bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II study of bortezomib with cisplatin as first-line treatment of malignant pleural mesothelioma (MPM): EORTC 08052.
Authors: O'Brien Mary , Gaafar Rabab Mohamed , Popat Sanjaykumar , Grossi Francesco , Price Allan , Talbot Denis Charles , Cufer Tanja , Ottensmeier Christian H.H , Danson Sarah , Pallis Athanasios G. , Hasan Baktiar , Van Meerbeeck Jan P. , Baas Paul
Published: March 2020

7081

Background: Cisplatin is one of the most active drugs available in MPM while bortezomib has shown some activity in single agent phase II studies against MPM. This was a prospective phase II study of cisplatin and bortezomib (CB) in the first line treatment of MPM. Methods: Patients with histological proven MPM, with performance status (PS) 0/1, were eligible. The doses were cisplatin 75mg/m2 /3 wks and bortezomib 1.3mg/m2 day 1, 4, 8, 11 every 3 wks. The primary end-point was progression free survival rate at 18 wks (PFSR=18). The 2-stage Simon design (a=0.1; b = 0.05, P0=0.50 and P1=0.675) was used. In the first step of the study 37 eligible patients were planned. If more than 19 patients were alive and free of progression at 18 wks the total sample size was increased to 76 eligible patients. Results: Between 2007 and 2010 82 patients were entered. The median follow-up time is 32.3 months The median age was 55 years (range: 22-77yrs), male/female: 55/27 , PS 0/1: 9/73, Stage T1: 10%; T2: 42%, T3: 25%; T4: 23% and N0: 57%; N1: 4%; N2: 33%; N3: 6%. The median number of cycles received was 4 and 38% received 6 cycles. Cisplatin/ bortezomib dose intensity was 98/ 80%. Toxicity (grade 3/4): neutropenia 10%, thrombocytopenia 11%, anaemia 1%. Grade 3-4 hyponatraemia/ hypokalaemia occurred in 46/ and 17%. Grade 2 tinnitus, grade 3 fatigue occurred in 16%, and 12%, of patients. Motor/sensory/other neurotoxicity was grade 1: 6/28/7%, grade 2: 2/26/2% and grade 3: 1/7/2% respectively. There were 2 toxic deaths at 32 and 74 days due to acute pneumonitis and cardiac arrest. The PFRS-18 (including symptomatic progression) was 53% (80% confidence intervals, CI, 42-64%). The overall survival was 13.5 months (95% CI 10.5-15) with 56% (95% CI 44-66%) alive at 1 year. The PFS was 5.1 months (95% CI 3.3-6.5). Conclusions: On the basis of the PFRS-18, the null hypothesis could not be rejected, although CB gave predictable toxicity and was as active as other reported regimens in MPM.
NGR-hTNF and doxorubicin in relapsed small-cell lung cancer (SCLC).
Authors: Cavina Raffaele , Gregorc Vanesa , Novello Silvia , Grossi Francesco , Santoro Armando , Viganò Maria Grazia , Levra Matteo G. , Lambiase Antonio , Bordignon Claudio
Published: March 2020

7085

Background: By selectively damaging tumor vasculature, NGR-hTNF (asparagine-glycine-arginine human tumor necrosis factor) is able to improve intratumoral uptake of doxorubicin (D). A phase I trial selected NGR-hTNF 0.8 µg/m2/day(d)1 and D 75 mg/m2/d1 every 3 weeks (q3w) for phase II. Methods: SCLC pts failing one or more platinum-based regimen received NGR-hTNF until progressive disease (PD) and D up to 550 mg/m2. This phase II trial (n=27 pts) had progression-free survival (PFS) as primary end point, with tumor response assessed q6w by RECIST, while secondary end points included adverse events (AEs), disease control rate (DCR), and overall survival (OS). Results: Among 28 pts enrolled (median age 63 years; M/F 19/9; PS 0/1-2 13/15; prior lines 1/2-3 20/8), 16 pts had platinum-resistant (R) disease (PD≤3 months) and 12 pts platinum-sensitive (S) disease (PD>3 months). At baseline, median neutrophil to lymphocyte ratio (NLR) was 4 (range 1-20). A total of 114 cycles were given (range 1-10), with 13 pts (46%) having ≥ 4 cycles and 9 pts (32%) ≥ 6 cycles. No grade 3/4 AEs related to NGR-hTNF were noted, while grade 1/2 AEs were transient chills (61%). NGR-hTNF did not apparently increase D-related AEs. Median PFS was 3.2 months (95% CI 2.6-3.8) and 1-year OS rate was 34%. Overall, DCR was 55% (95% CI 35-74), comprising 6 partial responses (22%; median duration: 6.3 months) and 9 stable diseases (33%; median duration: 4.1 months). Mean changes from baseline in target tumor size after 2, 4, and 6 cycles were -9%, -29%, and -32%, respectively for R disease and -11%, -20%, and -43%, respectively for S disease. In pts pretreated with ≥ 2 lines, DCR was 75%, median PFS was 5.1 months, and 1-year OS rate was 44%. In pts with R or S disease, DCR were 50% and 58% (p=.72), median PFS were 2.7 and 4.1 months (p=.07), and 1-year OS rates were 27% and 42% (p=.65), respectively. At multivariate analyses, PFS was not related to baseline characteristics, while an improved OS was associated only with a low NLR. The 1-year OS rate was 48% in pts with NLR ≤ 4 and 10% in pts with NLR > 4 (p=.007), while in pts with NLR ≤ 4, 1-year OS rate was 46% in R disease and 50% in S disease. Conclusions: This combination is well tolerated and active in platinum resistant and sensitive SCLC and further development is of interest.
Clinical trial design in small cell lung cancer: Surrogate endpoints and statistical evolution.
Authors: Nickolich Myles , Fu Pingfu , Babakoohi Shahab , Dowlati Afshin
Published: March 2020

