bluuebunny/crossref_metadata_2025 huggingface dataset:
Final results of a multi-center, double-blind, randomized, placebo-controlled phase II study to assess the efficacy of MAGE-A3 immunotherapeutic as adjuvant therapy in stage IB/II non-small cell lung cancer (NSCLC)
Authors: Vansteenkiste J. , Zielinski M. , Linder A. , Dahabre J. , Esteban E. , Malinowski W. , Jassem J. , Passlick B. , Lehmann F. , Brichard V. G.
Published: March 2020

7554

Background: After complete resection, about 50% of patients with stages IB-II NSCLC disease die within 5 years. Adjuvant chemotherapy improves overall survival at the expense of substantial toxicity. Activity of MAGE-A3 immunotherapeutic (i.e. recombinant MAGE-A3 protein and a potent GlaxoSmithKline adjuvant) was previously demonstrated in metastatic melanoma. As about 35% of NSCLCs express MAGE-A3 antigen, post-operative MAGE-treatment may be a tumor-specific, well tolerated, and effective adjuvant therapy. Methods: Patients with completely resected, MAGE-A3 (+), stage pIB or pII were randomly assigned to postoperative MAGE-A3 or placebo (2:1), with 5 administration at 3-week intervals, followed by 8 administrations every 3 months. Randomization was stratified for stage (IB vs. II), histology (squamous vs. other), and lymph-node (LN) procedure (sampling vs. dissection). Primary endpoint was disease-free interval (DFI); other endpoints were safety, disease-free survival (DFS), and overall survival (OS). This exploratory Phase II study was designed to detect a clinically relevant HR with a 10% one-sided a. Results: 182 patients (122 stage IB, 60 stage II) from 59 centers in 14 countries were randomized over 2 years: Median age 63 (45–81); 87% male; 65% squamous cell carcinoma; 65% lymph-node dissection. After a median follow-up of 28 months, 67 recurrences and 45 deaths were recorded. Group comparisons of DFI, DFS and OS gave respectively a hazard ratio (HR) of 0.74 (95% CI 0.44–1.20, p=0.107), 0.73 (95% CI 0.45–1.16) and 0.66 (95% CI 0.36–1.20) in favor of the MAGE-A3 group. Overall, treatment was well tolerated, with excellent protocol compliance. Subset analysis also suggests that LN dissection may have an effect on survival. Conclusions: The final analysis of this randomized phase II study shows a positive trend for activity of MAGE-A3 treatement in NSCLC with a relative improvement of DFI and DFS of 27%. Further phase III evaluation is planned. This study also suggests that complete lymph-node dissection may have an effect on survival and should be confirmed prospectively.

[Table: see text]
Impact of tumor size on survival in stage IB (T2N0M0) non-small cell lung cancer (NSCLC)
Authors: Rajan A. , Newman N. , Vajpayee N. , Husain J. , Graziano S. L. , Gajra A.
Published: March 2020

7557

Background: Patients with stage IB NSCLC have a relatively poor survival of ∼60% despite adequate surgical resection. The role of adjuvant chemotherapy in this disease remains controversial since the results of the IALT, JBR.10, ANITA and CALGB 9633 trials. It is important to risk stratify patients with Stage IB NSCLC and to offer adjuvant therapies to those at greatest risk for recurrence. Methods: We conducted a retrospective review of 216 consecutive, surgically treated patients with stage IB NSCLC. None of the patients received adjuvant chemotherapy. We studied the association of various clinical factors as well as tumor size and visceral pleural invasion upon tumor recurrence, disease free survival (DFS) and overall survival (OS) at 5 years. Results: Of 216 patients, 135 (62%) were male, 97 (45%) had adenocarcinoma, 115 (53%) had poorly differentiated tumors and the majority (88%) were treated with lobectomy. Visceral pleural invasion was noted in 37 (17%) patients. The 5 year OS and DFS rates were 59% and 54% respectively. Tumor size was = 4cm in 120 (56%) patients, 4.1–5 cm and >5cm in 48 (22%) patients each. The 5 year DFS was 40% and 58% for tumors > 5cm and = 5 cm respectively (p < 0.01). The 5 year OS was 49% and 61% respectively for tumors > 5cm and = 5cm. Pleural invasion was a predictor for DFS in the univariate analysis (p < 0.01) but not for OS. In the multivariable analysis, tumor size = 5cm was the only independent predictor of improved DFS (HR 0.46, C.I. 0.25–.84) and OS (HR=0.43, C.I. 0.23–0.80). Age, gender, histology, differentiation and visceral pleural invasion did not impact upon survival. Conclusions: In stage IB NSCLC, tumors > 5cm in diameter have a significantly worse prognosis. These findings if confirmed in other large series, make a case for subdividing Stage IB NSCLC. Tumor size appears to be the most important factor in risk stratification for patients with stage IB NSCLC. Hence patients with large tumors should be offered adjuvant therapy.

No significant financial relationships to disclose.
Fluorescence in situ hybridization (FISH) subgroup analysis of TRIBUTE, a phase III trial of erlotinib plus carboplatin and paclitaxel in NSCLC
Authors: Hirsch F. R. , Varella-Garcia M. , Bunn P. A. , Dziadziuszko R. , Xiao Y. , Gajapathy S. , Skokan M. , Lin M. , Waring P. , O'Neill V.
Published: March 2020

