bluuebunny/crossref_metadata_2025_split huggingface dataset:
Response to pembrolizumab in patients with mismatch repair deficient (dMMR) colorectal cancer (CRC).
Authors: Leal Alexis Diane , Paludo Jonas , Finnes Heidi D. , Grothey Axel 
Published: September 2018

3558 Background: Anti-programmed death-1 (PD-1) antibodies have been shown to be effective in the treatment of dMMR CRC. We describe an updated analysis from a cohort of 19 patients (pts) with dMMR CRC treated with pembrolizumab. Methods: Pts were identified through review of the Mayo Clinic electronic medical record (EMR) and chemotherapy administration records from May 2015 through January 2017. All pts with dMMR CRC who received treatment with pembrolizumab were included. The EMR was reviewed to identify demographic, clinical, pathologic and treatment details. Overall survival (OS), progression free survival (PFS) and disease control rate (DCR = CR+PR+SD) are reported. Time to event analysis was calculated using the Kaplan-Meier method. Results: Nineteen pts were included in this analysis; median age at diagnosis was 48.6 years (range 25-93); 53% were female. Most primary tumors were right sided (n = 12; 63%), 6 (32%) were left sided and 1 (5%) was a tumor of unknown primary within the bowel. Twelve (63%) pts received ≥2 lines of therapy prior to pembrolizumab (range 1-4). Five pts received 2 mg/kg every 3 weeks, 11 received 200 mg/day every 3 weeks and 2 pts received 10 mg/kg (1 every 2 weeks, the other every 3 weeks). The most common alterations identified were loss of MLH1 (11/15) and PMS2 (12/15); 4 pts had germline mutations (mut) identified. KRAS mut was identified in 6/16 pts and 2 pts had BRAF mut. Three pts had MLH1 hypermethylation. Median number of cycles of pembrolizumab was 8 (range 1-35+), with 13 (68%) pts receiving ≥6 cycles. DCR at first assessment was 68%, with 5% CR, 47% PR and 16% SD. Median follow-up from diagnosis was 29 months (95% CI 18-42). Median OS was 103 months (95% CI 85-103); 12-month OS was 89%. Median OS from PD-1 therapy was 16.1 months (95% CI 16-NR); 12-month OS from PD-1 therapy was 79%. Median PFS was NR (95% CI 5-NR); 12-month PFS was 54%. At time of analysis, 9 pts remain on PD-1 therapy; 5 pts have died; 3 have received subsequent therapy. Conclusions: Anti-PD1 blockade with pembrolizumab can provide long lasting benefit in dMMR mCRC, even in heavily pretreated pts.
Prospective study of biomarkers in squamous cell carcinoma of the anal canal (SCCAC) and their influence on treatment outcomes: Final results.
Authors: Moniz Camila Motta Venchiarutti , Riechelmann Rachel Pimenta , Ribeiro Suilane Coelho , Rivelli Thomas Giollo , Bariani Giovanni Mendonca , Chen André , Franco Rejane , Nahas Caio , Pereira Allan Andresson Lima , Ortega Cintia , Sabbaga Jorge , Meireles Sibele , Coudry Renata A. , Hoff Paulo Marcelo 
Published: September 2018

3577 Background: While chemoradiation (CRT) is a curative treatment for SCCAC, many patients (pts) present primary resistance. As a rare tumor, the predictors of response in this setting remain unknown. Methods: Prospective cohort study aimed to evaluate predictive biomarkers (Ki-67, PD-L1, Human papillomavirus (HPV), HIV status and mutations in tumoral DNA) associated with complete response (CR) following standard CRT for localized SCCAC. Eligible pts had T2-4/N0-3/M0 disease and were candidates to standard CRT. CR at 6 months (m) measured by RECIST 1.1 was the primary endpoint. DNA mutations were analyzed by next-generation (NGS) TruSight Tumor26 panel. HPV positivity was tested by PapilloCheck Test. KI-67 and PD-L1 were evaluated by immunohistochemistry. Results: 78 pts were recruited from Jan/2011 to Dec/2015. 