7087

Background: Small cell lung cancer (SCLC) is a devastating disease for which little recent therapeutic advance has been achieved. SCLC trial design and reporting may have an impact on the interpretation of studies conducted. Furthermore the use of surrogate endpoints in SCLC has not been explored. Methods: Through examining all phase II and III SCLC trials published in the Journal of Clinical Oncology (8,471 patients from 66 trials between 1983-2010), we examined how SCLC trial reporting and design has evolved, determining if the type I error, power, and sample size calculations were provided. We assessed primary endpoints for all trials and sought to discover if response rate (RR) or progression-free survival (PFS) correlated with overall survival (OS). We analyzed response and survival outcomes for associations using Pearson correlation coefficient and differences between data groups by ANOVA followed by Tukey’s multiple comparison procedure. Results: There were increased reporting trends of statistical design in power (16.7% in 1986-1996 to 77.8% of trials in 2006-2010 [p=0.001]) and type I error (22.2% in 1986-1996 to 72.2% in 2006-2010 [p=0.005]). 72.2% of trials published in 1986-1996 failed to report a primary endpoint whereas only 5.56% of trials in 2006-2010 failed to do so (p=0.004). Of phase II trials, primary endpoint was identified as RR in 65%, OS in 25%, and PFS in 10% (p<0.0001). There is a strong correlation between RR and both PFS (p=0.013) and OS (p=0.012) in extensive-stage disease (ED) but not limited-stage disease (LD) (p=0.978 for PFS, p=0.193 for OS). This correlation is for partial response rate (pRR) but not complete response rate. RR (p=0.029) exhibits a negative trend over time with a dramatic and significant decrease in RR across all studies starting in 2005. A strong positive correlation exists between PFS and OS for LD (p=0.036) and ED (p=0.058). We found no change in median overall survival (p=0.383). Conclusions: Over time there has been improvement in reporting the essential statistical data for proper interpretation of SCLC trials. No change in survival was seen over the past 28 years. RR should be evaluated as a surrogate endpoint for OS in ED but not LD. pRR correlates with OS and PFS in both LD and ED.
Phase II trial of huKS-IL2 with cyclophosphamide (CTX) in patients with extensive disease small-cell lung cancer (ED-SCLC).
Authors: Gladkov Oleg , Biakhov Mikhail , Ramlau Rodryg , Serwatowski Piotr , Milanowski Janusz , Tomeczko Janusz , Komarnitsky Philip B , Bernard Laurence , Kramer Daniel , Krzakowski Maciej Jerzy
Published: March 2020

7090

Background: huKS-IL2 immunocytokine is a humanized antibody specific for EpCAM, fused at its Fc end to two molecules of IL2. Results of a phase 1b study of huKS-IL2 plus low-dose CTX, and preclinical data, provided a rationale to evaluate this combination in SCLC, which is often EpCAM-positive. Methods: Patients (pts) with ED-SCLC responding (PR/CR) to 4 cycles of first-line Pt-based chemotherapy were randomized 1,5:1 to receive huKS-IL2/CTX or best supportive care (BSC). Pts in the huKS-IL2/CTX arm received six 21-day cycles of CTX 300 mg/m2 on day (d) 1, and 1.5 mg/m2/d huKS-IL2 on d2–4, followed by 21-d cycles of CTX on d1 and huKS-IL2 on d2 until progression. Pts were stratified for prophylactic cranial irradiation (PCI) and response to chemotherapy. Primary endpoint was PFS rate at 6 months (mo). Secondary endpoints included OS rates at 12 and 18 mo from start of Pt-based chemotherapy, median PFS and OS, safety, and immunogenicity. Results: 108 pts (64 huKS-IL2/CTX arm, 44 BSC arm) were randomized and treated. Baseline characteristics were balanced between arms; however, higher % of males (75 vs 61.4%) and of ECOG PS 0 (45.3 vs 38.6%) were observed in the active arm. Median age was 61.7 (32; 81) and 59.2 (45; 74) years in the active and BSC arm, respectively. Most pts were in PR at randomization (2 pts – 1 in each arm – had CR). PCI was used in 15 (23.4%) and 11 (25%) pts in the active and BSC arm, respectively. No significant differences in PFS or OS were observed in the active vs BSC arm: PFS rate was 6.4 vs 12.2%; median PFS was 1.5 vs 1.4 mo; OS rates at 12 and 18 mo were 52 vs 61% and 24 vs 29%, respectively; median OS was 12.3 vs 14.1 mo. One PR (45% reduction vs randomization baseline) was observed in the active arm. In a subset of pts who received PCI, median PFS was 1.7 vs 1.5 mo, median OS 21.5 vs 14.3 mo in the active vs BSC arm, respectively. AEs observed more frequently in the active arm were flu-like symptoms, rash, hypotension, lymphopenia, LFT and creatinine elevations; all Grade 3/4 AEs related to huKS-IL2 were reversible/manageable. Conclusions: HuKS-IL2/CTX was well tolerated, but showed no benefit in pts with ED-SCLC in PR/CR after chemotherapy. A trend for improved PFS and OS was observed in pts who received prior PCI.
Circulating tumor cells (CTCs) in patients (pts) with small cell lung cancer (SCLC) as a marker of disease burden and therapeutic response, and predictor of disease relapse.
Authors: Ranganathan Anjana , Schwed-Lustgarten Daniel , Aggarwal Charu , Werner Lynn , Torigian Drew A. , Troxel Andrea B. , Evans Tracey L. , Stevenson James , Cohen Roger B. , Vaidya Bhavesh , Rao Chandra , Connelly Mark C. , Albelda Steven , Langer Corey J.
Published: March 2020