7570

Background: TRIBUTE was a phase III, placebo-controlled study of patients with previously untreated advanced NSCLC. Patients received erlotinib (E) (150 mg/d) or placebo, plus a course of 6 cycles of carboplatin and paclitaxel (CP), followed by maintenance E monotherapy (for those in the CP+E arm who were responding to treatment). 1,059 patients were randomized and treated (526 E; 533 placebo). There were no significant differences in OS, RR, or TTP between the two arms. In subgroup analyses of the pivotal 2nd line trial (BR21) of E in patients with relapsed NSCLC in which E significantly increased median survival (HR=0.71, p <0.0001), patients who scored positively for increased EGFR copy number by fluorescence in situ hybridization (FISH) exhibited prolonged OS (HR=0.44, p=0.008). Here we report on a similar subgroup analysis for TRIBUTE. Methods: FISH analysis was performed on all available tissue samples. FISH+ samples had a high level of polysomy (=four copies of the gene in =40% of cells), or gene amplification (presence of tight gene clusters, gene/chromosome per cell ratio =2, or =15 copies of the genes per cell in =10% of analyzed cells). Results: FISH analysis was successfully performed on 245 patients (121 E, 124 placebo). Outcome in the placebo patients from this subgroup was better than the overall population, suggesting that this subgroup may not be representative. Of the 100 patients (41%) that were FISH+, 33 had amplification and 67 had high polysomy. In FISH+ patients, OS was similar between those treated with CP+E and those treated with CP alone. However, FISH+ patients in the CP+E arm experienced a decrease in RR compared to those in the CP alone arm, and had a marginally significant longer TTP (HR=0.59, 0.35–0.99). The benefit in TTP appeared after approximately 6 months, during the maintenance portion of the trial. Conclusions: In this retrospective analysis, FISH+ did not predict survival benefit in TRIBUTE. A longer TTP, but a lower RR, was observed in the FISH+ patients. The lower RR in the CP+E arm in this group, taken together with the improved TTP during maintenance therapy, suggests that a non-concurrent combination approach (CP followed by E) warrants further investigation.

No significant financial relationships to disclose.
Randomized phase II trial of two dose schedules of carboplatin/paclitaxel/cetuximab in stage IIIB/IV non-small cell lung cancer (NSCLC)
Authors: Saleh M. N. , Socinski M. A. , Trent D. , Dobbs T. , Zehngebot L. M. , Levine M. A. , Stella P. J.
Published: March 2020

7586

Background: Cetuximab, an IgG1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR) on both normal and tumor cells, has been investigated in advanced NSCLC as a single agent and in combination with chemotherapy. This ongoing randomized phase II open-label trial evaluates cetuximab in combination with carboplatin (Cb) and paclitaxel (Pac) when given in two dose schedules to patients (pts) with previously untreated stage IIIB/IV NSCLC. Methods: Eligible pts were randomized to 1 of 2 treatment arms. Cetuximab treatment was identical in both arms: 400 mg/m2 IV on day 1 and 250 mg/m2 weekly thereafter. Beginning on day 8, a schedule of Cb AUC=6 IV and Pac 225 mg/m2 IV given on a 3-week cycle was compared with a schedule of Cb AUC=6 IV q4 weeks and Pac 100 mg/m2 IV given weekly for 3 weeks of each 4-week cycle. Pts who achieve CR, PR, or SD after 4 cycles may continue weekly cetuximab monotherapy until disease progression or unacceptable toxicity. The primary objectives were to estimate median progression-free survival (PFS) and the PFS rate at 6 months. Secondary objectives included response rate. Results: The study has completed accrual, with 168 pts randomized and 165 treated. Data are available for 164 pts and confirmed responses for 155 pts. Conclusions: Cetuximab combined with Cb and Pac in both dose schedules demonstrated activity and an acceptable toxicity profile in pts with NSCLC. Final PFS and overall survival data are pending.

No significant financial relationships to disclose.

[Table: see text]
A phase II study of RAD001 (R) (everolimus) monotherapy in patients (pts) with advanced non-small cell lung cancer (NSCLC) failing prior platinum-based chemotherapy (C) or prior C and EGFR inhibitors (EGFR-I)
Authors: Papadimitrakopoulou V. , Soria J. C. , Douillard J. Y. , Giaccone G. , Wolf J. , Crino L. , Cappuzzo F. , Sharma S. , Gross S. H. , Shepherd F. A.
Published: March 2020

7589

Background: R is an oral inhibitor of mammalian target of rapamycin (mTOR) with anti-tumor activity. Single-agent R and in combination with other anticancer agents showed efficacy in in vitro and in vivo NSCLC models. In a phase I study, 4 disease stabilizations (SD) and 1 partial response (PR) were reported from 14 NSCLC pts treated with R monotherapy. Methods: Advanced NSCLC pts with adequate organ function, performance status ≤ 2, failing either ≤ 2 C (arm 1) or ≤ 2 C and an EGFR-I (arm 2) were treated with R at 10 mg qd if tolerable until progression (PD). Study applied a Simon-2-stage design with primary endpoint of objective tumor response rate (RR) according to RECIST. CT scans were performed every 28 days until month 4 and then every 2 months thereafter. Adverse events (AE) were assessed using NCI CTC v. 2.0. Results: This analysis is based on data acquired up to 20 Sep 2006. 85 pts were enrolled between 08/2005 and 05/2006. Demographics and patient disposition were (arm 1/arm 2): 42/43 (7 pts ongoing), female 38.1%/51.2%, never smoker 14.3%/44.2%, adenoca. 57.1%/62.8%, squamous cell ca. 21.4%/14.0%, BAC 2.4%/16.3%, others 19.1%/6.9%. Median age was 60 years (range 21–74). R was given on arm 1 as 2nd line therapy in 64.3% of pts., as 3rd line in 35.7% and on arm 2 as 3rd line in 58.1%, as 4th line in 41.9%. 90.6% pts had stage IV disease. The trial did not proceed to stage 2 based on RR for 74 pts in the efficacy population. Best overall tumor response (arm 1/2 in %): confirmed PR (5.3/2.8), SD (44.7/44.4); SD ≥ 12 weeks (34.2/41.7), duration of SD in days arm 1 (58 –267) and arm 2 (68 –231). Median PFS on arm 1 is 11.3 weeks (95% CI: 8.1; 12.4) and on arm 2 is 9.7 weeks (7.3; 13.0). Most frequent AEs (pts, all grades/grade 3 and 4): stomatitis/mucositis (43/5), cough (27/1), dyspnea (33/8), rash (26/0), fatigue (25/10), anorexia (25/1), nausea (20/0), anemia (18/3), epistaxis (18/0), diarrhea (17/2). Analyses of molecular markers in tumor tissue samples are ongoing. Conclusions: 10 mg qd R monotherapy is well tolerated and shows limited activity in pretreated advanced NSCLC pts. Combination trials with both standard chemotherapy and targeted agents are in progress.

