bluuebunny/crossref_metadata_2025 huggingface dataset:
Monitoring of peripheral lymphocyte and neutrophil counts to predict efficacy of nivolumab (nivo).
Authors: Kawashima Yosuke , Nishikawa Shingo , Ariyasu Ryo , Koyama Junji , Saiki Masafumi , Sonoda Tomoaki , Takano Natsuki , Oguri Tomoyo , Kitazono Satoru , Tambo Yuichi , Yanagitani Noriko , Ohyanagi Fumiyoshi , Horiike Atsushi , Horai Takeshi , Nishio Makoto
Published: September 2018

e20583

Background: Programmed death-1 (PD-1) antibody is a key drug for treating non-small cell lung cancer (NSCLC), but the response rate is about 20% in non-selected populations and efficacy is difficult to predict. We examined correlations between peripheral blood tests, including counts of lymphocytes (Lym), neutrophils (Neu), and C-reactive protein (CRP), and the efficacy of nivolumab (nivo) monotherapy. Methods: Eighty NSCLC patients treated with nivo (3mg/kg every 2 weeks) in our hospital between December 2015 and September 2016 were evaluated. Peripheral blood tests on day (d) 0 (the day before 1st nivo), d15 (the day of 2nd nivo), d29 (the day of 3rdnivo) were evaluated. Absolute counts and the change ratio (%) of Lym, Neu and CRP from baseline (d0) were calculated. Response to nivo was evaluated according to RECIST v1.1. Results: Response to nivo was partial response in 23 cases, stable disease in 13 and progressive disease (PD) in 44 patients (overall response rate, 28%; disease control rate, 45%). Absolute counts of Lym, Neu and CRP at baseline did not differ significantly between non-PD and PD (Lym, 1323/µl vs. 1376/µl; Neu, 4830/µl vs. 5189/µl; CRP, 3.48 mg/dl vs. 3.38 mg/dl). Neu was significantly increased from baseline to d15 and d29 in the PD population compared with the non-PD population (δNeu (d15): 25.2% vs. -6.3%, P= 0.008; δNeu (d29): 16.7% vs. -8.6%, P= 0.006). CRP was also significantly increased from baseline to d29 in the PD population compared with the non-PD population (δCRP: 60.1% vs. -21.2%, P= 0.010). In contrast, Lym was significantly increased from baseline to d29 in the non-PD population compared with the PD population (δLym: 9.6% vs. –6.7%, P= 0.010). Conclusions: Changes in peripheral blood test results after nivo differed between non-PD and PD populations. Monitoring of Neu and Lym and CRP may allow prediction of the efficacy of nivo.
Molecular matching and treatment strategies for lung cancer at Dartmouth-Hitchcock Medical Center: A three year review of a molecular tumor board.
Authors: Bernhardt Erica , Chamberlin Mary D. , Gorlov Ivan P , Blumental de Abreu Francine B , Bloch Katarzyna J , Peterson Jason D , Tsongalis Gregory J. , Shirai Keisuke , Dragnev Konstantin H. , Miller Todd W. , Tafe Laura J.
Published: September 2018

e20585

Background: Matching of actionable tumor mutations with targeted therapy has been shown to increase response rates and prolong survival in lung cancer patients. Drug development and trials targeting genetic alterations are expanding rapidly. We describe the role of a Molecular Tumor Board (MTB) in the design of molecularly informed treatment strategies in our lung cancer patient population. Methods: DNA from tumor specimens was sequenced to identify coding mutations using a 50-gene targeted next-generation sequencing panel (Ampliseq v2). Cases were evaluated by a multidisciplinary MTB that included medical oncologists, hematologists, molecular and anatomic pathologists, genetic counselors, and basic science researchers who suggested a course of treatment based on the patient’s molecular findings. Results: During a three-year period, 88 patients were presented to the MTB. Of these, 21 patients had lung cancer (23.9%). All patients lacked common (indicated for FDA approved drug) activating EGFR and ALK mutations. One patient was stage IIIb, all others were stage IV; 18 had previously received at least one prior line of therapy (range 0-5). Suggestions for treatment with a targeted therapy were made for 19 of 21 (90.5%) and four patients underwent treatment with a MTB-suggested targeted agent (21.1%); two as part of a clinical trial. One patient received targeted therapy for 27 months before his disease eventually progressed. Barriers to treatment with targeted therapy included: ineligibility for study (n = 2), lack of interest in study/distance to travel (n = 2), lack of disease progression (n = 2), death/hospice enrollment (n = 5), decision to treat with immunotherapy (n = 3), and unknown (n = 1). Conclusions: For the majority of lung cancer patients, the MTB was able to provide suggestions based on targetable genetic alterations. The largest barriers to treatment were death and hospice enrollment indicating that molecular testing and presentation to the MTB at earlier stages of disease may increase the number of patients who ultimately are eligible for treatment with a targeted agent.
A phase IV study using multi-omics to identify mechanisms of response and resistance to crizotinib in ALK+ advanced non-small cell lung cancer (NSCLC) patients with distinct progression free survival outcomes.
Authors: Couetoux du Tertre Mathilde , Tremblay Lise , Bouchard Nicole , Diaconescu Razvan , Blais Normand , Camlioglu Errol , Constantin Andre , Hoffert Cyrla , Gambaro Karen , Srivastava Archana , Greenwood Celia , Couture Christian , McNamara Suzan , Batist Gerald , Cohen Victor , Agulnik Jason Scott
Published: September 2018

