bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and safety of lorlatinib in patients (pts) with ALK+ non-small cell lung cancer (NSCLC) with one or more prior ALK tyrosine kinase inhibitor (TKI): A phase I/II study.
Authors: Shaw Alice Tsang , Ou Sai-Hong Ignatius , Felip Enriqueta , Bauer Todd Michael , Besse Benjamin , Gadgeel Shirish M. , Camidge D. Ross , Lin Chia-Chi , Seto Takashi , Soo Ross A. , Chiari Rita , James Leonard P. , Clancy Jill S. , Martini Jean-Francois , Abbattista Antonello , Pithavala Yazdi K. , Solomon Benjamin J.
Published: September 2018

9006

Background: Lorlatinib is a selective, potent, brain-penetrant, next generation ALK/ROS1 TKI active against most known resistance mutations. In Ph I of this Ph I/II study, lorlatinib showed robust clinical activity in ALK+ or ROS1+ advanced NSCLC pts, most of whom had CNS metastases (mets) and were heavily pre-treated. In Ph II of this study, efficacy was explored based on prior ALK TKI tx as well as safety across all patients treated at the recommended Ph II dose. Methods: In this ongoing Ph II study (NCT01970865), pts with ALK+ or ROS1+ NSCLC, ± asymptomatic untreated or treated CNS mets, were enrolled into 6 expansion cohorts (EXP) based on prior tx (EXP 1-5, ALK+) and rearrangement status (EXP 6, ROS1+). Pts received lorlatinib 100mg QD. Primary objective was ORR and intracranial ORR (IC-ORR) by independent central review (ICR). Results: Efficacy (ALK+ pts with prior tx): At data cut-off (15 Aug 2016), 82 ALK+ pts were enrolled in cohorts EXP 2-5, received C1 no later than 31 Mar 2016 and were evaluated for ORR (ITT population); 52 were evaluated for IC-ORR and 35 were evaluated for IC-ORR response based on target lesions only (≥5mm; no prior radiotherapy or progression post prior radiotherapy). Confirmed response rates by ICR are reported in the table below. Safety (all pts): 116 ALK/ROS1+ pts were evaluated for safety at data cut-off. Most common tx-related AEs (TRAEs) and grade 3/4 TRAEs were hypercholesterolemia (90%, 17%) and hypertriglyceridemia (72%, 17%). Dose interruptions and reductions due to TRAEs were reported in 29% and 20% of pts, respectively. 14% of pts had tx-related SAEs. 5 pts (4%) discontinued tx due to TRAEs and there were no tx-related deaths. 74/116 pts (64%) remain on tx. Conclusions: Lorlatinib showed compelling clinical activity, with substantial IC activity, in ALK+ pts who received ≥1 prior ALK TKI, many of whom were heavily pre-treated. Clinical trial information: NCT01970865. [Table: see text]
KEYNOTE-001: 3-year overall survival for patients with advanced NSCLC treated with pembrolizumab.
Authors: Leighl Natasha B. , Hellmann Matthew David , Hui Rina , Carcereny Costa Enric , Felip Enriqueta , Ahn Myung-Ju , Eder Joseph Paul , Balmanoukian Ani Sarkis , Aggarwal Charu , Horn Leora , Patnaik Amita , Gubens Matthew A. , Ramalingam Suresh S. , Lubiniecki Gregory M. , Zhang Jin , Piperdi Bilal , Garon Edward B.
Published: September 2018

9011

Background: Pembrolizumab (pembro) is approved as first-line (1L) treatment for advanced NSCLC patients (pts) with PD-L1 tumor proportion score (TPS) ≥50% and as treatment for previously treated advanced NSCLC pts with PD-L1 TPS ≥1%. Here we present 3-y OS results for pts enrolled in KEYNOTE-001 (NCT01295827), the first trial evaluating pembro in advanced NSCLC pts. Methods: 550 pts received pembro 2 or 10 mg/kg Q3W or 10 mg/kg Q2W until intolerable toxicity, progression, or investigator or pt decision to withdraw. PD-L1 expression was assessed by IHC using the 22C3 antibody. Survival was assessed every 2 mo after treatment discontinuation. Results: 550 advanced NSCLC pts enrolled; 101 were first line (1L), and 449 were previously treated. As of the Sept 1, 2016, data cutoff, median follow-up duration was 34.5 mo (range, 25.7-51.5 mo); 8 (7.9%) 1L pts and 28 (6.2%) previously treated pts were still on treatment. 3-y OS was 26.4% (95% CI, 14.3%-40.1%) in 1L pts and 19% (95% CI, 15.0%-23.4%) in previously treated pts. 3-y OS rate and median OS by PD-L1 status are in the Table. Additional description of the pts with long-term survival, including updated safety data as well as 3-y OS by smoking history, histology, EGFRstatus, and prior radiation therapy, will be presented. Conclusions: Pembro provides promising long-term OS benefit for 1L and previously treated advanced NSCLC pts expressing PD-L1. The current data represent the longest efficacy and safety follow-up for pts with advanced NSCLC treated with pembro. Clinical trial information: NCT01295827. [Table: see text]
MET amplification (amp) as a resistance mechanism to osimertinib.
Authors: Piotrowska Zofia , Thress Kenneth Stephen , Mooradian Meghan , Heist Rebecca Suk , Azzoli Christopher G. , Temel Jennifer S. , Rizzo Coleen , Nagy Rebecca J , Lanman Richard B. , Gettinger Scott N. , Evans Tracey L. , Hata Aaron N. , Shaw Alice Tsang , Sequist Lecia V.
Published: September 2018