No significant financial relationships to disclose.
Phase II study of erlotinib in chemo-naive women with advanced pulmonary adenocarcinoma
Authors: Jackman D. , Lindeman N. I. , Lucca J. , Morse L. K. , Rabin M. S. , Marcoux J. P. , Huberman M. , Johnson B. E. , Janne P. A.
Published: March 2020

7591

Background: Erlotinib is associated with a survival benefit over placebo for pts with advanced NSCLC who had received 1–2 prior regimens. Its role as initial therapy in clinically defined subgroups or in pts prospectively tested for EGFR mutations is less clear. Methods: Chemotherapy-naive women with adenocarcinoma, stage IIIB/IV, PS 0–1, who had formerly or never smoked, were enrolled and treated with erlotinib 150 mg PO daily, until the time of disease progression or unacceptable toxicity. Response rate was the primary endpoint. Secondary endpoints included overall survival, progression-free survival and toxicity. Tumor tissue adequate for genomic analysis was mandated and prospectively collected for determination of EGFR and KRAS mutations by direct sequencing. Results: From 11/04 to 10/06, 40 women were treated. Demographics: median age 65 yrs (range 36–87); 38 white, 1 black, 1 Asian; 30% PS 0, 70% PS 1; 20% BAC or adenoCA w/ predominant BAC features, 80% adenoCA w/o BAC features; smoking status: 63% former, 37% never. Toxicity: Rash (95%; 30% grade 3) and diarrhea (73%; 10% grade 3) were the most common toxicities. 50% of pts developed toxicity of grade 3 or greater. 5 pts were discontinued due to toxicity, with 2 deaths that were possibly treatment-related: 1 DIC, 1 hepatic failure. There were also two pts with PE (one fatal). Response: CR 0, PR 12 (30%), SD 11 (28%), and PD 10 (25%), 7 not evaluable. To date, 27 patients have progressed, with 14 deaths. Median PFS was 5.6 months; median overall survival has not yet been reached and exceeds 23 months. Of 32 patients sequenced for EGFR to date, there were 9 exon 19 deletions, 3 L858R mutations, and 1 exon 20 insertion. For the 12 pts prospectively determined to have classic EGFR mutations, RR was 75% (9 PR, 2 SD, 1 not evaluable). Of 15 pts w/ wild-type EGFR, only 1 response (7%) was achieved. The pt w/ the exon 20 insertion developed PD. Of 28 pts evaluated to date for KRAS, 6 KRAS mutations were found, w/ no responses in this group (2 PD, 4 SD). Conclusions: Preliminary results suggest that first-line erlotinib monotherapy may be a useful treatment strategy for women with adenocarcinoma and a limited smoking history. Response rate is particularly impressive for those subjects prospectively found to have an EGFR mutation, and poor for those with KRAS mutations.

No significant financial relationships to disclose.
Trends in stage distribution for patients with non-small cell lung cancer: A National Cancer Database Survey
Authors: Morgensztern D. , Goodgame B. , Chitneni P. , Baggstrom M. Q. , Gao F. , Govindan R.
Published: March 2020

7598

Background: We have previously reported a significant change in stage distribution for non-small cell lung cancer (NSCLC) among patients diagnosed at our institution (ASCO 2006 # 7205). To confirm this observation, a larger sample population was evaluated. Methods: Patients with NSCLC registered at the National Cancer Database (NCDB) and diagnosed between the years 1998 and 2003 were evaluated for demographic characteristics including age, race, gender, and stage at presentation. Results: 551,248 patients were identified. Patients with stage 0 or unknown stage were excluded from the study, leaving 510,942 eligible for the final analysis. The annual proportions of stage IV disease at the time of diagnosis are described in the table below. Stage distribution remained stable from 1998 to 2000, but a sharp increase in the percentage of stage IV was noticed between 2000 and 2001 (35.7% to 38.9%). This increase in the percentage of stage IV patients was sustained in the subsequent years and present across the other demographic variables. Conclusions: We have documented a significant change in the NSCLC stage distribution over the last six years. The NCDB is the largest database available and currently captures approximately 62% of all NSCLC patients diagnosed in the United States. The increase in stage IV disease coincides with the widespread adoption of FDG-PET, suggesting an earlier diagnosis of metastatic disease and confirming our previous findings.

No significant financial relationships to disclose.

[Table: see text]
Pilot phase II study of preoperative gefitinib in early stage non-small cell lung cancer with assessment of intratumor gefitinib levels and tumor target modulation
Authors: Haura E. B. , Sommers E. , Becker A. , McKillop D. , Bepler G.
Published: March 2020

7603

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) can provide clinical benefit in advanced non-small cell lung cancer patients. Here we examined the effect of single agent gefitinib in patients with early stage NSCLC with additional assessment of plasma and tumor concentrations of gefitinib. Previous studies have suggested considerably higher tumor concentrations of gefitinib compared to levels identified in blood, yet the results in human lung cancers is unknown. Methods: We conducted a pilot phase II study of a 28 day preoperative course of gefitinib 250 mg PO daily followed by surgical resection for patients with stage IA to selected IIIA non-small cell lung cancer. Response was assessed by RECIST using CT and changes in FDG metabolism were assessed using PET. Tumor penetration of gefitinib was assessed in surgically resected tumor samples along with plasma assessment on day 28. Results: Sixteen patients (7 men, 9 women) completed therapy on protocol and all who started on gefitinib were able to undergo a complete surgical resection. There were 0/16 objective responses (CR/PR), 14/16 SD, and 2/16 PD. Three of the 6 patients had more than 20% reductions in FDG SUVmax assessed by PET scanning. Day 28 plasma concentrations of gefitinib averaged 531 ± 344 nM (range 65 to 1,211 nM) while tumor concentrations of gefitinib averaged 33,108 ± 44,312 nM (range 474 to 134,669 nM). Conclusions: Our results demonstrate that NSCLC tumor penetration of gefitinib is much higher than concentrations found in plasma. Assessment of pharmacodynamic markers including tumor EGFR and downstream signaling pathways is ongoing. PET scanning may be an early marker of clinical benefit of EGFR TKI.