e20588

Background: Crizotinib is the current first-line standard of care for ALK+ NSCLC with response rates reaching 65% [1] . However, most patients progress within 1 or 2 years and mechanisms of resistance remain unknown for approximately 30% of patients [2] . [1] Shaw et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. NEJM 368: 2385-2394, 2013. [2] Doebele et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res 2012; 18:1472-1482 Methods: Eligible patients had locally advanced or metastatic ALK+ NSCLC. Patients were asked to undergo a repeat tumor biopsy at time of progression and serial bloods and archived primary tumor were collected. Responses were assessed by RECIST 1.1. ctDNA and protein expression on serial blood will be evaluated over the course of treatment. Tumors were profiled using exome sequencing and targeted genomic analysis to identify novel mutations associated with response. Results: 24 patients with stage IV adenocarcinoma received crizotinib as first-line (n = 22) and second-line (n = 2) treatment. Mean age was 60 y (range 41-80). 4% were smokers, 33.5% were former and 62.5% were never-smokers. At data cutoff (Jan 26, 2017), 16 patients have discontinued treatment (14 due to progression and 2 withdrew). The median PFS markedly differed in non-responders (patients with immediate progression) vs responders (patients with initial response or stable disease) (1.8 vs. 27 months). Profiling was performed to identify the genomic traits in tissue and blood that correlate to treatment response. Conclusions: We identified a previously unrecognized subset of patients treated with crizotinib with an exceptionally long PFS. We also observed a subset of patients intrinsically resistant to crizotinib despite harboring ALK+. There are no known predictive biomarkers which can identify patients that will have a long-lasting response or who may not derive benefit from crizotinib. The multi-omics profiling applied to these groups may provide novel insights into mechanisms of response and resistance to crizotinib. Clinical trial information: NCT02041468.
Patient-reported outcomes in patients with NSCLC who progress on 1st-/2nd-generation EGFR TKIs.
Authors: Skinner Karen E , Fernandes Ancilla , Walker Mark Stephen , Pavilack Melissa , Vanderwalde Ari M.
Published: September 2018

e20590

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are recommended for patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC). Limited data are available regarding patient-reported outcomes (PROs) in patients who experience progression on 1st-/2nd-generation TKI treatment, which was the focus of this study. Methods: A retrospective chart review of patients with advanced NSCLC (stage IIIb/IV) from 10 US community oncology practices was conducted. Patients were included if they were diagnosed between 1/1/2008 and 1/1/2015, were treated with erlotinib or afatinib (TKIs) either first line (1L) or second line (2L), and had disease progression (per clinician’s assessment) prior to 10/31/2015. Eligible patients with ≥1 Patient Care Monitor record were included in this subset analysis. Linear mixed models were used to evaluate select PROs. Results: The study included 364 patients: 77.7% white, 17.3% African American; and mean (SD) age 66.3 (11.3) years. Of the 241 patients who received systemic anticancer therapies after progression, 33.2% continued on TKIs ± chemotherapy (66.8% chemotherapy alone). PROs were available for 71 of 364 patients. We found that progression was associated with worsening in acute distress, despair, and difficulty breathing ( P< .001, P< .001, P= .048, respectively). Disease progression was also associated with worsening of vomiting and nausea ( P< .001, P= .023, respectively). Patient-reported rash symptoms improved from the TKI treatment period to the post-progression period ( P= .044), which aligned with the incidence of rash in the patient records (61.0% during TKI, 32.9% after progression). Conclusions: As expected, disease progression was associated with worsening of patient psychological symptoms and difficulty in breathing. Interestingly, as disease progressed and patients transitioned from TKI therapies to chemotherapies, there was worsening of vomiting and nausea and a decrease in patient-reported rash symptoms. These findings underscore the need for therapeutic options that improve patient symptomatology after progression on 1st-/2nd-generation EGFR TKIs.
Real-world treatment sequencing in advanced non-small cell lung cancer (aNSCLC).
Authors: Radtchenko Janna , Feinberg Bruce A.
Published: September 2018

e20593

Background: The rapidly expanding arsenal of systemic therapies for aNSCLC warrants a better understanding of treatment sequencing. This study evaluated the benefits of sequence choice through time to discontinuation (TTD). Methods: Using Inovalon’s MORE2 Registry®claims data for July 2013–2014, patients (pts) with aNSCLC identified by ICD-9 codes and treated with chemotherapy (chemo) or targeted therapy (TT; erlotinib, ceritinib, afatinib, or crizotinib) were selected. Pts >18 years of age and treated with first-line (1L) therapy within 6 months of diagnosis were eligible. Pts with small cell lung cancer or secondary malignancies, or pts enrolled in a trial, were ineligible. TTD (time from 1L start to 2L stop + 90 days, or switch to 3L were analyzed by sequence group: chemo-to-chemo (A), chemo-to-TT (B), TT-to-chemo (C), and TT-to-TT (D). All-cause TTD was assessed using Kaplan–Meier curves. Pt characteristics were assessed using descriptive statistics. Results: Of 5,319 pts, 567 (11%) received 1L TT and 4,752 (89%) received 1L chemo; 2,198 pts (41%) progressed to 2L. Significant differences were noted between groups (table). Group D had the most women and longest mean follow-up time and TTD. Group C had the lowest mean age and greatest proportion of 3L pts. Group B had the highest mutation testing rate and second longest mean TTD. Conclusions: The positive impact of precision medicine on TTD is striking. The fact that chemo following 1L TT resulted in the lowest TTD calls this strategy into question. Research is warranted to address the continued role of salvage chemo in TT eligible aNSCLC. [Table: see text]
Nutritional and functional status impairments to predict early death in elderly patients with advanced non-small-cell lung cancer (NSCLC).
Authors: Luciani Andrea , Careri Carmela , Bocci Barbara , Violati Martina , Guidi Alessandro , Blasi Miriam , Bordin Veronica , Caldiera Sarah , Zonato Sabrina , Ferrari Daris
Published: September 2018

