bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical implications of the T790M mutation in disease characteristics and treatment response in patients with EGFR-mutated NSCLC.
Authors: Gaut Daria , Sim Myung Shin , Wolf Brian R. , Abarca Phillip A. , Carroll James M. , Goldman Jonathan Wade , Garon Edward B.
Published: September 2018

9031

Background: The secondary T790M mutation accounts for more than 50% of acquired tyrosine kinase inhibitor (TKI) resistance in epidermal growth factor receptor (EGFR)-mutant NSCLC patients. Recent reports suggest this resistance mutation may be more common among patients with longer progression-free survival (PFS) on first-line TKI therapy, but much is still unknown about this resistance mechanism’s association with response to other therapies. Methods: Our group collected medical records from patients who underwent a biopsy for T790M mutation testing in the process of screening for clinical trials involving third generation EGFR inhibitors. Medical records were retrospectively analyzed for demographic data, PFS, best response (BR) to previous therapies, and presence or absence of an acquired T790M mutation. Progression-free survival was estimated using the Kaplan-Meier method and compared across two groups using the log-ranked test followed by univariate and multivariate cox proportional hazard regression analysis. Response rates were compared using Fisher’s exact test. Results: Out of 102 patients who obtained a diagnostic biopsy, 73 patients had a T790M mutation. Patients who later developed a T790M mutation had a longer PFS on first-line TKI therapy (12.0 months in T790M+ vs. 8.0 months in T790M-, p = 0.038, HR 1.66, 95% CI 1.03-2.67), though there was no difference in response rate (75.5% in T790M+ vs 77.3% in T790M-, p = 1.00). T790M+ patients also had a longer PFS on initial chemotherapy treatment (5.0 months in T790M+ vs. 4.0 months in T790M-, p = 0.020, HR 1.97, 95% CI 1.11-3.49) and a higher response rate to chemotherapy (22.7% in T790M+ vs 0% in T790M-, p = 0.033). Median PFS was short (3.0 months) for patients treated with immunotherapy with no difference based on T790M mutation status (p = 0.33). Conclusions: Our study confirms that tumors expressing T790M have a more indolent progression of disease compared to their T790M negative counterparts when treated with both first-line TKI and cytotoxic chemotherapy. This data provides context for therapeutic decision making in EGFR-mutant NSCLC patients.
Objective response rate and progression-free survival as surrogate endpoints for overall survival and the impact of crossover and unbalanced post-progression treatments: A systematic review and meta-analysis in first-line therapy of advanced non-small cell lung cancer.
Authors: Pfeiffer Boris , Hashim Mahmoud , Duran Monica , Postma Maarten , Heeg Bart
Published: September 2018

9049

Background: Correlations between overall survival (OS) and objective response rate (ORR) or progression-free survival (PFS) are poor. We aimed to evaluate the impact of crossover and unbalanced subsequent treatments on ORR and PFS as surrogate endpoints for OS in patients with advanced NSCLC receiving first-line therapy. Methods: A systematic literature review of randomized clinical trials of systemic treatment for patients with stage IIIB/IV NSCLC receiving first-line therapy was performed. Weighted (by trial size) linear regression models were fitted with the absolute difference in ORR or median PFS as an independent variable and the absolute difference in median OS as a dependent variable. The analysis was repeated in predefined subsets based on crossover and balance of post-progression therapies. Surrogate threshold effect (STE) was estimated using prediction intervals. Results: 317 trials (78,644 patients) fulfilled the eligibility criteria. In all treatment arms, the mean ORR, median PFS, and median OS were 28.2% (standard deviation (SD) = 12.4%), 5.1 months (SD = 2.1), and 10.4 months (SD = 2.5), respectively. ORR and PFS had weak (R = 0.351; 95% CI: 0.251-0.443) and (R = 0.397; 95% CI: 0.267-0.512) associations with OS, respectively. However, within phase III trials that did not allow crossover and reported balanced post-progression treatments, both ORR and PFS had stronger associations with OS (ORR and OS: R = 0.601, 95% CI: 0.399-0.747; PFS and OS: R = 0.695, 95% CI: 0.446-0.844). STE estimation indicated that trials that show statistically significant treatment effect size of ≥43% ORR or ≥3.2 median PFS months can be expected to show significant OS benefit with sufficient certainty. Conclusions: Surrogacy of ORR and PFS for OS might be better estimated in trials that do not allow crossover and report balanced post-progression treatments. Presented STE calculation can be used to estimate the expected effect on OS when either ORR or PFS are used as primary endpoints.
A phase II study of GDC-0032 (taselisib) for previously treated PI3K positive patients with stage IV squamous cell lung cancer (SqNSCLC): LUNG-MAP sub-study SWOG S1400B.
Authors: Wade James Lloyd , Langer Corey J. , Redman Mary , Aggarwal Charu , Bradley Jeffrey D , Crawford Jeffrey , Miao Jieling , Griffin Katie , Herbst Roy S. , Kelly Karen , Gandara David R. , Papadimitrakopoulou Vassiliki
Published: September 2018