No significant financial relationships to disclose.
Comparison of the epidermal growth factor receptor gene mutation in matched primary tumor and lymph node metastasis of non-small cell lung cancer
Authors: Park S. , Park B. , Hwang I. , Lee S. , Cho E. , Kang W. , Ahn J. , Ahn M. , Park K.
Published: March 2020

7614

Background: Mutations in epidermal growth factor receptor (EGFR) are considered as a strong predictive marker to EGFR tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC). Recent studies suggested EGFR status may change between primary NSCLC and corresponding metastatic site. However, it has not fully been evaluated whether EGFR mutation differs in metastases compared to primary NSCLC. Methods: In total, 128 tumor samples from 64 NSCLC patients were investigated comparing matched 64 primary tumors, and 64 lymph node metastases. The epidermal growth factor receptor mutation status was analyzed by a direct sequencing method (exons 18–21 in EGFR) on tumor samples of primary NSCLC and corresponding lymph node metastasis. Results: In 17.2% of patents (11/64), EGFR mutation was identified in either primary NSCLC or metastasis by DNA sequencing. Six (54.5%) out of eleven cases showed discordance of EGFR mutation in the primary tumor/metastasis site. Two cases showed EGFR mutation in the metastasis but not in the primary tumor, while, in four cases, EGFR mutation was detected in the primary tumor but not in the metastasis site. The majority of discordance of EGFR mutations was identified in exon 19 (83.3%, 5/6). The median overall survival (OS) was 17.7 months (95% confidence interval, 9.4–20.0). Median OS was not varied by the discordance of EGFR mutation status between primary NSCLC and corresponding metastatic site. Conclusions: The status of EGFR mutation in primary NSCLC and that in corresponding metastasis site varied in considerable cases by DNA sequencing. Whether the status of EGFR mutation changes during the process of metastasis remains to be evaluated. Future study to evaluate the correlation of tumour response to TKIs and the discordance of the EGFR mutation status is warranted.

No significant financial relationships to disclose.
A randomized phase II trial comparing pulsed erlotinib before or after carboplatin and paclitaxel in patients with stage IIIB or IV non-small cell lung cancer
Authors: Riely G. J. , Rudin C. M. , Kris M. G. , Senturk E. , Azzoli C. G. , Brahmer J. , Fogle M. , Ginsberg M. , Miller V. A. , Rizvi N. A.
Published: March 2020

7619

Background: A randomized phase 3 trial failed to show any improvement in response rate (RR) or overall survival (OS) when erlotinib was added to carboplatin and paclitaxel (TRIBUTE). However, preclinical data suggested that administration of erlotinib before or after chemotherapy may improve efficacy of chemotherapy [Gumerlock et al ASCO 2003, Solit et al Clin Can Res 2005]. We designed this trial to test the hypothesis that administration of pulsed erlotinib prior to or following chemotherapy would improve the response rate in patients with advanced NSCLC. Methods: All patients had chemotherapy naive, stage IIIB or IV NSCLC and were former or current smokers. All patients received carboplatin (AUC 6) and paclitaxel (200 mg/m2). Patients were randomly assigned to one of three arms: erlotinib 150 mg days 1,2, and chemotherapy on day 3; erlotinib 1500 mg days 1, 2 and chemotherapy on day 3; or chemotherapy on day 1 and erlotinib 1500 mg on days 2,3. Patients received up to six 21-day cycles of treatment. The primary endpoint was overall RR (CR+PR) using RECIST. We planned to enroll 29 patients to each arm in a “pick the winner” design comparing arms to the chemotherapy alone arm of TRIBUTE (RR 19%) with a desirable RR of 50%. Results: Eighty-seven patients were randomized to 3 arms. Accrual is complete. The most common grade 3/4 toxicities were neutropenia (39%), fatigue (15%), and anemia (12%). Grade 3/4 rash or diarrhea were uncommon. Conclusions: Treatment with erlotinib before (150 mg on days 1 and 2 or 1500 mg on days 1 and 2) or after (1500 mg on days 2 and 3) administration of carboplatin and paclitaxel failed to improve response rates compared to TRIBUTE. The benefit of pulsatile administration of erlotinib predicted by preclinical models was not evident in this clinical trial. Supported by Genentech, Inc.

[Table: see text] [Table: see text]
Distinctive characteristics of non-small cell lung cancer in the young: A SEER analysis of patients under 40 years old
Authors: Goodgame B. , Vlahiotis A. , Piccirillo J. , Baggstrom M. , Govindan R.
Published: March 2020

7621

Background: Non-small cell lung cancer (NSCLC) is diagnosed at a median age of 65 and is rare in younger people. The presentation and natural history of the disease in younger patients (age < 40) may not be the same as in typical, or older patients (age > 40). Methods: We identified in the SEER (Suveillance Epidemiology and End Results) registry, all patients diagnosed with NSCLC from 1990 to 2005. Patients were grouped by age at diagnosis, < 40 or = 40. Data on gender, cell type, extent of disease, overall survival, and cause of death were obtained from the SEER database. Cancer-specific survival was defined as time to death from cancer, in which case deaths from other causes are counted as censoring events. Results: In the SEER registry, 3,421 patients with NSCLC diagnosed at an age < 40 were identified, along with 323,566 patients age > 40. Younger patients were more likely to be women, 48% vs 43% (p < 0.0001), and more likely to present with distant disease 53% vs 49% (p < 0.0001). Adenocarcinoma and other, or non-specified types of NSCLC were more common in younger patients, 38% and 44% respectively, vs. 35% and 32% in the older patients. Squamous cell carcinoma was far less common in younger patients, 8.5% vs 23.5% in older patients (p<0.0001 for all comparisons). Overall and cancer specific survivals were higher for the younger cohort within each stage group. For example, 3 year overall survival for patients with distant (metastatic) disease was 8.8% in the younger patients and 4.7% in the older patients. For local disease, 5 year cancer specific suvivals were 92% in the younger patients and 62% in the older patients. Conclusions: Patients with NSCLC who are < 40 years old at diagnosis are more likely to be women and have adenocarcinoma and far less likely to have squamous cell carcinoma. Overall and cancer-specific survivals are better in these younger patients.