75 were evaluable for response. Median age 57 years; 49 (65%) were stage III, and 9 (12%) were HIV+. At 6m 47 (62.7%) had CR, 18 (24%) partial response (PR) and 10 (13.3%) disease progression. HPV was evaluated in 67 and found in 47 (70.1%), the majority HPV16. PD-L1 was tested in 61, 10 (16.4%) had > 1% positive expression. Ki-67 was performed in 65, a median was 50% (1-90%) per patient. Clinical stage, HIV status, median KI-67, HPV and PD-L1 positivity, and treatment interruption were tested as predictive factors of CR in 6m by logistic regression. On multivariable analyses, ECII patients were 4.7 more likely to achieve CR than ECIII (OR 4.70 CI95%1.36-16.30; p = 0.015). HIV was borderline significant (OR 2.53 CI95% 0.9-7.1; p = 0.079). Analyzing the patients with PR and CR HIV+ was significantly associated with poor response. Patients HIV- were 5.7 more likely to achieve CR or PR (OR 5.72 CI95%2.5-13.0; p < 0.001). 25 patients had tumor samples proper for NGS, 17 had at least one pathogenic mutation. The most common mutated genes were PIK3CA and MET in 6. There was no differences in CR rates according to MET (50% vs 47.3%, p = 1) or PIK3CA (33.3% vs 47.3%, p = 0.6) mutation status. TP53 codon 72 polymorphism was present in 72% (n = 18) and was not associated with CR (44% VS 57%, p = 0.6). Conclusions: Our study suggests that HIV+ pts are less responsive to CRT.
Identification of a novel predictive genomic biomarker for response to combination bevacizumab in metastatic colorectal cancer (mCRC).
Authors: Byrne Annette T. , Smeets Dominiek , Miller Ian S. , Das Sudipto , Boeckx Bram , Depreeuw Jeroen , Gaiser Timo , Betge Johannes , Barat Ana , Murphy Verena , Moran Bruce , Fender Bozena , Klinger Rut , Ebert Matthias Philip , van Grieken Nicole C.T. , Ylstra Bauke , Gallagher William M. , Prehn Jochen , O'Connor Darran , Lambrechts Diether 
Published: September 2018

3580 Background: Somatic copy number alterations (SCNA) are genomic alterations evident in cancers including mCRC. These alterations support biomarker discovery, allowing identification of variants that can be used to predict response to therapy. Herein, we studied the impact of SCNAs on mCRC patient response to bevacizumab (BVZ). Methods: SCNA data was assembled from mCRC tumors in the TCGA cohort (n = 676), from the CAIRO 2 study [n = 143] and from the ANGIOPREDICT cohort (n = 258) [Betge et al. Digestion 2016 94(3):129-137]. GISTIC v2.0 was used to identify the most frequent and overrepresented chromosomal aberrations. A region was considered deleted if the logR value was < 0.1 and amplified when the logR was > 0.1. A cutoff q-value of 0.25 was used to select significantly overrepresented SCNAs. To further explore the impact of new ANGIOPREDICT clusters and consensus molecular subtypes (CMS), [Guinney J et al Nat Med. 2015 21(11):1350-6], a panel of seven xenografts representing each CMS subtype was treated with FOLFOX (40mg/kg 5-FU, 13.4mg/kg folinic acid & 2.4mg/kg oxaliplatin) + B20 antibody (mouse avastin, 10mg/kg) for 4 weeks. Results: Unsupervised hierarchical clustering classified all 1077 tumors into 3 consensus SCNA subgroups termed ‘ANGIOPREDICT’ clusters 1-3. Concordance between CMS and ANGIOPREDICT clusters was evident: CMS1 - Cluster 1 78%, CMS3 - Cluster 1 50%. CMS2 - Cluster 2/3 92% and CMS4 - Cluster 2/3 84%. Tumors with intermediate or high copy number instability (ANGIOPREDICT cluster 2 & 3) showed improved progression free survival (PFS): 369d vs. 227d p = 1.36e-7) whereas tumors with low copy number alterations displayed a poor response to BVZ therapy (PFS: 147d vs 152d p = 0.906). Xenografts corresponding to CMS 2&4/ ANGIOPREDICT cluster 2-3 showed improved response to FOLFOX + B20 therapy and increased PFS (p < 0.001) vs. CMS1&3/ ANGIOPREDICT cluster 1. Conclusions: For the first time, in a large test and validation cohort including retrospectively collected and randomized controlled trial patient samples, we have identified a predictive genomic biomarker for BVZ therapy in mCRC. We have further demonstrated the utility of CMS subtyping to stratify patients to BVZ .
