AC: 42%, 95%CI: 39-46; SCC: 44%, 95%CI: 40-47; and LCS: 53%, 95%CI: 42-65), while for 5% threshold, prevalence was 34%, 95%CI: 32-36. PD-L1 1% positivity was a significant predictor only for AC: HRRFS: + vs - = 0.82; 95%CI: 0.69-0.97, HRTTR: + vs - = 0.83; 95%CI: 0.68-1.01, HROS: + vs -= 0.83; 95%CI: 0.69-1.01 (adjusted p = 0.024, 0.064, 0.063 respectively). This effect is found also for the 5% cut-off, and preserved in the overall model including all histologies. Using the 50% cut-off, PD-L1 positivity was detected in 17% of patients; 95%CI: 15-18, but was no longer a significant predictor of outcome, overall and by histology type. Conclusions: PD-L1 positivity (1% and 5% cut-offs) was present in more than one third of resected NSCLC and was associated with a better prognosis for AC patients.
Temporal trend in the use of surgery in the management of stage IIIa non-small cell lung cancer (NSCLC) between 2000-2013: A SEER analysis.
Authors: Iyer Veena , Hakim Hosam , Bagchi Arindam , Nai Qiang , Hamouda Danae , Barnett William , Skeel Roland T.
Published: September 2018

8524

Background: The optimal treatment of patients with Stage IIIA NSCLC, a heterogeneous group comprised of T1-T4, N0-N2 disease, is controversial. Lack of clear data and guidelines allows several options for treatment, and hence there has been significant variability in clinical practice. The purpose of this study was to evaluate the nationwide trends in rates of surgery for Stage IIIA lung cancer diagnosed between 2000-2013. Methods: The study included patients with Stage IIIA NSCLC, 18 years and older diagnosed between 2000 and 2013. We used Z-tests in SEER*Stat to compare relative survival rates for patients diagnosed between 2000-2010. Results: Among the 27,697 patients with Stage IIIA NSCLC, 45% were females and median age was 67. 35% were treated with surgery. Multivariate analysis demonstrated that year of diagnosis, race, marital status, geographic region, tumor size, tumor grade, nodal status all were significantly associated with the use of surgery. Relative survival at 24 months (RS24) was 62% for patients who had surgery and 29% for patients without surgery (z = -47.3). The proportion of patients receiving surgery decreased from 55.6% in 2000 to 32.6% in 2010 and 29.7 in 2013 (p < 0.0001) while the relative survival at 24 months (RS24) from 2000 to 2010 rose from 34.7% to 43.2% (z = -4.89). The RS24 for patients who received surgery rose from 55.3% in 2000 to 77.6 % in 2010 (z = -3.58). Change in RS24 for patients who did not have surgery also improved from 19.6% to 31.2%. The median RS of the surgical cohort changed from 28 m to 44 m. Conclusions: Based upon reporting within the SEER database, the proportion of stage IIIA NSCLC patients undergoing surgery has decreased over the study time period. However, the relative survival rates have improved significantly for both the overall group and those having surgery, suggesting that significant strides have been made both in selecting the group of patients who would benefit from surgical resection and in the overall management of this group of patients.
Survival benefit of systemic chemotherapy given as adjuvant (ACT) after thoracic surgery for N0-1 non-small cell lung cancer (NSCLC) patients (pts) with synchronous brain metastasis (SBM).
Authors: Shin Sarah , Yendamuri Saikrishna S. , Groman Adrienne , Dy Grace K.
Published: September 2018