7092

Background: Currently there are no validated biomarkers for assessment or prediction of disease burden or activity in SCLC. Enumeration of CTCs by CellSearch is FDA approved, highly reproducible and validated in other malignancies. Application as a prognostic and predictive marker in SCLC is limited due to a lack of studies documenting serial monitoring in pts on therapy. Methods: We are conducting a prospective study serially enumerating CTCs in pts with newly diagnosed SCLC. CTC number (per 7.5 ml peripheral blood) and percentage of CTCs demonstrating DNA damage and apoptosis based on γH2AX and M30 staining respectively, are being assessed prior to initiation of chemotherapy, during each cycle and at relapse. We are correlating CTC number with disease stage, number of metastatic sites, response to therapy, and time to progression (TTP). Results: 21 SCLC pts are evaluable. 9 pts with limited disease (LD) had median baseline CTC value of 1 (0-8); only 2 of 9 pts had >5 CTCs. 12 pts with extensive disease (ED) had median baseline CTC value of 80.5 (0-37780); 8 of 12 pts had >5 detectable CTCs (p value 0.02). Amongst the 12 pts with ED, median baseline CTC count was higher in pts with ≥3 (n=3) compared to 1-2 sites of metastatic disease (n=9) (2668 vs 71; p value 0.52). Median percentage of CTCs positive for γH2AX and M30 was also higher for pts with ≥3 compared to 1-2 metastatic sites (83, 164.5 vs. 2, 7.5) (p-value 0.40, 0.69). Serial CTC data are available on 3 pts with ED; all had responsive disease and reduction in CTC number to 0-1 after 2 cycles of chemotherapy. As this protocol is ongoing, correlation of CTCs with updated response status and TTP will be presented at the ASCO meeting. Conclusions: CTCs can be isolated and serially enumerated in pts with SCLC. Baseline CTCs correlate directly with disease stage. In pts with ≥ 3 metastatic sites, baseline CTCs tend to be greater and show higher levels of DNA damage and apoptosis compared to those with 1-2 metastatic sites. Reduction in CTCs is associated with radiographic response to therapy. Correlation between absolute number at baseline and TTP is not yet known.
Factors influencing outcome in thymic epithelial tumors (TET).
Authors: Porter Ryan Frederick , Radovich Milan , Rojas Luis , Suleiman Yaman , Conces Madison , Shirar Kristen L , Nelson Robert P , Spittler Aaron John , Burns Matthew , Kesler Kenneth , Badve Sunil S. , Schneider Bryan P. , Loehrer Patrick J.
Published: March 2020

7108

Background: TET represent a heterogeneous collection of rare tumors, thymoma and thymic carcinoma (TC). Prognosis is often based on WHO histology and Masaoka Stage (MS) with small series often lacking long-term follow-up or advance stage disease. We examined predictors of relapse, disease-free survival (DFS) and overall survival (OS) based on WHO classification and MS. Methods: A retrospective analysis was performed on patients(pts) with TET seen at IUSCC from 1976 to 2011 with available tissue blocks. MS, WHO histology, demographics, autoimmune co-existence and non-TET neoplasms were correlated with DFS and OS (via Kaplan-Meier analysis). Results: Of 251 pts identified, MS at diagnosis was I(n=74), II(n=43), III(n=71), IVa(n=38), IVb(n=12) and indeterminate (n=13). The histology were thymoma (n=195) and TC (n=56). Median age was 51(10-88) and (M:F =121:130). Autoimmune disease was present (n=82) (myasthenia gravis n=52) and non-TET neoplasms (n=36). Therapy after diagnosis included surgery alone (n=115), radiation (n=29), chemo (n=71), chemo-radiotherapy (n=29), indeterminate(n=7). Median follow up was 69 months (1 to 399.5). DFS for stages I,II,III at 5 years was 83%, 71% and 39%; DFS was associated with MS (p<.001) and WHO classification (p=.028). The 5yr and 10yr OS for stages I, II, III, IVa, IVb were 90%, 94%, 80%, 55%, 14% and 65%, 52%, 53%, 28%, 0%. The 5yr OS for WHO classification were: A/AB-89%, B1/B2/B3-98% and C-30% and 10yr survivals were 89%, 62%, 0%. OS was associated with MS (p<.01) , WHO classification (p<.001) and autoimmune disease (p=.03). Late relapses (>5yr) occurred in 13 (23%) pts, including 3 with Stage I and 2 with WHO A classification. Conclusions: MS, WHO classification and autoimmune disorders were statistically significant with OS and with DFS for MS and WHO. TC prognosis is significantly worse than thymoma. The improved OS with autoimmune disease requires further investigation but raises the possibility of benefit derived from earlier diagnosis and/or heightened immune surveillance. These data support the notion that all TET, regardless of histologic subtype or clinical stage, are malignant with a capacity for metastasis. As relapses beyond 5 years are common, lifelong follow-up for TET is recommended.
SELECT: Randomized phase III study of docetaxel (D) or pemetrexed (P) with or without cetuximab (C) in recurrent or progressive non-small cell lung cancer (NSCLC) after platinum-based therapy.
Authors: Kim Edward S. , Neubauer Marcus A. , Cohn Allen Lee , Schwartzberg Lee Steven , Garbo Lawrence E. , Caton John Robert , Robert Francisco , Katz Terry , Chittoor Sreenivas , Simms Lorinda , Saxman Scott
Published: March 2020

7502

Background: SELECT investigated whether the addition of C to standard chemotherapy improved progression-free survival (PFS) in patients (pts) with recurrent or progressive NSCLC after failure of platinum-based therapy. Methods: SELECT was a multicenter, open label, randomized phase III trial. Per investigator choice, pts received either P (500 mg/m2) or D (75 mg/m2) on day 1 and then were randomized within each group to chemotherapy plus C (400/250 mg/m2) (initial/weekly) or chemotherapy alone. Therapy was given for up to six 3-week cycles; pts randomized to C continued weekly monotherapy until disease progression or unacceptable toxicity. The primary objective was PFS for PC vs. P as determined by an Independent Review Committee (IRC). Secondary endpoints included overall survival (OS), objective response rate (ORR) and duration of response (DOR) by IRC, and safety. Preplanned subgroup analyses for epidermal growth factor receptor (EGFR) staining intensity by immunohistochemistry and histology were performed. Results for PC vs. P only are presented. Results: Between Jan 2005 and Feb 2010, 938 total pts were randomized. Baseline demographics were comparable between PC (n=301) and P (n=304): median age 64 years; male 60%; Caucasian 88%; KPS 80-100/60-70 84%/16%; squamous/non-squamous 24%/76%. Median PFS (months) PC: 2.89 and P: 2.76 (hazard ratio [HR] =1.03 [95% confidence interval (CI)=0.87-1.21]; p=0.76). Median OS (months) PC: 6.93 and P: 7.79 (HR=1.01 [95% CI=0.86-1.20]; p=0.86). ORR PC: 6.6% and P: 4.3% (odds ratio =1.59 [95% CI=0.78-3.26]; p=0.20). Median DOR (months) PC: 4.17 and P: 6.93 (HR=1.58 [95% CI=0.74-3.36]; p=0.24). There were no statistical differences in efficacy based on histology or EGFR staining intensity. More drug-related AEs/SAEs were observed in the PC arm, with differences mainly attributable to skin toxicities, GI (diarrhea/stomatitis), and hypomagnesemia. Conclusions: The addition of C to P did not improve efficacy in this pt population. Further biomarker analyses are planned. The safety profiles for C and P were consistent with existing data and no new safety signals were observed.
Analysis of resistance mechanisms to ALK kinase inhibitors in ALK+ NSCLC patients.
Authors: Doebele Robert Charles , Aisner Dara L , Le Anh T , Berge Eamon M , Pilling Amanda B. , Kutateladze Tatiana G. , Weickhardt Andrew James , Franklin Wilbur A. , Varella-Garcia Marileila , Camidge D. Ross
Published: March 2020