Right-sided colorectal cancer (RC): Response to first-line chemotherapy in FIRE-3 (AIO KRK-0306) with focus on early tumor shrinkage (ETS) and depth of response (DpR).
Authors: Holch Julian Walter , Stintzing Sebastian , Held Swantje , Fischer von Weikersthal Ludwig , Decker Thomas , Kiani Alexander , Vehling-Kaiser Ursula , Al-Batran Salah-Eddin , Heintges Tobias , Kahl Christoph , Kullmann Frank , Scheithauer Werner , Kirchner Thomas , von Einem Jobst C. , Modest Dominik Paul , Heinemann Volker 
Published: September 2018

3586 Background: Recent evidence suggests that benefit from anti-EGFR treatment is restricted to RAS wild-type left-sided colorectal cancer (LC) (Holch JW et al. Eur J Cancer 2017). However, these results are preliminary. We therefore investigated patients with RC enrolled in the FIRE-3 trial, which evaluated the efficacy of first-line FOLFIRI plus either cetuximab (cet) or bevacizumab (bev) in RAS wildtype mCRC. New metrics of tumor dynamics were used to characterize the patients. Methods: The splenic flexure was used to differentiate LC from RC. Survival analysis was done using Kaplan-Meier estimation and differences were expressed using Log-Rank test, hazard ratios (HR) and corresponding 95% confidence intervals. Central independent radiological data was used to calculate early tumor shrinkage ≥20% (ETS) and depth of response (DpR). Results: In total, 330 patients were assessable for central radiological evaluation. In patients with LC (n = 257), treatment with FOLFIRI + cet led to longer overall survival (OS) compared to FOLFIRI + bev (HR = 0.68, p = 0.016). In patients with RC (n = 68), OS was comparable between treatment arms (HR = 1.11, p = 0.715). In patients with RC and ETS < 20%, OS was inferior in patients treated with FOLFIRI + cet. In patients who reached ETS ≥20%, a comparable OS was evident between treatment arms (for further details of efficacy in patients with RC see table). Conclusions: Patients with RC do not represent a uniform population. ETS ≥20% defines a subgroup of patients where comparable treatment efficacy was observed with regard to OS, ORR and DpR by addition of cetuximab vs. bevacizumab to FOLFIRI. [Table: see text]
Early prediction of clinical outcomes in resected stage II and III colorectal cancer (CRC) through deep sequencing of circulating tumor DNA (ctDNA).
Authors: Diehn Maximilian , Alizadeh Ash A. , Adams Hans-Peter , Lee John J. , Klassen Susanne , Palma John F. , Hinzman Bernd , Lovejoy Alexander F. , Newman Aaron M. , Yao Lijing , Yaung Stephanie , Balasubramanyam Aarthi , Rohr Ulrich Peter , Rosenthal Andre , Kube Rainer , Steinmüller Thomas , Marusch Frank , Mantke Rene , Heise Michael , Pross Matthias 
Published: September 2018

3591 Background: Adjuvant chemotherapy is offered to most pts with Stage III CRC, and to a subset with Stage II disease deemed at high-risk for recurrence. Nevertheless, risk stratification strategies remain suboptimal. Detection of minimal residual disease (MRD) through ctDNA analysis has been shown to identify pts at high recurrence risk in Stage II CRC, but not Stage III disease. Methods: The next-generation sequencing based AVENIO ctDNA Surveillance Kit (Research Use Only) was used to identify single nucleotide variants (SNVs) in tumor tissue within a cohort of 145 Stage II and III CRC pts following R0 surgical resection (n = 86 and 59 respectively; median follow-up = 32.1 mo). The same assay was used to monitor ctDNA with a single post-operative blood sample (mean surgery-to-phlebotomy time: 10 days). Regions from 197 genes recurrently mutated in CRC were interrogated, and pts were classified as ctDNA positive (+) or negative (-) in plasma based on the detection of SNVs previously identified in tumor tissue. Results: Variants were identified in 99% of tumors (n = 144) with a median of 4 SNVs/sample (range 1-24) and all post-operative plasma samples were successfully profiled. Pts with detectable ctDNA (n = 12) displayed a significantly shorter 2-year relapse-free survival (RFS; 17% vs 88%; HR 10.3; 95% CI 2.3-46.9; p < 0.00001), time to recurrence (TTR; HR 20.6; 95% CI 3.1-139.0; p < 0.00001) and overall survival (OS; HR 3.4; 95% CI 0.5-25.8; p = 0.041) than ctDNA- pts (n = 132). 11 (92%) of ctDNA+ pts developed recurrence compared to 9 (7%) of ctDNA- pts. Monitoring multiple variants doubled sensitivity of MRD detection compared to tracking a single driver mutation. TTR was shorter in ctDNA+ vs ctDNA- Stage II (HR 23.1, 95% CI 0.28-1900.4; p < 0.00001) and stage III pts (HR 17.9; 95% CI 2.7-117.3, p < 0.00001). TTR of Stage II and III ctDNA- pts was similar (p = 0.7). Conclusions: Our results indicate that ctDNA analysis can detect MRD within days after complete resection of CRC and accurately identifies pts at high risk of recurrence in both Stage II and III CRC. MRD detection via ctDNA sequencing may allow personalization of adjuvant treatment strategies.
