bluuebunny/crossref_metadata_2025 huggingface dataset:
Frontline hyper-CVAD plus ponatinib for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: Updated results of a phase II study.
Authors: Short Nicholas James , Kantarjian Hagop M. , Ravandi Farhad , Daver Naval Guastad , Pemmaraju Naveen , Thomas Deborah A. , Yilmaz Musa , Kadia Tapan M. , Sasaki Koji , Garris Rebecca , Garcia-Manero Guillermo , Dinardo Courtney Denton , Konopleva Marina , Estrov Zeev , Jain Nitin , Wierda William G. , Jeanis Vicky , Cortes Jorge E. , O'Brien Susan Mary , Jabbour Elias
Published: September 2018

7013

Background: The combination of chemotherapy plus a TKI is highly effective in Ph+ ALL. In this phase II study, we evaluated the safety and efficacy of HCVAD in combination with the third-generation pan- BCR-ABL inhibitor, ponatinib. Methods: Patients (pts) with newly diagnosed Ph+ ALL received 8 cycles of HCVAD alternating with high dose MTX/Ara-C every 21 days. Ponatinib was given at 45 mg daily for the first 14 days of cycle 1. Initially ponatinib 45 mg daily was given indefinitely beginning at cycle 2. Due to concern for vascular events, a protocol amendment was made in which, beginning in cycle 2, pts in CR received 30mg daily and pts in CMR received 15mg daily. Rituximab and IT chemotherapy were given with the first 4 courses. After 8 cycles of HCVAD, pts in CR received maintenance with ponatinib, vincristine and prednisone for 2 years followed by indefinite ponatinib. Results: 64 pts have been treated, 10 of whom had received prior treatment with another regimen (8 in CR, 2 not in CR). Median age was 48 years (range, 21-80) and median follow-up was 33 months (range, 2-62). Median cycles received was 6 (range, 2-8). 63 pts (98%) achieved CR after 1 cycle; 1 pt achieved CRp. CCyR was achieved in 98%, MMR in 97% and CMR in 77%. Median time to CMR was 10 weeks (range, 2-96). Median times to platelet and ANC recovery in cycle 1 were 22 and 18 days, respectively, and for subsequent cycles were 22 and 16 days, respectively. Grade ≥3 pancreatitis was observed in 12 pts (19%), thrombotic events in 4 (6%) and MI in 3 (5%). 8 pts have died, with 2 deaths attributed to ponatinib (both from MI). No grade ≥3 vascular events occurred after the protocol amendment. 38 pts continue to receive treatment (7 in consolidation, 14 in maintenance and 17 post-maintenance). 10 pts (16%) underwent allogeneic SCT in CR1. 7 pts have relapsed, 3 of whom were still receiving ponatinib. The 3-year continued remission and OS rates were 79% and 76%, respectively. In a landmark analysis at 4 months, CR duration and OS did not differ significantly in pts with or without allogeneic SCT. Conclusions: HCVAD plus ponatinib is highly effective in pts with newly diagnosed Ph+ ALL, resulting in high rates of CMR and promising long-term survival. Clinical trial information: NCT01424982.
Prognostic significance of alterations of pathways regulating autophagy in acute myeloid leukemia.
Authors: Marconi Giovanni , Fontana Maria Chiara , Papayannidis Cristina , Padella Antonella , Lo Monaco Silvia , Abbenante Maria Chiara , Sartor Chiara , Bertamini Luca , Nanni Jacopo , Ghelli Luserna di Rorà Andrea , Robustelli Valentina , Tenti Elena , Tenti Elena , Fonzi Eugenio , Simonetti Giorgia , Ottaviani Emanuela , Baldazzi Carmen , Testoni Nicoletta , Martinelli Giovanni
Published: September 2018

7038

Background: Nowadays, science is debating if autophagy in cancer can lead to therapy resistance or it can favor apoptosis. Autophagy pathways are involved pro-apoptotic mechanism, or they can improve stresses survival eliminating damaged mitochondria and proteins. Levels and activity of pro-apoptotic and anti-apoptotic proteins (eg. bcl-2 and p53), high levels of cAMP, and a pink/park complex could play as fulcrum on this lever. Our study aims to define the role of autophagy in AML. Methods: We analyzed 148 consecutive non M3 AML with Affymetrix SNP array. We screened all patients for TP53, FLT3, NMP1 mutations. Patients was treated with intensive induction chemotherapy regimens. Survival data were collected prospectively, with a median follow-up of 18 months. Results: Autophagy alteration (gene group 1: ULK1 CHR11; ULK1 CHR17; BECN1; ATG14; AMBRA1; UVRAG; ATG9A; ATG9B; PIK3C3; PIK3R4) was related to lower Complete Remission rate (CR%) after induction in univariate (p < .001) and multivariable regression model with age, karyotype, secondary AML, TP53 mutation (p = .014); autophagy alteration shown to confer worst Overal Survival (OS) (p < .001) and was significantly associated with complex karyotype and TP53 mutation (p < .001). We detected significant differences in term of survival independently both in gain and loss in group 1 genes (p < .001). Alterations in genes in cAMP pathway (group 2: SESN1; PRKAA1 CHR 3; PRKAB1: PRKAA1 CHR 1: PRKAG1 CHR11; PRKAG1 CHR 7; PRKAG3; PRKAB1) and in genes that could be related to a switch from a physiological role of autophagy to a resiliency mechanism (group 3: CCND1; BCL2; PINK1; PARK2; TP53; MDM1; MDM4) showed to confer worst OS (p < .001 in both groups); Alteration in group 2 and group 3 were related to lower CR% after induction (p < .001 in both groups). Whole Exome Sequencing on 56 patients in our set did not found any significant mutation in genes we analyzed with the exception of TP53. Conclusions: Alterations in autophagy regulator genes are associated with poor prognosis and therapy resistance. A loss in autophagy could block apoptosis, a gain could confer cell resiliency. Acknowledgements: ELN, AIL, AIRC, Progetto Regione-Università 2010-12,FP7 NGS-PTL, HARMONY
Timing of initiation of defibrotide (DF) post-diagnosis of hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) after hematopoietic stem cell transplantation (HSCT): Final data from an expanded-access protocol.
Authors: Grupp Stephan A. , Richardson Paul G. , Smith Angela R. , Triplett Brandon , Kernan Nancy A. , Antin Joseph Harry , Lehmann Leslie , Giralt Sergio , Liang Wei , Hume Robin , Tappe William , Soiffer Robert
Published: September 2018

