bluuebunny/crossref_metadata_2025 huggingface dataset:
Cisplatin (Cis)/etoposide (VP16) compared to cis/irinotecan (CPT11) in extensive-stage small cell lung cancer (E-SCLC): Pharmacogenomic (PG) and comparative toxicity analysis of JCOG 9511 and SWOG 0124
Authors: Lara P. , Redman M. , Lenz H. , Gordon M. , Shibata T. , Fukuda H. , Tamura T. , Saijo N. , Natale R. , Gandara D.
Published: March 2020

7524

Introduction: J9511 demonstrated a significant survival benefit for Cis/CPT11 over Cis/VP16 in Japanese patients (pts) with E-SCLC (Noda, et al. NEJM 2002). S0124 is the confirmatory North American phase III trial (accrual completed) using the identical J9511 protocol. We hypothesized that toxicities would differ between North American & Japanese pts due in part to differences in the distribution of genetic polymorphisms involved in chemotherapy metabolism. Methods: Toxicity data were compared among 706 pts enrolled in J9511 & S0124 receiving common treatment using a logistic model adjusted for age, sex, and performance status (PS). Select polymorphisms of the UGT1A1, ABCB1, & OATP genes in genomic DNA were evaluated in 142 pts in S0124 only (67 Cis/CPT11; 75 Cis/VP16). Associations between toxicity & genotype within each arm were assessed using logistic regression. Results: Pt demographics for J9511 & S0124 respectively: Mean age − 61 & 62 years; Male sex − 131 (86%) & 315 (57%); PS 0 − 19 (13%) & 173 (31%); PS>0 − 133 (87%) & 372 (68%). Comparative toxicities (≥ grade 3) are summarized ( table ). PG analysis in S0124 pts: ABCB1 (C3435T) T/T was associated with an increased risk of CPT11 grade 3+ diarrhea (p=0.04) versus C/C and C/T. UGT1A1 (G3156A) A/A was associated with increased risk of CPT11 neutropenia (p=0.009) & leukopenia (p=0.05). UGT1A1*28 TA7, typically associated with increased CPT11 toxicity, was seen in only 4 pts (2 Cis/CPT11; 2 Cis/VP16); thus no correlation was done. No gene tested was associated with VP16 toxicity. Conclusions: Significant differences in treatment-related myelosuppression exist between J9511 and S0124 pt populations. Certain polymorphisms in genes involved in CPT11 metabolism are significantly associated with CPT11 toxicities in S0124. Additional analyses are ongoing. These results support the hypothesis that toxicities may be associated with distribution of genetic polymorphisms.

No significant financial relationships to disclose.

[Table: see text]
Induction chemotherapy followed by concurrent chemoradiotherapy (CCRT) versus CCRT alone for unresectable stage III non-small cell lung cancer (NSCLC): Randomized phase III trial
Authors: Kim S. , Kim M. , Choi E. , Sohn H. , Lee D. , Suh C. , Lee J. , Yang H. , Hong J. , Kim W.
Published: March 2020

7528

Background: We conducted a prospective randomized phase III trial comparing induction chemotherapy followed by concurrent chemoradiotherapy (CCRT) versus immediate CCRT to evaluate whether the addition of induction chemotherapy would result in improved survival. Methods: Patients with unresectable stage III NSCLC, ECOG PS 0–1, and weight loss up to 10% were eligible. They were randomized to receive either induction chemotherapy followed by CCRT (arm A) or immediate CCRT (arm B) after stratification for stage (T4N0–2, T1–3N3, T4N3, and stage IIIA), histology (squamous vs non-squamous), and SCLN positivity. Induction chemotherapy consisted of two cycles of gemcitabine (1,000 mg/m2 D1, D8) and cisplatin (70 mg/m2 D1) q 21days. Chemotherapy during CCRT consisted of 6 cycles of weekly paclitaxel (50 mg/m2) and cisplatin (20 mg/m2). Radiation therapy performed with hypofractionated scheme (2.2 Gy/fraction, once a day) and total dose was 66 Gy. Irradiated volume encompassed gross tumor plus 1.0 cm margin. Results: Between March 2003 and June 2006, 134 patients were enrolled. 92% of patients were male and 60% were age 60 or older. Objective tumor response was obtained in 38% after induction chemotherapy. Response rates after completion of CCRT were 72% (95% CI, 61%–83%) on arm A and 79% (95% CI, 69%–89%) on arm B. Grade 3/4 toxicities during induction chemotherapy consisted mainly of neutropenia (11%/3%). During CCRT, grade 3/4 neutropenia was noted in 8%/5% (arm A) versus in 8%/0% (arm B), grade 3 anemia was 8% vs 0%, grade 3 thrombocytopenia 5% vs 0%, and grade 3 esophagitis 16% vs 16%. At median follow-up of 28 months, median survival was 12.6 months (95% CI, 8.6–16.7 months) on arm A versus 18.2 months (95% CI, 11.7–24.8 months) on arm B (P=0.18). Two year survival estimates was 25% (15%–35%) and 43% (31%–55%), respectively. Median progression free survival was 7.5 months (95% CI, 5.6–9.4 months) on arm A and 11.6 months (95% CI, 9.6–13.6 months) on arm B (P=0.04). Conclusions: The addition of induction chemotherapy to CCRT failed to increase the survival of unresectable stage III NSCLC over immediate CCRT. Moreover, the progression free survival was inferior to immediate CCRT.