8525

Background: Pts with solitary SBM and otherwise early-stage NSCLC demonstrate prolonged survival with surgical resection of both primary and metastatic disease. The role of “ACT” after thoracic surgery in this circumstance is not well-defined. We seek to determine the effect on overall survival(OS) of ACT after resection of primary tumor in pts with surgically resectable primary NSCLC and SBM. Methods: The National Cancer Database (NCDB) was queried to identify pts who underwent resection of NSCLC as the primary cancer (without other malignancies) from years 2010-2014 (n = 90,518). We then focused on pts who also were diagnosed with SBM (n = 807). Only patients with pathologically confirmed N stage 0 (n = 419) or 1 (n = 101) status were included in the final analysis. Patients who received platinum-based ACT within 3 months after surgery were considered to have received ACT. Associations between treatment groups were analyzed using the Chi-square test for categorical variables and Wilcoxon Rank Sum test for continuous variables. Univariate and multivariate proportional hazards modeling results were used to assess the effect of treatment and the confounding variables on OS. Relative prognosis was summarized using estimates and 95% confidence interval(CI) for the hazard ratio (HR). Unadjusted differences in OS between the treatments are shown using Kaplan-Meier methods. All analyses were performed using SAS version 9.4. Results: There is no imbalance in terms of gender, race, income, nodal status, histology between groups. Non-ACT pts were older (n = 181, median 64 vs 58 years in ACT group, p < 0.001). Age, nodal status, ACT, and histology were associated with OS in both univariate and multivariate analysis, with OS HR 0.51 (95% CI 0.39-0.66) in favor of ACT (n = 339). One- and 5-year survival in ACT group versus non-ACT group was 83% (95% CI 78%-87%) and 33% (25%-40%), versus 57%(95% CI 48%-65%) and 18% (95% CI 11%-26%), respectively. Conclusions: ACT after thoracic surgery for N0-1 NSCLC with SBM is associated with improved OS in this analysis.
Early experience with IBM Watson for Oncology (WFO) cognitive computing system for lung and colorectal cancer treatment.
Authors: Somashekhar S.P. , Sepúlveda Martín-J. , Norden Andrew D , Rauthan Amit , Arun Kumar , Patil Poonam , Ethadka Ramya Y , Kumar Rohit C
Published: September 2018

8527

Background: IBM Watson for Oncology is an artificial intelligence cognitive computing system that provides confidence-ranked, evidence-based treatment recommendations for cancer. In the present study, we examine the level of agreement for lung and colorectal cancer therapy between the multidisciplinary tumour board from Manipal Comprehensive Cancer Centre in Bangalore, India, and Watson for Oncology. Methods: Watson for Oncology is a Memorial Sloan Kettering Cancer Center (New York, USA) trained cognitive computing system that uses natural language processing and machine learning to provide treatment recommendations. It processes structured and unstructured data from medical literature, treatment guidelines, medical records, imaging, lab and pathology reports, and the expertise of Memorial Sloan Kettering experts to formulate therapeutic recommendations. Treatment recommendations are provided in three categories: recommended, for consideration and not recommended. In this report we provide the results of the independent and blinded evaluation by the multidisciplinary tumour board and Watson for Oncology of 362 total cancer cases comprised of 112 lung, 126 colon and 124 rectal cancers seen at the Centre within the last three years. The recommendations of the two agents were compared for agreement and considered concordant when the tumour board recommendation was included in the recommended or for consideration categories of the treatment advisor. Results: Overall, treatment recommendations were concordant in 96.4% of lung, 81.0% of colon and 92.7% of rectal cancer cases. By tumour stage, treatment recommendations were concordant in 88.9% of localized and 97.9% of metastatic lung cancer, 85.5% of localized and 76.6% of metastatic colon cancer, and 96.8% of localized and 80.6% of metastatic rectal cancer. Conclusions: Treatment recommendations made by the Manipal multidisciplinary tumour board and Watson for Oncology were highly concordant in the cancers examined. This cognitive computing technology holds much promise in helping oncologists make information intensive, evidence based treatment decisions.
Comprehensive molecular and immune profiling of non-small cell lung cancer and matched distant metastases to suggest distinct molecular mechanisms underlying metastasis.
Authors: Lee Won-Chul , Gomez Daniel Richard , Zhang Jianhua , Jalali Ali , Roh Whijae , Reuben Alexandre , Lu Wei , Chow Chi-Wan , Wu Chia Chin , Fujimoto Junya , Antonoff Mara , Moran Cesar , Sulman Erik P. , Rao Ganesh , Swisher Stephen , Heymach John , Wistuba Ignacio Ivan , Futreal Andrew , Zhang Jianjun ,   Oligomets Study Team
Published: September 2018