9020

Background: Osimertinib (osi) is an EGFR T790M inhibitor. Mechanisms (mech) of acquired resistance (AR) are under study. We report a cohort of osi-AR pts with extensive pre/post-osi tissue and plasma. Methods: We analyzed 23 pts with AR to osi. Tumor biopsies (bx) underwent NGS (SNaPshot, MGH) and FISH for EGFR, MET amp (target:CEP7 > 2.2.) Plasma underwent ctDNA NGS (Guardant360). Results: Of the 23 osi-treated EGFR-mutants (13 with EGFR del19, 10 L858R), 2 had de novo T790M, 21 acquired T790M. 13 had prior 3rd gen EGFR TKIs before osi - rociletinib(11), ASP8273(1), EGF816(1). Median time on osi was 12 mo (range 2-25), med total time on 3rd-gen EGFR TKIs was 18 mo. Bx types were tissue (16), plasma (18), and both (11, med interval 31d). All pts retained their founder EGFR mutation, but 15/23 (65%) “lost” T790M post-osi, suggesting AR arose from a T790wt subclone (Table). Common AR mech were MET amp (7/23; 30%) and EGFR C797S (5/23; 22%). 1 pt each had SCLC transformation, PIK3CA E545K/PIK3CA amp and FGFR1 D60N/FGFR1 amp. 2 pts had 2 distinct post-osi tissue bx showing heterogeneity. Pt 8 had plasma and a lung nodule with C797S/T790M while a mediastinal LN was wt at both loci. Pt 22 had MET-amp in pleural fluid but no MET amp on lung bx. Plasma identified AR mech not seen in tissue in 2/11 pts with both bx types. Among 7 pts with MET amp, 3 received combo EGFR/ MET TKI; all 3 had a RECIST PR. Conclusions: In this osi-resistant cohort, we commonly saw MET amp (30%) and C797S (22%). MET amp seems more common post-osi than after 1st-line TKIs, and 3/3 pts responded to EGFR+MET TKIs. AR heterogeneity was seen in 2 pts with matched tissue/plasma and 2 with >1 tissue bx, underscoring the complementary roles of plasma and tissue. [Table: see text]
NGS to reveal heterogeneity between cerebrospinal fluid and plasma ctDNA among non-small cell lung cancer patients with leptomeningeal carcinomatosis.
Authors: Jiang Ben-Yuan , LI Yangsi , Chuai Shaokun , Zhang Zhou , Yang Jin-Ji , Zhong Wenzhao , Zhou Qing , Wu Yi-Long
Published: September 2018

9022

Background: In current clinical setting, NSCLC patients harboring specific driver mutation were usually treated guiding by prior profiling of the primary tumor when developed to brain metastasis. Some studies have shown that circulating tumor DNA (ctDNA) derived from cerebrospinal fluid (CSF) can reveal unique genomic alterations present in brain malignancies. We assessed CSF as a liquid biopsy media and compared to matched plasma. Methods: We performed capture-based ultra deep sequencing on ctDNA derived from matched CSF, plasma of 40 non-small cell lung cancer (NSCLC) patients with suspected leptomeningeal carcinomatosis (LC) using a panel consisting of 168 genes. Results: Among the 40 suspected LC cases, 35 were confirmed to have LC, ctDNA in CSF from the 5 non-LC cases are all undetectable. Circulating tumor DNA was detected in 93.8% of CSF and 66.7% of plasma. We compared mutation profiles and identified 86 and 46 SNVs from CSF and plasma, respectively, with 42 SNVs overlapping. Furthermore, ctDNA from CSF revealed many copy number variations (CNVs) that were not detected from plasma (189 CNVs vs. 3 CNVs). The average maximum allelic fraction (AF) of CSF ctDNA is significantly higher than in plasma (56.7% vs. 4.4% p < 10^-6). Twenty-eight patients were pre-treated with EGFR-TKIs and developed subsequent resistance. EGFR T790M and MET amplification were detected in 21% and 39% in CSF, respectively, showing a unique resistance profile among leptomeningeal metastases patients compared to the general population. Interestingly, 60% of CSF samples harbor TP53 loss of heterozygosity, only 11% of which were detected in the matched plasma samples. Such heterogeneity may reflect unique biological themes for brain metastatic tumor sub-clones. Furthermore, 26 patients received molecular targeted therapy based on the results from CSF, and 23 reported alleviation of symptoms at subsequent evaluations. Conclusions: Collectively, our data reveal that ctDNA derived from CSF provides a unique and more comprehensive characterization of genomic alterations of leptomeningeal carcinomatosis than plasma, supporting the importance of CSF as a liquid biopsy media.
Evaluation of stored liquid biopsies for molecular profiling in patients with non-small cell lung cancer (NSCLC).
Authors: Bradbury Penelope Ann , Ding Keyue , Ellis Peter Michael , Seymour Lesley , De Kievit Frank , Jones Greg , Morris Clive D. , Green Emma , Goss Glenwood D. , Tsao Ming Sound , Shepherd Frances A.
Published: September 2018

9024

Background: Molecular profiling is often limited by access to sufficient tumour tissue for comprehensive analysis and due to tumour heterogeneity, the complete range of tumor DNA abnormalities may not be represented nor accurately reflect the clinical evolution of disease. Circulating tumour DNA (ctDNA) can be used as a liquid biopsy for molecular abnormalities detection, quantification and monitoring for personalised treatment strategies. Methods: Plasma was collected at baseline (BL) and during study therapy from advanced NSCLC patients (pts) enrolled in a placebo controlled phase III trial of a novel irrerversible EGFR inhibitor; all patients had received standard therapy with chemotherapy and gefitinib or erlotinib. Archival tissue was collected when available but biopsy was not required prior to enrolment. BL Plasma ( < 3ml), stored for ~8 years was used to extract DNA and analysed using InVision (enhanced tagged-amplicon sequencing). Results: BL plasma from 387 pts was tested; 289 pts had available tissue results (from archival tissue collected at diagnosis) for EGFR (174WT/115Mut) and 243 for KRAS (205WT/38Mut). Despite age of plasma samples, ctDNA analysis detected cancer mutations in 310 pts (82%): TP53 (45%), KRAS (15%), and EGFR (43%; 56% were EGFR del19 and 29% L858R); T790M was detected in 80 patients. EGFR mutations were identified in 29 patients and KRAS in 10 patients with unknown tissue status. Also of note, STK11 (32 pts, 12 with KRAS), BRAF (5pts, 3 with V600E), MET(7 pts, 4 with METamp), ERBB2 (16pts, 10 with ERBB2amp) were identified in ctDNA analysis. Median time and median number of lines of systemic therapy between tissue biopsy and blood was 714 days and 3 lines respectively. Further analyses of ctDNA analyses in context of patient and trial outcomes are in progress. Conclusions: Liquid biopsies provide opportunity to evaluate molecular mutation profile in NSCLC patients. We demonstrate a highly sensitive method for ctDNA analysis which is complementary to tissue molecular analysis.
The predictive value of uncommon EGFR mutation in patients with non-small-cell lung cancer.
Authors: Tu Haiyan , Ke Ee , Sun Yue-Li , Zheng Ming-Ying , Yang Jin-Ji , Wang Zhen , Wu Si-Pei , Su Jian , Zhang Xuchao , Bai Xiao-Yan , Yang Xue-Ning , Zhong Wenzhao , Yan Hong-Hong , Zhou Qing , Wu Yi-Long
Published: September 2018