Phase III trial of lenvatinib (LEN) vs sorafenib (SOR) in first-line treatment of patients (pts) with unresectable hepatocellular carcinoma (uHCC).
Authors: Cheng Ann-Lii , Finn Richard S. , Qin Shukui , Han Kwang-Hyub , Ikeda Kenji , Piscaglia Fabio , Baron Ari David , Park Joong-Won , Han Guohong , Jassem Jacek , Blanc Jean-Frédéric , Vogel Arndt , Komov Dmitry , Evans T.R. Jeffry , López-López Carlos , Dutcus Corina E , Ren Min , Kraljevic Silvija , Tamai Toshiyuki , Kudo Masatoshi 
Published: September 2018

4001 Background: SOR is the only approved agent in uHCC and new options are needed. LEN, an inhibitor of vascular endothelial growth factor receptors 1‒3, fibroblast growth factor receptors 1‒4, platelet derived growth factor receptor α, RET, and KIT, showed activity in uHCC in a phase II trial. We report a phase III trial of LEN vs SOR as first-line therapy for uHCC. Methods: In this randomized, open-label, noninferiority (NI) study, pts had uHCC, ≥ 1 measurable target lesion, Barcelona Clinic Liver Cancer stage B or C, Child-Pugh class A, ECOG PS ≤ 1, and no prior systemic therapy. Pts were randomized 1:1 to LEN (body weight ≥ 60 kg: 12 mg/day; < 60 kg: 8 mg/day) or SOR 400 mg twice daily. The primary endpoint was overall survival (OS). The OS hazard ratio (HR) and its 95% CI were estimated with a stratified Cox proportional hazard model. The predefined NI margin was 1.08. Secondary efficacy endpoints were progression-free survival (PFS), time to progression (TTP) and objective response rate (ORR) by modified RECIST. Type I error rates for secondary efficacy endpoints were controlled with a fixed sequence procedure at 2-sided α = 0.05 after OS NI was claimed. Results: 954 Pts enrolled (LEN: 478; SOR: 476). Efficacy outcomes are shown in the table. A similar number of pts in both arms had treatment-emergent adverse events (TEAEs). Most common LEN TEAEs were hypertension (42%), diarrhea (39%), decreased appetite (34%), decreased weight (31%), and fatigue (30%). Median (range) treatment duration was 5.7 mos (0−35.0) for LEN and 3.7 mos (0.1−38.7) for SOR. 13% Of LEN-treated and 9% of SOR-treated pts discontinued due to adverse events. 33% Of LEN-treated and 39% of SOR-treated pts received second-line therapy. Conclusions: LEN is noninferior in OS, and achieves statistically significant and clinically meaningful improvements in PFS, TTP, and ORR, as first line therapy for uHCC. TEAEs were consistent with the known LEN safety profile. Clinical trial information: NCT01761266. [Table: see text]
Nivolumab ± ipilimumab in pts with advanced (adv)/metastatic chemotherapy-refractory (CTx-R) gastric (G), esophageal (E), or gastroesophageal junction (GEJ) cancer: CheckMate 032 study.