9054

Background: Lung-MAP (S1400) is a National Clinical Trials Network “umbrella” trial for previously-treated SqNSCLC. Sub-study S1400B included patients (pts) with tumors harboring PI3K mutations.Taselisib (GDC-0032), a potent, small molecule inhibitor of Class 1 PI3K with beta isoform sparing selectivity, has been shown to be a potent inhibitor in preclinical models of PIK3CA-mutant tumors. Methods: Eligibility stipulated progressive SqNSCLC after primary platinum-based therapy and presence of a PIK3CA mutation as determined by Foundation Medicine (FMI+) NGS. . The primary analysis population was a subgroup of the total PIK3CA mutation group (GNE+) with alterations limited to substitutions: E542K, E545A, E545G, E545K, E545Q, H1047L, H1047R, H1047Y. Primary endpoint was response rate (RR) in GNE+ pts. The initial protocol randomized PIK3 mt (+) pts to taselisib 4 mg po daily or docetaxel, but was amended to single arm phase II trial of taselisib with interim analysis based on first 20 eligible GNE+ pts evaluable for response, stipulating closure for futility if < 2 responses were observed. Results: 26 eligible pts, 7% of those registered to S1400, received taselisib; of these , 21 (81%) were GNE+. Of the 20 eligible, response-evaluable GNE+ pts, one pt with PIK3CA E545K gene alteration responded (5% RR, 95% Confidence Interval [CI] 1%, 24%). 13 pts had stable disease. Median PFS was 2.5 mos (95% CI, 1.7-4.0 mos) and 2.7 mos (95% CI, 1.8-3.4 mos) among GNE+ and FMI+ pts, respectively. 26 FMI+ pts were evaluable for toxicity: two grade 5 events (cardiac arrest, respiratory failure), neither clearly attributable to treatment, were recorded, along with one instance each of grade 4 AEs (dyspnea, thrombocytopenia, pneumonitis). Grade 3 AEs included 5 pts each with hyperglycemia or diarrhea, and 3 with lymphopenia. Overall survival data is premature. Conclusions: Study S1400B failed to meet its primary endpoint and was closed December 2016 at interim analysis for futility. Toxicities were manageable. The trial is unique in cataloguing the diversity of mutations in the PI3K pathways in SqNSCLC Clinical trial information: NCT02785913.
Safety and efficacy of nab-paclitaxel (nab-P)–based therapy in patients (pts) with non-small cell lung cancer (NSCLC) and performance status (PS) 2: Results from ABOUND.PS2.
Authors: Gajra Ajeet , Karim Nagla Abdel , Mulford Deborah A. , Villaruz Liza Cosca , Matrana Marc Ryan , Ali Haythem Y. , Santos Edgardo S. , Ong Teng Jin , Sanford Alexandra , Amiri Katayoun , Spigel David R.
Published: September 2018

9058

Background: Chemotherapy can benefit pts with advanced NSCLC with poor Eastern Cooperative Oncology Group (ECOG) PS, despite an increased toxicity risk vs those with good PS. Safety and efficacy of nab-P/carboplatin ( nab-P/C) induction followed by nab-P monotherapy in pts with advanced NSCLC and ECOG PS 2 are reported. Methods: Chemotherapy-naive pts with histologically/cytologically confirmed stage IIIB/IV NSCLC and ECOG PS 2 received 4 cycles of nab-P 100 mg/m2 d 1, 8 + C AUC 5 d 1 q3w. Pts without disease progression were eligible for monotherapy with nab-P 100 mg/m2d 1, 8 q3w until progression/unacceptable toxicity. Primary endpoint: percentage of pts discontinuing within the first 4 cycles due to treatment-emergent adverse events (TEAEs). Other endpoints: PFS, DCR, OS, ORR, and QoL. Results: Forty pts were treated during the first 4 cycles. Median age was 67.5 y, 60.0% were male, 92.5% were white, and 65.0% had nonsquamous histology. In the primary analysis, 9/40 pts (22.5%) discontinued due to TEAEs during induction. In total, 16/40 pts (40.0%) received nab-P as monotherapy. At the time of data cutoff, 4/40 pts remained on therapy beyond 11 cycles. In all treated pts, the median percentage of per-protocol dose of nab-P was 79.8% and the median nab-P dose intensity was 53.2 mg/m2/week (expected, 66.67 mg/m2/week). See table for other key safety and efficacy data. QoL by LCSS (global) was improved during the study, and similarly EQ-5D-5L dimensions were stable/improved at least once in the majority of pts. Conclusions: This nab-P–based regimen was well tolerated in PS 2 pts with advanced NSCLC. Efficacy outcomes are comparable with previous chemotherapy data with promising QoL. The results support the efficacy and tolerability of this regimen in these pts. NCT02289456. Clinical trial information: NCT02289456. [Table: see text]
Response of germline and somatic smoothened (SMO) mutations in non-small cell lung cancer (NSCLC) to hedgehog inhibitor vismodegib.
Authors: Tsao Anne S. , Wistuba Ignacio Ivan , Xia Dianren , Byers Lauren Averett , Diao Lixia , Wang Jing , Papadimitrakopoulou Vassiliki , Tang XiMing , Lu Wei , Kadara Humam , Gumus Zeynep H. , Tan Zhi , Zhang Shuxing , Nilsson Monique B. , Heymach John
Published: September 2018

9062

Background: Smoothened (SMO) gene somatic mutations activate hedgehog signaling in basal cell cancers (BCC) and medulloblastomas but have not been reported in NSCLC. We detected somatic and germline SMOmutations in NSCLC patients (A-C) and sought to characterize the mutations further. Methods: We performed tumor/blood germline sequencing of SMO mutations, familial germline mutation testing (saliva specimens), somatic mutation analysis of TCGA lung carcinoma datasets, and germline mutation analysis of the TCGA and 3 additional large cohorts (n = 1933). To evaluate the functional significance of SMOP641A, HCC4011 lung cancer cells were transfected with a wild-type SMO or SMOP641A expression vector and a predictive model was created. Results: NSCLC SMOP641A in vitro activated the hedgehog pathway, and vismodegib/cyclopamine inhibited tumor cell growth. Structural modeling suggests that SMO P641A induces conformational changes and disrupts PTCH-SMO interaction leading to constitutive activation. In the NSCLC TCGA databases, somatic SMO mutations occur 1.7%. In the overall TCGA database, germline SMO P641A occurred in 0.11% of cancer patients (multiple cancers) compared with 0% in cancer-free individuals. Patient A (never-smoking SCC) had a 46% RECIST reduction within 6 weeks for 6 months on vismodegib. His 3-generation family pedigree identified germline SMOP641A in one daughter (who developed BCC early). Two additional NSCLC patients (B – germline P641A and C –M525L received vismodegib; B initially stabilized but stopped vismodegib after 14 weeks for toxicity while patient C had no response. Conclusions: SMO mutations are targetable, potentially heritable, oncogenic drivers in NSCLC and other cancers. Tumor genetic profiling should consider including SMO gene, especially in never-smoking lung SCC patients. Additional studies are needed to define the role of germline/somatic SMO alterations in promoting carcinogenesis, interactions with P53 alterations, and the responsiveness of different SMO mutations to hedgehog inhibitors. Currently, the ongoing ECOG-ACRIN MATCH study (NCT02465060) treats SMO/PTCH mutated patients with vismodegib.
Updated efficacy and safety of the j-alex study comparing alectinib (ALC) with crizotinib (CRZ) in ALK-inhibitor naïve ALK fusion positive non-small cell lung cancer (ALK+ NSCLC).
Authors: Takiguchi Yuichi , Hida Toyoaki , Nokihara Hiroshi , Kondo Masashi , Kim Young Hak , Azuma Koichi , Seto Takashi , Nishio Makoto , Yoshioka Hiroshige , Imamura Fumio , Hotta Katsuyuki , Watanabe Satoshi , Goto Koichi , Nakagawa Kazuhiko , Mitsudomi Tetsuya , Yamamoto Nobuyuki , Kuriki Hiroshi , Inagaki Naohito , Tanaka Tomohiro , Tamura Tomohide
Published: September 2018