No significant financial relationships to disclose.
Gene predictors for extrathoracic metastases (EM) in advanced bronchioloalveolar carcinoma (BAC) of the lung obtained from formalin-fixed, paraffin-embedded tissue (FFPE)
Authors: Weiss G. J. , Franklin W. A. , Zeng C. , Tran Z. V. , Coldren C. D. , Magree L. , Sugita M. , Bunn P. A. , Kelly K.
Published: March 2020

7622

Background: Advanced BAC is typically a more indolent tumor confined to the lungs, thus raising the question of the role for bilateral lung transplantation (BLT). In a small series, BLT produced a 5-year survival rate of 50%. Determining biological predictors of EM could identify the most ideal candidates for curative BLT. Methods: We retrospectively reviewed patient records from 1/1/98–10/1/06. RNA was extracted from FFPE tissue. RNA was amplified using Arcturus kits and profiled by Affymetrix X3P chips, which contain 47,000 transcripts and 61,000 probe sets. Chi-square and t-tests were used to compare clinical characteristics. Log-rank and Cox hazards modeling were used to determine clinical factors that predict either overall survival or time to EM. Logistic regression modeling was used to examine clinical factors predicting rate of EM. Hybridization signals and detection calls were generated in BioConductor, using gcrma and affy tools, and normalized to benign tissue. Univariate analysis was performed to identify genes of interest. Results: Patients with advanced BAC/adenocarcinoma with BAC features at diagnosis, (TanyNanyM1 [lung only]; n=20), and matched cohort of locally-advanced adenocarcinoma (TanyN2–3M0) and pure adenocarinoma with pulmonary metastases only, (TanyNanyM1 [lung only]), were identified (n=45). There was no significant difference for age, gender, smoking history, survival, or EM between the 2 groups. Arrays have been performed on 12 samples (4 BAC, 5 lung adenocarcinoma, 2 benign lung, and 1 benign lymph node). Preliminary analysis shows 27 genes were significantly up- and down-regulated vs. benign tissue (p<0.01). Seven of these genes were highly altered and may differentiate risk for EM. Conclusions: Gene expression profiling may discern risk for EM not readily apparent from clinical characteristics and could serve to identify advanced BAC patients with low risk for EM that may benefit from BLT. Gene profiling of 12 additional tumor samples is ongoing and results will be updated. We plan future validation of candidate genes in collaboration with cooperative groups or other multi-center sites. Supported by a grant from Cancer League of Colorado.

No significant financial relationships to disclose.
New perspectives on metastatic patterns in lung cancer: The M. D. Anderson thoracic medical oncology database
Authors: Oh Y. , Lee J. J. , Hanneken J. M. , Liu S. , Camarillo M. C. , Taylor S. H. , Lippman S. M. , Hong W. K. , Stewart D. J. , Karp D. D.
Published: March 2020

7630

Background: We previously reported a retrospective study suggesting that sites of metastatic disease characterize distinct prognostic groups with non-small cell lung cancer (NSCLC) (ASCO 2005 Abstract No: 7197). To confirm these observations, we prospectively evaluated pts with newly diagnosed NSCLC to correlate extent of disease with survival. Methods: We developed a prospective comprehensive database of 2,487 pts registered in the Thoracic Medical Oncology Department from 9/1/2004 - 8/31/2006, with up to 845 days follow-up. 694 were untreated stage IV NSCLC pts with data for ECOG performance status (PS), TNM staging, histology, identification of all metastatic sites, and survival. Results: Bone was the most common metastatic site, affecting 280 pts, 114 having bone only metastases (280/114). Similarly, the following results were found for lung (261/137), brain (143/46), adrenal (112/36), and liver (98/31). PS = 0 (101), PS = 1 (329), PS = 2 (103), PS = 3 (74), PS = 4 (10), PS = unknown (77). As of January 2007, median survival for the group was 8 months. By the Cox regression model, statistically significant effects on overall survival were seen for gender, smoking status, age, performance status, and number of metastases. The following hazard ratios [with 95% CI] of death were seen for males vs. females 1.41 ([1.13, 1.75], p = 0.0025), former smokers vs. non-smokers 1.66 ([1.18, 2.31], p = 0.0032), active smokers vs. non-smokers 1.79 ([1.21, 2.64], p = 0.0036), for one year increase in age 1.02 ([1.00, 1.03], p = 0.0046), for one unit increase in performance status 1.63 ([1.45, 1.82], p < 0.0001) and for one unit increase in number of metastases 1.48 ([1.32, 1.66], p < 0.0001). Pts with one metastatic site had superior survival over pts with more sites. Six of 10 metastatic sites were found to have significant independent effects on overall survival, based on log-rank test. Conclusions: Number and sites of metastases were strong independent determinants of survival in NSCLC. Furthermore, our work suggests marked heterogeneity of metastatic patterns at presentation. Pts with fewer metastatic sites demonstrate better survival. Future targeted therapy protocols should stratify according to metastatic sites to better analyze patterns of failure and outcomes.