7047

Background: VOD/SOS is an unpredictable, potentially life-threatening complication of HSCT. VOD/SOS with multi-organ dysfunction (MOD) may be associated with > 80% mortality. DF is approved to treat hepatic VOD/SOS with renal/pulmonary dysfunction post-HSCT in the US and to treat severe hepatic VOD/SOS post-HSCT in the European Union. Methods: In an expanded-access study, VOD/SOS patients (pts) with or without renal/pulmonary MOD after HSCT or chemotherapy received DF 25 mg/kg/d (6.25 mg/kg q6h) for a recommended ≥21 days. For these exploratory analyses, D ay +100 survival rates in HSCT pts were examined post hoc by time from diagnosis to start of DF for (1) all pts before/after days 1, 2, 3, 4, 7, and 14, using Fisher’s exact test and (2) pts starting DF on a particular day: 0, 1, 2, 3, 4, 5, 6, 7, 8–14, and ≥15, by Cochran-Armitage test for trend across days. Causes of treatment delay were not assessed. Results: In the final dataset, timing of initiation was available for 1000 HSCT pts (512 with MOD) who received ≥1 dose of DF. In 31.0% of pts, DF was started the day of diagnosis; in 92.9%, by Day 7. In the analysis of initiation before/after days 1, 2, 3, 4, 7, and 14 post-diagnosis, earlier initiation was associated with significantly higher Day +100 survival rates for all days ( P≤.001), except Day 14 (2.6% of pts started DF after Day 14). The trend test for particular initiation days also showed a significant trend over time for higher Day +100 survival with earlier DF initiation post-diagnosis ( P< .001). Adverse events (AEs) and serious AEs occurred in 70.8% and 53.4% of pts. Other than VOD/SOS and MOD, the most common AE was hypotension (11.7%) and most common serious AE was respiratory failure (7.3%). Conclusions: In this exploratory analysis of final study data, earlier DF initiation post-VOD/SOS diagnosis improved Day +100 survival, confirmed by the Cochran-Armitage test ( P< .001). No specific day provides a clinically meaningful cutoff for better Day +100 survival, suggesting that later intervention retains value if treatment must be delayed. Support: Jazz Pharmaceuticals. Clinical trial information: NCT00628498.
Relationship of bone marrow blast (BMBL) response to overall survival (OS) in a multicenter study of rigosertib (Rigo) in patients (pts) with myelodysplastic syndrome (MDS) with excess blasts progressing on or after treatment with a hypomethylating agent (HMA).
Authors: Al-Kali Aref , Hiwase Devendra , Baer Maria R. , Greenberg Peter , Shortt Jake , Collins Robert , Steensma David P. , Verma Amit , Roboz Gail J. , Shammo Jamile M. , Ottmann Oliver G. , Seymour John Francis , Szer Jeffrey , Meyer Wolfgang , Zbyszewski Patrick Simon , Petrone Michael E. , Fruchtman Steven M. , Garcia-Manero Guillermo , Silverman Lewis R.
Published: September 2018

7056

Background: No therapies are approved for MDS after HMA failure. 04-24 was a single-arm study to evaluate best BMBL response as a potential surrogate for OS in higher-risk (HR) MDS pts who progressed on or after an HMA. Rigo is a Ras-mimetic that inhibits the RAS-RAF-MEK pathway, which is frequently activated in HR MDS (Athuluri-Divakar Cell 2016; Gil-Bazo Cancer Biol Ther 2016). Methods: Eligible MDS pts had 5-30% BMBL confirmed within 6 wks pre-study and progression per International Working Group (IWG) 2006 criteria on or after HMAs within 2 yrs. Rigo 1800 mg/24 hrs was continuously infused over 72 hrs q 2 wks × 8 cycles, then q 4 wks until progression or unacceptable toxicity. Primary endpoint was relationship of best BMBL IWG response to OS by Kaplan Meier method. Results: 64 pts were treated (median 5 cycles, range 1-32+), with 61% male, median age 73 (range 47-87), median prior HMA duration 10.8 mos (range 1.2-70.2). Revised International Prognostic Scoring System scores were low 2%, intermediate 11%, high 27%, very high 53%, and unknown 8%. ≥Grade 3 adverse events in ≥10% of pts were anemia 19%, thrombocytopenia 19%, and febrile neutropenia 16%. At the analysis time 40 pts (63%) had died. Best BMBL IWG response was marrow complete response (mCR) 14 pts (22%), stable disease (SD) 30 (47%), progressive disease (PD) 15 (23%), and failure (early death/withdrawal) 5 (8%); 2 mCR pts had transplant. Median OS was 7.0 mos (95% confidence interval 4.8-10.8). Landmark median OS (from day of best BMBL response) was mCR not reached; SD 6.3 mos; PD 3.3 mos. Median OS of mCR+SD was 8.5 mos, with log-rank p = 0.011 (mCR+SD OS to PD OS). Conclusions: BMBL response is a predictor of survival for MDS pts receiving Rigo after HMA failure, confirming findings in earlier Phase 1/2 studies (Silverman ASCO 2015 Abstr 7017). Based on earlier results identifying an MDS subset benefitting from Rigo (Garcia-Manero Lancet Oncol 2016; ASCO 2016 Abstr 165681), a randomized Phase 3 trial of Rigo vs physician’s choice (INSPIRE) is ongoing to determine if Rigo improves survival after HMA failure within 9 cycles. Clinical trial information: NCTO 1928537.
Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent lymphomas: Nine-year updated results from the StiL NHL1 study.
Authors: Rummel Mathias J. , Maschmeyer Georg , Ganser Arnold , Heider Andrea , von Gruenhagen Ulrich , Losem Christoph , Heil Gerhard , Welslau Manfred , Balser Christina , Kaiser Ulrich , Weidmann Eckhart , Dürk Heinz Albert , Ballo Harald , Stauch Martina , Blau Wolfgang , Burchardt Alexander , Barth Juergen , Kauff Frank , Brugger Wolfram
Published: September 2018