No significant financial relationships to disclose.
Erlotinib as initial therapy in patients with advanced non-small cell lung cancer (NSCLC) and a performance status (PS) of 2: A SWOG phase II trial (S0341)
Authors: Hesketh P. J. , Chansky K. , Wozniak A. J. , Mack P. , Lara P. N. , Franklin W. A. , Hirsch F. R. , Crowley J. , Gandara D. R.
Published: March 2020

7536

Background: Patients (pts) with advanced NSCLC and PS 2 have an inferior survival compared with good PS pts. Single agent and combination chemotherapy have been used with modest success with toxicity often limiting treatment. Targeted agents such as the EGFR tyrosine kinase inhibitor erlotinib (E) offer an alternative which may confer comparable benefit with better tolerance. This phase II trial of E in unselected chemotherapy-naive pts with advanced NSCLC and PS 2 was performed to obtain preliminary data regarding efficacy and EGFR biology in this pt population, and to set the stage for a subsequent randomized trial of E vs.chemotherapy, in pts selected for EGFR expression. Methods: Eligibility: stage IIIB (pleural effusion)/IV NSCLC; measurable disease; PS 2; no prior chemotherapy/biologic treatment for NSCLC. Treatment: E 150 mg orally daily. Molecular correlative studies:EGFR protein expression (IHC), gene copy (FISH), mutation analysis. Results: Pts: 82; 73 eligible; 72 fully evaluable; age (median) 74.4; M/F 47%/53%; current/former smoker 91%; stage IIIB/V 12%/88%; adenoca 54%. Treatment was well tolerated. Five pts (7%) had a grade 4 toxicity (fatigue 3 pts; dyspnea 2 pts). Most common grade 3 toxicities: fatigue 9 pts (13%); rash 7 pts (10%); diarrhea 5 pts (7%); anorexia 5 pts (7%). There was 1 possible treatment related death due to pneumonitis. One complete (1%) and 5 (7%) partial responses were noted. Stable disease was seen in 25 pts (35%) for an overall disease control rate (DCR) of 43% (31 pts). Progression free survival: 2.1 months (95% CI 1.5 –3.1); Median survival: 5.0 months (95 % CI 3.5 –7.3). One year survival: 22% (95% CI 12 –32%). Analysis of molecular correlates is ongoing. Conclusions: Single agent erlotinib is a well tolerated treatment for chemotherapy- naive patients with advanced NSCLC and PS 2 with an overall DCR of 43% and median survival of 5 months. These efficacy results are comparable to the outcome seen in SWOG trial S0027 in PS 2 pts employing sequential vinorelbine and docetaxel. We hypothesize that pt selection by an EGFR biomarker strategy will improve results with E, and that E will be superior to chemotherapy in this selected population.This trial design is under development within SWOG at present.

[Table: see text]
Randomized phase II study of vandetanib (VAN) alone or in combination with carboplatin and paclitaxel (CP) as first-line treatment for advanced non-small cell lung cancer (NSCLC)
Authors: Heymach J. , Paz-Ares L. , De Braud F. , Sebastian M. , Stewart D. J. , Eberhardt W. , Herbst R. S. , Krebs A. , Langmuir P. , Johnson B. E.
Published: March 2020

7544

Background: VAN (ZD6474) is a once-daily oral agent that selectively inhibits VEGFR, EGFR and RET signaling. This randomized phase II trial investigated VAN alone or in combination with CP vs CP. Methods: Eligible patients (pts) had previously untreated locally advanced or metastatic (IIIB-IV) NSCLC. The primary objective was to determine whether VAN (300 mg/day) ± CP (C, target AUCss = 6 mg/ml·min; P; 200 mg/m2 iv) prolonged progression-free survival (PFS) vs CP (75% power to detect 30% prolongation; 1-sided P=0.2). An initial run-in phase had established VAN 300 mg/day as an appropriate dose to be given with CP. Results: A total of 181 pts (median age 61 yrs, range 27–83) received VAN (n=73), VAN + CP (n=56) or CP (n=52). The primary objective was met, with VAN + CP prolonging PFS vs CP (HR = 0.76, 95% CI 0.50–1.15; P=0.098): median PFS = 24 wks (VAN + CP) and 23 wks (CP). The VAN monotherapy arm was stopped early after a planned interim PFS analysis met the criterion for discontinuation (HR > 1.33 vs CP). The objective response rates were 32%, 25% and 7% for VAN + CP, CP and VAN, respectively. Overall survival (OS), a secondary endpoint, was not significantly different between pts receiving VAN + CP or CP (HR = 1.07, 95% CI 0.63–1.81; P=0.595). Exploratory subgroup analyses suggest advantages in PFS and OS for VAN + CP vs CP for the 56 female pts. There was a higher incidence of some adverse events with VAN + CP vs CP, including rash (64% vs 33%), diarrhea (53% vs 32%), asymptomatic QTc-related events (22% vs 4%) and hypertension (32% vs 4%). Pts receiving VAN + CP, including 7 who entered with CNS metastases and 11 with squamous histology, did not experience any intracranial bleeding, or hemoptysis of CTC grade 2 or higher. A biomarker analysis, including circulating endothelial cells and 35 plasma angiogenic factors and cytokines, suggests several potential markers predictive of clinical outcome and will be reported separately. Conclusions: In this randomized phase II trial of 1st-line advanced NSCLC, VAN + CP met the primary endpoint of prolonging PFS vs CP alone but did not provide a detectable survival advantage.