e20600

Background: Early death for some patients can be explained by direct effect of tumor or can be secondary to cancer treatment.As for many patients it is not fully predictable, the factors influencing and determining early death in older individuals receiving chemotherapy for advanced NSCLC were analyzed. Methods: Advanced NSCLC patients, > 70 years, ECOG performance status 0-1, treatment naïve, stage IIIB and IV, EGFR and ALK negative, were eligible. Geriatric assessment was performed at baseline and included: Performance status, ADLs, IADLs, CIRSG score and index, Mini Nutritional Assessment (MNA), Mini Mental State Evaluation (MMSE), educational and social status assessment, Geriatric Depression Scale (GDS).All patients, according to their classification in frail, vulnerable or fit, received best supportive care, monotherapy or doublet chemotherapy.For all patients data on number of cycles, response, discontinuation of treatment, dose reductions, grade 3/4 hematological and non-hematological toxicity were recorded. Patients who died within 90 days of diagnosis were considered.A descriptive statistic was calculated and a logistic regression analysis with the assessment of factors and covariates influencing early death events was performed. Results: From June 2010 to March 2016, 204 patients were assigned to platinum-based doublet (n = 73) or single-agent chemotherapy (n = 131).Median age was 75, 72% were males, 52% had non-squamous histology. Median number of cycles was 4, and was 3 for comorbidities. IADLs were impaired in 42%, ADLs in 6%,MNA in 15% and MMSE 10% of patients.Sixty-eight percent of patients were dead at the time of the analysis; 24% (49/204) had partial response, 25% (51/204) had stable disease and 51% (104/204) had progressive disease.At multivariate logistic model IADLs (p 0.001, OR 1.4 95%CI 0.4-1.6),MNA (p 0.001, OR 1.35 CI 0.1-1.35) and polypharmacy (p 0.008, OR 1.2 CI 1-1.4) were significantly associated with the occurrence of early death. Conclusions: The identification and management of patients with nutritional and functional impairments could help oncologists to reduce the risk of early death during chemotherapy for advanced NSCLC.
Presence of genetic aberrations in patients with brain metastases from non-small cell lung cancer (NSCLC) and clinical outcomes.
Authors: Press Robert H. , Zhang Xinyan , Cassidy Richard John , Ferris Matthew Jeffrey , Zhong Jim , Steuer Conor Ernst , Pillai Rathi Narayana , Owonikoko Taofeek Kunle , Ramalingam Suresh S. , Patel Pretesh R , Curran Walter John , Shu Hui-Kuo George , Sica Gabriel , Higgins Kristin Ann
Published: September 2018

e20604

Background: Historically, survival in patients (pts) with NSCLC brain metastases (BM) is poor, however, improved systemic therapies are now available including targeted therapies and immunotherapy. We sought to evaluate the prevalence of genetic alterations in pts with BM from non-squamous (NS) lung cancer, and to determine clinical outcomes in the modern era. Methods: With IRB approval, pts with BM from NS-NSCLC from 1/2010-1/2016 with genetic testing were captured and retrospectively reviewed. Snapshot genotyping was performed prior to 1/2014, after which Next Generation Sequencing was utilized, along with FISH lung cancer panel. Genes examined included: EGFR, ALK, RET, ROS1, TP53, KRAS, NRAS, MET, PTEN, BRAF, FBXW7, MAP2K1, APC, PIK3CA, CTNNB1, and SMAD4. Univariable and multivariable analysis (MVA) were utilized to assess factors associated with overall survival (OS). Results: 92 pts were included. Median number of BM was 4 (range 1-45). Median age was 64 (32-90 years). 59.8% were male. 38% received targeted therapy, 11% received immunotherapy, and 70% received conventional chemotherapy. 52.2% and 47.8% received whole brain radiotherapy and stereotactic radiosurgery, respectively. Median OS from first brain radiotherapy (RT) was 10.7 months (0.1-56.4). EGFR mutation, ALK fusion, ROS1 rearrangement, and RET rearrangement occurred in 27.5%, 5.2%, 1.7%, and 0% of pts. EGFR L858 and EGFR T790 mutations occurred in 19.2% and 2.7% of all pts. TP53, KRAS, and NRAS mutations occurred in 63.9%, 28.8% and 7% of pts. All other mutations had an incidence of less than 3%. On MVA, targeted therapy (HR 0.43 95% CI 0.22-0.86), immunotherapy (HR 0.04 95% CI 0.01-0.3), surgical resection (HR 0.38 95% CI 0.18-0.81), and ECOG performance status (0.23 95% CI 0.1-0.54) were associated with improved OS. No specific genetic aberration, RT modality, or number of BM was associated with OS. Conclusions: In pts with BM from NS-NSCLC, the most common molecular aberrations include TP53, EGFR, and KRAS mutations. Treatment with brain RT and modern systemic therapies yields a median survival greater than ten months. The use of targeted therapy or immunotherapy was associated with increased OS.
Patterns of disease progression in advanced non-small cell lung cancer patients treated with PD-1 inhibitors.
Authors: Qin Angel , Kalemkerian Gregory Peter , Schneider Bryan J. , Hassan Khaled Aref , Cease Kemp Bailey , Zhao Lili , Warren Edus H. , Ramnath Nithya
Published: September 2018