9064

Background: ALC is a highly selective, CNS-active ALK tyrosine kinase inhibitor. In the J-ALEX study, ALC proved superior efficacy and tolerability compared to CRZ at the pre-planned interim analysis at 83 progression free survival (PFS) events (51% of target events) . Here we report the updated data with a further 10 months of follow up. Methods: Patients with advanced ALK+ NSCLC were randomized 1:1 to receive ALC 300 mg b.i.d or CRZ 250 mg b.i.d and stratified by ECOG PS, treatment line, and clinical stage. Study Treatment was continued until disease progression or unacceptable toxicity. The primary endpoint was PFS according to the blinded independent review. Secondary endpoints included investigator-assessed PFS, overall survival, objective response rate and safety. Results: From Nov 2013 to Aug 2015, 207 patients were enrolled. Data cut off for the present analysis was Sep 2016. Median durations of PFS follow up were 20.5 months in the ALC arm and 20.4 months in the CRZ arm with 116 events by independent review observed. The updated PFS HR was 0.38 (95% CI: 0.26-0.55, p< 0.0001). Median PFS was 25.9 months (95% CI: 20.3-not estimated) with ALC and 10.2 months (95% CI: 8.3-12.0) with CRZ. For patients without brain metastasis at baseline (n = 164), ALC prevented CNS metastasis onset compared to CRZ (HR = 0.19, 95% CI: 0.07-0.53). For patients with brain metastasis at baseline (n = 43), ALC also prevented CNS progression compared to CRZ (HR = 0.51, 95% CI: 0.16-1.64). Adverse events (AEs) with frequency of more than 30% were constipation (37.9%) and nasopharyngitis (32.0%) in the ALC arm, while in the CRZ arm nausea (76.0%), diarrhea (74.0%), vomiting (57.7%), visual disturbance (54.8%), dysgeusia (51.9%), constipation (46.2%), increased ALT (32.7%), and increased AST (31.7%) were observed. Grade 3-4 AEs occurred with greater frequency in the CRZ arm (ALC: 32.0% vs CRZ: 56.7%). There were no Grade 5 AEs in either arm. Conclusions: In the updated analysis, ALC consistently showed superior efficacy compared to CRZ in systemic disease and prevention of CNS progression. ALC was also associated with a more favorable tolerability profile than CRZ. Clinical trial information: JapicCTI-132316.
Activity of brigatinib (BRG) in crizotinib (CRZ)-resistant ALK+ NSCLC patients (pts) according to ALK plasma mutation status.
Authors: Bazhenova Lyudmila , Hodgson J. Graeme , Langer Corey J. , Simon George R. , Gettinger Scott N. , Ou Sai-Hong Ignatius , Reckamp Karen L. , West Howard Jack , Chiappori Alberto , Koh Han A. , Molina Julian R. , Shaw Alice Tsang , Patel Jyoti D. , Favaro Justin Peter , Haney Jeff , Reichmann William , Kerstein David , Rivera Victor M. , Camidge D. Ross
Published: September 2018

9065

Background: BRG is a potent and selective ALK inhibitor with preclinical and clinical activity against wild-type ALK and a broad range of mutants associated with clinical CRZ resistance, including G1202R. Herein we examine the association between BRG efficacy and ALK mutation status using plasma specimens from the initiation of BRG treatment (baseline [BL]) and the end of BRG treatment (EOT) in CRZ-resistant ALK+ NSCLC pts enrolled in the BRG Ph1/2 or pivotal Ph2 (ALTA) trials. Methods: Plasma samples were analyzed using the Resolution Bioscience ctDx Lung Panel v3.0. BRG activity was described using the confirmed objective response rate (cORR) (RECIST v1.1). Data are reported as of May 31, 2016 for the Ph1/2 (NCT01449461) and ALTA (NCT02094573) trials. Results: Of 291 CRZ-resistant ALK+ NSCLC pts enrolled in the Ph1/2 (N = 69) and ALTA (N = 222) trials, evaluable plasma samples were obtained from 67 pts at BL. cORR to BRG in these pts was 49% (33/67). An ALK fusion was detected in plasma in 45% (30/67) of these pts (cORR 57% [17/30]), of whom 33% (10/30) had secondary ALK mutations (cORR 50% [5/10]) and 67% (20/30) did not (cORR 60% [12/20]). Best responses in pts with secondary ALK mutations were: 2 CR (ALK amplification [Amp] copy number [CN] = 10; T1151M); 3 PR (L1196M; E1408V; Amp CN = 6); 4 SD (L1196M; E1419K; F1174C; C1156Y+S1206F+G1269A); 1 PD (T1151R+C1156Y+E1161D+F1174L). Of 67 pts with evaluable plasma at BL, 35 discontinued BRG therapy, of whom 20 had evaluable samples collected at EOT. No new mutations were detected at EOT in 75% (15/20) of pts. Complex mutation patterns were associated with resistance in the remaining 25% (5/20): High-level ALK-Amp (CN = 58); ALK-Amp (CN = 14)+MET-Amp (CN = 6); ALK-S1206F+S1206C+Amp (CN = 6); ALK-G1202R+L1196M+L1198Q; ALK-G1202R+BRAF-V600E+KRAS-G12D. Conclusions: ALK fusions were detected in plasma in < 50% of CRZ-resistant ALK+ NSCLC pts. BRG had substantial activity in ALK fusion–positive pts with a range of CRZ-resistance mutations. Neither primary nor secondary resistance to BRG was associated with any single plasma ALK mutation. The therapeutic implications of complex secondary resistance patterns associated with BRG require further exploration. Clinical trial information: NCT01449461, NCT02094573.
A single-arm phase II trial of afatinib in pretreated patients with advanced NSCLC harboring a HER2 mutation: The ETOP NICHE trial.
Authors: Smit Egbert F. , Peters Solange , Dziadziuszko Rafal , Dafni Urania , Wolf Juergen , Wasąg Bartosz , Biernat Wojciech , Finn Stephen , Kammler Rosita , Tsourti Zoi , Rabaglio-Poretti Manuela , Ruepp Barbara Ursula , Roschitzki-Voser Heidi , Stahel Rolf A. , Felip Enriqueta
Published: September 2018