7501

Background: This multicenter, randomized, phase III study compared B-R and CHOP-R as first-line treatment in patients (pts) with indolent lymphomas or mantle cell lymphoma and was first published in The Lancet in 2013. The final analysis demonstrated a significantly prolonged progression-free survival (PFS) in the B-R group compared to the CHOP-R group, with a median PFS of 69.5 vs. 31.2 months, respectively. In the current analysis, we present updated results for overall survival (OS), time-to-next-treatment (TTNT), and secondary malignancies (sNPL) with a median follow-up of 113 months for patients with indolent lymphomas (excluding MCL). Methods: 447 pts with indolent lymphomas were randomized to receive B-R or CHOP-R for a maximum of 6 cycles. The primary endpoint was PFS; secondary endpoints included OS, TTNT, and sNPL. Results: Patient characteristics were well balanced between arms; median age was 64 years. The difference in OS between the two treatment arms was not statistically significant, with 60 deaths in the B-R group vs 68 deaths with CHOP-R (HR 0.82, 95% CI 0.58 – 1.15, p = 0.249). The estimated 10-year survival rates were 71% for B-R and 66% for CHOP-R. TTNT was significantly prolonged with B-R compared with CHOP-R (HR 0.52, 95% CI 0.38 – 0.69, p < 0.001). Median TTNT was not yet reached in the B-R group (95% CI 124.9 – n.y.r) vs. 56 months in the CHOP-R group (95% CI 39.1 – 82.0). Patients treated initially with B-R needed fewer second-line treatments due to disease progression compared to CHOP-R treated pts: 73 pts (34%) in the B-R group received salvage treatment compared with 106 pts (52%) in the CHOP-R group. For B-R pts, CHOP-R was used as second-line therapy 26 times (36%), whereas B-R was used for pts initially treated with CHOP-R 49 times (46%). 36 pts with sNPL were observed in the B-R group compared with 39 in the CHOP-R group, with 7 hematological malignancies in both groups to date. Conclusions: In pts with previously untreated indolent lymphomas, B-R demonstrates a PFS and TTNT benefit over CHOP-R. Clinical trial information: NCT00991211.
Combination ibrutinib (Ibr) and venetoclax (Ven) for the treatment of mantle cell lymphoma (MCL): Primary endpoint assessment of the phase 2 AIM study.
Authors: Tam Constantine Si Lun , Roberts Andrew Warwick , Anderson Mary Ann , Dawson Sarah-Jane , Hicks Rodney J , Burbury Kate , Turner Gillian , Di Iulio Juliana , Bressel Mathias , Westerman David A. , Agarwal Rishu , Pott Christiane , Dreyling Martin H. , Dawson Mark A , Seymour John Francis
Published: September 2018

7520

Background: Both ibr and ven have activity in relapsed/refractory (R/R) MCL, but complete remissions (CR) are attained in <25% with either. We sought to determine the activity of the combination in an investigator-initiated, phase 2 study. Methods: Enrolment of 24 patients (pts) with R/R (n=23) or frontline (n=1) MCL completed in 09/16. Pts received 4 weeks of ibr (560mg/d), followed by introduction of ven (weekly ramp-up to target 400mg/d). The primary endpoint was CR rate at week 16, as assessed by PET/CT, BMAT, flow & molecular MRD, and endoscopy (if baseline gut involvement). Response was calculated separately with and without knowledge of the PET result by IWG criteria (Cheson JCO 2007), in order to compare with published studies (ibr, 9% CR at wk16; ven, best CR rate 21%). Results: Median age of pts was 68 (range, 47-81) years. For the R/R pts (n=23), median lines of prior therapy was 2 (1-6), 48% were refractory to last treatment, and 30% had failed previous autologous SCT. As of data cutoff on Jan 11 2017, 18 pts remain on therapy, and 6 stopped treatment due to progressive disease (4), adverse event (1) or unrelated death (1). At week 16, ORR was 71% (63% CR) and 80% of complete responders were flow-cytometry negative in the marrow (sensitivity 10-3 to 10-4). Using CT without PET, the comparison responses were CR 42%, CRu 17%, PR 17% (ORR 78%). After a median follow-up of 8.3 (range 1.4-17.7) months, the 8-month estimates of PFS and OS months are 74% and 81%. Adverse events ≥20%, irrespective of attribution, were fatigue (71%), diarrhea (67%), nausea (50%), URTI (38%), gastro-esophageal reflux (33%), neutropenia (33%), cough (25%) and bruising (21%); with the exception of neutropenia (25% grade 3-4), these were predominantly grade 1-2 in severity. Tumour lysis syndrome occurred in 2 pts with high tumour burden, leading to revision of the protocol ven starting dose from 50mg, to 20mg/d. Conclusions: The combination of ibr and ven was tolerable and achieved CR rate of 63% at week 16 in pts with MCL. The efficacy results compare favorably with historical results, and warrant further phase III investigation. Clinical trial information: NCT02471391.
Ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (GA101) (iFCG) for previously untreated patients with chronic lymphocytic leukemia (CLL) with mutated IGHV and non-del (17p).
Authors: Jain Nitin , Thompson Philip A. , Burger Jan Andreas , Borthakur Gautam , Bose Prithviraj , Estrov Zeev , Ferrajoli Alessandra , Gandhi Varsha , Plunkett William , Lopez Wanda , Kantarjian Hagop M. , O'Brien Susan Mary , Keating Michael J. , Wierda William G.
Published: September 2018