8541

Background: Despite complete resection, many non-small cell lung cancer (NSCLC) patients still develop and succumb to distant metastases. Previous studies suggested distant metastasis may be due to genomic evolution and/or suppressed immune surveillance. However, the relationship between specific genomic alterations and immune surveillance has not been systemically studied. Methods: We performed whole exome sequencing, RNA-Seq, methylation microarray, immunohistochemistry using multiple immune markers, and T cell receptor sequencing on 7 pairs of NSCLC primary tumors and matched metastases including 6 metachronous brain and 1 synchronous liver metastases. Results: On average, 84% of all somatic mutations (54% to 97%) and all 28 canonical cancer gene mutations were shared between primary tumors and paired distant metastases. Metastases also resembled paired primary tumors closely in regard to somatic copy number aberration profiles, methylation profiles. Subclonal analysis showed almost identical clonal architectures in 4 of 7 pairs of primary tumor and metastasis comparable to the similarity observed between different regions within the same tumors. The other 3 pairs, however, displayed clear evidence of clonal evolution. We validated these findings in a published dataset consisting of 38 pairs of primary NSCLC tumors and matched distant metastases. The RNA-Seq data showed that 25 of the top 35 significantly down-regulated signaling pathways in metastases relative to primary tumors were related to immune activation, which was validated in an independent cohort of 41 primary NSCLC tumors and distant metastases using NanoString’s PanCancer Immune Profiling Panel. Conclusions: Our data suggest that molecular mechanisms underlying postsurgical distant metastasis may be variable among NSCLC patients. While genomic evolution may play a role in development of metastasis in some patients, distant metastasis may be early event during carcinogenesis without further genomic evolution in a substantial proportion of NSCLC patients. Furthermore, immune suppression may be a characteristic of cancer cells of metastatic capacity.
Detailed pathologic evaluation of low dose CT (LDCT) detected stage I/0 lung adenocarcinomas (ADCA).
Authors: Burks Eric , Sands Jacob , Sullivan Travis B. , Rieger-Christ Kimberly M.
Published: September 2018

8543

Background: Although LDCT lung screening improves survival, some worry that indolent BAC-like ADCA may be over-detected/treated. Comprehensive histologic subtyping has recently been adopted to improve grading and thus risk stratification in lung ADCA. We report a detailed pathologic comparison of stage I/0 lung ADCAs detected by LDCT screening vs. incidentally discovered ADCAs stratified by NCCN risk criteria. Methods: We performed comprehensive histologic subtyping on 35 consecutive stage I/0 LDCT screen detected ADCAs in patients meeting NCCN group 1/2 high risk (HR) criteria and compared to incidentally detected stage I/0 ADCAs meeting HR (n = 41) or low-risk (LR, n = 28) criteria. Results: Screen detected and incidentally detected ADCAs from HR groups show an equally low-rate of indolent, non-invasive/minimally invasive ADCAs (9%) compared to LR patients (36%). Aggressive solid predominant ADCAs were equally more frequent in HR patients from screen and incidentally detected patients (19%) compared to LR patients (6%). The rate of angiolymphatic invasion (59%) and air space invasion (32-34%) were similarly elevated in HR screen and incidental patients compared to LR patients (39% & 17% respectively). A collection of lepidic predominant (BAC-like) ADCAs associated with aggressive non-predominant cribriform and/or solid patterns, elevated mitotic rates, and high proportion of lymphatic invasion were uniquely observed in the screen-detected group (12%). Subgroup analysis of screen detected NCCN group 1 vs. 2 shows group 2 tumors exhibit histologic features which are at least as aggressive as group 1 tumors, albeit at smaller invasive sizes (1.2 cm vs. 1.5 cm) and lower stage (IA 75% vs. 61%). Conclusions: This is the first detailed pathologic comparison of LDCT screen detected vs incidentally discovered stage I/0 ADCA. Tumors from HR patients are pathologically more aggressive than LR tumors. Not all BAC-like tumors in LDCT screen detected patients should be presumed indolent given that approximately half of these bear histologic features of aggressive ADCAs while still in a lepidic predominant phase. NCCN group 2 tumors are similar to group 1 and should be further studied.
Phase Ib study of tepotinib in EGFR-mutant/c-Met-positive NSCLC: Final data and long-term responders.
Authors: Wu Yi-Long , Soo Ross A. , Kim Dong-Wan , Yang James Chih-Hsin , Scheele Jürgen , Chen Wenfeng , Becker Andreas , Park Keunchil
Published: September 2018