No significant financial relationships to disclose.
Phase II study of eribulin mesylate (E7389), a mechanistically novel inhibitor of microtubule dynamics, in patients with advanced non-small cell lung cancer (NSCLC)
Authors: Spira A. I. , Iannotti N. O. , Savin M. A. , Neubauer M. , Gabrail N. Y. , Yanagihara R. , Datta K. K. , Zang E. A. , Fields S. Z. , Das A.
Published: March 2020

7546

Background: Eribulin is a structurally-simplified, fully synthetic analog of the marine sponge natural product halichondrin B. Eribulin inhibits microtubule dynamics via a mechanistically novel mode of action. Methods: An open-label, single-arm, Phase II study of eribulin was conducted in patients with advanced NSCLC (ECOG of 0 or 1) who were treated with platinum-based doublet chemotherapy and stratified by prior taxane exposure. A total of 103 patients (83 with prior taxanes and 20 taxane naïve) were treated with eribulin (1.4 mg/m2), administered as a bolus infusion over 2 –5 minutes on Days 1, 8, and 15 of a 28-day cycle (N=77). Due to delays or skipped doses secondary to myelosuppression at Day 15 with recovery by Day 21, the protocol was amended to a schedule of Days 1 and 8 of a 21-day cycle (N=26). The primary efficacy endpoint was objective response rate. Independent radiologic review was used to confirm responses. Results: Of 106 enrolled patients, 103 received eribulin. Median age was 65 years and median number of prior therapies was 2, including taxanes (81%), gemcitabine (40%), pemetrexed (23%), and EGFR inhibitors (34%). Median number of cycles administered was 3 (range 1–15). Drug related toxicities included neutropenia grade 3 (23%) and 4 (26%), febrile neutropenia (4%), grade 3 fatigue (11%), grade 3 nausea (2%), and peripheral neuropathy grade 1/2 (37%) and 3 (2%). Based on RECIST criteria, the overall response rate (all partial responses) was 9.7% (95% CI: 4.0–15.4 %), with 10.8% PR in taxane pre-treated, and 5% PR in taxane naïve patients. Overall disease control rate (PR + SD) was 55.3%. 12-week progression free survival (PFS) rate was 53.0% (95% CI: 42.6–63.3%) and median PFS was 102 days (range 1–408+). Median duration of response was 176 days (range 50–291+), and median overall survival was 287 days (range 16–423+). The one year survival rate was 46.4% (95% CI: 34.9–58.0%). Conclusions: In this group of NSCLC patients who were treated with a median of two prior therapies, consisting in the majority of cases of two cytotoxic regimens, eribulin demonstrated an overall PR rate of 9.7% (10.8% in the taxane pre-treated) and 9.6 months median survival.

No significant financial relationships to disclose.
High insulin-like growth factor 1 receptor (IGF1R) expression is associated with poor survival in surgically treated non-small cell lung cancer (NSCLC) patients (pts)
Authors: Merrick D. T. , Dziadziuszko R. , Szostakiewicz B. , Szymanowska A. , Rzyman W. , Jassem E. , Jassem J. , Franklin W. A. , Bunn P. A. , Hirsch F. R.
Published: March 2020

7550

Background: IGF1R represents a novel molecular target in NSCLC. We aimed to evaluate the association between IGF1R expression, clinical characteristics and survival in operable NSCLC pts. Methods: 184 consecutive surgically treated pts (median follow up of 32 months [range: 13–51 months]) were included in the study. There were 23% females, 55% pts with squamous cell carcinoma, 28% with adenocarcinoma, 3% with large cell carcinoma, 13% with mixed carcinoma and 1% with other types, 5% were never-smokers. Median age was 64 years (range: 37–85 years). Pathological stage I was diagnosed in 41%, stage II –22%, stage III –33% and stage IV –4% pts. Induction or adjuvant treatment was not routinely used. IGF1R was evaluated in tissue microarray by immunohistochemistry and scored by two observers according to H-score, taking into account proportion of cells with positive staining times staining intensity (scale 0–400). Results: IGF1R IHC expression was low in analyzed samples (median H-score 20, range: 0–223). Higher IGF1R score was observed in adenocarcinomas vs. squamous-cell carcinomas (p=0.02) and never-smokers vs. smokers (p=0.02). IGF1R score did not depend on stage (p=0.98) and sex (p=0.83). When analyzed as a continuous variable, IGF1R score tended to associate with worse survival in the entire cohort (p=0.10), and was significantly associated with inferior survival in patients with complete (R0) resections (p=0.04). When categorized with cut-off point of 50 (30% of patients positive), IGF1R expression was again associated with poor survival (p=0.05). This association was confined to pathological stage I (hazard ratio, HR=3.07; 95% confidence interval, CI=1.41–6.70, p=0.005) vs. all other stages (HR=1.03; 95% CI=0.63–1.70, p=0.90), and to patients with adenocarcinoma histology (HR=2.67; 95%CI=1.17–6.70, p=0.02 vs. all other histologies (HR=1.28; 95%CI=0.79–2.11, p=0.32). Conclusion: In this cohort of operable NSCLC pts, high IGF1R expression was associated with never-smoking history, adenocarcinoma histology, and poor survival, particularly in stage I disease and in patients with adenocarcinoma. These results support involvement of IGF pathway in the progression of early-stage NSCLC.