Authors: Janjigian Yelena Yuriy , Ott Patrick Alexander , Calvo Emiliano , Kim Joseph W. , Ascierto Paolo Antonio , Sharma Padmanee , Peltola Katriina Johanna , Jaeger Dirk , Evans T.R. Jeffry , De Braud Filippo G. , Chau Ian , Tschaika Marina , Harbison Christopher T. , Cai Weiguo , Bendell Johanna C. , Le Dung T. 
Published: September 2018

4014 Background: In the phase 3 ONO-12 study, 3rd- or later-line nivolumab (N) monotherapy prolonged OS vs placebo in Asian pts with adv G/GEJ cancer (median OS, 5.3 vs 4.1 mo; HR, 0.63; P < 0.0001; ASCO-GI 2017, Kang YK et al. J Clin Oncol. 2017;35 (suppl 4S) [abstract 2]). The phase 1/2 CheckMate 032 study showed favorable clinical activity of N ± ipilimumab (I) in Western pts with adv CTx-R G/E/GEJ cancer (NCT01928394). We report updated long-term follow-up data of G/E/GEJ pts in CheckMate 032. Methods: Pts received N 3 mg/kg Q2W (N3), N 1 mg/kg + I 3 mg/kg Q3W (N1+I3), or N 3 mg/kg + I 1 mg/kg Q3W (N3+I1). Primary endpoint was ORR. Secondary endpoints included DOR, OS, PFS, and safety. Efficacy in pts by PD-L1 status was assessed. Results: 160 heavily pretreated pts (79% had ≥ 2 prior Tx) were enrolled (N3, n = 59; N1+I3, n = 49; N3+I1, n = 52); 24% had PD-L1+ (≥ 1%) tumors. ORR was 12% in N3, 24% in N1+I3, and 8% in N3+I1. In pts with PD-L1 ≥ 1%, ORR was 19% (3/16) in N3, 40% (4/10) in N1+I3, and 23% (3/13) in N3+I1; in pts with PD-L1 < 1%, ORR was 12% (3/26), 22% (7/32), and 0% (0/30), respectively. Median DOR was 7.1 mo in N3, 7.9 mo in N1+I3, and NA in N3+I1. OS in all pts and in pts with PD-L1 ≥ 1% is in the Table. Grade 3–4 treatment-related AEs reported in ≥ 10% of pts in any treatment arm were diarrhea (N3, 2%; N1+I3, 14%; N3+I1, 2%), ALT increased (N3, 3%; N1+I3, 14%; N3+I1, 4%), and AST increased (N3, 5%; N1+I3, 10%; N3+I1, 2%). Conclusions: N ± I led to durable responses and long-term OS in heavily pretreated Western pts with adv G/E/GEJ cancer, which is consistent with the clinical activity observed in Asian pts in the ONO-12 study. Safety was consistent with prior reports. These data support ongoing investigation of N ± I in pts with adv G/E/GEJ cancer. Clinical trial information: NCT01928394. [Table: see text]
A randomized phase III trial on the role of esophagectomy in complete responders to preoperative chemoradiotherapy (CRT) for esophageal squamous cell carcinoma (ESCC).
Authors: Park Sook Ryun , Yoon Dok Hyun , Kim Jong Hoon , Kim Yong-hee , Kim Hyeong Ryul , Lee Hyun Joo , Jung Hwoon-Yong , Lee Gin-Hyug , Song Ho June , Kim Do Hoon , Choi Kee Don , Lee Jeong Hoon , Ryu Jin-Sook , Cho Kyung-Ja , Kim Sung-Bae 
Published: September 2018

4020 Background: To investigate the role of esophagectomy in pts who achieved clinical complete response (cCR) with CRT for locally advanced ESCC. Methods: Pts with resectable cT3-T4a anyN M0 or anyT N+ M0 thoracic ESCC, 20-75 yrs, and ECOG PS ≤2 received 2 cycles of induction XP (capecitabine 1000 mg/m2 bid D1-14 + cisplatin 60 mg/m2 D1 q3w) followed by CRT (50.4 Gy/28 fx, X 800 mg/m2 bid x 5 d/w and P 30 mg/m2 weekly). Pts with cCR were randomized to surgery (S) or observation (O). The primary endpoint was disease-free survival (DFS). Results: From Nov 2012 to March 2016, 86 pts (17.7% of the target number) were enrolled. The slow accrual caused early closure of the study. 81 pts completed CRT, and 38 pts (44.2%) achieved cCR among whom 37 pts were randomized to S (n=19) or O (n=18). The compliance rates differed between the allocated arms (68.4% in the S arm vs 100% in the O arm; P=0.020). In both Intent-to-treat (ITT) and as-treated analysis, there were no significant differences in DFS, PFS, TTP, and OS in both arms although the S arm tended to have better DFS, PFS and TTP than the O arm (Table 1). In the as-treated analysis, the relapse rate was 23.1% (3/13) in the S arm and 45.8% (11/24) in the O arm ( P=0.288). All 10 locoregional only relapse in the O arm were considered resectable, of whom 8 pts underwent surgery (n=7) or endoscopic dissection (n=1). In the as-treated analysis, the S arm had a higher R0 resection rate (92.3% vs 42.9%; P=0.031) and lower pTNM stages ( P=0.0005) than the O arm. Conclusions: Watchful waiting might be a valuable option in pts with thoracic ESCC who have cCR to CRT. Further large-scale studies are necessary to confirm our results and to optimize treatment decision in the individual pt. Clinical trial information: NCT01740375. [Table: see text]
Correlation of benefit from immune checkpoint inhibitors with next gen sequencing (NGS) profiles in esophagogastric cancer (EGC) patients.