9028

Background: Non-small-cell lung cancers with uncommon epidermal growth factor receptor ( EGFR) mutations are regarded as a heterogeneous group with variable responses to EGFR-targeted drugs. Here we designed this retrospective study to describe the epidemiology and clinical outcomes of uncommon EGFR mutations in a Chinese cohort of lung cancer patients. Methods: Between June 2007 and June 2014, 5363 lung cancer patients whose EGFR genotyping was performed successfully at Guangdong Lung Cancer Institute (GLCI, Guangzhou, China) were screened. 1837 patients were included in the epidemiological analysis. The clinical outcome was analyzed in 97 advanced-stage patients harboring uncommon EGFR mutations with follow-up data. Results: 218 patients harbored uncommon EGFR mutations, making up 11.9% of all cancers with documented EGFR mutations. Compared with common mutants, those with uncommon mutations were more commonly found in smokers and male patients. The most frequently detected uncommon mutations were exon 20 insertions, G719X mutations and L858R complex mutations, occurring in 30.7%, 21.1% and 17.0% of all EGFR-uncommon-mutation cases. G719X and L858R complex mutations were associated with similar benefit from EGFR-TKI; median PFS was 15.2 (95% CI 8.7-21.7) and 11.6 (95% CI 3.6-19.6) months, respectively. T790M or 20INS was associated with a poorer EGFR-TKI response; median PFS was 1.0 (95% CI 0.0-2.2) and 3.0 (95% CI 1.3-4.7) months, respectively. Of note, two patients with 23% and 65% tumor shrinkages had N771_P772insN and H773_V774insQ, with PFS of 5.7 and 6.1 months respectively. Conclusions: Favorable responses were observed in specific subtypes including complex L858R and G719X, and our results suggested first-line EGFR-TKI should be preferable in such patients.
The novel detection of EGFR-T790M mutations in exhaled breath condensate.
Authors: Smyth Robert , Toomey Sinead , Sartori Alexander , Hanrahan Emer O. , Cuffe Sinead , Murray Hazel , McDonnell Deirdre , Breathnach Oscar S. , Finn Stephen P. , Grogan William , Morris Patrick G. , Morgan Ross , Hennessy Bryan
Published: September 2018

9032

Background: The EGFR-T790M somatic mutation is the most common mechanism of resistance to Tyrosine Kinase Inhibitors (TKI) in NSCLC. However patients with advanced disease are not always amenable to repeat biopsy for further molecular analysis. Developing non-invasive methods to detect T790M in cell-free DNA (cfDNA), in the absence of tissue is being actively investigated. Furthermore these 'liquid biopsies' may also overcome the problem of tumour genomic heterogeneity. Unfortunately the sensitivity of plasma for T790M detection has been disappointing with a significant chance of a false negative result. Exhaled breath condensate (EBC) is an easily collected sample and is known to harbour cfDNA, including lung cancer mutations. We explored the potential of EBC as a novel method of T790M detection. Methods: We recruited 26 patients who were either 1) known T790M positive pre/during Osimertinib therapy or 2) other mEGFR positive patients on 1st/2nd generation TKI. We collected matched plasma and EBC samples in the majority of cases. EBC samples were collected using the RTube device. Plasma was collected using standard EDTA tubes and extracted within 90 minutes. Using UltraSEEK chemistry, a targeted PCR for ultra-sensitive somatic mutation profiling on the MassARRAY system (Agena Bioscience), we compared the performance of EBC to plasma for the detection of T790M. Results: See Table. Conclusions: In this pilot study we describe the first ever report of the successful and consistent detection of T790M in the EBC of patients with EGFR mutated NSCLC, using a commercially available targeted assay. Our results suggest EBC is responsive to recognised dynamic molecular changes that occur on TKI treatment. We believe this makes EBC analysis an attractive avenue for future research, to optimise the detection of T790M mutations in liquid biopsies. [Table: see text]
EGFR analysis of 21,039 patients with NSCLC: Age-related gradual increase of the L858R mutation frequency in adenocarcinomas and high occurrence of ex19del/L858R mutations in squamous cell carcinomas from females and/or nonsmokers.
Authors: Imianitov Evgenii , Demidova Irina , Gordiev Marat , Filipenko Maxim , Kekeeva Tatiana , Moliaka Yuri , Gervas Polina , Kozhemyako Valeriy , Vodolazhsky Dmitriy I. , Aleksakhina Svetlana , Kharitonova Ekaterina , Tsimafeyeu Ilya , Tjulandin Sergei
Published: September 2018

9040

Background: EGFR testing in Russia is carried out upon the patronage of Russian Society of Clinical Oncology (RUSSCO), and the results are accumulated in a centralized database. Squamous cell carcinomas (SCC) constitute 60-70% of NSCLC incidence in Russia, however physicians are often discouraged to send NSCLC-SCC for EGFR testing due to low frequency of mutations. Methods: We considered all NSCLC patients analyzed by means of PCR for the presence of EGFR mutations (ex19del and L858R) within years 2012-2017. Results: 21,039 NSCLC patients were tested. EGFR analysis was successful in 20,768 patients (98.7%). EGFR mutations were detected in 3566/17717 (20.1%) adenocarcinomas (AdCa) of the lung (ex19del: 2203 (12.4%); L858R: 1363 (7.7%)). There was an evident age-related increase in the frequency of L858R substitution in AdCa patients (p =0.000, Table). This set of patients included 1,139 NSCLC-SCC cases, and the EGFR mutation was observed in 41 (3.6%) subjects. Among 189 females with NSCLC-SCC, ex19del or L858R were detected in 25 (13.2%) cases. Stratification by smoking status revealed EGFR mutation in 19/242 (7.9%) non-smokers. Conclusions: Elderly NSCLC patients have particularly increased probability to be diagnosed with L858R mutation. In the real-world setting, patients with NSCLC-SCC may have high frequency of EGFR mutations, either due to imprecise histological subtyping or due to yet unknown reasons. All female and non-smoking patients with NSCLC have to undergo EGFR testing irrespectively of tumor histology. [Table: see text]
Molecular panel sequencing of pre-treatment samples to reveal mechanisms of innate resistance to 3rd generation EGFR TKI treatment in T790M-positive NSCLC patients.
Authors: Michels Sebastian Yves Friedrich , Heydt Carina , Deschler-Baier Barbara , Ruesseler Vanessa , Stratmann Jan , Steinhauser Susanne , Fischer Rieke Nila , Scheffler Matthias , Fassunke Jana , Nogova Lucia , Brandes Vanessa , Kostenko Anna , Griesinger Frank , Gautschi Oliver , Sebastian Martin , Hellmich Martin , Heukamp Lukas C. , Merkelbach-Bruse Sabine , Buettner Reinhard , Wolf Juergen
Published: September 2018