No significant financial relationships to disclose.
A double blind phase II study of BIBF 1,120 in patients suffering from relapsed advanced non-small cell lung cancer (NSCLC)
Authors: Von Pawel J. , Kaiser R. , Eschbach C. , Stefanic M. , Love J. , Gatzemeier U. , Reck M.
Published: March 2020

7635

Background: Vascular endothelial-(VEGF), platelet derived- (PDGF), and fibroblast growth factor (FGF) with their receptors compose critical cellular pathways controlling angiogenesis. BIBF 1120 is an oral potent triple angiokinase inhibitor targeting VEGFR, PDGFR, FGFR kinases. Methods: In this double blind multi-center trial, patients with an ECOG score of 0–2 with locally advanced or metastatic (stage IIIB/IV) relapsed NSCLC after failure of first or second line chemotherapy were randomly assigned to daily treatment with 2x250 mg or 2x150 mg of BIBF 1,120 until progression. In the event of dose limiting toxicity, a single dose reduction to open label treatment with 2x150 or 2x100 mg of BIBF 1,120 was allowed. Patients with stable brain metastases or squamous cell carcinoma were not excluded. Primary endpoints were progression free survival (PFS) and objective tumor response (RECIST, determined every 6 weeks). Results: Seventy three of 74 patients enrolled received BIBF 1120 (61% males, median age: 64 years, range 36–80). The most common histology was adenocarcinoma (55%), followed by squamous cell carcinoma (23%). The median PFS of all patients (n= 73) was 1.6 months without significant difference between both treatment arms. The stable disease rate was 48% without objective tumour responses. However, patients with an ECOG performance status of 0 or 1 (n= 57) had a median PFS of 2.9 months and a three- and 5 months PFS rate of 46% and 31%, without any difference between both treatment arms. The stable disease rate was 59%. Patients treated with 2x250 mg per day had more dose limiting CTCAE Grade 3 and 4 toxicities compared with patients treated with 2x150 mg (27% versus 2.8%, p=0.006, two-sided Fisher-test). The most frequent adverse events irrespective of relatedness observed in 73 patients were of CTCAE Grade 1 or 2 and included nausea (41%), diarrhoea (41%), vomiting (33%), fatigue (29%) and abdominal pain (22%). Grade 3 and 4 toxicities included nausea (8%), diarrhoea (7%), vomiting (4%), abdominal pain (4%) and AST and/or ALT elevations (5.4%). Conclusions: BIBF 1120 is safe and well tolerated and showed promising efficacy data in ECOG 0–1 patients. A high disease control rate of 59% could be observed.

[Table: see text]
Single-agent compared to combination first-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) and a performance status (PS) of 2
Authors: Bonomi P. , Villaflor V. M. , Oldham F. B. , Sandilac L. , Singer J. W.
Published: March 2020

7637

Background: Impaired performance status in NSCLC is associated with poor prognosis and reduced tolerance for treatment- related toxicities. Current treatment guidelines agree that PS 2 patients with advanced NSCLC benefit from systemic chemotherapy; however, no consensus exists on specific treatment recommendations; i.e., single-agent vs. combination chemotherapy. Methods: Two recent phase III randomized trials in advanced NSCLC (STELLAR 3 and 4) enrolled exclusively PS 2 patients and compared experimental treatment to either standard combination chemotherapy (paclitaxel/carboplatin; P/C), or single agent chemotherapy (vinorelbine or gemcitabine; V or G). An exploratory comparison of the control arms was performed to determine the degree of benefit and amount of added toxicity associated with standard combination vs. single agent chemotherapy. Results: Combination chemotherapy resulted in improved time to progression compared to single agent ( Table ). However, no statistical difference between treatment arms was noted for overall survival and 1-yr survival. Adverse events are listed in the table . Overall, the frequency of serious adverse events was 40% in the combination-arm and 35% in the single agent-arm. When only considering drug-related toxicities, the frequency of serious adverse events was 21% in the combination-arm and 5% in the single agent-arm. Conclusions: PS 2 patients receiving single agent chemotherapy have a similar outcome compared to those receiving combination chemotherapy; serious treatment related toxicities are less frequent with single agent therapy. Based on the currently available evidence, the use of single-agent therapy seems reasonable in PS 2 patients.

[Table: see text] [Table: see text]
Phase II study of cetuximab in combination with carboplatin and docetaxel for patients with advanced/metastatic non-small cell lung cancer (NSCLC)
Authors: Belani C. P. , Ramalingam S. , Schreeder M. , Steis R. , Guidice R. , Marshland T. , Butler B.
Published: March 2020

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Background: Cetuximab, a chimeric IgG1 monoclonal antibody against the external domain of the epidermal growth factor receptor (EGFR), has demonstrated single-agent activity against NSCLC. When administered in combination with carboplatin and docetaxel, a commonly used regimen for advanced NSCLC, cetuximab exhibits synergistic interaction in preclinical studies. Therefore, we conducted a phase II study to evaluate the efficacy of the combination of cetuximab, carboplatin, and docetaxel for the treatment of advanced NSCLC. Methods: Chemotherapy-naive patients = 18 years with histologically/cytologically confirmed stage IIIB (w/ effusion) or stage IV NSCLC received cetuximab (400 mg/m2 on day 1 and 250 mg/m2 on days 8 and 15) plus docetaxel (75 mg/m2 on day 1) and carboplatin (AUC=6 on day 1) every 21 days for up to 6 cycles. Thereafter, patients without evidence of disease progression (CR/PR/SD) were continued on single-agent cetuximab (250 mg/m2/week) for a maximum of 1 year or until disease progression. The primary endpoint was response rate. Results: 81 patients were enrolled and 76 are evaluable for response. Patient characteristics included: gender male/female, 43/38; median age 63 years (range 42–83); ECOG performance status 0/1/, 31/50; and stage IIIB/IV- 5/76. The median number of cycles administered was 4 (range 1–6). The response rate (CR/PR) was 14.5% (95% CI, 7.5 to 24.4), with a median progression-free survival of 4.7 months and a median overall survival of 11 months. With combination therapy, the salient grade 3/4 events were neutropenia (28%), febrile neutropenia (3.8%), hypotension (4%), hypokalemia and hypomagnesemia (5%), hypersensitivity (1%), acne-like rash (3%), peripheral neuropathy (1%), and myalgia (1%). Twenty-five patients received maintenance therapy with single-agent cetuximab (median duration of treatment was 12 weeks) and this was well tolerated. Conclusions: This large multicenter phase II study of the novel combination of cetuximab with docetaxel and carboplatin shows promising efficacy for patients with advanced and metastatic NSCLC and has an acceptable toxicity profile.