e20607

Background: The PD-1 inhibitors nivolumab and pembrolizumab are approved for the treatment of advanced non-small cell lung cancer (NSCLC), but little is known about patterns of disease progression when these agents fail. Understanding patterns of failure is key to developing strategies to improve duration of response to these agents. Methods: We gathered clinical and radiographic data on patients treated at the University of Michigan and the Ann Arbor VA for advanced NSCLC with standard-dose nivolumab (n = 68) or pembrolizumab (n = 23) after progression on platinum-based chemotherapy. Sites of disease progression were described as local (within the same lobe as primary disease), nodal (thoracic), or distant. Results: 91 patients were evaluable, of whom 56 (61.5%) had progression of disease after an average duration of therapy of 3.2 months (95%CI, 2.6-3.8). 10 (17.9%) patients had progression at local sites alone, 3 (5.4%) at nodal sites alone, 12 (21.4%) at distant sites alone, and 31 (55.4%) at a combination of sites. Overall, 41 (73.2%) had progression at distant sites. There was no statistically significant difference in clinical factors ( i.e. age, histology, comorbidity index) between progressors vs. non-progressors or distant-progressors vs. non-distant progressors. Of 37 patients who had prior radiation, 17 (45.9%) had progression at an irradiated site, with patients who had local and/or nodal progression more likely to have received radiation at site of progression (p = 0.01). The most common distant sites of progression were liver (13), bone (10), and brain (9). Conclusions: The most common site of disease progression was distant, with the liver being the most commonly involved site. This may be due to the immunotolerogenic environment of the liver, which is characterized by high IL-10 concentration and propagation of suppressive regulatory T cells, which can dampen activation of cytotoxic T cells. Prior irradiation did not seem to prevent disease progression. Our preliminary analysis suggests that the efficacy of checkpoint inhibitors is hindered in immune-privileged sites. Strategies to overcome immune tolerance should be investigated to improve duration of response to these agents.
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 second- and further-line therapy of advanced non-small cell lung cancer.
Authors: Pfeiffer Boris , Hashim Mahmoud , Bartsch Robert , Postma Maarten , Heeg Bart
Published: September 2018

e20609

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 second- and further-line therapy. Methods: A systematic literature review of randomized clinical trials of systemic treatment for patients with stage IIIB/IV NSCLC receiving second- and further-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: 146 trials (43,061 patients) fulfilled the eligibility criteria. In all treatment arms, the mean ORR, median PFS, and median OS were 12.2% (standard deviation [SD] 11.2%), 3.2 months (SD 1.3), and 9.6 months (SD 4.1), respectively. ORR and PFS had very weak (R = 0.181; 95% CI: 0.016-0.337) and weak (R = 0.254; 95% CI: 0.074-0.418) relationships, respectively, with OS. However, within trials that did not allow crossover and reported balanced post-progression treatments, ORR and PFS had moderate (R = 0.528; 95% CI: 0.081-0.798) and strong (R = 0.778; 95% CI: 0.475-0.916) relationships, respectively, with OS. STE estimation indicated that trials that show statistically significant treatment effect size of ≥41.0% ORR or ≥4.15 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.
Coexistence of rearranged during transfection (RET) variants and activating EGFR mutations with their molecular implications in lung adenocarcinomas.
Authors: Kim Jeong-Oh , Shin Jung-Young , Kim Min Young , Son Kyoung Hwa , Jung Chan-Kwon , Kim Tae-Jung , Kim Su Young , Sung Sook-Whan , Park Jae Kil , Ro Sang Mi , Bae Sang-Ju , Min Hyun-Jung , Kang Jin Hyoung
Published: September 2018

e20610

Background: RET rearrangements have been identified in 1-2% of lung adenocarcinomas. The most common fusion is the KIF5B-RET, the function and roles of the RET fusion oncogene, and its downstream signaling molecules remain unclear. Methods: We constructed a tissue microarray (TMA) comprising 581 resected tumor tissues from lung adenocarcinoma patients and investigated them using FISH with RET break-apart and KIF5B-RET SY translocation probes. NanoString’s nCounter technology was used to assay RETtranscripts. We evaluated the protein expressions of RET and RET-related signaling molecules, including p-AKT and p-ERK, using TMA-based IHC staining. Results: Using FISH, we identified 51 cases (8.8%) of RET variants and 10 cases (1.7%) of KIF5B-RET fusion genes among the 581 cases. RET protein expression was lower in the group harboring KIF5B-RET fusion gene than that in the group harboring a wild type RET gene. We found the activating EGFR mutations in 11 (21.6%) cases of 51 RET variants. For the group with KIF5B-RET fusion gene, the expression of p-ERK was significantly lower in EGFR mutation subgroup with presence of RET protein compared to EGFR mutation subgroup with absence of RET protein. For the group with RET rearrangement, there were significant differences in the expression level of p-AKT (P = 0.028) and, p-ERK protein expression was remarkably increased, especially in cases with no RET protein expression. Conclusions: Taken together, the expression of p-ERK protein was meaningfully increased in the RET variants group regardless of RET protein expression. This result suggests that RET inhibitors combined with ERK inhibitors may be an effective treatment strategy for lung adenocarcinoma patients harboring the RET variants.
A phase 1B study of SNX-5422 plus carboplatin (C) and paclitaxel (P) in patients with advanced non-small-cell lung cancer (NSCLC).
Authors: Gutierrez Martin , Giaccone Giuseppe , Liu Stephen V. , Hao Zhonglin , Hilton Christie , Hinson James M , Orlemans Everardus Otto , Drilon Alexander E.
Published: September 2018