9041

Background: Resistance to early generation epidermal growth factor receptor ( EGFR) tyrosine kinase inhibitors (TKI) inevitably develops in EGFR-mutant lung cancer. The secondary EGFR p.T790M mutation is the driving factor in 60% of cases and 3rd generation EGFR TKIs have been developed to overcome T790M-mediated resistance. However, besides T790M other genetic aberrations such as amplifications of MET may contribute to resistance to EGFR inhibition in the same patient. We here report on the systematic analysis of co-occurring genetic aberrations that may influence response to 3rd generation EGFR TKIs. Methods: Thirty-six patients were treated with 3rd generation EGFR TKIs in the setting of acquired resistance to EGFR inhibition in cancer centers in Germany and Switzerland. Pre-treatment samples were analyzed for co-occurring genetic aberrations in a subset of resistance-related genes including MET, HER2, RAS-gene family, PIK3CA, CTNNB1 and PTEN using next-generation sequencing and fluorescence in-situ hybridization assays. We investigated the association between clinical, epidemiological and molecular data and response to treatment (RECIST 1.1). Results: Co-occurring genetic aberrations were found in 68% of the pre-treatment samples where both, analyses by sequencing and FISH were feasible (N = 25). Efficacy of 3rd generation EGFR TKIs significantly dropped in the presence of high-level MET amplification as compared to wild-type MET (ORR, 0.0%; 95% CI, 0.0-60.4 vs. 70.0%; 95% CI, 45.7-87.2; p = 0.02; median PFS, 1.0 month; 95% CI, 0.37-1.72 months vs. 8.2 months; 95% CI, 1.69-14.77 months; p ≤ 0.001). No statistically significant association was found between treatment efficacy and the molecular status of the genes analyzed or the number of prior EGFR TKIs. Conclusions: Prevalence of additional genetic aberrations is frequent in the setting of acquired resistance to early generation EGFR TKIs and may not necessarily mediate resistance to 3rd generation EGFR TKIs. However, in our analysis high-level amplification of MET was associated with primary treatment failure and might be the main factor underlying resistance in this setting.
Microwave ablation in combination with chemotherapy versus chemotherapy in advanced non small cell lung cancer: A prospective, randomized, phase III clinical trial.
Authors: Wei Zhig , Ye Xin , Geng Dian zhong , Dong Yu ting , Wang Chun tang , Bi Jing wang , Sun Ya hong , Wang Jun ye , Feng Qing liang , Xu Xing lu , Zhang Ben hua , Zhang Li cheng , Ren Hai peng , Zhang Kai xian , Sun Deng jun
Published: September 2018

9048

Background: Previous studies showed that advanced non small cell lung cancer (NSCLC) benefited from microwave ablation in combination with platium-based doublet chemotherapy. This prospective, randomized, phase III clinical trial aimed to determining the survival benefit and safety of MWA combined with chemotherapy compared with chemotherapy alone, which was registered in Clinical Trials. gov (NCT02455843). Methods: Patients with untreated, stage IIIB or IV NSCLC and at least one additional measurable site other than the primary tumor site were recruited. They were divided into MWA/chemotherapy group and chemotherapy group, the former received MWA in the primary tumor sites, followed by chemotherapy and the latter treated with chemotherapy only. The primary endpoint was progression-free survival (PFS), the second endpoint included objective response rate (ORR), overall survival (OS) and adverse events (AE). Results: From Mar 1st, 2015 to Oct 31th, 2016, Two hundreds and eighty-six patients were enrolled, including 141 in MWA/chemotherapy group and 145 in chemotherapy group. Complete ablation was observed in 95.0 % patients. ORR were 38.3 % and 34.1 % in the MWA/chemotherapy group and chemotherapy group, respectively(p = 0.677). MWA prolonged PFS [MWA/chemotherapy group 7.3 (95 % CI,5.3–13.6) ms vs. chemotherapy group 5.2 (95 % CI, 4.0–12.4) ms, p = 0.003]. Multivariate analyses showed that MWA was an independent prognostic factor of PFS. OS was immature. AEs of MWA were observed in 67.4 % patients, mainly was pheumothorax, and only 15% needing chest tube insertion. No ablation associated death was observed. Chemotherapy-associated AEs were observed in 49.1 and 53.6 % of patients in the MWA/chemotherapy and chemotherapy group, respectively. Conclusions: MWA plus chemotherapy combination improved the PFS of advanced NSCLC compared to chemotherapy alone. Adverse events of MWA was tolerable. Clinical trial information: NCT02455843.
Updated survival of patients (pts) with previously treated BRAF V600E–mutant advanced non-small cell lung cancer (NSCLC) who received dabrafenib (D) or D + trametinib (T) in the phase II BRF113928 study.
Authors: Planchard David , Besse Benjamin , Kim Tae Min , Quoix Elisabeth A. , Souquet Pierre Jean , Mazieres Julien , Barlesi Fabrice , Groen Harry J.M. , Smit Egbert F. , Baik Christina S. , Cho Byoung Chul , Kelly Ronan Joseph , Socinski Mark A. , Novello Silvia , Rigas James R. , Giannone Vanessa , D'amelio Anthony Michael , Zhang Pingkuan , Mookerjee Bijoyesh , Johnson Bruce E.
Published: September 2018