7522

Background: Pts with mutated IGHV ( IGHV-M) have favorable long-term outcomes after FCR. Methods: We designed an investigator-initiated phase II trial with ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) for previously untreated pts with IGHV-M CLL (NCT02629809). The intent was to limit FC to 3 courses, potentially reducing short- and long-term toxicity, while maintaining efficacy through addition of ibrutinib and obinutuzumab. Key eligibility included age ≥18, IGHV-M, no del17p. Pts received 3 courses of iFCG. G-CSF was not mandated. Primary endpoint: CR/CRi with bone marrow (BM) MRD-neg (4-color flow-cytometry) after 3 courses of iFCG. Pts meeting primary endpoint received ibrutinib with obinutuzumab (iG) for C3-6, then ibrutinib C7-12. Pts not achieving primary endpoint received iG (C4-12). All pts who are MRD neg at 1 year will stop all therapy, including ibrutinib. Pts MRD+ at 1 year may continue ibrutinib. Historic C3 BM MRD-neg with FCR in IGHV-M 26% (Strati, Blood 2014). Target BM MRD-neg after iFCG x3 is 45%. Sample size 45. Results: 23 pts started treatment. Median age 59 yrs (25-71). Prognostic markers [del13q (n=17), negative (n=3); trisomy 12 (n=3)]. 18 pts completed 3 courses of iFCG and had initial response assessment (the remaining 5 pts too early). All 18 pts had a response; 14/18 (78%) achieved MRD-neg in BM at 3 month with 7/18 achieving CR/CRi (all MRD neg). No pt has progressed, and all but one continue to receive treatment. Of the 23 pts, 11 pts had G3-4 neutropenia and 5 pts had G3-4 thrombocytopenia. 4 pt had neutropenic fever. 1 pt who achieved MRD-neg CR developed pulmonary MAC infection, and declined further therapy. 1 pt had atrial fibrillation. G3 ALT developed in 3 pts. FC was dose reduced in 10 pts; ibrutinib dose-reduced in 2 pts. Conclusions: iFCG achieves high rate of MRD-neg remission after 3 courses. Pt enrollment continues, and updated results will be presented at the ASCO meeting. Clinical trial information: NCT02629809. [Table: see text]
Significance of MYC rearrangement and chemotherapy type on survival outcomes of patients with central nervous system lymphoma.
Authors: Grover Natalie Sophia , Deal Allison Mary , Mathews Stephanie , Freeman Ashley , Dittus Christopher , Park Steven I.
Published: September 2018

7548

Background: Central nervous system lymphoma (CNSL) has a poor prognosis and an optimal treatment regimen has not been established. Due to the rarity of this disease and frequently poor performance status at diagnosis, there have been few prospective therapeutic clinical trials in this patient population. We therefore performed a retrospective analysis of prognostic factors and treatment outcomes of patients with CNSL treated at a single institution. Methods: Pathology records were used to identify patients diagnosed with CNSL from 1/1/2005 to 9/1/2016 at the University of North Carolina Cancer Hospital. Information about demographics, disease characteristics, treatment, and outcomes was gathered from the electronic medical record. Overall (OS) and progression free survival (PFS) were estimated using the Kaplan-Meier method. Results: We identified 100 patients with CNSL. 49% had primary CNSL (PCNSL). 78% of cases were diffuse large B cell lymphoma. Out of 51 patients evaluated for MYC translocation by FISH, 13 were positive (3 PCNSL and 10 secondary CNSL). Out of 74 patients treated with chemotherapy, 51% received methotrexate (MTX), procarbazine, and vincristine (MPV), with or without rituximab, 28% were treated with other high dose MTX based regimens, with or without rituximab, and 20% received a non-MTX based regimen. There was no significant difference in OS between PCNSL and secondary CNSL (13.7 vs 7.9 months, p = 0.97). Patients with MYC translocation had a worse OS compared to those without MYC translocation (5.1 vs 29.5 months, p = 0.004). Patients treated with MPV had a longer PFS compared to those treated with other high dose MTX based regimens or those who were treated with a non-MTX based regimen (19.1 vs 10.9 vs 3.9 months, p = 0.05), but difference in OS did not reach statistical significance (29.5 vs 22.4 vs 10.6 months, p = 0.12). Conclusions: In this single institution analysis of CNSL, MYC translocation was associated with worse survival. MPV was associated with improved PFS compared to other chemotherapy regimens. Further prospective studies are needed comparing MPV to other MTX-based regimens in CNSL.
Daratumumab (DARA) in combination with carfilzomib, lenalidomide, and dexamethasone (KRd) in patients (pts) with newly diagnosed multiple myeloma (MMY1001): An open-label, phase 1b study.
Authors: Jakubowiak Andrzej J. , Chari Ajai , Lonial Sagar , Weiss Brendan M. , Comenzo Raymond L. , Wu Kaida , Khokhar Nushmia Z. , Wang Jianping , Doshi Parul , Usmani Saad Zafar
Published: September 2018

8000

Background: DARA in combination with established standard of care regimens prolongs PFS, deepens responses, and demonstrates a favorable safety profile in relapsed or refractory multiple myeloma (MM). The tolerability and efficacy of DARA-KRd in newly diagnosed MM pts was examined. Methods: Newly diagnosed pts regardless of transplantation eligibility were enrolled. Pts received DARA 16 mg/kg QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W thereafter. All pts received the 1st dose of DARA split over 2 days. Carfilzomib (K) was administered on Days 1, 8 and 15 of each 28-day cycle (20 mg/m2 on C1D1, 36 or 70 mg/m2 subsequently based on tolerability of first dose) for ≤13 cycles or elective discontinuation for ASCT. Lenalidomide 25 mg was given on Days 1-21 and dexamethasone 20-40 mg per week. The primary endpoint was tolerability. Results: Twenty-two pts (median [range] age, 60 [34-74] y) were enrolled and received a median of 8 (1-10) treatment cycles. Nineteen pts escalated K dose to 70 mg/m2 by C1D15. Median (range) duration of follow-up was 7.4 (4.0-9.3) months. Six (27%) pts discontinued treatment (1 AE [pulmonary embolism]; 1 PD; 4 other [ASCT]). Serious AEs occurred in 46% of pts, and 14% were possibly related to DARA; 18 (82%) experienced a grade 3/4 TEAE. The most common grade 3/4 TEAEs (>10%) were lymphopenia (50%) and neutropenia (23%); 1 (5%) cardiac grade 3 TEAE was observed (congestive heart failure) which resolved; pt quickly resumed study treatment with reduced K dose. No grade 5 TEAE was reported. All DARA-associated infusion reactions (27% of pts) were grade ≤2. Treatment with DARA-KRd yielded an ORR (≥partial response) of 100% (5% complete response, 86% ≥very good partial response) in 21 response-evaluable pts. The 6-month PFS rate was 100%. Conclusions: The addition of DARA to KRd was well tolerated; the overall safety profile was consistent with that previously reported for KRd, with no additional toxicity observed with the addition of DARA. Deep and durable responses were observed. These data support further investigation of DARA-KRd as a frontline treatment regimen. Updated data will be presented based on longer follow up. Clinical trial information: NCT01998971.
Carfilzomib-lenalidomide-dexamethasone (KRd) vs carfilzomib-cyclophosphamide-dexamethasone (KCd) induction: Planned interim analysis of the randomized FORTE trial in newly diagnosed multiple myeloma (NDMM).
Authors: Gay Francesca Maria , Rota Scalabrini Delia , Belotti Angelo , Offidani Massimo , Petrucci Maria Teresa , Esma Fabrizio , Palmas Angelo D. , Caravita Tommaso , Grasso Mariella , Aquino Sara , Gamberi Barbara , Zambello Renato , Ledda Antonio , Montefusco Vittorio , Omedè Paola , Galli Monica , Cavo Michele , Palumbo Antonio , Musto Pellegrino , Boccadoro Mario
Published: September 2018