7504

Background: Patients with anaplastic lymphoma kinase (ALK) gene fusions derive significant clinical benefit from crizotinib, an ALK inhibitor; moreover, next generation ALK kinase inhibitors are in development. Unfortunately, drug resistance develops after initial benefit (acquired) or occurs in patients who never derive a benefit (intrinsic). This study aimed to define molecular mechanisms of resistance to ALK kinase inhibitors in ALK+ non-small cell lung cancer (NSCLC) patients. Methods: 30 ALK+ crizotinib-treated NSCLC patients experienced radiologic disease progression, of whom 7 progressed only in the CNS. Of the 23 patients with extra-CNS progression, a biopsy was attempted on 19. One of the patients without tissue post-crizotinib then proceeded to a second generation ALK inhibitor and tissue was obtained post progression on this drug. We performed molecular analysis and initiated cell lines from tumor tissue for these 19 patients. Results: 15 patients had material evaluable for molecular analysis. Six patients (40%) developed secondary mutations in the kinase domain of ALK. Two novel mutations were identified in samples from ALK+ NSCLC patients, F1174C and D1203N. Two patients each demonstrated G1269A or L1196M mutations. Two patients each, one with a resistance mutation, exhibited new onset ALK copy number gain (CNG). Four patients demonstrated the presence of another oncogenic driver (1 with EGFR mutation; 3 with KRAS mutation) with or without a persistent ALK gene rearrangement. One patient lacked an ALK gene fusion on progression biopsy, but had no identifiable alternate oncogene alteration. 3 patients retained ALK positivity with no identifiable resistance mechanism. Data on additional patients and an in vitro model of copy number gain will be presented. Conclusions: ALK kinase inhibitor resistance in ALK+ NSCLC occurs through a diverse array of kinase domain mutations, ALK gene fusion CNG, and emergence of second (same cell) or separate (different cell) oncogenic drivers. In order to overcome resistance it will be important to differentiate patients that preserve ALK dominance (secondary mutations and CNG) versus those that have diminished ALK dominance (separate or second oncogenic drivers).
SWOG S0635 and S0636: Phase II trials in advanced-stage NSCLC of erlotinib (OSI-774) and bevacizumab in bronchioloalveolar carcinoma (BAC) and adenocarcinoma with BAC features (adenoBAC), and in never-smokers with primary NSCLC adenocarcinoma (adenoCa).
Authors: West Howard Jack , Moon James , Hirsch Fred R. , Mack Philip C , Wozniak Antoinette J. , Lau Derick , Fehrenbacher Louis , Bury Martin Joseph , Redman Mary Weber , Gandara David R.
Published: March 2020

7517

Background: Despite recent changes to lung adenoCa pathologic classification, adv stage BAC remains a definable and clinically applicable entity. Patients (pts) with BAC, as well as never-smoking (NS) pts with adv lung adenoCa, have emerged as relevant clinical subpopulations with a high probability of clinical benefit from epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), likely related to the high proportion of activating mutations in the EGFR gene in such pts. Based on these results and the potential for increased clinical activity conferred by addition of B to E, SWOG initiated a pair of phase II trials of this combination in pts with adv BAC (S0635) or NS pts with adv lung adenoCa (S0636). Methods: NS pts with BAC or adenoBAC were preferentially enrolled on S0636. A total of 78 and 85 eligible pts were enrolled and treated on the S0635 and S0636 trials, respectively. Patients received E 150 mg PO daily and B 15 mg/kg IV q21 days until progression or prohibitive toxicity. Tumor tissue submission for pathologic review and assessment of molecular markers was mandated. Results: Pt demographics of the two trials are as shown in the table below. RECIST response rate among 61 BAC pts on S0635 with measurable disease was 18%, and among 53 NS pts on S0636, it was 47%. Median progression-free survival is 5 and 8 months (mo) on S0635 and S0636, respectively; median overall survival (OS) is 17 and 26 mo on S0635 and S0636, respectively. Toxicity consisted primarily of rash, diarrhea, and hypertension; no treatment-related deaths were reported. Molecular marker studies will be presented separately. Conclusions: In populations selected by clinical parameters, E withB is associated with modest toxicity and encouraging clinical efficacy that exceeded the prespecified OS threshold of 16 mo in studies of both adv BAC and NS pts, exceeding two years in NS pts. [Table: see text]
EGFR compound mutants and survival on erlotinib in non-small cell lung cancer (NSCLC) patients (p) in the EURTAC study.
Authors: Rosell Rafael , Molina-Vila Miguel Angel , Taron Miquel , Bertran-Alamillo Jordi , Mayo Clara , Vergnenegre Alain , De Marinis Filippo , Massuti Bartomeu , De Castro Javier , Gervais Radj , Carcereny Enric , Buges Cristina , Moran Teresa , Santarpia Mariacarmela , Felip Enriqueta , Majem Margarita , Bosch Joaquim , Cardenal Felipe , Drozdowskyj Ana , Bivona Trever Grant
Published: March 2020