9075

Background: BRAF V600E mutations occur in 1% to 2% of lung adenocarcinomas and act as oncogenic drivers. Initial cohorts of the BRF113928 (NCT01336634) trial evaluated efficacy and safety of D monotherapy (cohort A; n = 78) or D + T (cohort B; n = 57) in pts with previously treated BRAFV600E–mutant metastatic NSCLC. At primary analysis, overall response rates (ORRs) were 33.3% and 63.2% in pts who received D or D + T, respectively. Furthermore, durable response (median duration of response [DOR], 9.0 mo) was observed in D + T pts. Here, we present an updated survival analysis based on additional follow-up. Methods: In this phase 2 trial, 2 cohorts (A and B) of pts with previously treated metastatic BRAFV600E–mutant NSCLC were enrolled sequentially. The primary endpoint was investigator-assessed ORR. Secondary efficacy endpoints included progression-free survival (PFS), DOR, and overall survival (OS). D and T were dosed orally at the established phase 2 dose of D 150 mg twice daily and T 2 mg once daily. Results: This updated analysis had a median follow-up of 16.2 mo, which represented an additional 10 mo of follow-up. Median OS was 12.7 mo (95% CI, 7.3-16.3) with 57 deaths reported for pts treated with D monotherapy and 18.2 mo (95% CI, 14.3-not estimable [NE]) with 33 deaths reported for pts treated with D + T. Detailed efficacy results are presented in the table. Investigator-assessed ORR, DOR, and PFS were supported by independent review committee assessments. No new safety signals were observed for D + T. Conclusions: This update of the BRF113928 study confirms that durable responses and encouraging survival were achieved with combination D + T in pts with BRAFV600E–mutant NSCLC. Clinical trial information: NCT01336634. [Table: see text]
Exposure-response and PD-L1 expression analysis of second-line avelumab in patients with advanced NSCLC: Data from the JAVELIN Solid Tumor trial.
Authors: Gulley James L. , Spigel David R. , Kelly Karen , Aisner Joseph , Chand Vikram K. , Koenig Andre , Dolgos Hugues , Wang Shaonan , Verschraegen Claire F.
Published: September 2018

9086

Background: Avelumab is a fully human anti‒PD-L1 IgG1 antibody showing promising efficacy and safety in patients (pts) with non-small cell lung cancer (NSCLC) and other tumors. Here, we present exposure–response (E–R) and PD-L1 expression analyses of second-line (2L) avelumab treatment in pts with NSCLC from a phase 1 trial (NCT01772004). Methods: Pts with NSCLC received 2L avelumab 10 mg/kg IV every 2 weeks (Q2W) until progression or unacceptable toxicity. Serum samples were taken at various time points for pharmacokinetic (PK) analysis. Trough concentrations after first dose (Ctroughfirst-dose) were predicted using an identified linear 2-compartment population PK (popPK) model without covariates other than pt body weight. Objective response rate (ORR) was evaluated (RECIST v1.1), and correlated with tumor cell (TC) PD-L1 expression (clone 73-10). Pooled safety data from various tumors in the large phase 1 trial were assessed. Results: In 184 avelumab-treated pts, unselected for PD-L1 expression, ORRs were 8.7%, 10.9%, 19.6%, and 17.4% for increasing quartiles of Ctroughfirst-dose (Q1–4). Using ≥1%, ≥5%, ≥50%, and ≥80% PD-L1 staining cutoffs, pts in the upper half of exposure (Ctroughfirst-dose Q3–4 [n = 92]), had ORRs of 25% (n = 59), 26% (n = 39), 33% (n = 21), and 43% (n = 14), respectively. Higher avelumab exposure was associated with a modest increase in immune-related adverse events (irAEs). PopPK modeling suggested Ctroughfirst-dose could be optimally increased with alternate avelumab dosing (10 mg/kg weekly vs Q2W, or 20 mg/kg Q2W [simulated median Ctroughfirst-dose 48 μg/mL vs 18 μg/mL, or 36 μg/mL]). Conclusions: Avelumab has shown clinical activity and acceptable safety in multiple tumors similar to other agents in class. Preliminary analysis of a cohort of pts with 2L advanced NSCLC shows a trend for higher ORR with increasing avelumab Ctroughfirst-dose quartiles and with higher levels of TC PD-L1 expression. Although this apparent E–R observation may be confounded by single-dose testing or other factors, this analysis provides rationale for studies of more intensive avelumab dosing regimens to assess further clinical benefit in pts with advanced NSCLC. Clinical trial information: NCT01772004.
The demand for psycho-oncological support in 820 melanoma patients: What are the determinants for the development of distress?
Authors: Forschner Andrea , Riedel Petra , Gassenmaier Maximilian , Scheu Alexander , Kofler Lukas , Garbe Claus , Schäffeler Norbert , Mayer Simone , Eigentler Thomas K.
Published: September 2018

9514

Background: There is limited data about the impact of melanoma on the psychological burden of patients. Despite some known predictors for distress like female gender or younger age, melanoma stages have not been found being related to distress in melanoma patients and there is no data concerning distress in melanoma patients under systemic treatment for metastases. Methods: Between July and September 2016, 820 melanoma patients at the outpatient clinic at the Department of Dermatology at the University of Tuebingen underwent psycho-oncological screening. The patients routinely completed the distress thermometer (DT), supplemented by a problem list, before consulting the physician. DT scores ≥ 5 are above-threshold, indicating the need for psycho-oncological support. We matched psycho-oncological data with tumor and patient specific data to examine tumor or patient specific influence on distress using logistic regression. Results: 406 (49.5%) men and 414 (50.5%) women were included, mean age was 62.35 years (IQR 52-75), mean time since primary diagnosis of melanoma was 54.84 months (IQR 15-76). 359 (44%) of the patients suffered from advanced melanoma (stage III n = 182, stage IV n = 177). 120 patients (14.6%) received systemic treatment for metastases: 90/120 (75%) checkpoint inhibitors, 27/120 (22.5%) targeted therapy and 3/120 (2.5%) chemotherapy. 338/820 (41.2%) of the patients met the cut-off score for distress. Significant influencing factors (p < 0.05) for DT values of ≥ 5 were: female gender, younger age, melanoma stage III and IV. Interestingly we found a lower risk for values above-threshold for patients under systemic treatment, although this was not significant (p = 0.252). Conclusions: This is the first analysis to demonstrate the impact of advanced melanoma stages on DT scores above-threshold. Our study is also the first to indicate a lower risk for distress in patients under systemic treatment. This might be due to the closer contact between these patients and their physicians. Nevertheless, more than 40% of our patients needed psycho-oncological support. Departments that care for melanoma patients should therefore be fitted by a sufficient number of psycho-oncologists.
Management of gastrointestinal (GI) toxicity associated with nivolumab (NIVO) plus ipilimumab (IPI) or IPI alone in phase II and III trials in advanced melanoma (MEL).
Authors: Weber Jeffrey S. , Larkin James M. G. , Schadendorf Dirk , Wolchok Jedd D. , Wagstaff John , Dummer Reinhard , Hogg David , Guidoboni Massimo , Sosman Jeffrey Alan , Chmielowski Bartosz , Gerritsen Winald , Bhore Rafia , Walker Dana , Gonzalez Rene
Published: September 2018