No significant financial relationships to disclose.
Surgery and adjuvant chemotherapy (CT) compared to surgery alone in non-small cell lung cancer (NSCLC): A meta-analysis using individual patient data (IPD) from randomized clinical trials (RCT)
Authors: Stewart L. A. , Burdett S. , Tierney J. F. , Pignon J.
Published: March 2020

7552

Background: A previous IPD meta-analysis (BMJ 1995;311:899) that suggested CT may have a role in the treatment of NSCLC has been updated. This includes RCTs, regimens and outcomes that were not available in 1995. The meta-analysis examines the role of CT in 7 treatment comparisons. Here we report on the effectiveness of surgery plus adjuvant CT compared with surgery alone. Methods: We conducted a systematic search for RCTs followed by the central collection, checking and re-analysis of updated IPD. Results from RCTs were combined using the stratified (by trial) log rank test to calculate individual and pooled hazard ratios (HRs). Previously included RCTs using long-term alkylating agents were excluded from this analysis due to their antiquity. Results: IPD were obtained on 8147 patients from 30 RCTs. 15 RCTs used a cisplatin combination without Tegafur/Tegafur+Uracil (UFT), 8 RCTs used Tegafur/UFT without cisplatin and 7 RCTs used Tegafur/UFT and cisplatin. This represents 95% of all known randomised patients and adds 18 trials and 5835 patients to the 1995 analyses. The results show a highly significant benefit of CT on survival (HR=0.86 95% CI 0.81–0.93, p<0.000001), with an absolute benefit of 4% (from 60% to 64%) at 5 years. Results were similar for recurrence-free survival and time to distant recurrence, but there was a larger effect on time to local recurrence ( Table ). There was no clear difference in effect by type of CT given. There was no clear evidence that any patient subgroup defined by age, sex or histology benefited more or less from CT. There was a suggestion of a trend in effect by stage (p=0.047), this will be explored further. Conclusion: The results demonstrate conclusively and consistently a benefit of adjuvant CT in resected NSCLC, irrespective of the regimen used, the patient subgroup treated or the endpoint assessed, thus providing reliable estimates on which to base future policy and research.

[Table: see text] [Table: see text]
A pooled analysis of the effect of age on adjuvant cisplatin-based chemotherapy for completely resected non-small cell lung cancer (NSCLC)
Authors: Fruh M. , Tribodet H. , Pignon J. , Winton T. , Le Chevalier T. , Scagliotti G. V. , Douillard J. Y. , Seymour L. , Spiro S. G. , Shepherd F. A.
Published: March 2020

7553

Background: Adjuvant cisplatin-based chemotherapy (CT) has been shown to increase survival in NSCLC, but uncertainty exists concerning its efficacy and toxicity in elderly patients (≥ 70). Methods: We performed a pooled analysis using individual patient data from 4,584 patients in the LACE database with resected stage IA-III NSCLC enrolled in 5 randomized trials, comparing postoperative CT to no CT (ALPI, ANITA, BLT, IALT and JBR10). Patient and treatment characteristics, CT toxicity and delivery, overall survival, disease-free survival (DFS) and cause-specific mortality were compared among 3 age groups: 3,269 (71%) young (<65), 901 (20%) mid-category (65–69) and 414 (9%) elderly (≥70). The analysis was performed on an intent-to-treat basis. Cox models stratified by trials and adjusted for age, associated drug, planned radiotherapy, total dose of cisplatin (<300, 300, >300), gender, stage, performance status, type of surgery and histology were used with a test for trend to study the effect of CT on survival according to age. Results: Baseline characteristics differed among the age groups, but this was due mainly to the different trial populations and designs. No difference in severe toxicity rate was observed among the age groups. Elderly patients received significantly smaller total doses of cisplatin than the other patients (Chi2-test: p<0.0001) and also the cisplatin doses received were more often lower than the planned one (Kruskal-Wallis test: p<0.0001). The Hazard ratio (HR) of death for the young patients was 0.82 (95% CI 0.73–0.92), 0.86 (95% CI 0.70–1.07) for the mid category and 1.01 (95% CI 0.78–1.32) for elderly patients (test for trend: p=0.17). The HR for DFS was 0.79 (95% CI 0.71–0.87) for the young, 0.76 (95% 0.62–0.93) for the mid category and 0.94 (95% CI 0.73–1.22) for the elderly patients (test for trend: p=0.35). More elderly patients died from non- lung cancer related causes (10% young, 16% mid category and 20% elderly; p<0.0001). Conclusions: The survival benefit from cisplatin-based adjuvant therapy for NSCLC patients was not significantly different according to age, but this may be due to lack of power. Supported by unrestricted grants from PHRC and LNCC

No significant financial relationships to disclose.
Number of lymph nodes harvested from a mediastinal lymphadenectomy: Results of the randomized, prospective ACOSOG Z0030 trial
Authors: Allen M. S. , Darling G. E. , Decker P. A. , Putnam J. B. , Malthaner R. A. , Inculet R. I. , Jones D. R. , McKenna R. J. , Landreneau R. J.
Published: March 2020

7555

Background: Lymph node status is a major determinant of stage and survival in patients with lung cancer; however, little information is available about the yield of a mediastinal lymphadenectomy done at the time of pulmonary resection. Methods: The ACOSOG Z0030 trial is a prospective, randomized trial of mediastinal lymph node sampling versus complete mediastinal lymphadenectomy during an operation for early stage lung cancer. Total enrollment from July 1999 to February 2004 was 1,111 patients, of which 1,023 were eligible and/or evaluable. There were 524 patients who underwent complete mediastinal lymph node resection after randomization to this arm that were declared eligible and/or evaluable with lymph node data available. The number of lymph nodes examined from each station was collected beginning in January 2002. Prospectively collected data from these patients was analyzed to determine the number of lymph nodes obtained. Results: Median age was 67 (range 37–87) and 267 (52%) were men. Histology was squamous cell in 141 (27%), adenocarcinoma in 227 (44%), large cell in 22 (4%), bronchoavelolar in 32 (6%) and other non-small cell in 99 (19%). There were 317 right sided cancers and 207 left sided cancers. For lymphadenectomy for cancers in the right lung the yield from station 2R was a median of 2 lymph nodes (range 1 to 15), station 4R was 2 (1 –17), station 7 was 2 (1–24), station 8 was 1 (1–5), station 9 was 1 (1–6) and station 10R was 1 (1–10). For lymphadenectomy for cancers on the left side the yield from station 2L was 2 (1–4), station 4L was 1 (1–12), station 5 was 2 (1–18), station 6 was 2 (1–11), station 7 was 2 (1–16), station 8 was 1 (1–3), station 9 was 1 (1–8) and 10L was 2 (1–12). The total number of lymph nodes or fragments obtained for right sided cancers was a median of 13.5 (range 1 to 56) and for left sided tumors 15 (range 4 to 81). Conclusions: Although high variability exists in the actual number of lymph nodes obtained from various nodal stations, a complete mediastinal lymphadenectomy should obtain one or more lymph nodes from each mediastinal station. Adequate mediastinal lymphadenectomy should include exploration and remove of lymph nodes from stations 2R, 4R, 7, 8, and 9 for right sided cancers and stations 4L, 5, 6, 7, 8 and 9 for left sided cancers.