e20622

Background: SNX-5422 is an orally bioavailable pro-drug of SNX-2112, a highly potent and selective heat shock protein (Hsp) 90 inhibitor with synergy with platinum and paclitaxel. In this study, SNX-5422 + C/P followed by SNX-5422 maintenance therapy was examined in patients (pts) with NSCLC. Preliminary study results from the first 12 pts established the maximum tolerated dose (MTD) for SNX-5422 as 100 mg/m2 for the combination, with one G3 dose limiting toxicity (DLT) of diarrhea. The updated efficacy and safety results following enrollment completion (N = 20) are presented. Methods: Eligible pts had NSCLC (EGFR wild-type or non-sensitizing mutation) and ≤1 prior line of chemotherapy. Pts received C (AUC 5) and P (175 mg/m2) every 3 weeks for up to 6 cycles and SNX-5422 every other day (starting at 50 mg/m2) for 21 of 28 days, with a standard 3+3 dose escalation design during the combination, followed by SNX-5422 (100 mg/m2 every other day) monotherapy for maintenance until disease progression. Results: Twenty pts with NSCLC (pathology assessment: 18 adenocarcinoma, 2 squamous cell carcinoma) were enrolled (mean age, 59 yrs), with 19 evaluable for efficacy. Best response was partial response in 37% (7/19) of pts, stable disease in 58% (11/19) of pts, and progressive disease in 5% (1/19) of pts. Twelve of the 19 pts (63%) continued maintenance SNX-5422 monotherapy, and 7 of the 12 (58%) received therapy for ≥8 cycles. Four pts had G3 DLTs with combined therapy (considered possibly related to ≥1 agent): diarrhea (1 pt discontinued), increased alanine aminotransferase/aspartate aminotransferase (ALT/AST) (1), nausea, vomiting, and diarrhea (1), and peripheral sensory neuropathy (1). The most common adverse events considered possibly related to the combination were diarrhea (n = 14), nausea (n = 10), fatigue (n = 8), alopecia (n = 5), and vomiting (n = 5), and the majority of these events were G1/2. Conclusions: SNX-5422 added to C/P was well-tolerated at doses up to 100 mg/m2, and preliminary efficacy of this combination in NSCLC warrants further study. Clinical trial information: NCT01892046.
Costs and values of nivolumab in second-line cancer.
Authors: Guirgis Helmy M.
Published: September 2018

e20629

Background: Nivolumab (Nivo) has been approved in 2nd-line treatment of melanoma, squamous (sq) and non-sq- non-small cell-lung (NSCLC), renal cell, and sq-cell of head and neck (SCCHC). Our objective was to screen and compare values (V) of Nivo in cancer. Methods: Nivo median overall survival gain over control (OS), hazard ratios (HR), doses and frequency were extracted from previously published clinical trials. Data and prices posted by the parent company were utilized. Probability of survival (PoS) was calculated as (1.0- HR). Costs (C) were computed at 4 week (w), V as 4wC/PoS (4wV) and year-C/life-year gain (C/LYG). Relative values (RV) were expressed as $100,000/C/LYG. Adverse events C were not accounted for. Results: Estimated Nivo 4wC in early 2016 was $10,021. Conclusions:HR- based platform was proposed to screen and compare V of Nivo. At 0.42 HR in melanoma and >150 day-OS in renal cell, the results suggested that Nivo was fairly-priced for its V. In non-enriched non-sq-NSCLC and SCCHN, the PD-L1 enrichment was necessary to enhance V significantly and justify C. [Table: see text]
PD-L1 immunohistochemistry in clinical diagnostics: Inter-pathologist variability is as high as assay variability.
Authors: Micke Patrick , Johansson Anna , Westbom-Fremer Anna , Backman Max , Djureinovic Dijana , Patthey Annika , Isaksson-Mettävainio Martin , Gulyas Miklos , Brunnstrom Hans
Published: September 2018

e20637

Background: Several checkpoint inhibitors targeting the PD1 axis are now approved for the treatment of non-small cell lung cancer (NSCLC). The best predictor for therapy response is PD-L1 expression on tumor cells assessed by immunohistochemistry (IHC). However, the PD-L1 assays have been developed independently for each available drugs. In this study, we evaluated the different assays to determine the comparability between the assays and the concordance between pathologists under conditions reflecting the clinical situation. Methods: We tested four IHC assays (28-8, 22C3, SP263 and SP142) and one in-house protocol (28-8 on the Ventana system) on a tissue microarray (TMA) including 55 resected tissue specimens of NSCLC patients. The TMAs were independently annotated by seven pathologists with regard to the percentage of tumor cell membrane staining using a six-grade scale ( < 1%; 1-≤5%; 5%-≤10%; 10-≤25%; 25-≤50%; ≥50%). Results: The staining scores were comparable for the three assays with clones 28-8, 22C3 and SP263 as well as the in-house 28-8 protocol (κ-value: 0.75-0.91). The use of the SP142 clone resulted in a lower percentage of positive tumor cells and positive cases (κ: 0.44-0.63). When a reference score was defined based on the majority of scores, the proportion of positive cases (≥1%) were 38% for 28-8, 29% for 22C3, 42% for SP263, 37% for 28-8 in-house and 16% for SP142%. With ≥1% cut-off 3-8 of the 55 cases (5-15%) were differently classified as positive or negative when comparing any two assays excluding SP142. Analysing the scoring of the seven pathologists a clear inter-rater variability (κ: 0.71-0.96) was observed independent from the assay. With a ≥1% cut-off, 20% of cases were annotated differently by at least one pathologist. Conclusions: The concordance between the three antibody clones 28-8, 22C3 and SP263 was acceptable and was in the similar range as inter-rater variability of different pathologists. The results suggest that assessment of tumor cell staining for Nivolumab, Pembrolizumab and Durvalumab might be performed with only one of these assays. The assessment of the pathologist presents an intrinsic source of error that should be considered especially at low PD-L1 scores.
Response to crizotinib in advanced ALK-rearranged NSCLCs with different variants and abundance of ALK-fusion alleles.
Authors: Ying Jianming , Li Yan , Zhang Tongtong , Li Wenbin , Xing Pu-Yuan , Zhang Jing , Junling Li
Published: September 2018