9523

Background: NIVO and IPI are approved as monotherapy and in combination for treatment of MEL. These treatments are associated with select (potentially immune-related) adverse events (AEs) of the GI tract, most commonly diarrhea and colitis. We describe the management of GI toxicity in patients (pts) treated with NIVO+IPI or IPI from phase II (CheckMate 069) and III (CheckMate 067) trials. Methods: Pts received NIVO 1 mg/kg + IPI 3 mg/kg Q3W x 4, followed by NIVO 3 mg/kg Q2W until progression or unacceptable toxicity, or IPI 3 mg/kg Q3W x 4, followed by placebo. Minimum follow-up was 2 yrs for CheckMate 069 and 18 months for CheckMate 067. Results: Of 407 pts treated with NIVO+IPI, 195 (48%) experienced any grade select GI AEs, and of 357 pts treated with IPI, 132 (37%) experienced any grade select GI AEs. Grade 3/4 select GI AEs were reported in 67 (16%) pts treated with NIVO+IPI and in 41 (11%) pts treated with IPI; median time to onset was 7.1 weeks (range 0.9-48.9) with NIVO+IPI and 7.3 weeks (range 0.6-14.9) with IPI. To manage these AEs, immune-modulating medications (IMM) were used in 61/67 (91%) pts in the NIVO+IPI group and in 41/41 (100%) in the IPI group. Corticosteroids (CS) were used in 61/67 (91%) and 41/41 (100%) pts, and infliximab (IFX) was used in 21/67 (31%) and 14/41 (34%) pts in the NIVO+IPI and IPI groups, respectively. In the NIVO+IPI group, the resolution rate of grade 3/4 select GI AEs was 96%, 97%, and 95% with a median time to resolution of 3.3, 3.0, and 3.9 weeks in all treated pts, CS, and CS+IFX managed pts, respectively; 88%, 92%, and 79% resolved with a median time to resolution of 3.9, 2.4, and 7.8 weeks in the IPI group, respectively. Objective response rates (ORR) were unchanged in the presence of any grade select GI AEs, or by using CS or CS+IFX (Table). Conclusions: NIVO+IPI or IPI alone is associated with a high incidence of GI select AEs, but most are effectively managed by IMMs, which do not appear to inhibit tumor response. Clinical trial information: NCT01844505; NCT01927419. [Table: see text]
Distinct gene expression, mutational profile and clinical outcomes of V600E and V600K/R BRAF-mutant metastatic melanoma (MM).
Authors: Pires Da Silva Ines Esteves Domingues , Wang Kevin Y. X. , Wilmott James S. , Holst Jeffrey , Park John J , Quek Camelia , Wongchenko Matthew , Yan Yibing , Mann Graham J , Carlino Matteo S. , Kefford Richard , Scolyer Richard A. , Yang Jean , Long Georgina V. , Rizos Helen , Menzies Alexander M.
Published: September 2018

9541

Background: BRAF V600E and V600K/R mm have distinct clinicopathologic features suggesting different etiology. V600K/R mm appears less responsive to MAPK inhibitors (MAPKi) compared to V600E MM. We investigated potential mechanisms for this by comparing the gene expression and mutation profiles of these two melanoma subgroups. Methods: BRAF V600 mutant mm patients (pts) treated with MAPKi (BRAFi +/- MEKi) between July/2009 and July/2013 were selected. Demographics, clinicopathologic features and clinical outcomes were examined. Pre-treatment FFPE tumors underwent RNA expression profiling (795-gene nanostring panel) and DNA sequencing (239 gene NGS panel). Molecular results were validated using an independent cohort from the The Cancer Genome Atlas (TCGA). Results: 95 mm pts were included (78 V600E, 17 V600K/R), with median (med) follow-up of 18.4 months (mo). 74 (78%) had BRAFi, 21 (22%) had BRAF/MEKi. At MAPKi start, there were no differences between subgroups regarding age, gender, ECOG, AJCC stage or LDH level. V600K/R pts had a trend to less tumour regression by RECIST (med 30% vs 51%, p = 0.08) and shorter PFS (med 5.1 vs 7.1mo, p = 0.08) than V600E, with no difference in OS (20.8mo vs 17.9mo, p = 0.64). V600K/R had lower expression of the MAPK-pathway feedback regulator DUSP6 and glycosyltransferase GCNT1, compared to V600E (p < 0.05). Analysis of TCGA data (122 V600E, 21 V600K/R) confirmed these findings. There was a trend toward higher mutational load in V600K/R than V600E, confirmed with TCGA data (p < 0.05). V600K/R had a higher proportion of mutations in PIK3CA and several tumour suppressor genes (FBXW7, NF2, RB1 and SMAD4), with only FBXW7 confirmed using TCGA data. Conclusions: V600K/R mm has inferior response and shorter survival with MAPKi than V600E, potentially due to less reliance on MAPK pathway activation (lower DUSP6 expression) and greater use of alternative drivers of oncogenesis (higher mutational load, particularly in tumor suppressor genes). Further analyses will be performed, including comparison of MAPK and additional pathway signalling in cell models. Response to immunotherapy will also be examined.
Survival trends among patients with metastatic melanoma in the United States: A population based study.
Authors: Kunwor Ranju , Nepal Mahesh , Ho Dominic , Ghimire Krishna Bilas
Published: September 2018