8003

Background: Phase I/II studies showed the safety and efficacy of KRd and KCd in NDMM pts (Jakubowiak Blood 2012, Bringhen Blood 2014). Methods: NDMM pts ≤65 yrs were randomized (1:1:1; stratification ISS and age) to: 4 28-day KCd cycles (carfilzomib:20/36 mg/m2 IV d 1,2,8,9,15,16; cyclophosphamide 300 mg/m2 d 1,8,15; dexamethasone:20 mg d 1,2,8,9,15,16) followed by MEL200-ASCT and consolidation with 4 KCd cycles; or 4 28-day KRd cycles (carfilzomib and dexamethasone as above; lenalidomide:25 mg d 1-21) followed by MEL200-ASCT and 4 KRd cycles; or 12 KRd cycles. After the 4th induction cycle, all pts received Cyclophosphamide 2 g/m2, followed by PBSC collection. We report results of the first planned safety interim analysis on induction and mobilization and preliminary efficacy data. We pooled the 2 KRd groups since treatment was the same until mobilization. Data cut-off was October 30, 2016. Results: 281 pts were evaluated (KCd, n=94; KRd, n=187). The most frequent grade 3-4 AEs plus SAEs in both arms were hematological (mainly neutropenia) and infections (mainly pneumonia/fever); increased AST/ALT/GGT (mainly reversible) and dermatological (rash) AEs were higher in KRd; cardiac AEs were 2% (atrial fibrillation[1%]/ischemic heart disease[1%]) in KRd vs 1% (atrial fibrillation) in KCd. In KCd, 1 pt died of infection (not treatment-related) vs 3 in the KRd (2 cardiac arrest [1 not treatment-related],1 infection not treatment-related). In the KCd vs KRd arms, 99% vs 95% (P=0.44) of pts mobilized stem cells (median number of PBSC collected:9 vs 6x10^6CD34/Kg with KCd vs KRd); 10% vs 24% (P=0.01) required Plerixafor. Rate of ≥VGPR was 61% with KCd vs 74% with KRd (P=0.05). Conclusions: Safety profile was acceptable; more pts required plerixafor in KRd. Rate of VGPR was higher with KRd. Updated data on more patients will be presented at the meeting. Clinicaltrials.gov NCT02203643. [Table: see text]
WT1 heteroclitic epitope immunization following autologous stem cell transplantation in patients with high-risk multiple myeloma (MM).
Authors: Koehne Guenther , Devlin Sean , Chung David J. , Landau Heather Jolie , Korde Neha , Mailankody Sham , Hassoun Hani , Lesokhin Alexander M. , Lendvai Nikoletta , Giralt Sergio , Landgren Carl Ola
Published: September 2018

8016

Background: Host T-cells mount immune responses (IR’s) against Wilms tumor 1 (WT1) in A*0201+MM pts through formation of WT1 peptide fragment (RMFPNAPYL)/HLA-A*0201 complex. We report initial results from MM pts immunized with the WT1 heteroclitic peptide mixture galinpepimut-S (GPS) after autoSCT. Methods: 16 MM pts underwent autoSCT with melphalan conditioning followed by (f/b) lenalidomide maintenance starting 3 months (mos) post-SCT. 13/16 pts presented with high-risk (HR) cytogenetics [t(4;14), t(14;16), del17p, 1q21/25 gain and/or del13q]. GPS was administered with montanide s.c. starting 2 wks post-SCT and q.2 wks thereafter x 6 initial doses f/b boosters q.4 wks x 6 additional doses. GM-CSF was given on days -2 and 0 of each cycle. GPS consisted of 4 peptides: WT1-A1: Y*MFPNAPYL; 427-L (long): RSDELVRHHNMHQRNMTKL; 331-L: PGCNKRYFKLSHLQMHSRKHTG, and 122A1-L: SGQAY*MFPNAPYLPSCLES. 2 of the 4 peptides were mutated at a single residue (*) to induce stronger HLA-binding/reduce tolerance. WT1-specific IR’s were assessed by intracellular IFN-g analyses post-challenge with PBMC’s pulsed with a ‘total pool’ of overlapping 15mers along the entire WT1 protein; or each of the 4 WT1 peptides in GPS; or the non-mutated (native) WT1 peptides corresponding to the 2 heteroclitic sequences. Results: 16 pts; median follow-up: 18 mos (range: 5-31 mos) for survivors; median age: 61.6 y. Overall survival (OS) and progression-free survival (PFS) (95% CI) at 18 mos: 0.88 (0.73-0.99) and 0.62 (0.42-0.97) respectively. Current median PFS: 23.6 mos (15.2 - not reached). No >G2 systemic side effects were observed, however, all pts developed local nodularity at the site of injections which resolved over 2 – 6 wks. Both CD8+ and CD4+ IR’s could be detected at various levels and were induced not only against the heteroclitic peptides (within GPS), but also against the corresponding native WT1 peptide sequences as well as the ‘total pool’ of WT1-derived overlapping peptides. Conclusions: Administration of the novel WT1 heteroclitic peptide immunizer GPS post auto SCT demonstrates favorable safety profile along with encouraging mPFS of currently 23.6 mos in this high-risk MM population. Clinical trial information: NCT01827137.
HDAC11 as a candidate therapeutic target in multiple myeloma.
Authors: Distler Allison , Brayer Jason B. , Meads Mark , Sahakian Eva , Powers John Joseph , Alsina Melissa , Nishihori Taiga , Baz Rachid C. , Pinilla-Ibarz Javier , Sotomayor Eduardo M. , Shain Kenneth H.
Published: September 2018