Authors: Ku Geoffrey Yuyat , Sanchez-Vega Francisco , Chatila Walid , Margolis Matthew , Fein Carly , Ilson David H. , Hechtman Jaclyn Frances , Tuvy Yaelle , Bouvier Nancy , Kundra Ritika , Shia Jinru , Heins Zachary J. , Middha Sumit , Zehir Ahmet , Ladanyi Marc , Berger Michael F. , Tang Laura H. , Solit David B. , Schultz Nikolaus , Janjigian Yelena Yuriy 
Published: September 2018

4025 Background: Immuno-oncology (IO) with anti-PD-1 and –PD-L1 antibodies (Abs) is active in EGC but only benefits a minority of Pts. Biomarkers are needed to identify responders. Methods: We reviewed our experience of Pts treated with anti-PD-1/PD-L1 Abs and correlated their outcomes with PD-L1 and mismatch repair protein (MMR) status by immunohistochemistry (IHC), as well as MSK-IMPACT (≥340-gene) NGS profile. MSIsensor from IMPACT assesses microsatellite instability phenotype, while ≥20 mutations (or 17 mutations/Mb) strongly correlates with MMR-deficiency (dMMR) by IHC (J Clin Oncol 2016;34:2141). Progression-free (PFS) and overall survival (OS) were analyzed from the start of IO. Results: 71 Pts were identified, with 3 Pts receiving 2 IO regimens. 66 had adenoCAs and 5 had squamous CAs. Median age 58, 77% male, 96% had received ≥2 prior chemo regimens. 39 (55%), 18 (25%) and 17 Pts (24%) respectively received anti-PD-1, anti-PD-L1 and anti-CTLA-4 plus anti-PD-1/PD-L1 Abs. 6 Pts (8%) had objective response (2 complete responses or CRs) and the median PFS and OS are 1.6 and 4.7 mos; 2-yr OS is 17%. PD-L1 IHC was performed in 16 Pts (23%; 7 +ve), MMR was tested in 20 Pts (28%; 4 dMMR) and IMPACT was obtained in 44 Pts (62%). All 4 dMMR tumors were also MSI by MSIsensor and had a median of 46 mutations (range, 29-63) or, equivalently, 33 mutations/Mb (range, 21-46); 2 of 2 dMMR tumors tested PD-L1 +ve. 3 of the 4 Pts with dMMR/MSI tumors had a response (including 1 CR) and the median OS of these 4 Pts is not reached with 23+ months of follow-up. Finally, a patient whose tumor is MMR-proficient, not MSI but has 15 mutations (including in POLD1), achieved an ongoing CR at 37+ mos. For the 44 Pts with IMPACT testing, there appeared to be improved OS for tumors with ≥10 vs. <10 mutations/Mb (2-yr OS 80% vs. 12%, p=0.03). Conclusions: Pts with tumors that are MSI or have ≥10 mutations/Mb on MSK-IMPACT appear to derive significant benefit from IO. MSK-IMPACT can offer novel information, identify novel mutations (e.g. POLD1) and may be used to help select Pts for IO. We are seeking to define a mutation no. cut-off that can serve as a biomarker and updated data will be presented.