9070

Background: HER2mutations are identified in about 2% of lung adenocarcinomas and are critical for lung carcinogenesis. Afatinib is a selective and irreversible erbB family blocker with a manageable toxicity profile and promising results in small retrospective studies targeting HER2 in NSCLC. Methods: NICHE is a single-arm phase II trial exploring the potential of afatinib to control disease (complete or partial response or disease stabilization for ≥12 weeks) in pre-treated patients with advanced NSCLC harboring HER2 exon 20 mutations. Patients were treated with afatinib 40 mg/day p.o. until tumor progression or lack of tolerability. A Simon’s two stage phase II design was adopted, to explore whether afatinib can achieve a DCR of 75%, as opposed to a DCR of 50% under the current treatment options. For a 1-sided type I error of 10% and power of 80%, a total of 22 patients were needed. Results: As of 24 November 2016, 13 patients were recruited into the trial. Median age was 60 years, 69% female and 62% never smokers. The overall toxicity profile was in the expected range, with 5 patients experiencing serious adverse events (dyspnea, diarrhea, dehydration, epistaxis, pleural, pericardial and renal insufficiency). The median follow-up was 23 weeks (IQR 12 – 39). Three patients died and 10 were still on follow-up, among them five were still on treatment. Total of 7 patients (54%) achieved DC at 12-weeks, 3 patients had PD before and 3 at 12-weeks. The 12-week PFS was 51% (95% CI: 22 - 75) and the median PFS 13 weeks (95% CI 6 - NE). In the 1st stage analysis of the Simon’s design, with 9 patients included, the stopping boundary was crossed. Therefore and upon recommendations of the ETOP IDMC, recruitment into the trial was stopped prematurely in December 2016. Treatment and follow-up of the enrolled patients continues as planned. Conclusions: Based on the interim results, afatinib did not show the expected potential to control disease in this patient population. However in the full analysis set with 13 patients, clear signs of activity were seen. A comprehensive biomolecular analysis of the tumors is currently ongoing in order to identify a subgroup of patients who might still derive benefit from afatinib treatment. Clinical trial information: NCT02369484.
Afatinib in patients with metastatic HER2-mutant lung cancers: An international multicenter study.
Authors: Lai Wei-Chu Victoria , Lebas Louisiane , Milia Julie , Barnes Tristan Alexandra , Gautschi Oliver , Peters Solange , Ferrara Roberto , Ni Ai , Sabari Joshua K. , Clarke Stephen John , Pavlakis Nick , Rudin Charles M. , Arcila Maria E. , Leighl Natasha B. , Shepherd Frances A. , Kris Mark G. , Mazieres Julien , Li Bob T.
Published: September 2018

9071

Background: Human epidermal growth factor 2 ( HER2, ERBB2) mutations have been identified as oncogenic drivers in 3% of lung cancers. Afatinib is an irreversible tyrosine kinase inhibitor of HER1 (EGFR), HER2 and HER4 and has been described in case reports to have activity in HER2-mutant lung cancers. However, there is little data to inform the clinical use of afatinib. Methods: We reviewed patients with metastatic HER2-mutant lung cancers treated with afatinib among 7 institutions between 2009 and 2016. The primary endpoint was investigator assessed overall response rate using RECIST v1.1. Other data collected included types of HER2mutations, duration of afatinib treatment and overall survival. Results: We identified 27 patients with metastatic HER2-mutant lung cancers treated with afatinib. Median age at diagnosis was 63 (range 40 to 84); majority were men (n = 16; 59%) and never-smokers (n = 18; 67%). All tumors were adenocarcinomas, and the majority were Stage IV at initial diagnosis (n = 16; 59%). A 12-base pair (bp) in-frame insertion YVMA in exon 20 (p.A775_G776insYVMA) was present in 16 patients (59%). In addition, there were three 9-bp insertions, two 3-bp insertions and two single bp substitutions (L755F and D769H) in exon 20; two single bp substitutions (S310F) in exon 8; one exon 17 V659E mutation; and one single-nucleotide polymorphism (Ile655Val). Median duration on afatinib was 2 months (range 1 to 27); median line of prior treatment was 3 (range 1 to 6). Eight patients had previously received trastuzumab prior to afatinib and one concurrently with afatinib. Overall response rate was 15% (n = 4; 95% CI 4 to 34%); the four partial responses lasted 5, 5, 6 and 10 months. The 3 longest partial responders had a 12-bp insertion in exon 20 (YVMA); the remaining partial responder had a 9-bp insertion in exon 20. Median overall survival from diagnosis date of metastatic disease was 23 months (95% CI 18 to 62). Conclusions: Afatinib produced partial responses in 15% of patients with metastatic HER2-mutant lung cancers, including insertion YVMA. Our findings confirm the activity of afatinib and provide data supporting a framework for its use in the care of patients with HER2-mutant lung cancers.
Immune marker profiling and PD-L1, PD-L2 expression mechanisms across non-small cell lung cancer mutations.
Authors: Toki Maria , Mani Nikita , Smithy James William , Liu Yuting , Altan Mehmet , Wasserman Brad , Tuktamyshov Rasikh , Syrigos Konstantinos N. , Rimm David L.
Published: September 2018