8029

Background: Histone deacetylase (HDAC) inhibitors (HDI) have a therapeutic niche in multiple myeloma (MM) due to their ability to salvage proteasome inhibitor and immunomodulatory drug responsiveness in refractory patients, thus raising interest in this therapeutic class. Selective HDI may further improve therapeutic efficacy. Methods: B cell lymphopoiesis was evaluated using Tg-HDAC11-eGFP mice expressing eGFP regulated by the HDAC11 promoter and congenic mouse strains deficient in HDAC11 expression globally (B6.HDAC11-/-) or targeted to the B cell lineage (CD19Cre.HDAC11-/-). Molecular and pharmacologic means were used to impair HDAC11 in established MM cell lines. Viability was measured by activated caspase-3, Annexin/PI (A/PI) staining, and CCK-8 viability assay. Subcellular localization changes induced by HDI and identification of the novel binding partner IRF4 were assessed by proximity ligation assay (PLA). Results: Profound eGFP increases in PC of Tg-HDAC11-eGFP mice suggest HDAC11 influences late stage B cell development. In addition, HDAC11 deficiency results in dramatically reduced PC in the bone marrow and periphery. PC depletion in CD19Cre.HDAC11-/-mice suggests activity inherent in B cells rather than via externally derived signals. Quisinostat (QS), an HDI with enhanced HDAC11 selectivity, showed dose-dependent cytotoxicity in 10 MM cell lines (EC50 1-10nM). This activity was synergistic with bortezomib (BTZ) and carfilzomib (CFZ) in RPMI-8226 cells, while synergism was amplified in the BTZ-resistant RPMI-8226-B25 cell line. Exposure of RPMI-8226 cells to QS decreased detection of nuclear, but not cytosolic, HDAC11. Targeted siRNA–mediated silencing of HDAC11 in RPMI-8226 cells activated caspase-3 and reduced viability by A/PI staining. PLA of MM cell lines showed a novel interaction between HDAC11 and IRF4, an essential regulator of PC differentiation and MM survival, unmasking a potential mechanism for HDAC11-induced cytotoxicity in MM. This interaction was disrupted by QS. Conclusions: We show that HDAC11 inhibition reduces MM cell survival in vitro. Furthermore, we identify IRF4 as a binding partner for HDAC11 and propose this interaction as a candidate mechanism regulating PC maturation and MM survival.
Synergism of gambogenic acid with bortezomib induce apoptosis of multiple myeloma.
Authors: Chen Runzhe , Zhang Hongming , Liu Ping , Wu Xue , Chen Baoan
Published: September 2018

8035

Background: Multiple myeloma (MM) is one of the most common primary tumors of the bone marrow that accounts for approximately 10% of all hematological cancer. Gambogenic acid (GNA) is one of the natural compound isolated from gamboge and has demonstrated advantages such as a more potent anticancer effect and less systemic toxicity according to early investigations. In this study, we hypothesized that GNA could synergistically potentiate BTZ-induced apoptosis of MM cells and that combining BTZ and GNA may provide a more effective approach to treat MM. Methods: CCK-8 assay, CI isobologram, flow cytometry, western blot, xenograft tumour models, TUNEL and immunochemistry were used in this study to detect to possible mechanisms of apoptosis led by GNA and BTZ in vitro and in vivo. Results: The percentage of MM.1S in G2/M phase after 48h of 4.0nM BTZ, 0.90μM GNA and combination treatment were 31.09±2.16%, 26.68±1.96% and 19.88±1.89% respectively. The percentage of MM.1S in G2/M phase of control group was 17.23±1.65%. The apoptosis rates of MM.1S cells for 48h were 6.57±0.15% in control group, 89.67±5.15% after treatment with 4.0nM BTZ, 97.80±0.81% after treatment with 0.90μM GNA, and 98.9±3.86% after treatment with 4.0nM BTZ plus 0.9μM GNA respectively. All the treatment groups showed a more significant apoptosis rate compared to that of the control group ( p<0.01). MM.1S tumors were implanted in BALB/Ca nu/nu male mice. The tumor weights of GNA and BTZ plus GNA groups decreased significantly when compared with those of control group (p<0.01 and p<0.001, respectively) and the tumor weight of combination group was significantly less than that of BTZ or GNA group (p<0.001). When mice were treated with BTZ combined with GNA, the tumor inhibition rate was 41.94%, whereas those of mice treated with BTZ or GNA alone were 9.68% and 19.35%, respectively. We also found that the combined treatment could induce more markedly increased apoptosis of MM.1S cells via the activation of PARP cleavage, P53, Caspase-3 cleavage and Bax and inhibition of Bcl-2 expression. Conclusions: Our data support that a synergistic antitumor activity exists between BTZ and GNA, and provide a rationale for successful utilization of dual BTZ and GNA in MM chemotherapy in the future.
CALGB/ECOG 100104 (Alliance) study: Lenalidomide (LEN) vs placebo (PBO) maintenance (maint) after stem cell transplant (SCT) for patients (pts) with multiple myeloma—Overall survival (OS) and progression-free survival (PFS) adjusted for treatment (tx) crossover (XO).
Authors: McCarthy Philip L. , Holstein Sarah A. , Jung Sin-Ho , Cooper Miranda , Gibson Craig J , Stadtmauer Edward Allen , Winograd Benjamin , Richardson Paul G.
Published: September 2018

8037

Background: At a prespecified interim analysis (Dec 2009), the phase 3 CALGB study results surpassed the prespecified superiority boundary (significantly improved PFS for LEN maint vs PBO after SCT) and the majority of PBO arm pts without progressive disease (PD) crossed over to LEN maint. An updated analysis (cutoff Mar 2015), showed significantly longer OS with LEN maint (HR, 0.56; 95% CI, 0.42-0.76). We examined the effect of LEN vs PBO on OS and PFS from randomization, adjusting for XO effects. Methods: The rank-preserving structural failure time model (RPSFTM; Robins, Commun Stat Theory Methods, 1991) was used for XO adjustment; the iterative parameter estimation (IPE; Branson, Stat Med, 2002) algorithm was used as validation. Survival was portioned assuming a residual LEN effect after discontinuation. A landmark analysis was also performed at the Dec 2009 interim for pts who remained on Tx. Results: Pts were randomized to LEN maint (n = 231) and PBO (n = 229) (intent-to-treat [ITT] population); 76 pts without PD crossed over from PBO to LEN. Median time from randomization to XO was 11.5 mos. The relative Tx effect for OS and PFS increased for LEN vs PBO when adjusting for XO using RPSFTM and IPE (Table). The landmark analysis at the Dec 2009 interim (PBO XO, n = 76; No XO, n = 34) showed the Tx effect is not dissimilar to the ITT analysis (HR 0.53; 95% CI, 0.25-1.13). Sensitivity analyses showed consistent results. Conclusions: Adjusting for the potential diluting effects of XO reduced median OS and PFS with PBO, and improved the Tx effect in the ITT analyses for OS and PFS for LEN vs PBO maint after SCT. The statistical significance of the ITT analyses was maintained throughout. Support: U10CA180821, U10CA180882, CA180820. Clinical trial information: NCT00114101. [Table: see text]
Gefitinib (G) versus vinorelbine+cisplatin (VP) as adjuvant treatment in stage II-IIIA (N1-N2) non-small-cell lung cancer (NSCLC) with EGFR-activating mutation (ADJUVANT): A randomized, Phase III trial (CTONG 1104).
Authors: Wu Yi-Long , Zhong Wenzhao , Wang Qun , Xu Song-Tao , Mao Wei-Min , Wu Lin , Shen Yi , Liu Yong-Yu , Chen Chun , Cheng Ying , Xu Lin , Wang Jun , Fei Ke , Li Xiao-Fei , Li Jian , Huang Cheng , Liu Zhi-Dong , Chen Ke-Neng , Yan Hong-Hong , Yang Xue-Ning
Published: September 2018