No significant financial relationships to disclose.
Population characteristics and prognostic factors in metastatic non-small cell lung cancer (NSCLC): The Fox Chase Cancer Center (FCCC) experience
Authors: Paralkar V. , Li T. , Langer C. J.
Published: March 2020

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Background: With increasing use of MRI and PET to stage NSCLC, the demographics, performance status and distribution of metastases at diagnosis in this patient (pt) population are changing; it is important to reassess the prognostic roles played by baseline clinical variables in the modern therapeutic era. Methods: We retrospectively evaluated the charts of 189 consecutive, unselected pts with stage IV NSCLC seen and followed at the Fox Chase Cancer Center between Oct 2000 and Aug 2003. Data on a variety of pt variables including demographics, histology, metastases, key laboratory tests and treatment were compiled. We intended to identify those that played statistically significant prognostic roles. Results: Median age at diagnosis was 62 years; 77% of pts had PS 0–1 at first presentation. 58% had single organ metastasis; 35% had metastases to the brain (half of these had brain only and a third had solitary brain metastasis). 51% of all pts received palliative radiation to the brain at some point after dx. Overall median survival was 10.8 months. The 1-yr, 2-yr, 3-yr and 4-yr overall survival rates were 44.2%, 21.9%, 11.6% and 7.8% respectively. On multivariate analysis, statistically significant negative prognostic factors included PS ≥ 2 (HR: 1.9, 95% CI: 1.1–3.3), serum albumin ≤ 3 (HR: 1.7, 95% CI: 1.1–2.8) and metastases to > 1 organ (HR: 1.6, 95% CI: 1.03–2.3). Bone and liver metastases, though associated with worse survival in univariate analysis, were not found to be independent predictors of survival. Gender had no bearing on outcome. Conclusions: Survival rates in this advanced NSCLC cohort equal or exceed contemporaneous ECOG figures. PS, serum albumin and number of organs with metastases are independent prognostic factors in NSCLC. The increasing detection of brain metastases at 1st presentation of metastatic NSCLC suggests that the role of prophylactic cranial irradiation in the management of early NSCLC should be explored.

No significant financial relationships to disclose.

[Table: see text]
Global histone modifications predict prognosis of resected non-small cell lung cancer patients
Authors: Barlesi F. , Giaccone G. , Gallegos-Ruiz M. I. , Loundou A. , Span S. W. , Lefesvre P. , Kruyt F. A. , Rodriguez J.
Published: March 2020

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Background: Epigenetic modifications, such as methylation and/or acetylation of histones, may contribute to the development and progression of cancer. We investigated whether histone modifications influence prognosis of non-small cell lung cancer (NSCLC). Methods: We used immunohistochemistry to assess histone 3 lysine 4 dimethylation (H3K4diMe), and acetylation of histone 2A lysine 5 (H2AK5Ac), histone 2B lysine 12 (H2BK12Ac), histone 3 lysine 9 (H3K9Ac), and histone 4 lysine 8 (H4K8Ac), in resected tumor samples of 138 NSCLC patients. In addition, the genotype of a tandem repeat polymorphism in the histone 3 methyltransferase SMYD3 gene was determined using PCR and capillary electrophoresis. Data were analyzed using a recursive partitioning analysis (RPA). Results: The overall median expression of H3K4diMe, H2AK5Ac, H2BK12Ac, H3K9Ac, and H4K8Ac were 75, 10, 0, 25, and 80%, respectively. The RPA classified the patients into seven distinct prognostic groups based on TNM stage (first node), histology (second node) and histone modifications (third node). H3K4diMe (< or =85% tumor cells), H3K9Ac (< or =68% tumor cells) and H2AKAc (< or =5% tumor cells) were retained by RPA. The SMYD3 genotype was not retained by RPA. The seven groups were associated with significantly different disease- free (p<0.0001) and overall survival (p<0.0001). Interestingly, the four groups determined by stage I patients (below the first node) displayed dramatic differences in survival (median from 10 months in adenocarcinoma, H3K9Ac=68%, to 147 months in non-adenocarcinoma, H3K4diMe=85%). Conclusions: The prognostic influence of global histone modifications is greater in early stage NSCLC and it may help in the selection of early stage NSCLC patients for adjuvant treatment and provides a rationale for the use of combination of standard chemotherapy with drugs interacting with histone modifications such as histone deacetylases (HDAC) inhibitors.

No significant financial relationships to disclose.
Novel mutations and mutation pattern of epidermal growth factor receptor (EGFR) gene in Chinese patients with primary lung adenocarcinoma
Authors: Mok T. , Lui P. , Lam K. C. , Yim A. , Wan I. , Lee S. , Hsin M. , Leung L. , To K.
Published: March 2020