9076

Background: PD-1/PD-L1 axis inhibitors have been proven effective, especially in patients expressing Programmed Death Ligand 1 (PD-L1). Their clinical efficacy in patients with epidermal growth factor receptor (EGFR) activating mutations is still unclear, while KRAS mutations seem to be associated with high response rates. In this study we investigated the expression of PD-L1, PD-L2 and Tumor Infiltrating Lymphocyte (TIL) status as a function of mutation status in Non-Small Cell Lung Cancer (NSCLC). Methods: We used the AQUA method of quantitative fluorescence (QIF) to compare PD-L1 and PD-L2 expression and to characterize TILs populations and their activation status in over 150 NSCLC patient tumors with known mutation status. EGFR activation was assessed in situ using the proximity ligation assay (PLA) for EGFR and GRB2 and T cell activation was assessed using a novel multiplexed QIF assay including CD3, Granzyme B and Ki67. Results: PD-L1 tumor and stroma expression was significantly lower in EGFR mutant compared to KRAS mutant (p = 0.009) and EGFR/KRAS Wild Type (p < 0.0001) tumors, while they had a higher frequency of PD-L2 expression. Conversely, KRAS mutants had significantly lower PD-L2 tumor and stroma expression but they were also more inflamed with higher CD4+, CD8+ and CD20+ TILs. Subgroup analysis of patients by their TILs activation status revealed that EGFR mutants had a very high frequency of inactive TILs even though lymphocytes were present in the tumor microenvironment. In contrast, in KRAS mutants, when TILs were present, they were almost always active. Finally, we find that PLA-defined activated EGFR correlated with increased PD-L1 expression in EGFR mutants but not in EGFR WT, while TIL activation was associated with higher PD-L1 in EGFR/KRAS WT. Conclusions: Our findings are consistent with the unique biology of EGFR mutant tumors. The high frequency of inactive TILs could explain the low immune therapy response rates in this patient group. Similarly, in this group, the reason PD-L1 expression fails to predict response may be due to expression as a result of constitutive oncogenic signaling rather than immune signaling, which would be associated with high PD-L1 levels and TILs activation.
Factors associated with better overall survival (OS) in patients with previously treated, PD-L1–expressing, advanced NSCLC: Multivariate analysis of KEYNOTE-010.
Authors: Herbst Roy S. , Baas Paul , Kim Dong-Wan , Felip Enriqueta , Perez-Gracia Jose Luis , Han Ji-Youn , Molina Julian R. , Kim Joo-Hang , Dubos Arvis Catherine , Ahn Myung-Ju , Majem Margarita , Fidler Mary J. , Castro Gilberto , Garrido Marcelo , Ellison Misoo C. , Samkari Ayman , Lubiniecki Gregory M. , Garon Edward B.
Published: September 2018

9090

Background: We identified factors associated with better OS for previously treated, PD-L1–expressing advanced NSCLC using data from KEYNOTE-010 (NCT01905657; Herbst et al. Lancet. 2016;387:1540-50), in which pembrolizumab had superior OS over docetaxel. Methods: 1033 patients were randomly assigned 1:1:1 to pembrolizumab 2 or 10 mg/kg every 3 weeks (Q3W) or docetaxel 75 mg/m2 Q3W. Response was assessed per RECIST v1.1 by independent central review. Multivariate analyses were performed using a Cox proportional hazards regression model on OS in the pembrolizumab arms. A set of variable selection methods was applied to 19 baseline demographic and disease characteristics, including smoking status, and identified 7 factors that contributed to OS. Data cut was September 30, 2016. Results: Adjusted hazard ratios (HRs) for the factors in the pembrolizumab arm from the model are shown in the Table. Updated OS with an additional 6 months of follow-up from this data lock for KEYNOTE-010 will be presented. Conclusions: While the overall result of KEYNOTE-010 revealed improved OS with pembrolizumab compared with docetaxel in previously treated patients with PD-L1–positive advanced NSCLC, exploratory, post hoc multivariate analyses showed that some laboratory and tumor characteristics such as nonsquamous histology, normal baseline lactate dehydrogenase (LDH), PD-L1 TPS ≥50%, and wild-type EGFR mutation status were associated with better OS among patients treated with pembrolizumab. Clinical trial information: NCT01905657. [Table: see text]
Atezolizumab (atezo) plus platinum-based chemotherapy (chemo) in non-small cell lung cancer (NSCLC): Update from a phase Ib study.
Authors: Liu Stephen V. , Camidge D. Ross , Gettinger Scott N. , Giaccone Giuseppe , Heist Rebecca Suk , Hodi F. Stephen , Ready Neal E. , Zhang Wei , Wallin Jeffrey , Funke Roel , Waterkamp Daniel , Foster Paul , Iizuka Koho , Powderly John D.
Published: September 2018

9092

Background: Platinum-based chemo is a standard first-line (1L) therapy for NSCLC lacking actionable gene alterations. Preclinical evidence suggests that chemo can play an immunomodulatory role and induce tumor antigen release, supporting combining chemo with immunotherapy. Atezo is a humanized and Fc-region-modified monoclonal anti-programmed death-ligand-1 (PD-L1) antibody that blocks interaction with PD1 or B7.1. The GP28328 study (NCT01633970) assessed safety and efficacy of atezo plus 1L chemo regimens in multiple tumor types. Methods: In this multicenter, multi-arm study, patients (pts) with locally advanced or metastatic NSCLC with no prior chemo for advanced disease received 15 mg/kg atezo IV q3w with standard doses of chemo (Arm C: carboplatin [carbo]+paclitaxel q3w; Arm D: carbo+pemetrexed q3w; Arm E: carbo+nab-paclitaxel qw) all for ≤6 cycles followed by atezo maintenance until loss of clinical benefit (+ pemetrexed maintenance until progression, Arm D). The primary endpoint was safety; secondary endpoints were overall response rate (ORR), PFS, and OS. Results: By the 30 Aug 2016 cut-off, 76 NSCLC pts were evaluable (n = 25, 25, 26 for Arms C, D, E, respectively). At this cut-off, the most common treatment-related grade 3–4 adverse events (AEs) were neutropenia (36% C, 36% D, 42% E) and anemia (16% C, 16% D, 31% E). Three potentially related grade 5 AEs were seen (arm C: pneumonia; arm D: systemic candida; arm E: autoimmune hepatitis). Confirmed ORRs were 36%, 64%, 46% for Arms C, D (1 CR), and E (4 CR). Median PFS (95% CI) was 7.1 months (4.2–8.3) for C, 8.4 months (4.7–11) for D, and 5.7 months (4.4–14.8) for E. Median OS (95% CI) was 12.9 months (8.8–not evaluable) for C, 19.3 months (14.7–27.4) for D, and 14.8 months (12.7–not evaluable) for E. Conclusions: Atezo was well tolerated when combined with various chemo regimens for advanced NSCLC. Clinical activity in terms of ORR was favorable supporting potential synergy between atezo and chemo. PFS and OS data show promising benefits, but are limited by small numbers and wide confidence intervals. Phase III studies that include chemotherapy and atezolizumab are currently ongoing. Clinical trial information: NCT01633970.
First-line carboplatin and pemetrexed (CP) with or without pembrolizumab (pembro) for advanced nonsquamous NSCLC: Updated results of KEYNOTE-021 cohort G.
Authors: Papadimitrakopoulou Vassiliki , Gadgeel Shirish M. , Borghaei Hossein , Gandhi Leena , Patnaik Amita , Powell Steven Francis , Gentzler Ryan D. , Martins Renato G. , Stevenson James , Jalal Shadia Ibrahim , Panwalkar Amit W. , Yang James Chih-Hsin , Gubens Matthew A. , Sequist Lecia V. , Awad Mark M. , Fiore Joseph , Ge Joy Yang , Raftopoulos Harry , Langer Corey J.
Published: September 2018