8547

Background: Patients (pts) with NSCLC that is initially responsive to EGFR tyrosine kinase inhibitors (EGFR TKI) typically develop resistance, often associated with aberrant c-Met activity. Dual inhibition of EGFR and c-Met is therefore a rational option to treat c-Met+ EGFR TKI-resistant NSCLC. Tepotinib is a highly selective c-Met inhibitor with good tolerability and promising activity against solid tumors. We report final data from a phase Ib trial of tepotinib + gefitinib in pts with c-Met+/EGFR-mutant NSCLC conducted in Asia. Methods: Eligible pts were adults with locally advanced/metastatic NSCLC and ECOG PS 0–1. Tumors had to express EGFR with an activating mutation be resistant to EGFR TKI therapy and be c-Met+ by IHC. Pts received tepotinib 300 or 500 mg QD combined with gefitinib 250 mg QD (T300G250 or T500G250). The primary objective was to determine the recommended phase II dose (RP2D) of tepotinib in combination with gefitinib; secondary objectives included pharmacokinetics (PK), safety, and antitumor activity. Results: 18 pts were enrolled (median age 65 [41–78]; 8 male); 6 received T300G250, 12 T500G250. No dose-limiting toxicities were observed, and tepotinib 500 mg QD was confirmed as the RP2D. 17 pts experienced treatment-related treatment-emergent adverse events (TRTEAEs), mostly grade ≤2 and most commonly diarrhea (12), rash (8), and amylase increase (6). Grade ≥3 TRTEAEs were increased amylase (n = 4), increased lipase (3), neutropenia (1), and hyperglycemia (1). The best overall response was partial response in 6 pts; 4/7 pts with IHC 3+ tumors responded (all treated with T500G250) vs 2/11 with IHC 2+ tumors. Response durations of pts with PR were 4.2–12.5 months. 4/18 pts (IHC 2+, n = 3) had stable disease. 8 pts experienced progression free survival > 5 months, 3 pts > 10 months. PK were as expected from previous studies. Conclusions: Tepotinib in combination with gefitinib was well tolerated. The RP2D of tepotinib for use in combination with gefitinib in NSCLC is 500 mg QD. T500G250 showed signs of activity against c-Met+ tumors. A phase II trial is randomizing ≈156 pts with c-Met+/T790M– tumors who have failed first-line EFGR TKI 2:1 to tepotinib + gefitinib or pemetrexed + cisplatin/carboplatin. Clinical trial information: NCT02864992.
Patterns of metastases in malignant pleural mesothelioma in the modern era: Redefining the spread of an old disease.
Authors: Collins Dearbhaile Catherine , Constantinidou Anastasia , Sundar Raghav , Chenard-Poirier Maxime , Yap Timothy Anthony , Banerji Udai , De Bono Johann S. , Lopez Juanita Suzanne , Tunariu Nina
Published: September 2018