7522

Background: When EGFR compound mutants (exon 19 deletions or L858R plusT790M) are present at the time of clinical resistance to erlotinib, patients attain longer overall survival (OS) (Oxnard et al. CCR 2011). The H1975 cell line, harboring L858R plus T790M prior to treatment, is sensitive to gefitinib (Sordella et al. Science 2004; Faber et al. Cancer Discovery 2011), though the compound mutant may become dominant after multiple passages in vitro, leading to resistance (Pao et al. PLoS Med 2005). Methods: The EURTAC trial (clinicaltrials.gov NCT00446225) randomized 174 p with EGFR exon 19 deletions or L858R mutations to receive erlotinib or chemotherapy. Progression-free survival (PFS) was 9.7 months (m) vs 5.2 m, respectively (P<0.0001). No differences in OS were observed.123 p with remaining available pre-treatment tumor tissue were re-analyzed for the concomitant presence of the T790M mutation with an allelic discrimination Taqman assay in the presence of a PNA clamp designed to inhibit the amplification of the exon 20 wild-type (wt) allele. This assay is capable of detecting the T790M allele at a ratio of 1:5000 wt alleles. Results: The T790M mutation was detected in 21/64 (32.8%) p in the erlotinib arm and 26/59 (44.1%) in the chemotherapy arm. PFS was 12.1 m for p with mutant T790M in the erlotinib arm, 8.8 m for p with wt T790M in the erlotinib arm, 6.3 m for p with mutant T790M in the chemotherapy arm, and 4.5 m for p with wt T790M in the chemotherapy arm (P<0.0001). OS was not reached for p with mutant T790M in the erlotinib arm, 16.1 m for p with wt T790M in the erlotinib arm, 22.6 m for p with mutant T790M in the chemotherapy arm, and 18.4 m for p with wt T790M in the chemotherapy arm (P=0.04). Conclusions: Our unexpected finding that p with EGFR compound mutants attain the maximum benefit from erlotinib suggests a need for more sensitive assays to detect EGFR compound mutants and for studies of inhibitors targeting the EGFR T790M mutation. Whole genome sequencing may provide greater understanding of the genetic factors involved in the differences in OS.
Chemotherapy with erlotinib or chemotherapy alone in advanced NSCLC with acquired resistance to EGFR tyrosine kinase inhibitors (TKI).
Authors: Goldberg Sarah B. , Oxnard Geoffrey R. , Digumarthy Subba , Muzikansky Alona , Jackman David Michael , Lennes Inga Tolin , Sequist Lecia V.
Published: March 2020

7524

Background: EGFR-mutant NSCLC has an oncogene-addicted phenotype that confers sensitivity to EGFR TKIs. Prior data suggests EGFR addiction persists after development of TKI resistance, leading many clinicians to continue TKI along with chemotherapy (chemo); however, this strategy has not been formally evaluated. Methods: An institutional database was reviewed to identify patients (pts) with advanced NSCLC and acquired resistance to EGFR TKIs by Jackman criteria. Pts were included if they subsequently received chemo. Objective response rate (RR) to chemo/erlotinib or chemo alone was assessed by blinded radiographic review and compared by Fisher’s exact test and multivariable logistic regression. Progression-free survival (PFS) and overall survival (OS) from TKI failure (defined as chemo initiation date) were compared by log-rank test and multivariable Cox analysis. Results: 78 pts were eligible (34 chemo/erlotinib, 44 chemo alone). 70 pts (90%) had a documented EGFR mutation and were on TKI for a median of 15 months (range 4-51); in the 8 pts with unknown genotype the median duration on TKI was 11 months (range 5-16). Baseline characteristics were well balanced except more pts received erlotinib as initial TKI in the chemo/erlotinib group. RR was evaluable in 57 pts and was higher with chemo/erlotinib compared to chemo alone (41% vs 18%; OR 0.31, 95% CI 0.09, 1.04; p=0.08). RR adjusted for chemo regimen and time to TKI failure yielded OR 0.20 (95% CI 0.05, 0.78; p=0.02), favoring chemo/erlotinib. Median PFS was 4.4 months in the chemo/erlotinib group and 4.2 months in the chemo alone group (crude HR=0.84, 95% CI 0.52, 1.38; p=0.50; adjusted HR 0.79, 95% CI 0.48, 1.29; p=0.34). There was no significant difference in OS in the crude or adjusted analyses. Conclusions: This is the first study, to our knowledge, to show that continuation of an EGFR TKI with chemo compared to chemo alone significantly increases the RR in pts with advanced NSCLC and acquired TKI resistance, though we did not observe an impact on PFS or OS. Continued concurrent TKI may be a valuable strategy, particularly for pts with symptomatic progression, when a higher response rate may be beneficial. Further study is warranted.
Characteristics of NSCLCs harboring NRAS mutations.
Authors: Ohashi Kadoaki , Sequist Lecia V. , Sos Martin , Chen Xi , Rudin Charles M. , Moran Teresa , Arcila Maria E. , Lovly Christine Marie , Vnencak-Jones Cindy L , Sasaki Hidefumi , Dias-Santagata Dora , Dubinett Steven M. , Riely Gregory J. , Ladanyi Marc , Franklin Wilbur A. , Kris Mark G. , Camidge D. Ross , Bunn Paul A. , Pao William
Published: March 2020

7532

Background: We sought to determine the frequency and clinical characteristics of patients with non-small cell lung cancers (NSCLCs) harboring NRAS mutations. We used preclinical models to identify targeted therapies likely to be of benefit against NRAS mutant lung cancer cells. Methods: We reviewed data in the Catalogue of Somatic Mutations in Cancer (COSMIC) and clinical history from patients with NSCLC whose tumors underwent systematic screening for driver mutations including NRAS. Patient characteristics examined included age, gender, race, smoking history, disease stage, treatment history, and overall survival (OS). 6 NSCLC cell lines with NRAS mutations were screened for sensitivity against multiple targeted agents. Gene expression was profiled using Affymetrix U133A arrays in 5 NRAS mutant NSCLC cell lines, 8 with EGFR mutations and 17 with KRAS mutations. Results: Among 4524 patients with NSCLC tested, NRAS mutations were present in 29 (0.64%). The types of substitutions found were Q61H/K/L/R and G12A/C/D/R/S, with NRAS Q61L the most common (n=14; 48%). One tumor had a concurrent KRAS mutation. 83% had adenocarcinoma histology, with no significant differences in gender. While 90% of patients were former or current smokers, smoking-related G:C>T:A transversions were significantly less frequent in NRAS than in KRAS-mutant NSCLC (KRAS: 66%, NRAS: 13%, p<0.05). Systemic chemotherapy showed limited efficacy in 7 patients with metastatic disease (median OS 7 mos). 5 of 6 NRAS mutant lung cancer cell lines were sensitive to the MEK inhibitors, AZD6244 and GSK1120212, while other targeted agents (against EGFR, ALK, MET, IGF-1R, PIK3CA, BRAF) were minimally effective. Gene expression profiles of NRAS mutant cell lines were distinct from those with KRAS or EGFR mutations. Conclusions: NRAS mutations define a distinct subset of NSCLCs (~1%) with potential sensitivity to MEK inhibitors. While NRAS gene mutations are more common in current/former smokers, the types of mutations are not those classically associated with smoking.
Phase III study (MONET1) of motesanib plus carboplatin/paclitaxel (C/P) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC): Asian subgroup analysis.
Authors: Ichinose Yukito , Kubota Kaoru , Scagliotti Giorgio , Spigel David R. , Kim Joo-Hang , Shinkai Tetsu , Takeda Koji , Kim Sang-We , Hsia Te-Chun , Li Rubi , Tiangco Beatrice , Yau Stephen , Lim Wan-Teck , Yao Bin , Hei Yong Jiang , Park Keunchil
Published: March 2020