9094

Background: Data from the randomized, phase 2 cohort G of KEYNOTE-021 (NCT02039674) showed that adding pembro to first-line CP in patients (pts) with advanced nonsquamous NSCLC significantly improved the primary end point of ORR (55% vs 29%, P = 0.0016) and the key secondary end point of PFS (HR 0.53, P= 0.0102) compared with CP alone and had a manageable safety profile (grade 3-4 treatment-related AEs, 39% vs 26%; treatment-related AEs leading to discontinuation, 10% vs 13%). We present updated efficacy for cohort G based on 5 mo additional follow-up. Methods: 123 pts with stage IIIB/IV, chemotherapy-naive, nonsquamous NSCLC and no EGFR mutation or ALK translocation were randomized to 4 cycles of carboplatin AUC 5 + pemetrexed 500 mg/m2 Q3W ± 24 mo of pembro 200 mg Q3W; maintenance pemetrexed was permitted in both arms. Eligible pts in the CP arm who had radiologic progression could crossover to pembro monotherapy. Response was assessed per RECIST v1.1 by blinded, independent central review. All Pvalues are nominal. Results: As of Dec 31, 2016, median follow-up was 14.5 mo (range, 0.8-24.0). 36 of 48 pts (75.0%) in the CP arm who discontinued CP received subsequent anti–PD-1 or PD-L1 therapy. There was 1 additional response in each arm, and ORR was 56.7% (95% CI 43.2%-69.4%) with pembro + CP vs 30.2% (95% CI 19.2%-43.0%) with CP ( P = 0.0016). Median DOR was not reached for pembro + CP (range, 1.4+ to 18.6+ mo) and was 16.2 mo (range, 2.8 to 20.7+) for CP alone. PFS remained longer with pembro + CP (HR 0.49, 95% CI 0.29-0.83, P = 0.0035; median [95% CI] NR [9.7 mo-NR] vs 8.9 mo [6.2-10.3]; 12-mo estimate, 56% vs 34%). With 16 deaths in the pembro + CP arm and 23 deaths in the CP arm, HR for OS was 0.69 (95% CI 0.36-1.31, P= 0.13). Median OS was not reached in either arm; at 12 mo, estimated OS was 76% in the pembro + CP arm and 69% in the CP alone arm. Conclusions: With 5 mo additional follow-up, first-line pembro + CP continues to provide a substantial, clinically relevant improvement in efficacy over CP alone in pts with advanced nonquamous NSCLC, including an almost doubled ORR, halved risk of progression or death, and a trend toward improved OS despite a 75.0% crossover rate in the CP arm. Clinical trial information: NCT02039674.
Long-term outcomes in patients (pts) with ipilimumab (ipi)-naive advanced melanoma in the phase 3 KEYNOTE-006 study who completed pembrolizumab (pembro) treatment.
Authors: Robert Caroline , Long Georgina V. , Schachter Jacob , Arance Ana , Grob Jean Jacques , Mortier Laurent , Daud Adil , Carlino Matteo S. , McNeil Catriona M. , Lotem Michal , Larkin James M. G. , Lorigan Paul , Neyns Bart , Blank Christian U. , Petrella Teresa M. , Hamid Omid , Zhou Honghong , Homet Moreno Blanca , Ibrahim Nageatte , Ribas Antoni
Published: September 2018

9504

Background: Pembro demonstrated superior PFS and OS vs ipi in ipi-naive pts with advanced melanoma in the phase 3 KEYNOTE-006 study (NCT01866319). Here, we present long-term outcomes for all pts and in those pts who completed pembro therapy. Methods: Eligible pts (N = 834) were randomized 1:1:1 to pembro 10 mg/kg Q2W, pembro 10 mg/kg Q3W, or ipi 3 mg/kg Q3W for 4 doses. Treatment was continued for 2 yr (pembro only) or until disease progression, intolerable toxicity, or pt/investigator decision to discontinue. Per protocol, pts could interrupt pembro for ≤12 wk before discontinuation was required. Tumor imaging was performed at wk 12, then every 6 wk up to wk 48 and every 12 wk thereafter. After the prespecified final analysis, response assessments were per immune-related response criteria (irRC) by investigator review. Results: As of the data cutoff (Nov 3, 2016), median follow-up in the total population was 33.9 mo (range, 32.1-37.6). 33-mo OS rates were 50% in the pooled pembro arms (n = 556) and 39% in the ipi arm (n = 278); 33-mo PFS rates were 31% and 14%. ORR was 42% and 16%. Median duration of response was not reached for pembro (range 1.0+ to 33.8+ mo) or ipi (1.1+ to 34.8+ mo); 46 (68%) pembro-treated pts and 7 (58%) ipi-treated pts had a response lasting ≥30 mo. Among the 104/556 (19%) pts who completed pembro, median exposure to pembro was 24.0 mo (range 22.1-25.9). After a median follow-up of 9.0 mo after completion of pembro, 102 (98%) pts were alive. Responses were durable in pts who completed pembro; 9.7 mo after completion of pembro, estimated PFS (95% CI) was 91% (80-96) in all 104 pts, 95% (69-99) in pts with complete response (n = 24), 91% (74-97) in pts with partial response (n = 68), and 83% (48-96) in pts with stable disease (n = 12). Conclusions: Pembro provides durable efficacy after stopping the protocol-specified duration of treatment in pts with ipi-naive advanced melanoma in KEYNOTE-006. The estimated risk for progression or death nearly 10 mo after completing pembro is 9% and does not appear to differ by best response to pembro. Clinical trial information: NCT01866319.
Five-year overall survival (OS) update from a phase II, open-label trial of dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600–mutant unresectable or metastatic melanoma (MM).
Authors: Long Georgina V. , Eroglu Zeynep , Infante Jeffrey R. , Patel Sapna Pradyuman , Daud Adil , Johnson Douglas Buckner , Gonzalez Rene , Kefford Richard , Hamid Omid , Schuchter Lynn Mara , Cebon Jonathan S. , Sharfman William Howard , McWilliams Robert R. , Sznol Mario , Weber Jeffrey S. , Mookerjee Bijoyesh , Gasal Eduard , Redhu Suman , Flaherty Keith T.
Published: September 2018