8556

Background: Malignant pleural mesothelioma (MPM) has been historically documented as a locally infiltrative disease in large series from the early 1980s. With the changing landscape of cancer diagnosis and treatment, increased areas of unusual metastases have been published as case reports. With no standard second-line therapies for MPM, referral to early phase trial units is common. We report the metastatic patterns of a large cohort of MPM patients treated at the Royal Marsden Drug Development Unit (DDU). Methods: Clinical data was gathered for MPM patients referred to the DDU from 1992 to 2016. Radiographic details were collected from CT, bone scan and FDG PET imaging. Prior treatment, response, somatic mutations, clinical trial and survival data was obtained from medical records. Results: From the database, 165 evaluable patients with MPM were identified. Median age at diagnosis was 64 years (range 37–90) and 76% were male. Epithelioid MPM comprised 81% and 65% were right sided. Bone metastases were reported in 20%, with the majority lytic in nature ( Table). Peritoneal and omental disease was evident in 24% with ascites in 16%. In 11% of cases lung metastases presented as diffuse miliary-type pattern. Visceral metastases (15%) were predominantly liver (78%), but also occurred in adrenals, spleen and kidneys. Symptomatic brain metastases were recorded in 3%. Median overall survival was 24.2 months (95% CI: 20.8 - 29.2). Conclusions: This large study documents the metastatic patterns of advanced MPM in the 21st century and highlights an increased frequency of traditionally unexpected sites of metastases. Higher than expected incidence of lytic bone metastases (20%) suggests consideration of bone imaging in advanced MPM clinical workflow and trial protocols. [Table: see text]
Biomarkers of pembrolizumab (P) activity in mesothelioma (MM): Results from a phase II trial.
Authors: Kindler Hedy L. , Karrison Theodore G. , Rose Buerkley , Tan Y-H Carol , Khattri Arun , Acharya Rajesh , Straus Christopher M. , Seiwert Tanguy Y.
Published: September 2018

8557

Background: PD-L1 expression and the Interferon-Gamma gene expression profile (IFN-G GEP) are predictive of response to checkpoint blockade in several solid tumors. Relevant biomarkers in mm pts treated with these agents have not been determined; these were evaluated in a phase 2 trial of P in mm (NCT02399371). Methods: Eligible pts had histologically confirmed MM, PS 0-1, disease progression on 1-2 prior regimens. P 200 mg was given Q21 days. Part A (N = 35) determined the response rate (RR) of P in PD-L1 unselected mm pts and assessed an optimal PD-L1 threshold (22C3 IHC assay). If ≥3 responses, the study proceeded to Part B (N = 30), using a biomarker enrichment strategy if a threshold was found. Nanostring nCounter was used to assess IFN-G GEP (6 gene). Results: 35 pts enrolled in Part A 5/15-2/16; 1 withdrew. Median age 66 (range 26-85); PS 0: 62%; male: 82%; epithelial/sarcomatoid/biphasic/NOS: 74%/21%/3%/3%; pleural/peritoneal: 85%/15%; 2nd-line: 59%. Partial response (PR): 7 (21%), stable disease (SD): 20 (59%). Median response duration: not reached. Median progression-free survival (PFS): 6.2 months (95% CI: 3.2, 8.2). Median overall survival: 11.9 months (95% CI: 6.4, --). Toxicity ≥ grade 3: adrenal insufficiency, fatigue, pneumonitis 6%; colitis, confusion, hepatitis, hyponatremia, neutropenia, rash 3%. PD-L1 expression by tumor proportion score (N = 32): none (53%); 1-49%: (22%); ≥50%: (25%). PD-L1 IHC (ROC area 0.63; 95% CI: 0.37, 0.89), CD274 mRNA expression, and IFN-G GEP did not correlate statistically with response. Responses occurred in GEP low, non-inflamed tumors, and in PD-L1- tumors. RR was numerically higher in PD-L1+ (27%) than in PD-L1- pts (12%); there was a trend towards longer PFS and OS in PD-L1+ pts. Conclusions: P has clinically meaningful single-agent activity in PD-L1 unselected, previously treated mm pts, achieving a 21% RR and a disease control rate of 80%. Biomarkers established in other cancers, such as PD-L1 IHC and IFN-G GEP, may not be as useful in MM. Novel biomarkers including MM-specific gene signatures may be necessary and are being evaluated. Part B of the study is ongoing with no PD-L1 pre-selection (19/30 pts enrolled), and will be used as a biomarker validation cohort. Funded by a MARF grant. Clinical trial information: NCT02399371.