7549

Background: MONET1 evaluated overall survival (OS) in patients (pts) with nonsquamous NSCLC receiving motesanib (an oral VEGFR 1, 2 and 3, PDGFR and Kit inhibitor) plus C/P compared with pts receiving placebo plus C/P. Analysis of the total population (N=1090) showed that motesanib + C/P did not significantly improve OS vs C/P alone (primary endpoint). Here we present results of a subgroup analysis of Asian pts. Methods: Asian pts (Japan, S. Korea, Philippines, Hong Kong, Taiwan, Singapore) with stage IIIB/IV or recurrent nonsquamous NSCLC and no prior systemic therapy for advanced NSCLC were analysed. Pts were randomized to up to six 3-wk cycles of C (AUC 6 mg/mL·min) and P (200 mg/m2) with either motesanib 125 mg QD (Arm A) or placebo QD (Arm B) orally continuously. Results: 227 Asian pts (incl. 106 Japanese pts) with nonsquamous NSCLC were randomized (Arm A/B, n=110/117); 198 had adenocarcinoma (n=97/101). Median age was 60 y (range 30–78); 80% had stage IV disease. At the time of analysis, 139 pts had died (118 pts with adenocarcinoma). Pts received a median of 164 days of motesanib vs 125 days of placebo (vs 106 and 126 days in non-Asian pts). Median follow-up was 63 wks. Efficacy results are shown in the table. Motesanib/placebo-related AEs were seen in 94/74% of pts respectively; Gr ≥3 related AEs in 48/22%. Most common emergent AEs were (Arm A/B) alopecia (78/76%), diarrhea (63/33%), and nausea (55/43%); gallbladder disorders (Gr 1–2) were seen in 9/2% of pts. Gr ≥3 AEs more frequent in Arm A vs B included neutropenia (36/22%) and hypertension (13/3%). Emergent Gr 5 events were seen in (Arm A/B) 5/4% vs 16/11% in non-Asian pts. Conclusions: In contrast to non-Asian pts, in the subgroup of Asian pts with advanced nonsquamous NSCLC, motesanib plus C/P treatment was associated with increased OS, PFS, and objective response rates (ORR) compared with C/P alone, with no excess of treatment-related mortality. [Table: see text]
Targeting EGFR and ERBB3 in lung cancer patients: Clinical outcomes in a phase I trial of MM-121 in combination with erlotinib.
Authors: Sequist Lecia V. , Modiano Manuel R. , Rixe Olivier , Jackman David Michael , Andreas Karen , Pearlberg Joseph , Moyo Victor M. , Harb Wael A.
Published: March 2020

7556

Background: Erlotinib is effective in NSCLCs with wild-type EGFR and shows enhanced benefit in EGFR mutation-positive cancers. However, resistance invariably develops, often involving persistent ErbB3 signaling and activation of the PI3K/AKT survival pathway. We present the full results of the Phase 1 study evaluating the safety and tolerability of erlotinib plus MM-121 a fully human IgG2 monoclonal antibody (mAb) to ErbB3. Methods: Eligible patients had advanced stage NSCLC, and ECOG 0-2. Seven cohorts were enrolled, evaluating varying levels of the MM-121 and erlotinib, as well as alternate MM-121 infusion schedules. Tumor response was assessed every 8 weeks. Dose levels were determined by safety and pharmacokinetic (PK) data, and immunogenicity, efficacy endpoints and exploratory biomarker evaluations were performed. Results: From February 2010 – July 2011 32pts entered the study (median age 63y; 45% male; 18% ECOG 0, 82% ECOG 1. 56% had adenocarcinoma and 30% pts received 3 or more lines of prior therapies (range 0-7) with 91% having had prior platinum. 65% had wild-type EGFR status and were never treated or never responded to EGFR-TKIs (EGFRwt) and 28% had acquired resistance to erlotinib treatment (EGFRresist). The most common toxicities (any grade) observed were diarrhea (82%), rash (64%), and fatigue (64%). DLTs observed in different cohorts were diarrhea, mucositis, rash and failure to thrive. Clinical activity was observed including 1 PR (an EGFR TKI naïve EGFR mutant) and 14 SD. Average duration of disease stabilization was 21.6 wks (range 7.1 -89.3 wks). Median PFS is 8.1 weeks and the 16 week PFS rate was 41% in the overall population. For EGFRwt and EGFRresist pts the median PFS were 7.7 weeks and 15.1 weeks, and the 16 week PFS rates were 32% and 44%, respectively. 7/20 EGFRwt pts and 5/9 EGFRresist pts achieved SD. Conclusions: This study suggests that the combination of erlotinib and MM-121 has an acceptable safety profile in heavily pre-treated NSCLC patients with and without EGFR mutations. Early signals of patient benefit were seen and a large randomized phase II study is ongoing.
Phase I/II study of amrubicin and nedaplatin in patients with untreated, advanced non-small cell lung cancer.
Authors: Senju Hiroaki , Ogawara Daiki , Nakamura Yoichi , Fukuda Minoru , Nakatomi Katsumi , Gyotoku Hiroshi , Nakano Hirofumi , Yamaguchi Hiroyuki , Tomonaga Nanae , Ikeda Takaya , Mizoguchi Kosuke , Motoshima Kohei , Doi Seiji , Tsukamoto Kazuhiro , Kohno Shigeru
Published: March 2020