9505

Background: D (BRAF inhibitor) + T (MEK inhibitor) combination therapy is associated with rapid clinical responses and has improved clinical outcomes in pts with BRAFV600–mutant MM, but long-term (˃ 3 y) clinical efficacy and safety data are limited. The longest follow-up to date of a randomized trial evaluating D+T at the approved dose (150 mg BID/2 mg QD [150/2]) was of the phase II study BRF113220 (part C; median, 45.6 mo) in which durable outcomes were achieved in some pts with BRAFV600–mutant MM (3-y OS, 38%). Here, we report updated 5-y landmark analyses to further characterize the impact of D+T in MM. Methods: Pts with BRAFV600–mutant mm enrolled in BRF113220 part C (NCT01072175) were randomized 1:1:1 to receive monotherapy D (150 mg BID), D+T (150 mg BID/1 mg QD), or D+T (150/2). Pts who progressed on D alone could cross over to the D+T 150/2 arm. Pt disposition, pt demographics, and 4- and 5-y efficacy and safety were analyzed for both the D-alone and D+T (approved 150/2 dose) arms. Results: This updated analysis represents an additional ≈ 2 y of follow-up (D and D+T arms; n = 54 each). As of 13 Oct 2016, 45 pts (83%) on D alone had crossed over to D+T. 20 pts were ongoing (D, n = 7 [13%]; D+T, n = 13 [24%]); 80% of D pts and 70% of D+T pts had died. D+T OS remained superior to D alone. The 4- and 5-y OS rates with D+T were 30% and 28%, respectively, demonstrating a stabilization of the OS curve. The PFS curve for D+T also remained stable (4- and 5-y: both 13%). Consistent with earlier results, the best OS for pts who received D+T was seen in pts with normal LDH (5-y, 45%) and normal LDH with disease in < 3 organ sites (5-y, 51%). At the 5-y landmark, 1 additional pt who received D+T improved from a partial to a complete response. Additional follow-up revealed no new safety signals with D+T. Detailed analyses of D crossover pts, responders, and post-progression therapy will be presented. Conclusions: This longest follow-up to date of BRAF + MEK inhibitor combination therapy in pts with BRAFV600–mutant mm revealed stable OS and PFS lasting ≥ 5 y with consistent tolerability. These results demonstrate that some pts with mm can achieve durable benefit with D+T therapy. Clinical trial information: NCT01072175.
Efficacy and safety of nivolumab (NIVO) plus ipilimumab (IPI) in patients with melanoma (MEL) metastatic to the brain: Results of the phase II study CheckMate 204.
Authors: Tawbi Hussein Abdul-Hassan , Forsyth Peter A. J. , Algazi Alain Patrick , Hamid Omid , Hodi F. Stephen , Moschos Stergios J. , Khushalani Nikhil I. , Gonzalez Rene , Lao Christopher D. , Postow Michael Andrew , Atkins Michael B. , Ernstoff Marc S. , Puzanov Igor , Kudchadkar Ragini Reiney , Thomas Reena Parada , Tarhini Ahmad A. , Jiang Joel , Avila Alexandre , Demelo Sheena , Margolin Kim Allyson
Published: September 2018

9507

Background: Brain metastases (BMts) are a major cause of morbidity/death in MEL. We report the first efficacy data in MEL patients (pts) with BMts who received NIVO+IPI in study CheckMate 204. Methods: In this multicenter US trial (NCT02320058), MEL pts with ≥1 measurable BMt 0.5-3.0 cm and no neurologic symptoms or steroid Rx received NIVO 1 mg/kg + IPI 3 mg/kg Q3W x 4, then NIVO 3 mg/kg Q2W until progression or toxicity. Pts with severe adverse events (AEs) during NIVO+IPI could receive NIVO when toxicity resolved; stereotactic radiotherapy (SRT) was allowed for brain oligo-progression if an assessable BMt remained. The primary endpoint was intracranial (IC) clinical benefit rate (complete response [CR] + partial response [PR] + stable disease [SD] > 6 months). The planned 90-pt accrual is complete; we report efficacy and updated safety for 75 pts with disease assessment before the Nov 2016 database lock. Results: Median age was 59 yrs (range 22–79). Median number of induction doses was 3; 26 pts (35%) received 4 NIVO+IPI doses and 38 pts (51%) began NIVO maintenance. Response data are reported at a median follow-up of 6.3 months (Table). The IC objective response rate (ORR) was 56% (95% CI: 44–68); 19% of pts had a complete response. IC and extracranial responses were largely concordant. Rx-related grade 3/4 AEs occurred in 48% of pts, 8% neurologic, including headache and syncope. Only 3 pts (4%) stopped Rx for Rx-related neurologic AEs. One pt died of immune-related myocarditis. Conclusions: In CheckMate 204, prospectively designed to investigate NIVO+IPI in MEL pts with BMts, NIVO+IPI had high IC antitumor activity with objective responses in 56% of pts, CR in 19%, and no unexpected neurologic safety signals. The favorable safety and high anti-melanoma activity of NIVO+IPI may represent a new Rx paradigm for pts with asymptomatic MEL BMts and could change practice to avoid or delay whole brain RT or SRT. Clinical trial information: NCT02320058. [Table: see text]
Initial efficacy of anti-lymphocyte activation gene-3 (anti–LAG-3; BMS-986016) in combination with nivolumab (nivo) in pts with melanoma (MEL) previously treated with anti–PD-1/PD-L1 therapy.
Authors: Ascierto Paolo Antonio , Melero Ignacio , Bhatia Shailender , Bono Petri , Sanborn Rachel E. , Lipson Evan J. , Callahan Margaret K. , Gajewski Thomas , Gomez-Roca Carlos A. , Hodi F. Stephen , Curigliano Giuseppe , Nyakas Marta , Preusser Matthias , Koguchi Yoshinobu , Maurer Matthew , Clynes Raphael , Mitra Priyam , Suryawanshi Satyendra , Muñoz-Couselo Eva
Published: September 2018