e20651

Background: Anaplastic lymphoma kinase ( ALK) rearrangements are present in approximately 5% of non-small-cell lung cancers (NSCLCs). NSCLCs with ALK-rearrangement can be effectively treated with crizotinib. However, magnitude and duration of responses are found to be heterogeneous. This study explored the clinical efficacy of crizotinib in different ALK variants and abundance levels using next-generation sequencing (NGS). Methods: Among 89 ALK-rearrangement patients treated with crizotinib, 47 patients were identified with tumor specimens that could be evaluated by NGS. We retrospectively evaluated the clinical efficacy of crizotinib in different ALK variants and the abundance of ALK-fusion alleles. Results: The median PFS of the 89 ALK-rearrangement patients was 14.1 months (95%CI: 11.27-18.43 months). Among the 47 patients with NGS results, the most frequent variants were variant 3a/b (29.79%, 14/47), variant 1 (25.53%, 12/47) and variant 2 (14.89%, 7/47). Rare EML4- ALK variants were detected in 6 cases (12.77%). Other new fusion partners were detected in 8 cases (17.02%). Patients with EML4- ALK variant 2 appeared to have longer PFS than other EML4- ALK variants with a borderline p value. Patients were categorized into three groups based on the abundance of ALK-fusion alleles: low-abundance group ( < 35%), middle-abundance group (≥35% and < 55%), and high-abundance group (55%). Middle-abundance group had a better PFS than both low-abundance group and high-abundance group (P = 0.01). After adjusting for other baseline characteristics, abundance levels of ALK-positive alleles and ALKvariant type were identified as important factors for predicting clinical efficacy of crizotinib. Conclusions: Our results indicate prolonged PFS in patients with EML4- ALK variant 2 versus other EML4- ALK patients. The abundance of ALK-fusion alleles also correlated with the extent of benefit from crizotinib treatment.
Circulating tumor DNA (ctDNA) to monitor treatment response and progression in patients treated with tyrosine kinase inhibitors (TKIs) and immunotherapy for EGFR-mutant non-small cell lung cancer (NSCLC).
Authors: Henick Brian S. , Goldberg Sarah B. , Narayan Azeet , Rossi Chiara , Rodney Simon , Kole Adam J , Politi Katerina A. , Gettinger Scott N. , Herbst Roy S. , Patel Abhijit
Published: September 2018

e20652

Background: Detection of EGFR mutations in ctDNA can help determine appropriateness of TKI therapy for patients with NSCLC. We investigated whether longitudinal monitoring of ctDNA levels can be used to assess response to therapy and disease progression, with a focus on EGFR mutation-positive patients treated with immunotherapy. Methods: Serially collected blood from patients with EGFR mutation-positive NSCLC treated with TKIs and/or immunotherapy was analyzed using an ultrasensitive 24-gene next-generation sequencing assay. Clinical characteristics and outcomes were analyzed retrospectively by chart review. Results: We studied quantitative changes in ctDNA levels during treatment by analyzing somatic mutations in 91 plasma samples from 8 patients with EGFR-mutant NSCLC, including samples collected around the time of disease progression for a subset of patients. Two patients treated with PD-1 inhibitor monotherapy experienced a rise in ctDNA harboring EGFR-sensitizing mutations prior to radiographic progression. A third patient was started on anti-PD-1 monotherapy following disease progression on erlotinib. Plasma levels of L858R, T790M, and TP53 mutations were detectable on treatment initiation and decreased with radiographic response. The levels of these mutations rose at progression,fell with response to EGFR-directed therapy, and increased again before disease progression. Another patient was found to have mutations in EGFR, T790M, and TP53 that fell upon treatment with combination TKI therapy. The remaining four patients studied were treated with concurrent TKI and immunotherapy. In all of these cases, sensitizing EGFR mutations were present in plasma at low levels during response to treatment. Two of the four patients had a rise in ctDNA level at the time of radiographic progression; the other two patients had durable responses with persistently low ctDNA levels. Analysis of additional cases is ongoing. Conclusions: Monitoring quantitative changes in ctDNA may enable assessment of response or disease progression in immunotherapy- and TKI-treated EGFR-mutant NSCLC patients.
An updated analysis of ICOGEN to demonstrate utility of a blood-based proteomic test to predict outcomes in EGFR TKI treated patients.
Authors: Shi Yuankai , Han Xiaohong , Zhang Li , Ding Lieming , Dupuis Nicholas , Nickel Alex , Feng Lana , Chuang Yishan , Pestano Gary Anthony , Liu Xiaoqing , Zhou Caicun , Zhang Li , Zhang Shucai , Wang Dong , Li Qiang , Qin Shukui , Hu Chunhong , Chen Jianhua , Tan Fenlai , Sun Yan
Published: September 2018