9555

Background: Ipilimumab was approved by FDA in March 2011 for the treatment of Metastatic Melanoma. We conducted this study to compare survival outcome in patients with Metastatic Melanoma in pre- (1973-2010) and post- (2011-2013) ipilimumab era in the United States using U.S. Surveillance, Epidemiology, and End Result (SEER) registry database. Methods: We selected patients with metastatic melanoma age ≥ 20 years from the SEER database. We used SEER 18 registry database to evaluate relative survival (RS) rate during 1973-2010 and 2011-2013. The RS rate at 1year and 2 year were analyzed for cohorts by age (20-49 years, 50-74 and ≥75 years), race [White, African American (AA), and others] and gender. The RS rates (%) accompany standard error (SE). We used SEER Stat software for statistical analysis. Results: There were a total of 129,362 (106,516 and 22,846 in pre and post ipilimumab era) metastatic melanoma patients, male (n = 71,220), female (n = 58,142), white (n = 121,843), AA (n = 854) other (n = 1,315) reported in the registry. RS in pre vs post-ipilimumab era for age group 20-49 was: 96.50 ± 0.1% vs 97.20 ±0.3%, P = 0.013; and 94.10 ± 0.1% to 95.60 ±0.40, P = 0.0009; for age group 50-74 was: 94.10 ± 0.1% vs 95.30 ± 0.2%, P = 0.0001; and 90.70 ± 0.1%vs 92.90 ± 0.3%, P = 0.0001; and for age group ≥75 was 90.80 ± 0.3% vs 91.40 ± 0.7%, P = 0.23; and 85.0 ± 0.4% vs 88.10 ± 1.0%, P = 0.011 at 1 and 2 years respectively. Overall RS in pre and post ipilimumab era for white population was: 93.83 ± 0.16% vs 94.567 ± 0.4%, P = 0.017; and 90.0 ± 0.2% vs 92.033 ± 0.6%, P = 0.0008 at 1 and 2 years respectively. Similarly RS for AA was: 78.07 ± 2.93% vs 73.33 ± 8.23%, P = 0.37; and 65.87 ± 3.47% vs 65.33 ± 9.73%, P = 0.94; and for other race was: 85.2 ± 2.13% vs 77.97 ± 5.6%, P = 0.04; and 74.43 ± 5.2% vs 69.67 ± 6.7%, P = 0.1 at 1 year and 2 years. Conclusions: Our study showed that younger (20-74 years) patients with metastatic melanoma have improvement in 1 and 2-year RS rates in post ipilimumab era. Subgroup analysis by race showed no improvement in RS in AA and other races patients during this period. There was also no significant survival benefit seen in older (≥ 75 years) patients of all races and gender in post ipilimumab era.
Clinical presentation of immune-related colitis associated with PD-1 inhibitor monotherapy (MONO) and combination PD-1/CTLA-4 inhibitors (COMBO) in melanoma.
Authors: Wang Daniel Ying , Kim Dae Won , Shah Neil J. , Conry Robert Martin , Mehta Rutika Jitesh , Silk Ann W. , Zhou Alice , Voorhees Amber L , McKee Svetlana B , Norrell Jacqueline , Mehnert Janice M. , Puzanov Igor , Gibney Geoffrey Thomas , Rapisuwon Suthee , Eroglu Zeynep , Johnson Douglas Buckner
Published: September 2018

9566

Background: Ipilimumab-related colitis has been well described, but the clinical presentation of colitis related to MONO or COMBO therapy has not. We aimed to characterize clinical features that define this serious adverse event. Methods: This retrospective study included melanoma pts with colitis screened from 6 academic centers treated with either MONO or COMBO therapy. Clinically relevant colitis was defined as diarrhea/colitis symptoms requiring systemic steroids. The onset, management, and outcomes related to colitis were summarized. Results: We screened 866 pts and identified 72 with clinically relevant colitis. For the MONO cohort, the incidence was 3.5% (23/657) and 23.4% (49/209) in the COMBO cohort. MONO-colitis occurred at a median 33 weeks (wks) into therapy, while median onset was 8 wks with COMBO therapy. One pt had grade 5 colitis from COMBO therapy. Despite the use of systemic steroids, COMBO-colitis needed more infliximab therapy (38.8% vs 26.1%). The median prednisone equivalent dose was higher for COMBO therapy (1.5 vs 1 mg/kg), and the median taper was shorter for MONO-colitis (4 vs 6 wks). Steroid dose-escalation for worsening symptoms during taper was more common with COMBO-colitis (42.9% vs 17.3%). Relapse was similar between cohorts (MONO: 26.1%, COMBO: 20.4%). Relapses occurred more frequently in COMBO therapy with tapers shorter than the median (38.1% vs 25.0%), and more frequently in MONO therapy with steroid doses lower than the median (60% vs 21.7%). MONO-colitis pts (17.4%) were less likely than COMBO-colitis pts (46.9%) to be restarted on PD-1 therapy. When restarted, only 13% with COMBO therapy relapsed as compared to 50% with MONO therapy. Objective response rates for MONO and COMBO cohorts were 72.7% and 56.1%, respectively. Conclusions: Colitis occurred with a much higher incidence in COMBO therapy. MONO-colitis was associated with a milder course with later onset, shorter duration and lower dose of steroids, fewer dose-escalations, and need for infliximab as compared to COMBO therapy. Relapse of colitis was generally associated with shorter steroid tapers for COMBO therapy and lower steroid doses for MONO therapy.
Prognostic factors for overall survival (OS) in metastatic melanoma (MM) patients (pts) treated with immune checkpoint inhibitors: A single institution study of 696 pts.
Authors: McKean Meredith Ann , Haydu Lauren Elaine , Ma Junsheng , Bassett Roland L. , Hwu Wen-Jen , Patel Sapna Pradyuman , Diab Adi , Glitza Isabella Claudia , Tawbi Hussein Abdul-Hassan , Wong Michael K , McQuade Jennifer Leigh , Hwu Patrick , Davies Michael A. , Amaria Rodabe Navroze
Published: September 2018