8500

Background: Cisplatin-based adjuvant chemotherapy is standard of care for patients (pts) with stage II-IIIA non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have shown no benefits in the adjuvant setting for pts with unselected resected NSCLC in the BR19 and RADIANT trials. ADJUVANT (NCT01405079) is the first randomized trial to compare gefitinib (G) with vinorelbine+cisplatin (VP) in completely resected pathological stage II-IIIA (N1-N2) NSCLC with EGFR-activating mutation. Methods: Completely resected stage II-IIIA (N1-N2) NSCLC pts with EGFR-activating mutation were randomized 1:1 to receive G (250 mg once daily) for 24 months or vinorelbine (25 mg/m2 Day 1 and Day 8) plus cisplatin (75 mg/m2 Day 1) every 3 weeks for 4 cycles. Stratification factors were lymph node status (pN1/N2) and EGFRmutation status. The primary endpoint was disease-free survival (DFS) in the intent-to-treat population. Results: A total of 222 pts were randomly assigned (Sep 19 2011 to Apr 24 2014). Baseline characteristics were balanced. At the time of data cutoff, the median duration of treatment was 21.9 months in the G arm, and 4 cycles in the VP arm. The median follow-up period was 36.5 months (range 0.1 to 62.8). G had significantly longer median DFS (28.7 months, 95% confidence interval [CI] 24.9 to 32.5) than VP (18.0 months, 95% CI 13.6 to 22.3; hazard ratio 0.60; 95% CI 0.42 to 0.87; p= 0.005). 3-year DFS was significantly better with G (34.0% vs 27.0%; p= 0.013). The number of overall survival events was 76 (34.2%). In the subgroup analysis of patients treated with G, lymph node status (pN1/N2) demonstrated significant correlation with DFS ( p< 0.05). Grade 3 or higher adverse events were less common with G than with VP (12.3% vs 48.3%; p< 0.001). No interstitial lung disease was observed with G. Conclusions: Adjuvant G significantly prolonged DFS compared with VP in pts with resected stage II-IIIA (N1-N2) NSCLC with EGFR-activating mutation. Adjuvant gefitinib should be considered as an important option for stage II-IIIA lung cancer pts with EGFR mutation. Clinical trial information: NCT01405079.
Prophylactic cranial irradiation (PCI) versus observation in radically treated stage III non-small cell lung cancer (NSCLC): A randomized phase III NVALT11 study.
Authors: Groen Harry J.M. , Dingemans Anne-Marie C. , Belderbos Jose , Tissing-Tan Caroline , Herder Gertruda , Haitjema Tjeerd , Ubbels Fred , Lagerwaard Frank J , El Sharouni Sherif , Stigt Jos , Smit Egbert F. , van Tinteren Harm , van de Noort Vincent , De Ruysscher Dirk
Published: September 2018

8502

Background: Brain metastases are one of the major sites of tumor failure in patients (pts) with radically treated stage III NSCLC. The value of PCI in these pts remains unsettled. This study is designed to investigate whether PCI reduces the incidence of symptomatic brain metastases (sBM). Methods: Pts were randomized between observation and PCI after concurrent or sequential chemo-RT with or without surgery. PCI dose was left to the physician(36 Gy/18F, 30 Gy/12F, 30 Gy/10F). Pts were registered before randomization, those progressing after chemo-RT were not randomized. Pts were followed for sBM (defined as increased intracranial pressure, headache, nausea, vomiting, cognitive, affective disturbances, seizures, focal neurological symptoms andMRI/CT), side effects, survival, quality of life (QLQ-C30, EuroQol 5D). The primary endpoint is the proportion of patients developing sBM. Randomizing 300 pts the study has 90% (2-sided p = 0.05) power to detect 17% decrease in pts developing sBM at 24 months (mo). Results: Between 2009 and 2015, 195 pts were registered, 175 were randomized, 87 received PCI and 88 pts were in the observation arm. In 2013 due to slow accrual, it was decided to reduce the number of randomized pts to 175 pts. With 75 events a 2-sided log-rank test would have 80% power to detect HR 0.52 and alpha 0.05. One pt in PCI arm was withdrawn after randomization. Pts characteristics were male (n = 114, 66%); adeno/squa/other 72 (41%), 62 (36%), 40 (23%); PS 0/1/2 66 (38%), 99 (57%), 9 (5%); stage IIIA/B 93 (53%), 80 (46%), unknown 1 (1%). Median follow up was 48.5 mo (95% CI, 39 - 54). Proportion of pts with sBM was 4/86 (4.6%) in PCI and 25/88 (28.4 %) in observation (p < 0.00001). Seven (8.1%) pts in PCI and 26 (29.7%) pts in observation arm had BM on imaging (p < 0.001). Median time to sBM was not reached in either arm. Median OS was 24.2 mo in PCI and 21.9 mo in observation arm (p = 0.52). Global QoL at 3 mo was worse in PCI arm (p = 0.02) but not afterwards. Conclusions: PCI significantly decreases the proportion of patients developing both symptomatic BM without influencing overall survival. PCI decreases 3 months global quality of life measures but not beyond. Clinical trial information: NTR 1601.
Multi-modality therapy for stage IIIa N2 non-small cell lung cancer: Does the answer lie in the components?
Authors: Spicer Jonathan David , Shewale Jitesh B. , Bott Matthew Joseph , Jones David Randolph , Vaporciyan Ara A. , Darling Gail Elizabeth , Swisher Stephen , Sepesi Boris
Published: September 2018