e20655

Background: ICOGEN was a randomized Phase III clinical trial comparing two EGFR tyrosine kinase inhibitors (TKI), icotinib (I) and gefitinib (G), in EGFR gene mutation status unknown non-small-cell lung cancer (NSCLC) patients previously treated with platinum doublet chemotherapy. Plasma samples from study patients were retrospectively analyzed with a commercially-available blood-based proteomic test which has been shown to have prognostic and predictive properties in NSCLC. This study represents an updated analysis of ICOGEN to evaluate the ability of the test to predict outcome based on therapeutic regimen. Methods: Available pre-treatment plasma samples from ICOGEN were retrospectively analyzed with the proteomic test which classifies subjects as Good or Poor. Progression free survival (PFS ) and over-all survival (OS) were analyzed within treatment (TX) arms and test classification. Results: 352 subjects were evaluated, with 277(78.7%) classified as Good and 75(21.3%) classified as Poor. Among all patients evaluated with the proteomic test, the median PFS was 4.9 mo. and 2.3 mo. (HR [95% CI] 0.61 [0.46 – 0.81]; p = 0.0004) and median OS was 16.6 mo. and 5.5 mo. (HR [95% CI] 0.39 [0.29 – 0.50]; p < 0.0001) for the Good and Poor sub-groups, respectively. Association between test result and PFS was significant in patients treated with I (6.0 mo vs. 1.9 mo, HR = 0.43, p < 0.0001), but not significant in patients treated with G (3.7 mo vs. 2.5 mo, HR = 0.85, p = 0.429). Further evaluation demonstrated that the proteomic test predicted differential therapeutic benefit between icotinib and gefitinib for PFS (pint = 0.036). In OS, a significant association between test result and outcome was shown in both the I (16.3 mo vs. 4.0 mo, HR [95% CI] 0.27[0.19-0.39]; p < 0.0001) and G (16.6 mo vs. 7.0 mo, HR [95% CI] 0.51[0.35-0.76; p = 0.0008) arms, which trended towards prediction of differential therapeutic benefit between icotinib and gefitinib for OS (pint = 0.086). Conclusions: For ICOGEN’s primary study endpoint, the proteomic test was predictive of differential therapeutic benefit between icotinib and gefitinib in EGFR mutations status unknown NSCLC patients.
Icotinib as first-line or maintenance therapy in patients with advanced lung adenocarcinoma with positive EGFR mutation and the influence of cytokines shift on survival.
Authors: Sun Shengjie , Jiao Shun Chang , Fang Jian , Sun Qiong , Han Jindi , Liu Wei , Bai Chunmei , Tan Fenlai , Ding Lieming
Published: September 2018

e20658

Background: To compare the efficacy of first-line icotinib or chemotherapy plus icotinib maintenance in EGFR-mutated NSCLC patients, and analyze the correlation between changes in cytokine levels and survival. Methods: Treatment-naive patients with EGFR-mutated NSCLC were enrolled and randomly assigned to recieve icotinib or 2- or 4-cycle chemotherapy (pemetrexed + platinum [PP] or docetaxel + platinum [DP]) with icotinib maintenance. The primary endpoints were progression-free survival (PFS). Plasma samples were collected at baseline and after 6-week treatment. Cytokines, including interleukin-2 (IL-2), interleukin-6 (IL-6), transforming growth factor (TGF), programmed death (PD) 1, PD-ligand (PD-L) 1, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), and hypoxia-inducible factor-1 (HIF-1), were tested by ELISA. Results: 66 eligible patients were enrolled (November, 2011 to June, 2016), in which 56 patients were treated, including 20 patients receiving icotinib [PFS: 8.17 months (5.5-13.97)], 11 patients receiving 2-cycle chemotherapy (DP) followed by icotinib maintenance [PFS: 12.07 (6.2-12.83)], 10 patients receiving 2-cycle chemotherapy (PP) followed by icotinib maintenance [PFS: 15.37 (4.03-NR)], 4 patients receiving 4-cycle chemotherapy (DP) followed by icotinib maintenance [PFS: 15.37 (7.13-NR)], 9 patients receiving 4-cycle chemotherapy (PP) followed by icotinib maintenance [PFS: 13.82 (1.5-22.93)]. Samples were collected from 20 patients. The shift of level was seen in all cytokines and multivariate analysis showed that the change of IL-6, HIF, PD-L1, and PD1 were associated with significantly longer survival in patients with EGFR-mutated NSCLC. Conclusions: First-line chemotherapy plus icotinib maintenance seems to offer better efficacy in advanced NSCLC patients with EGFR mutation. The shift of level of IL-6, HIF-1, PD 1, and PD-L1 in peripheral blood correlates with a better prognosis, however, further study with larger size is warranted to detect the potential role of immune response in regulating survival of patients with EGFR-mutant NSCLC. Clinical trial information: NCT01665417.
Fibroblast kinase 1-3 inhibitor BGJ398 in patients with FGFR1 amplified squamous non-small cell lung cancer treated in a phase I study: Evaluation of tumor tissue and response at a single center.
Authors: Nogova Lucia , Malchers Florian , Bitter Elisabeth , Michels Sebastian Yves Friedrich , Fischer Rieke Nila , Scheffler Matthias , Gardizi Masyar , Brandes Vanessa , Scheel Andreas H. , Kambartel Karl-Otto , Krüger Stefan , Serke Monika Heidi , Isaacs Randi , Porter Dale , Buettner Reinhard , Thomas Roman K. , Wolf Juergen
Published: September 2018