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Background: EGFR mutation is a diverse and complex phenomenon. Shigematsu et al (JNCI 97:339,2005), analyzing NSCLC samples from multiple ethnicities and histologic cell types, reported 11 types of in-frame deletions in exon 19 (46%), 9 missense mutation in exons 18, 20, 21 (45%) and 8 in-frame insertion in exons 20 (9%). 3/130 tumors (2.3%) had multiple mutations. Here we report the incidence, mutation pattern and novel finding of EGFR mutation in a homogenous ethnic group with adenocarcinoma of lung. Methods: Between 2004 and 2006 we isolated genomic DNA from 194 (archival 53, prospective 141) primary lung adenocarinoma for PCR amplification of EGFR exon 18–21. We isolated tumor cell by micro-dissection. PCR products were purified and sequenced using the BigDye Terminator Cycly Sequencing Ready Reaction Kit (Applied Biosystem) and run on Applied Biosystem 3100 Genetic Analyzer. Results: We found 79 EGFR mutations in 73 tumors (37.6%). Six (8.2%) had double mutations. IN-FRAME DEL: 10 types in exon 19 (39 cases, 49.4%); 1 type in exon 18 (1 case). MISSENSE MUTATION: 2 types in exon 18 (2 cases); 4 types in exon 20 (5 cases) and 2 types in exon 21 (29 cases, 36.7%) IN-FRAME INSERTION: 3 types in exon 20 (3 cases). Typical exon 19 E746-A750del and exon 21 L858R mutations accounted for 31% and 34%, respectively. We found 11 types of mutations not previously described.( Table ) Four pts with novel mutations received EGFR TKI and 3 attained PR (all with exon 19 del). Two pts have T790M mutations without prior exposure to EGFR TKI and both with double mutations. Conclusion: Mutation pattern of EGFR gene in Chinese pts with adenocarcinoma is similar to the Shigematsu report. The overall incidence of EGFR mutation and multiple mutations are higher but in-frame insertion in exon 20 is less common. Majority of the novel mutations are rare mutations involving exon 18 and 20.

No significant financial relationships to disclose.

[Table: see text]
Serum-free estradiol (E2) levels are prognostic in men with chemotherapy-naive advanced non-small cell lung cancer (NSCLC) and performance status (PS) 2
Authors: Ross H. , Oldham F. B. , Bandstra B. , Sandalic L. , Bianco J. , Bonomi P. , Singer J. W.
Published: March 2020

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Background: In women with advanced NSCLC, premenopausal estradiol levels are associated with a worse survival than postmenopausal levels, suggesting an adverse effect of estradiol on prognosis in NSCLC (JCO 2006, 24(18S):7038; JCO 2006, 24:59–63). Levels of E2, produced from testosterone by aromatase, are often higher in men than in postmenopausal women (Ann Intern Med. 2000, 133:951–63). To investigate the effect of E2 on prognosis in male patients (pts) with advanced NSCLC, total and free E2 levels were assayed in pretreatment samples from men participating in 2 randomized phase III studies, STELLAR 3 and 4. Methods: Free serum E2 levels were measured prior to chemotherapy using a radioimmuno-assay in samples from 289/307 male pts with advanced NSCLC and PS2 enrolled in STELLAR 3 (paclitaxel + carboplatin (C) v. paclitaxel poliglumex (PPX) + C) and STELLAR 4 (vinorelbine or gemcitabine v. PPX). The effect of free E2 levels on survival was evaluated by log rank test. Male pts were categorized as high or low E2 based on values above or below the median (0.42 pg/ml; range: 0.1–2.95).The assay range for normal men is 0.2 - 0.5 pg/ml; in pre- and postmenopausal women, the range is 0.80- 3.45 and 0.12 - 0.39 pg/ml, respectively. Results: Hazard ratio's (HR), median, and 1-yr survival are summarized in the table . Survival was worse for male pts with E2 values higher than the median compared to those below the median (HR 1.56, p = .0008). This difference in survival was not dependent on treatment arm as survival was similar for male pts > 0.42 pg/ml receiving either PPX or control. Conclusions: High serum free E2 levels are associated with shorter survival in men with advanced NSCLC, consistent with the shorter survival noted in NSCLC in premenopausal compared to older women. While PPX is associated with improved survival in women with premenopausal E2 levels (JCO 2006, 24(18S):7039), the relatively low levels of E2 in men may be insufficient to affect survival in male pts receiving PPX.

[Table: see text] [Table: see text]
Integrated genomic analysis of lung adenocarcinomas identifies loss of the MAPK phosphatase gene DUSP4 in most EGFR mutant tumors
Authors: Broderick S. R. , Chitale D. , Motoi N. , Gong Y. , Pao W. , Venkatraman E. , Rusch V. , Brennan C. , Gerald W. , Ladanyi M.
Published: March 2020

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Background: Genomic analyses of lung adenocarcinoma have yielded striking advances that are already impacting on clinical management. Further advances in understanding the biological heterogeneity of this disease will require integration of multiple types of genomic data. To this end, we have assembled a large integrated genomics dataset of lung adenocarcinomas. Here, we highlight one of the novel findings emerging from its initial analysis. Methods: 173 primary lung adenocarcinomas were included in this analysis. Profiling of genomic gains and losses was done by array comparative genomic hybridization (aCGH) on Agilent 44K arrays. Expression profiling was based on Affymetrix U133A arrays. The dataset was annotated for EGFR mutations (exon 19 deletion and L858R) by sensitive PCR-based assays and for KRAS mutations by sequencing. Results: By unsupervised analysis of the aCGH data, the 173 tumors clustered robustly into two or three patterns of co-occurring gains and losses. One aCGH cluster was strongly associated with EGFR mutation (p<10−4) and was characterized by 7p gains (in the EGFR region) and 8p losses. Remarkably, by expression profiling the most consistently underexpressed gene (p<10−9) in EGFR mutant cases compared to EGFR wild type cases was a MAPK phosphatase gene at 8p12, DUSP4 (MKP-2). The DUSP4 region showed genomic loss in 27/35 EGFR mutant cases vs 47/138 non-mutated cases (p<10−4). A limited screen (n=11) has so far revealed no DUSP4 mutations. Western blotting shows low DUSP4 in most EGFR mutant lines, compared to KRAS mutant lines. Conclusions: EGFR mutations in lung adenocarcinomas are strongly associated with genomic loss and low expression of DUSP4. DUSPs are known to be transcriptionally upregulated by MAPK signaling as a negative feedback mechanism and DUSP family members are emerging as putative tumor suppressors in other cancers. We hypothesize that DUSP4 loss cooperates with EGFR mutation to allow full oncogenic activation of the MAPK pathway. Functional studies of DUSP4 in lung adenocarcinoma cell lines are in progress. Our data highlight the value of large, integrated, highly annotated genomic datasets in generating novel insights and hypotheses.

No significant financial relationships to disclose.