9520

Background: Signaling via LAG-3 and other T-cell inhibitory receptors (eg, PD-1) can lead to T-cell dysfunction and tumor immune escape. Simultaneous blockade of LAG-3 + PD-1 may synergistically restore T-cell activation and enhance antitumor immunity. In a phase 1/2a study, BMS-986016 (IgG4 mAb targeting LAG-3) ± nivo (IgG4 mAb targeting PD-1) demonstrated tolerability, peripheral T-cell activation, and preliminary clinical activity (NCT01968109; Lipson E, et al. J Immunother Cancer. 2016;4[s1]:173 [P232]). Here we describe preliminary efficacy of BMS-986016 + nivo in pts with MEL whose disease progressed on/after prior anti–PD-1/PD-L1 therapy, along with updated safety from all dose expansion pts. Methods: Pts with MEL must have had prior anti–PD-1/PD-L1 (± anti–CTLA-4 or BRAF/MEK inhibitors) and progressive disease (PD). Pts received BMS-986016 80 mg + nivo 240 mg IV Q2W. Primary objectives were safety and objective response rate (ORR; complete [CR] + partial [PR] response), disease control rate (DCR; CR + uCR + PR + uPR + stable disease [SD] > 12 wk), and duration of response (RECIST v1.1). Results: At data cutoff, 43 pts with MEL had been treated with BMS-986016 + nivo following PD on/after prior anti–PD-1/PD-L1 with known prior best responses of 1 CR, 9 PR, 12 SD, and 16 PD. Of the 43 pts, 30 (70%) also had prior anti–CTLA-4, 20 (47%) had ≥ 3 prior therapies, and 15 (35%) had BRAFmutations .In the 31 efficacy-evaluable pts to date, ORR was 16% (confirmed/unconfirmed) and DCR was 45% with benefit observed even in some pts refractory to prior anti–PD-1. Evaluations are ongoing for most pts, with median treatment duration of 10 wk for all 43 pts. Immunopathologic (eg, PD-1/PD-L1 and LAG-3 expression) and clinical characteristics of responders vs nonresponders will be presented. Any grade and grade 3/4 treatment-related AEs occurred in 46% and 9%, respectively, across all dose expansion pts (n = 129). Conclusion: Addition of BMS-986016 to nivolumab demonstrates encouraging initial efficacy in pts with MEL whose disease progressed on/after prior anti–PD-1/PD-L1 therapy, and a safety profile similar to nivolumab monotherapy. Clinical trial information: NCT01968109.
Efficacy and safety of nivolumab (NIVO) in patients with advanced melanoma (MEL) and poor prognostic factors who progressed on or after ipilimumab (IPI): Results from a phase II study (CheckMate 172).
Authors: Schadendorf Dirk , Ascierto Paolo Antonio , Haanen John B. A. G. , Espinosa Enrique , Demidov Lev V. , Garbe Claus , Lorigan Paul , Gogas Helen , Hoeller Christoph , Guren Tormod Kyrre , Rorive Andree , Rutkowski Piotr , Muñoz-Couselo Eva , Dummer Reinhard , Carneiro Ana , Hospers Geke , Grigoryeva Elena Borisovna , Bhore Rafia , Nathan Paul
Published: September 2018

9524

Background: In the phase III CheckMate 037 study, NIVO improved the objective response rate and progression-free survival with less toxicity vs chemotherapy in patients (pts) with MEL who progressed after prior IPI treatment. We report the first efficacy and updated safety data from pts with MEL in CheckMate 172, including those with rare melanoma subtypes (uveal, mucosal), brain metastases, or an ECOG performance status (PS) of 2. Methods: In this ongoing phase II, single-arm, open-label, multicenter study, pts with MEL who progressed on or after IPI were treated with NIVO 3 mg/kg Q2W for up to 2 years until progression or unacceptable toxicity (NCT02156804). We report efficacy and updated safety data from 734 treated pts with ≥1 year of follow-up (database lock: November 2016). Results: Of 734 pts, 50% had LDH>ULN, 7% ECOG PS 2, 66% M1c disease, 15% a history of brain metastases, and 23% received ≥3 prior therapies. Overall, 593 pts (81%) received more than 4 doses of NIVO. Overall, response rate at 12 weeks was 32%, with a complete response in 1% (Table). The 1-year overall survival (OS) rate was 63%. Any grade and grade 3/4 treatment-related adverse events (AEs) occurred in 66% and 17% of pts, respectively. Discontinuations due to treatment-related AEs occurred in 4% of pts. The most common treatment-related select (potentially immune-related) AEs were diarrhea (12%), hypothyroidism (9%), and pruritus (7%). Conclusions: CheckMate 172 is the largest study of NIVO efficacy and safety in pts with MEL who progressed on or after IPI. NIVO demonstrated a safety profile consistent with that of prior clinical trials. Efficacy outcomes were encouraging in some difficult-to-treat subgroups of pts with poor prognostic factors, such as mucosal melanoma and brain metastases. Clinical trial information: NCT02156804. [Table: see text]