e20664

Background: Fibroblast growth factor receptor 1 ( FGFR1) amplification in squamous cell non-small cell lung cancer (sqNSCLC) has been described as potential oncogenic and targetable driver in cell lines and murine models. However, a phase I study evaluating FGFR 1-3 inhibitor BGJ398 showed moderate response rate of 11% in FGFR1amplified sgNSCLC treated with dose ≥ 100mg. To identify underlying mechanisms of resistance, we analyzed tumor tissues of selected patients. Methods: Within the phase I BGJ398 study, patients (pts) with FGFR1amplified sqNSCLC were treated orally with escalating dose (5 to 150mg) of BGJ398 once daily (QD) or 50mg twice a day. In the expansion phase, pts received BGJ398 either continuously QD or on a 3-weeks on/1-week off schedule. CT scans for response were performed every 8 weeks. Available tumor tissue of pts treated with BGJ398 at our center was analyzed using hybrid capture–based massively parallel sequencing (CAGE). Results: Twenty-one pts with FGFR1 amplified sqNSCLC were treated with ≥ 100mg BGJ398 at our site. As best response, 3 pts showed partial response (PR), 7 pts stable disease (SD) and 7 pts progressive disease (PD). Two pts withdrew their consents and 2 pts died ahead of first CT scan: one due to infection and one due to sudden death. We performed CAGE covering 256 genes on 9 patients: on 3 pts with PR, 2 pts with SD, 2 pts with PD and 2 pts who died before first CT scan. All analyzed patients harbored mutations in TP53. Additionally, we detected two CDKN2A (one patient with PR and one patient who died before first CT) and three MLL2 stop codon and frame shift mutations (two patients with SD and one patient with PD). Of interest, we identified three patients with two canonical (one patient with SD and one patient who died before first CT) and one non-canonical mutations in PIK3CA(one patient with SD). Conclusions: In our analysis, MLL2 and PIK3CA mutations seem to have a negative impact on response in FGFR1 amplified pts treated with BGJ398. Further analysis with higher patient number is needed to identify the role of MLL2 and PIK3CA mutations in FGFR1 amplified sqNSCLC. Clinical trial information: NCT01004224.
Survival impact of aggressive treatment on patients with oligometastatic non-small cell lung cancer (NSCLC).
Authors: Gauvin Camille , Blais Normand , Tehfe Mustapha , Florescu Marie
Published: September 2018

e20669

Background: The new 2016lung cancer classification differentiates oligometastatic (M1b) better prognostic from plurimetastatic (M1c) disease. A prospective study presented at 2016 ASCO showed improved PFS in patients with oligometastatic brain disease treated aggressively compared to a more palliative treatment but OS data is pending. Methods: This study is a single-center retrospective study including 643 patients with metastatic lung cancer diagnosed in an University center (CHUM) from 2005-2015 and followed more than 6 months (median follow up 13.3mo) . Only 67 patients (10.4%) were found to have synchronous oligometastatic disease at diagnosis. Results: Amongst the 67 patients, the localization of metastatic disease was as follows: 74% brain (n = 50), 9% adrenal gland (n = 6), 7% contralateral pulmonary lobe (n = 5), 6% bone (n = 4) and 3% liver (n = 2). 29 patients received radical treatment to primary and metastatic site (group A) and 36 patients received non-aggressive treatments (group B). There was no statistically significant difference between the two groups in terms of demographic and histological characteristics. The radical treatment group A had a mOS of 26mo and a mPFS of 12.8m compared to mOS of 5mo (p = 0.0001) and mPFS of 4.8mo (p = 0.010) for group B. This difference was observed when stratifying according to stage of primary lung disease (stage I mOS 42mo vs 16mo, stage II mOS 34mo vs 6mo and stage III mOS 22mo vs 4mo) and according to to oligometastatic site. Interestingly, addressing aggressively the primary lung cancer improved median survival even when the oligometastasis was not resected (26mo v and 24mo respectively), but not when oligometastasis only was resected and primary was treated palliatively (5mo vs 3 mo). Adjuvant chemotherapy given after radical treatment did not improve mPFS or mOS (12.83 vs12.47 months, p = 0.860). Conclusions: Radical treatment of oligometastatic NSCLC in this unselected population improved mPFS and mOS compared to other treatment strategies. As overall survival data of the prospective trial presented at 2016 ASCO meeting is pending, the more radical approach should be emphasized when patients present with oligometastatic lung cancer disease.
Generalizability of clinical trials in metastatic melanoma.
Authors: Sam Davis , Gresham Gillian K. , Cheung Winson Y.
Published: September 2018

e21004

Background: Results from clinical trials are not always generalizable to real world patients (pts). Clinicians may not adhere to the studies’ original inclusion/exclusion criteria because of differences in clinical circumstances or institutional variations in treatment policies. Our aims were to determine the pattern in which melanoma trial findings are applied in a population-based setting and to describe the treatment outcomes of these pts. Methods: We focused on melanoma as several novel therapies have been recently introduced. Pts with unresectable disease from 2013 to 2014 and referred to any 1 of 6 cancer centers in British Columbia were reviewed. Based on eligibility criteria as described in registration trials of vemurafenib (Vem) and ipilimumab (Ipi), we classified pts into trial eligible (TE) and ineligible (TI) and those treated and untreated with these agents. During the study period, Vem was approved for 1st line use in BRAF mutant pts and Ipi was funded for 2nd line use. Results: We identified 185 pts with known BRAF status for the Vem analysis and 114 pts for the Ipi analysis: median ages 64 and 59 years, 57% and 61% men, and 89% and 88% ECOG 0-1, respectively. For Vem, BRAF wild type was the most common reason for being TI. Of the remaining 86 BRAF mutant pts, 59 (69%) were considered TE of whom 51 (86%) received treatment. For Ipi, poor ECOG including rapidly progressive disease was a prevalent cause of being TI. In the Ipi cohort, 96 (84%) cases were deemed TE of whom 63 (66%) received therapy. Factors most frequently associated with non-treatment in both Vem and Ipi TE pts included comorbidities (41%), pt refusal (23%), and toxicities from prior treatments (14%). Compared to TI pts as well as those considered TE but did not receive treatment, pts deemed TE and received treatment achieved the best survival (adjusted HR 0.53, 95% CI 0.28-1.00 for Vem and adjusted HR 0.33, 95% CI 0.13-0.83 for Ipi). Conclusions: There was favorable uptake of new melanoma treatments, but a fair number of pts were considered TI, suggesting the need for trials with better external validity. Non-use of novel agents in TE pts was due to physician factors, pt preferences, and concerns about toxicities, highlighting areas that limit real world effectiveness of new melanoma drugs.