9574

Background: Limited OS data, including prognostic and predictive factors of response, is available in mm pts treated with immune checkpoint inhibitors. Methods: A single-institution retrospective review was conducted on 696 mm pts treated with single-agent anti CTLA-4 or anti PD-1 on and off clinical trial between 2011-2015. Median OS was calculated from mm diagnosis. Results:Median age at mm diagnosis was 60 years old (range 15-86) and 65.2% were male. Subtypes were 63.2% non-acral cutaneous, 17.2% unknown primary, 7.8% mucosal, 6.5% acral, and 5.3% uveal. AJCC v7 staging at diagnosis was 7.9% M1a, 16.5% M1b, 33.0% M1c, and 42.5% not staged due to unknown LDH. LDH was elevated in 18.0% (400 pts). Mutation rates were 30.0% BRAF V600E/K (636 pts tested) and 24.5% NRAS (429 pts tested). First-line therapy for BRAF V600E/K mm pts included anti CTLA-4 (24.1%), BRAF/MEK targeted therapy (21.5%) and anti PD-1 (8.9%). First-line therapy for BRAF WT mm pts included anti CTLA-4 (28.1%) and anti PD-1 (12.8%). Median OS from mm for the cohort was 36.5 months (95% CI 33.3-44.9). Elevated LDH and staging correlated with OS (p < 0.001, p < 0.001, respectively) on univariate analysis. Age, gender, subtype and mutation status were not significantly associated with OS. Compared to BRAF WT, pts with BRAF V600E/K mutation were younger (median = 53 vs 62 yrs, p < 0.001), more likely to have non-acral cutaneous mm (83.2% vs 58.0%, p < 0.001) and have a diagnosis of brain metastasis during the disease course (57.0% vs 28.8%, p < 0.001). While adjusting for stage, there was no significant difference in OS based on first or second line therapy in pts with BRAF V600E/K mm or first line therapy in BRAF WT MM; however, BRAF WT pts treated second line with anti-PD1 were observed to have improved OS compared with pts receiving anti-CTLA 4 (HR 0.43 95% CI:0.23-0.84 p = 0.012). Conclusions: This study demonstrates that LDH and stage are prognostic of OS in all mm pts treated with single agent immune therapy. Second line therapy in BRAF WT pts treated with single agent immune therapy is also prognostic of OS thus prompting further investigation to determine advantageous therapy sequencing in MM.
A toll-like receptor agonist to drive melanoma regression as a vaccination adjuvant or by direct tumor application.
Authors: Royal Richard Eldon , Vence Luis M , Wray Tara , Cormier Janice N. , Lee Jeffrey Edwin , Gershenwald Jeffrey E. , Ross Merrick I. , Wargo Jennifer Ann , Amaria Rodabe Navroze , Davies Michael A. , Diab Adi , Glitza Isabella Claudia , Hwu Wen-Jen , Patel Sapna Pradyuman , Woodman Scott Eric , Overwijk Willem W , Hwu Patrick
Published: September 2018

9582

Background: Toll like receptor (TLR) agonists may enhance vaccination or direct immune activation at the tumor microenvironment. This trial evaluates the biologic and clinical effects of Resiquimod, a TLR 7/8 agonist that can activate both myeloid (mDC, TLR 8) and plasmacytoid (pDC, TLR 7) dendritic cells, in patients with advanced stage melanoma. Methods: Class I HLA-A0201+ subjects with in-transit melanoma metastases or high risk for recurrence were vaccinated weekly with peptide vaccination (class I restricted peptide GP100209-2m and, if HLA-DP4+, also with class II restricted peptide MAGE-3243-258). Subjects were randomized 1:1 to receive Resiquimod as an adjuvant applied to the GP100 vaccination site. Subjects with in-transit disease were thereafter treated with resiquimod topically on half of the target lesions. Results: All patients (n = 47) underwent GP100209-2m vaccination, a majority (39) also received the MAGE-3243-258 peptide. The type I interferon-inducible genes (Mx A and IRF7), IFNg, and IP-10 RNA expression were up-regulated only in vaccination sites treated with Resiquimod (each p < 0.01) , demonstrating pDC activation (Type I interferon) and possibly T and NK cell activation (IFNg and IP-10). Nineteen subjects had in-transit disease at entry into the trial. In response to peptide vaccination alone, tumor regression was more likely in patients who received Resiquimod at the vaccination site (group A) compared to those who did not (group B). (4/9 vs 0/10, p = 0.033). In group A, 5 patients continued treatment with Resiquimod topically on the tumors, and all had tumor response (4PR, 1CR). In group B, 5 continued to tumoral resiquimod and 3 had regression (3 PR). Conclusions: Resiquimod increases Type I interferon and IFNg at the peptide vaccination site by activation of pDC/mDC and increases the antitumor response sufficiently to mediate regression of in-transit melanoma metastasis. Resiquimod on in-transit melanoma, in vaccinated hosts, drives regression of metastases, regardless of previous exposure at vaccination. Clinical trial information: NCT00960752.
Clonality of T cell repertoire in the tumor (TME) and peripheral blood of regionally advanced melanoma patients (pts) treated with neoadjuvant ipilimumab (ipi) and high dose interferon-α (HDI).
Authors: Vallabhaneni Priyanka , Achkar Tala , Vignali Marissa , Benzeno Sharon , Rytlewski Julie , Tarhini Ahmad A.
Published: September 2018

9585

Background: Pts with regionally advanced melanoma were treated with neoadjuvant ipi and HDI in a reported study ( Tarhini. J Clin Oncol suppl, 2016; abstr 9585). Pathologic complete response (pCR) was found in 32% of pts. Clonality of T cell repertoire was investigated in TME and peripheral blood mononuclear cells (PBMC). Methods: Pts were randomized to neoadjuvant ipi 3 or 10 mg/kg combined with HDI. Tumor biopsies were evaluable for testing at pretreatment (N = 20 pts) and definitive surgery (week 6-8; N = 25). When available, primary (N = 24) and relapse tumors (N = 6) were tested. PBMC: pretreatment (N = 29), 6 weeks (wk) (N = 24), then 3 (N = 23), 6 (N = 21), 12 (N = 14) months. T cell receptor beta chain (TCRB) repertoire was immunosequenced in PBMC and TME to determine repertoire clonality and T cell fraction in blood and TME (TIL; fraction of all nucleated cells identified as T cells). Results: PBMC T cell fraction when measured early on-treatment (6 wks) was significantly higher in pts who had pCR or microscopic residual disease vs. gross disease at the 6-8 wks surgery (p = 0.047). PBMC clonality was significantly lower at 12 wks (p = 0.025) for pts who continued to be relapse free (NED) long term vs. those who eventually relapsed. In TME, except for trends no significant difference in clonality was seen, but in pts with pCR TIL fraction was significantly higher when measured in primary tumors (p = 0.033). The number of tumor-associated clones that were expanded in blood post-treatment was strongly correlated with both TIL fraction (Rho 0.7299, p = 0.0003) and TIL clone diversity (Rho 0.882, p = 2.7-7). Conclusions: Higher T cell fraction and lower clonality in PBMC when measured early on-treatment, and higher TIL fraction in primary tumor constituted promising biomarkers of response. Pts with higher TIL fractions were more likely to have tumor-associated clones detectable in blood, suggesting these may be useful for tracking the immune response. These findings warrant validation in an independent cohort and exploration with other immunotherapeutics. Clinical trial information: NCT01608594.