No significant financial relationships to disclose.
Pemetrexed plus cisplatin (P+Cis) or pemetrexed plus carboplatin (P+Cb) for chemonaive patients (pts) with malignant pleural mesothelioma (MPM): Results of the International Expanded Access Program (EAP)
Authors: Santoro A. , O'Brien M. , Stahel R. , Nackaerts K. , Baas P. , Paz-Ares L. , Sundstrom S. , Visseren-Grul C. , Blatter J. , Manegold C.
Published: March 2020

7562

Background: In a phase III study of P+Cis versus Cis, MPM pts demonstrated a significant survival benefit (12.1 mo vs 9.3 mo median survival; 50.3% vs 38.0% 1-yr survival) and clinical benefit in favor of P+Cis (Vogelzang 2003). Other studies similarly demonstrated efficacy associated with P+Cb. Before and during review by regulatory agencies, EAP provided access to P alone or P plus a platinum (Cis or Cb) for 3311 MPM pts in 13 countries. Safety and efficacy data for chemonaïve pts receiving P+platinum are summarized in this abstract. Methods: Eligible pts had histologic or cytologic diagnosis of MPM not amenable to curative treatment with surgery. P 500 mg/m2 was given in combination with either Cis 75 mg/m2 or Cb AUC 5 once every 21 days with standard pre- medication consisting of vitamin B12, folic acid, and dexamethasone. Investigator-determined response (RR) and survival data (with censoring) were recorded at the end of study participation. Myelosuppression data were also collected. Results: 1,704 chemonaïve pts received =1 dose of P+Cis (843 pts) or P+Cb (861 pts) and were evaluable for safety. For the P+Cis group, the median age was 62 yrs (range, 24–78) and 85.3% of pts were male. For the P+Cb group, the median age was 66 yrs (range, 35–89) and 80.5% of pts were male. More than 90% of pts in both groups had performance status (PS) data; 86.8% of P+Cis pts and 85.8% of P+Cb pts had Karnofsky PS =80. Among the study participants, 745 P+Cis pts and 752 P+Cb pts were evaluated for efficacy. See the table for efficacy and safety data. Conclusions: This large study confirmed the activity of P+Cis and P+Cb, demonstrating clinically similar one-year survival for the treatment of chemonaive pts with MPM.

No significant financial relationships to disclose.

[Table: see text]
CALGB 30206: Phase II study of induction cisplatin (P) and irinotecan (I) followed by combination carboplatin (C), etoposide (E), and thoracic radiotherapy for limited stage small cell lung cancer
Authors: Kelley M. J. , Bogart J. A. , Hodgson L. D. , Ansari R. H. , Atkins J. N. , Wang X. F. , Green M. R. , Vokes E. E.
Published: March 2020

7565

Background: We sought to determine the efficacy of using both irinotecan- and etoposide-containing regimens for patients with untreated LS-SCLC. Methods: Eligibility: measurable disease, performance status (PS) 0–2, no prior therapy, and adequate organ function. Treatment: Induction with P 30 mg/m2 and I 65 mg/m2 both IV day 1 and 8 q21 days ×2 cycles. Beginning day 43 daily chest irradiation (200 cGy/fraction) to 70 Gy concurrent with C AUC=5 IV day 1 and E 100 mg/m2 days 1–3 q 21 days x3 cycles (5 chemotherapy cycles total). Endpoints: Primary - to differentiate a 45% and 60% 2-year survival rate (>39 pts alive/75 pts; a=0.091, β=0.098); secondary-response rates to induction and overall therapy, overall and progression-free survival, and toxicity. Results: Characteristics: Between 11/03 and 9/05, 78 patients were enrolled (2 ineligible): male/female, 43/33; white/black, 74/2; median age 61 (range, 41–79); PS 0/1, 50/26; wt loss >5% in 10 (2 missing data). Two full induction cycles were delivered to 73 (96%) patients; all planned treatment was delivered to 50 pts (66%). Efficacy: To date, 41 (54%) pts have died before 2 yrs. P+I induction chemotherapy resulted in 4 (5 %) CR, 45 (59 %) PR; Overall RR 64% (95% CI 53–74%). Best response to therapy among 76 evaluable pts was 23 (30%) CR and 40 (53%) PR. The 95% CI for ORR is 73–90%. With median follow-up of 18 m, median PFS and OS are 12.6 m (95% CI 10.1–14.7) and 16.1 m (14.1–23.9). Toxicity: Frequent (>20%) grade 3/4 toxicities over all therapy in 77 patients were: neutropenia 25%/58%, hemoglobin 35%/1%, platelets 26%/26%. Maximum hematological toxicity was grade 3/4 in 16%/70% of patients. Maximum non-hematological toxicity was grade 3/4 in 47%/12% including: esophagitis in 27%/3% and dehydration in 21%/1%. No fatal toxicities. Conclusions: This treatment regimen, employing irinotecan doublet induction therapy followed by 70 Gy concurrent radiation and “standard” etoposide carboplatin has tolerable toxicity but did not produce a 2 year survival rate of >50%. New strategies for augmenting median and overall survival among patients with LS-SCLC are needed.