8537

Background: Neoadjuvant chemoradiation prior to surgery offers excellent locoregional control, while neoadjuvant chemotherapy I meant to offer improved systemic therapy in stage IIIA N2 non-small cell lung cancer (NSCLC). Data are lacking to select the optimal regimen. We compared oncologic outcomes for stage IIIA N2 NSCLC utilizing granular data from three experienced lung cancer treatment centers. Methods: This collaborative retrospective study unites 3 major thoracic centers with differing approaches to IIIA N2 NSCLC. Patients undergoing surgical resection post-neoadjuvant chemotherapy (CxT) or concurrent chemoradiation (CxRT) were included. Primary outcomes were overall and disease- free survival (OS and DFS). Results: Demographic data and outcome data are in Table 1. There were no differences in 5-year OS (CxT 40% vs CxRT 42%, p=0.265) nor in DFS (CxT 30% vs 31%, p=0.275). Recurrence rates (CxT47%vsCxRT48%,p=0.799) and patterns were identical (Local: CxT 10% vs CxRT 8%; and Distant: CxT 30%vsCxRT29%,p=0.764). There was no difference in peri-operative mortality. To address potential bias from differing staging strategies, we excluded patients without invasive mediastinal staging and there were still no differences in OS (CxT 40% vs CxRT 42%, p=0.364) and DFS (CxT 30% vs CxRT 31%, p=0.332) Multivariable analysis identified pnemonectomy (HR1.66,p<0.001) and ypN2 (HR1.84,p<0.001) to be associated with overall survival. Conclusions: Both treatment strategies produce equivalent and better than expected outcomes compared to historical controls for IIIA N2 NSCLC. [Table: see text]
Results of stereotactic body radiation therapy (SBRT) for T2 lung cancer: Outcomes of longer term follow-up.
Authors: Shamp Stephen , Chang Tangel C. , Biswas Tithi , Linden Philip Aaron , Perry Yaron , Kazakov Jordan , Dowlati Afshin , Machtay Mitchell
Published: September 2018

8542

Background: SBRT is a well-established, highly efficacious treatment for T1N0 non-small cell lung carcinoma (NSCLC). Its efficacy in T2N0 cancers is less clear. This is a review of our institutional experience with long-term follow-up. Methods: 45 patients with medically inoperable T2 N0/Nx M0 NSCLC who were treated with definitive SBRT between 2009 and 2013 were analyzed retrospectively. All patients underwent PET/CT staging and fiducial marker placement for image guided therapy with the Cyberknife platform. Radiation dose was 50 Gray in 5 fractions (N = 24), 50 Gray in 4 fractions (N = 11) or 54-60 Gray in 3 fractions (N = 10) delivered over 7 to 14 days. We analyzed overall survival from the date of start of SBRT, and we performed analyses actuarially using Cox regression analysis and Kaplan-Meier survival analysis for comparisons of hazard ratio (HR) among subgroups. Results: 45 patients were studied (median age 74). The 5-year actuarial overall survival was 18.7% (39.3% at 2 years), with most patients dying from lung cancer recurrence/progression outside of the treatment field. Subgroup analyses showed no statistically significant differences with respect to age, gender, histology, nominal radiation prescription dose, tumor diameter or PTV target volume (median PTV 87cc). There was statistically significantly better survival associated with increased maximum biologically effective dose (BED10) of radiation at the center of the tumor (p = 0.03). Conclusions: Unlike the outcomes for T1 NSCLC, our results in T2 NSCLC were disappointing, with a high rate of out-of-field failure and death from lung cancer. We stress the importance of diagnosis and treatment of NSCLC at the T1N0 stage. We suggest that patients with T2N0/Nx NSCLC be considered for SBRT dose intensification and/or combined modality therapy protocols.
Patterns of comorbidity, treatment, resource utilization, and referral in malignant pleural mesothelioma patients in the US.
Authors: Zauderer Marjorie Glass , Tsao Anne S. , Fennell Dean A , Wong William Bruce , Pattipaka Thirupathi , Bretscher Michael T , Peake Michael
Published: September 2018

8554

Background: Malignant pleural mesothelioma (MPM) is a rare but aggressive cancer, which may be challenging to diagnose. The standard of care for MPM is cisplatin plus pemetrexed. In the recent phase III MAPS trial, addition of bevacizumab provided a significant survival benefit. There is limited data on real-world MPM treatment patterns to provide context to trial results. Consequently, the present study was conducted to evaluate treatment and referral patterns, co-morbidities and resource use in patients with MPM in the U.S. Methods: Patients ≥18 years old with a diagnosis of MPM between Jan 2004 and September 2015 were identified from the MarketScan claims database. Patients were required to have data for 12 months prior, and at least 3 months post, the diagnosis index date. Patients with other (non-MPM) cancers, malignant mesothelioma of non-pleural origin and those enrolled in clinical trials were excluded from the analysis. Treatment and resource utilization were identified by their corresponding HCPCS and DRG codes. Referral patterns were estimated starting from the first lung-related visit during the year preceding MPM diagnosis. Results: In the cohort of 1,869 patients, the median age was 71 years (range 61–79) and 65% were male. 4.1% of patients underwent radical surgery and of the remaining 96%, 15.6% had first-line chemotherapy, 33.2% had first-line chemotherapy plus radiotherapy, 11.7% received radiotherapy, and 39.5% received no chemotherapy or radiotherapy. The most common diagnosis on the first lung-related visit was pleural effusion (16.5%), followed by chest pain (10.7%), shortness of breath (9.6%) and cough (8.5%). The median time from first lung-related visit to MPM diagnosis was 77 days (mean 134 days, IQR 23–258). Conclusions: This real-world analysis showed that only a small proportion of MPM patients (~4%) received radical surgery and a large number of patients did not receive any treatment at all, indicating a large unmet need for effective treatments in this disease area. Additionally, the pathway to MPM diagnosis may be challenging in this population with a poor prognosis, often involving multiple healthcare contacts over an extended period of time.