7569

Background: We conducted a phase I/II study of combination chemotherapy with nedaplatin (CDGP) and amrubicin (Amr) for patients with untreated, advanced non small-cell lung cancer (NSCLC). Methods: Eligible patients were having adequate organ function and PS of 0-1. CDGP was given on day 1 and amrubicin on days 1, 2 and 3. The treatment was repeated every 3 weeks. We fixed the dose of CDGP as 100 mg/m2, and escalated the dose of amrubicin from a starting dose of 25 mg/m2 by 5mg/m2 per each levels until the maximum tolerated dose (MTD). The MTD was defined as the dose level at which at least two of three or two of six patients experienced a dose-limiting toxicity (DLT). Results: Between June 2009 and May 2011, 36 patients were enrolled. In the phase I study, two DLTs occurred in six patients at level 2; dose level 1 was therefore recommended (25 mg/m2 Amr, 100mg/m2 CDGP). DLTs included cerebral infarction and grade 4 thrombocytopenia. In the phase II study, including phase I study, a total of 36 patients were enrolled and 132 cycles of chemotherapy were conducted. Grade 3 or 4 neutropenia, grade 3 anemia and grade 3 or 4 thrombocytopenia occurred in 75%, 16.6% and 19.4% in all cycles, respectively. Febrile neutropenia occurred in 4cycles (3%) but all of them were controllable. Eighteen patients achieved a partial response and the overall response rate was 51.4%. Conclusions: Combination of CDGP and Amr was highly effective and well tolerable in patients with untreated, advanced NSCLC.
Treatment with EGFR tyrosine kinase inhibitors beyond progression in long-term responders to erlotinib in advanced non-small cell lung cancer: A case-control study of overall survival.
Authors: Faehling Martin , Eckert Robert , Kamp Torsten G. , Kuom Sabine , Spengler Werner
Published: March 2020

7572

Background: EGFR-tyrosine kinase inhibitor (TKI) such as erlotinib lead to prolonged disease stabilization in some patients with advanced NSCLC. It is so far not clear how to treat patients who progress after prolonged response to erlotinib. TKI therapy beyond progression with added chemotherapy, radiotherapy or best supportive care (BSC) may improve survival compared to chemotherapy, radiotherapy or BSC alone. Methods: We retrospectively analyzed all NSCLC patients treated with erlotinib at our institutions since 2004 who progressed after at least stable disease on erlotinib for at least six months (n=41). Twenty-seven patients were treated with TKI beyond progression (TKI patients), of whom 24 received erlotinib and 3 afatinib. Fourteen patients did not receive further TKI treatment after progression (controls). Overall survival (OS) from progression on TKI and OS from diagnosis of lung cancer was analyzed for the whole population and case-control subpopulations of pairs matched for gender, smoking status, and histology. Results: Treatment with TKI and chemotherapy was well tolerated with no increase in grade 3 and 4 toxicities. TKI-patients had a significantly longer OS from progression on TKI (case control: median 21.0 vs. 3.0 months, HR 0.175) and longer OS from diagnosis of lung cancer (case control: median 28.5 vs. 15.3 months, HR 0.335). Conclusions: In long-term erlotinib responders, treatment with TKI beyond progression in addition to chemotherapy or radiotherapy is feasible and well tolerated with limited toxicity. TKI-treatment beyond progression improved OS compared to treatment with TKI-free chemotherapy or radiotherapy.
The relevance of stable disease (SD) as a surrogate end-point in advanced non-small cell lung cancer (NSCLC) patients treated with erlotinib (E) as the second/third line.
Authors: Grossi Francesco , Sini Claudio , Barletta Giulia , Rijavec Erika , Genova Carlo , Dal Bello Maria Giovanna , Pronzato Paolo , Venturino Paola , Pappagallo Giovanni L.
Published: March 2020

7577

Background: SD has often been viewed as a result with an uncertain clinical value.With the advent of E in advanced NSCLC, increasing numbers of patients (pts) achieve SD as a best response. A common observation in clinical practice is that a high proportion of patients receiving E have durable SD.The aim of this analysis was to compare the progression-free survival (PFS) and overall survival (OS) in pts with advanced NSCLC who achieved confirmed SD or complete/partial response (CR+PR) after second/third line treatment with E. Methods: Data from 684 Italian pts from the TRUST trial (Tiseo M et al. Lung Cancer 2008) were analyzed. E was administered orally at 150 mg per day and was continued until disease progression, development of unacceptable toxicity or patient’s refusal. We define confirmed SD (cSD) if the patients’ PFS was ≥5 months (response to E was evaluated per protocol every two months) and reconfirmed SD (rSD) if the patients’ PFS was ≥8 months. Results: Pts’ characteristics included the following: median age, 67 years (31-89); females/males= 219/465 pts (32%/68%); never/former smokers= 191/493 pts (28%/72%); squamous/adeno/BAC/large cell/NOS= 163/361/26/21/113 pts (24%/53%/4%/3%/16%); ECOG PS 0-1/2-3= 557/127 pts (81%/19%). In 83 pts (12%), E was administered as the first-line therapy in pts who were unable to receive chemotherapy; 305 pts (45%) had received 1 prior line of chemotherapy, and 296 pts (43%) had received 2 prior lines of chemotherapy. A total of 428 pts were evaluable for a response: 44 pts (10%) exhibited CR+PR, 226 pts (53%) attained SD, which consisted of 139 pts (32%) with cSD and 83 pts (19%) with rSD. The median PFS estimates (with 95% CI) were 13.1 months (9.8-16.4) for CR+PR pts, 9.9 months (8.2-11.4) for cSD pts and 14 months (12-16) for rSD. The median OS estimates (with 95% CI) were 24.0 months (17-31) for CR+PR pts, 17.9 months (14.4-21.5) for cSD pts and 24.9 months (18.1-31.7) for rSD. Conclusions: Our findings are the first to demonstrate the relevance of achieving stable disease with E treatment. Pts obtaining cSD or rSD had durable PFS and OS comparable, particularly for rSD, with PFS and OS of those having CR+PR.
Comparison of the KRAS/EGFR mutation profile and survival of “collegiate smokers” and never smokers with advanced lung cancers.
Authors: Varghese Anna M. , Sima Camelia S. , Chaft Jamie E. , Johnson Melissa Lynne , Janjigian Yelena Yuriy , Drilon Alexander Edward Dela Cruz , Yu Helena Alexandra , Riely Gregory J. , Ladanyi Marc , Kris Mark G.
Published: March 2020