[Table: see text]
Supportive care and chemotherapy (CT) versus supportive care alone in advanced non-small cell lung cancer (NSCLC): A meta-analysis using individual patient data (IPD) from randomised clinical trials (RCTs)
Authors: Burdett S. , Stewart L. A. , Tierney J. F. , Le Pechoux C.
Published: March 2020

7582

Background: Building on a previous IPD meta-analysis of CT (BMJ 1995;311:899–909) which suggested that CT may have a role in the treatment of NSCLC, we have carried out a new, up-to-date IPD meta-analysis. This includes RCTs, regimens and outcomes that were not available in 1995. This new meta-analysis examines the role of CT in 7 treatment comparisons. Here we report the effectiveness of supportive care plus CT compared with supportive care alone. Methods: We conducted a systematic search for RCTs followed by the central collection, checking and re-analysis of updated IPD. Results from individual RCTs were combined using the stratified (by trial) log rank test to calculate individual and pooled hazard ratios (HRs). Previously included RCTs using long-term alkylating agents were excluded from this analysis due to their antiquity. Results: IPD were obtained on 2,666 patients from 15 RCTs. 11 RCTs used cisplatin-based CT regimens, 4 RCTs used single agent CT (etoposide, navelbine, gemcitabine, paclitaxel). This added 6 RCTs and 1,702 patients to the 1995 analyses. The results show a highly significant benefit of CT on survival (HR=0.78 95% Confidence Interval 0.71–0.84, p<0.000001), with an absolute benefit of 8% (from 20% to 28%) at 12 months across all patients. There was no evidence of a difference in effect (p=0.69) between trials that used cisplatin-based regimens (11 RCTs, HR=0.76), etoposide alone (1 RCT, HR=0.87) or newer single agents (3 RCTs, HR=0.79) (Interaction p=0.69). There was no evidence that any patient subgroup defined by age, sex, stage or histology benefited more or less from CT. The absolute benefit of CT at 12 months did vary according to WHO/ECOG (or equivalent) performance status. PS 0=8% (from 26% to 34%), PS 1=8% (from 18% to 26%), PS 2=5% (from 6% to 11%) and PS 3=4% (from 5% to 9%). Conclusion: The results demonstrate a substantial and consistent relative benefit of CT in advanced NSCLC. The effectiveness of newer agents such as navelbine, paclitaxel and gemcitabine (used as single agents) appears to be similar to that of cisplatin combined with older agents such as vindesine and mitomycin C. The absolute effect of CT varied according to performance status.

No significant financial relationships to disclose.
Anatomic segmentectomy for stage I non-small cell lung cancer: Comparison of outcomes with the VATS versus open approach
Authors: Schuchert M. J. , Pettiford B. L. , d’Amato T. A. , Keeley S. , Santos R. , Kilic A. , Fernando H. C. , Luketich J. D. , Landreneau R. J.
Published: March 2020

7616

Background: Anatomic segmentectomy for early-stage NSCLC has been proposed as a means of achieving a complete resection in high-risk patients with poor lung function, who might not otherwise tolerate conventional lobectomy. Historically, anatomic segmentectomy has been associated with increased recurrence rates and postoperative air leaks. In the current study, we present our experience with VATS versus open segmentectomy for stage I NSCLC. Methods: A total of 181 consecutive anatomic segmentectomies (114 Open, 67 VATS) were performed for Stage IA (n=110) or IB (n=71) NSCLC from 2002–2006. A VATS approach was employed in 67 patients, and an open approach in 114 patients. Outcome variables include hospital course, complications, mortality, recurrence patterns and survival. Results: The mean age was 70 years (range: 45–100). Average tumor size was 2.3 cm (2.0 cm VATS; 2.4 cm open, NS). Lymph node sampling or dissection was performed in 169 (93%) of patients with an average node harvest of 8.2 nodes (Open = 9.2; VATS = 6.2, p=0.006). There were two perioperative deaths (1.1%), both open. Complications occurred in 59 patients (33%). Median length of stay was 6 days (VATS=5, Open=7). Mean follow-up was 15.6 months. There were fewer major (7 vs. 31, p=0.005) and infectious (3 vs. 12%, p=0.026) complications in the VATS group, with no significant difference in pulmonary complications or air leaks. Twenty-nine recurrences (16%; VATS=7, Open=22) occurred at a mean of 12.7 months [11 locoregional (6%), 18 distant (10%)]. Overall mortality, complications, recurrence and two-year actuarial survival (78%) were similar between VATS and open segmentectomy. Conclusions: VATS segmentectomy can be performed safely with acceptable morbidity, mortality, recurrence and survival. The VATS approach affords a shorter length of stay and fewer postoperative complications (major and infectious) compared with open techniques. The potential benefits of segmentectomy will need to be further validated by prospective, randomized trials (ACOSOG Z4032). Sublobar resection techniques represent an important adjunct in treating compromised patients with early stage NSCLC.