7580

Background: In practice, we encounter patients (pts) with lung cancers who state they smoked only while in college. The impact of this degree of tobacco use on cancer biology is unknown. We have shown that EGFR mutations are less common in pts who smoked > 15 pack years (PY). We hypothesize that among pts with lung cancer the KRAS / EGFR mutation profile and overall survival (OS) of “collegiate smokers” (former smokers who smoked between 101 lifetime cigarettes and 5 PY) will be distinct from never smokers and former smokers with ≥ 15 PY. Methods: We collected age, sex, stage, and survival for pts evaluated from 2004 - 2009 with stage IIIB/IV lung cancer with known KRAS and EGFR status. ALK testing was not available routinely during this time. Smoking history was obtained using a patient completed survey. The Fisher exact test was used to compare mutation profiles. The log rank test was used to compare OS. Results: Smoking history and clinical data were available for 852 pts with Stage IIIB/IV lung cancer with known KRAS and EGFR status: 307 never smokers, 178 current smokers, and 367 former smokers. Of the former smokers, 55 were “collegiate smokers”, 61 had smoked 5-15 PY, and 251 had smoked ≥ 15 PY. The KRAS / EGFR mutation profiles by smoking history are shown below (Table). The KRAS / EGFR mutation profile of “collegiate smokers” is distinct from those of pts who were never smokers (p < .001) and former smokers with ≥ 15 PY (p < .001) but similar to that of pts who were former smokers with 5-15 PY (p = 0.9). Median OS after diagnosis of stage IIIB/IV lung cancer for “collegiate smokers” was 25 months (mos), compared to 32 mos for never smokers (p = 0.4) and 21 mos for former smokers with ≥ 15 PY (p = 0.63). Conclusions: “Collegiate smokers” are a distinct group of pts with a higher incidence of KRAS mutations and lower incidence of EGFR mutations compared to never smokers. These data suggest that even a small amount of cigarette smoking influences the biology of lung cancer. These findings reinforce the importance of doing mutation testing routinely for all pts with lung cancer to guide clinical care. [Table: see text]
Thymidylate synthase (TS) gene expression in patients with ALK positive (+) non-small cell lung cancer (NSCLC): Implications for therapy.
Authors: Gandara David R. , Huang Eric , Desai Sonal , Mack Philip C. , Beckett Laurel , Stephens Craig , Zeger Gary , Danenberg Kathleen D. , Maus Martin Karl Herbert , Li Tianhong
Published: March 2020

7582

Background: ALK+ NSCLC represents a molecular target-defined patient population highly responsive to the ALK inhibitor crizotinib. Previous reports have also suggested increased sensitivity of ALK+ NSCLC to the chemotherapeutic agent pemetrexed. Thymidylate synthase (TS) is a candidate predictive biomarker for pemetrexed activity. Here we report analysis of the Response Genetics Inc. (RGI) database for this association and implications for therapy. Methods: ALK fusion was identified by a novel RT-PCR assay (Danenberg et al: ASCO 2010). For TS, RNA from microdissected formalin-fixed paraffin-embedded tumors was analyzed as previously described, reported as the ratio of gene expression to β-actin. For reference, a TS level <2.33 is the cutpoint for sensitivity. Results: TS levels were available from 63 ALK+ patients and 1,698 ALK- control lung adenocarcinoma patients. All ALK+ patients had adenocarcinomas without EGFR or KRAS mutations. Median age: 59.0 (range 33-88), gender (male/female) 32/31 (51%/49%). Median TS RNA level in ALK+ patients was 2.02, range (0.55-19.44), and in ALK- patients was 3.32 (0.36-53.51), p<0.0001 (Mann-Whitney test). The majority of ALK+ patients (N=43, 68%) had a TS level <2.33 cutpoint, compared to only 32% of ALK- patients (N=551, p<0.0001). Conclusions: This analysis demonstrates relatively low TS gene expression in ALK+ patient tumors as determined by RT-PCR. These data provide a mechanism of action supportive of pemetrexed sensitivity for ALK+ NSCLC. [Table: see text]
ALK and MET genes in advanced lung adenocarcinomas: The Lung Cancer Mutation Consortium experience.
Authors: Varella-Garcia Marileila , Berry Lynne D , Su Pei-Fang , Franklin Wilbur A. , Iafrate A. John , Ladanyi Marc , Camidge D. Ross , Garon Edward B. , Haura Eric B. , Horn Leora , Khuri Fadlo Raja , Pao William , Rudin Charles M. , Shaw Alice Tsang , Schiller Joan H. , Kris Mark G. , Johnson Bruce E. , Minna John D. , Kwiatkowski David J. , Bunn Paul A.
Published: March 2020

7589

Background: The Lung Cancer Mutation Consortium (LCMC) consisting of 14 US Cancer Centers was established to evaluate a panel of molecular mutations in advanced lung adenocarcinoma. ALK gene fusions and MET gene amplification were assessed by FISH in CLIA certified laboratories. Methods: Molecular tests were performed in stage IIIB or IV lung adenocarcinoma. To date, FISH assays have been completed in 901 patients for ALK (ALK break-apart, Abbott Molecular) and in 654 patients for MET (in house/Abbott Molecular reagents). ALK+ specimens were defined by split 3’ALK/5’ALK signals (gap >2 signal diameters) or single 3’ALK signals in >15% of tumor cells. MET gene amplification (MET+) was defined by ratio mean MET/mean CEP7 ≥2. Results: The ALK+ patient subset (N=75, 8.3%) compared to the ALK- had significantly lower age at diagnosis (52 vs. 60, p<0.001) and less frequent heavy smoking history (61% never-smokers among ALK+ vs. 31% among ALK-, p<0.001; pack-year for current/former smokers 17 vs. 40, p=0.003). Liver metastases were significantly more frequent among ALK+ than ALK- (23% vs.10%, p=0.004); no difference was detected in bone, brain and adrenal gland metastases. MET+ (N=29, 4.4%) was significantly associated with female sex (72% female among MET+ vs. 39% among MET-, p<0.001) and marginally more frequent in patients with adrenal metastasis; no difference was detected for age at diagnosis and smoking history. Follow-up on 73 ALK+ patients indicated that 56% received crizotinib as targeted therapy. Response was unknown in 8% and unreportable in 22% patients enrolled in ongoing randomized trials. Among patients with evaluable response, complete response, partial response, stable disease, and progressive disease were found respectively in 3%, 66%, 28%, and 3%. Conclusions: The LCMC successfully tested ALK and MET FISH in a large number of lung adenocarcinomas. It was demonstrated that directing positive patients to specific interventions is feasible, and that grouping of testing and trials within consortia may maximise relevant trial accrual in rare molecular subtypes. Supported by NCI-GO award. Submitted on behalf of the LCMC.