No significant financial relationships to disclose.
Elevated levels of thioredoxin (Trx) in serum correlate with poor outcome in docetaxel (doc)/cisplatin (cis)-treated stage IV non-small cell lung cancer (NSCLC) patients (p)
Authors: Molina M. , Camps C. , de las Peñas R. , Alonso G. , Lopez-Vivanco G. , Provencio M. , Gonzalez-Larriba J. , Salazar F. , Sanchez J. , Rosell R.
Published: March 2020

7628

Background: Chemotherapy causes the production of reactive oxygen species (ROS), which facilitates cancer cell death. Trx protein functions as a ROS scavenger and a negative regulator of apoptosis signal regulating kinase-1 (ASK-1). High levels of Trx are associated with chemoresistance. 14–3-3s proteins are involved in cell cycle control and protein trafficking. Methods: Trx ELISA and 14- 3–3s methylation-specific PCR were performed in baseline serum from 107 stage IV NSCLC p treated with doc/cis. Results: Median age, 60 (range, 32–79); male, 87 (81.3%). PS: 0, 27 (25.2%); 1, 80 (74.8%). Adenocarcinoma, 46 (43.8%); squamous cell carcinoma, 40 (38.1%); 21 p had large cell or unspecified histology. Complete response, 1 p; partial response, 20 p; overall response rate, 20%. Median Trx level, 97.4 (range, 18.8–763.1). Serum was available for 14–3-3s methylation analysis in only 88 p. 14–3-3s was methylated in 43 p (48.9%). A significant correlation was observed between 14–3-3s methylation status and Trx levels ( Table ). 4 p with methylated and 17 with unmethylated 14–3-3s had Trx levels >182.8 (P=0.003). Median Trx levels were 103.5 in responders and 94.3 in non-responders (P=0.96). Time to progression (TTP) was 5.6 months (m) for 27 p with Trx <49.6, 4.4 m for 53 p with Trx 49.6–182.8, and 3.8 m for 27 p with Trx >182.8 (P=0.02). In a Cox multivariate analysis, Trx levels emerged as an independent variable for TTP when 14–3-3s was included in the model. Hazard ratios: 1.3 for PS1 (P=0.84); 1.05 for 14–3-3s unmethylated (P=0.22); 1.4 for Trx 49.6–182.8 and 1.95 for Trx >182.8 (P=0.04). Conclusions: Serum Trx levels can predict TTP in doc/cis-treated p. The additional role of 14–3-3s methylation may be more clearly demonstrated in cis/gemcitabine regimens.

No significant financial relationships to disclose.

[Table: see text]
Decline in serum soluble E-cadherin and low baseline matrix metalloproteinase-9 are associated with response to combination celecoxib and erlotinib therapy in advanced non-small cell lung cancer
Authors: Reckamp K. L. , Gardner B. K. , Figlin R. A. , Elashoff D. , Krysan K. , Dohadwala M. , Inge L. , Rajasekaran A. , Dubinett S. M.
Published: March 2020

7640

Background: Cyclooxygenase-2 (COX-2) overexpression may mediate resistance to EGFR TK inhibition through prostaglandin E2 (PGE2)-dependent promotion of epithelial to mesenchymal transition (EMT). Thomson, et al. reported that the suppression of epithelial markers such as E-cadherin led to resistance to erlotinib (Cancer Res 2005;65:9455). In addition, PGE2 downregulates E-cadherin expression by upregulating transcriptional repressors including ZEB1 and Snail, as described by Dohadwala et al (Cancer Res 2006;66:5338). These findings suggest that COX-2 inhibition may enhance the efficacy of EGFR TKI therapy in NSCLC. Methods: A phase I, dose escalation trial to was performed investigating the combination of celecoxib and erlotinib in pts with advanced NSCLC. Soluble E-cadherin (sEC) was evaluated by ELISA in pt serum at baseline and weeks 4 and 8 of treatment. Other markers of COX-2 gene expression were evaluated by ELISA, including matrix metalloproteinase (MMP)-9, MMP-2 and tissue inhibitor of MMP (TIMP1). Results: 22 pts were enrolled and 21 were evaluable for the determination of the optimal dose, toxicity assessment and response (reported in Clin Cancer Res 2006;12:3381). Here we report serum sEC and MMP-9 levels, which were analyzed according to best response (PR, SD or PD) in 21 pts. SEC was analyzed according to best response (PR, SD or PD). We found a significant decrease in sEC between baseline and week 8 in pts with PR when compared to those with SD or PD (p = 0.021). In pts who responded to the combination therapy, baseline MMP-9 was significantly lower compared to non-responders (p = 0.006). Conclusions: SEC, MMP-9 and other downstream markers of COX-2 gene expression may be useful for assessing response to combination celecoxib and erlotinib in pts with advanced NSCLC. A randomized Phase II trial is planned comparing erlotinib and celecoxib with erlotinib plus placebo in advanced NSCLC, to evaluate the efficacy of this combination therapy and to assess these and other biomarkers in both serum and tumor tissue. Supported by ASCO Young Investigator Award, UCLA Lung Cancer SPORE NCI P50 CA 90388 and GLAVAHS Career Development Award.

No significant financial relationships to disclose.
Clinical prognostic factors in advanced non-small cell lung cancer (NSCLC): Cox regression analysis based on 789 patients treated in three consecutive randomized trials
Authors: Pilz L. R. , Thatcher N. , Kortsik C. , Koschel G. , Mezger J. , Schott von Römer K. , Manegold C.
Published: March 2020

7648

Background: Treatment efficacy and toxicity of the three studies have been presented at ASCO (2006, Abstract # 7035). Patients (pts) received gemcitabine or docetaxel either as single agents in different schedules and doses or as a platinum free doublet. Our retrospective analysis is to identify the clinical factors which would influence patient prognosis. Methods: Patients eligibility criteria included histologically confirmed stage IIIB or IV, performance status (PS) 0–2, and no prior chemotherapy. Overall survival (OS) was similar in all three studies. 819 pts were enrolled in 1998–2004 and 798 pts of them were evaluable for this analysis: 85% of pts had stage IV disease and PS=1. Univariate and multivariate (stepwise) Cox regression analyses were performed to evaluate the impact of baseline characteristics and quality of life (QoL) on OS. Results: Factors which have a significant impact on OS are the laboratory parameters hemoglobin (HGB) and LDH (p<0.0001), WHO performance status (PS) (p=0.001) and the quality of life measure for lung cancer of the EORTC, LC13, (p=0.0006), respectively (see table ). Gender measured univariately also influences significantly OS (p=0.0085) but has less impact in the multivariate model (p=0.07). Age (<65 vs 65 and older) is not of prognostic value with OS (HR=0.92, p=0.39), as well as histology (adeno/sqamous/other) (HR=0.99, p=0.90). Other factors as tumor stage (wet IIIB vs IV), presence of extra-thoracic metastases, number of co-morbidities, and surgical and radiological pretreatment also have no prognostic influence on OS. Analysis for the effect of smoking on OS could not be performed since only few pts never smoked. Conclusions: Our retrospective analysis confirms the prognostic value of serum HGB, and LDH, WHO-PS, and QoL LC13 as clinical determinants for OS.

[Table: see text] [Table: see text]
Vandetanib with pemetrexed in patients with previously treated non-small cell lung cancer (NSCLC): An open-label, multicenter phase I study
Authors: De Boer R. , Vansteenkiste J. , Humblet Y. , Wolf J. , Nogova L. , Ruffert K. , Smith R. , Godwood A. , Milenkova T.
Published: March 2020

7654

Background: Vandetanib (ZD6474) is a once-daily oral anticancer drug that selectively inhibits VEGF-dependent tumor angiogenesis and EGFR- and RET-dependent tumor cell proliferation and survival. Methods: Eligible patients had locally advanced or metastatic NSCLC (stage IIIB/IV) after failure of 1st-line chemotherapy. An initial cohort of 10 patients received once- daily oral vandetanib (100 mg) with pemetrexed (500 mg/m2 i.v. infusion every 21 days). If <2 patients experienced a vandetanib- related dose-limiting toxicity (DLT), an additional cohort received vandetanib 300 mg + pemetrexed. The planned duration of treatment was =6 weeks. The primary objective of the study was to establish the safety and tolerability of vandetanib + pemetrexed. Secondary objectives included an assessment of pharmacokinetic (PK) interaction and preliminary assessment of efficacy (RECIST). Results: Twenty- one patients (14 male, 7 female; mean age 60 years, range 44–77) received vandetanib 100 mg + pemetrexed (n=10) or vandetanib 300 mg + pemetrexed (n=11). One DLT was reported in each cohort: QTc prolongation (>100 ms from baseline, but absolute QTc <500 ms) in a male patient who had electrolyte imbalance and short baseline QTc interval of 318 ms (100 mg cohort); and interstitial lung disease, which resolved after steroid therapy, in a Caucasian female patient with bronchoalveolar carcinoma and a long smoking history (300 mg cohort). The most common adverse events (AEs) were rash, anorexia, fatigue and diarrhea (all n=10; 48%). The most frequent CTC grade 3/4 AEs were increased gamma-glutamyltransferase (n=4), anorexia (n=3) and dyspnea (n=3), which are generally consistent with previous experience with vandetanib and pemetrexed as monotherapies. There was no apparent PK interaction between vandetanib and pemetrexed. In 18 patients evaluable for efficacy, there was one confirmed partial response (female; 100 mg cohort) and 13 stable disease =6 weeks. Conclusions: In patients with advanced NSCLC, vandetanib + pemetrexed was generally well tolerated, with no apparent PK interaction. A Phase III trial of vandetanib 100 mg + pemetrexed in 2nd-line NSCLC has begun.

No significant financial relationships to disclose.
Expression of protein kinase C beta (PKCß) as a prognostic marker in non-small cell lung cancer (NSCLC) and mesothelioma
Authors: Faoro L. , Loganathan S. , Husain A. , Westerhoff M. , Janamanchi V. , Vokes E. , Salgia R.
Published: March 2020

7656

Background: The protein kinase C (PKC) family of serine-threonine protein kinases has been shown to be involved in tumor cell growth, survival, and progression. Tumor-induced angiogenesis requires activation of PKCs, particularly PKCβ, through vascular endothelial growth factor (VEGF) pathways. PKCβ-2 appears to be a major down-stream signaling protein for the VEGFR. This makes PKCβ an attractive target in treatment of malignancies, including lung cancer. Methods: 135 tumor samples (111 Non-small cell lung cancer tissues (52 adenocarcinomas (AC), 34 large cell (LC), 25 squamous cell carcinoma (SCC)) and 24 mesotheliomas (MT)) arranged in tumor microarrays (TMAs) were subject to immunohistochemical staining of PKCβ-1 and PKCβ-2. Results were analyzed manually and scored for intensity (1+, 2+, 3+). Clinical information was available for the AC, LC, and SCC group. Survival curves were generated and median survival between groups was compared utilizing the Log-rank methodology. Results: In NSCLC the expression of PKCβ1 was negative in 1% (1/107), 1+ in 14% (15/107), 2+ in 43% (46/107), 3+ in 42% (45/107); PKCβ2 immunostaining was negative in 28.4% (29/102), 1+ in 12.7% (13/102), 3+ in 23.6% (24/102) and 3+ in 35.3% (36/102). Median survival was superior for patients who expressed PKCβ1 (2+ or 3+) as compared to non-expressors (median survival 1258 days versus 124 days, p<0.001). There was no difference in median survival in patients whose tumors expressed PKCβ2 and those that did not express it. In mesothelioma, staining for PKCβ1 was negative in 0, 1+ in 0, 2+ in 8.3% (2/24) and 3+ in 91.7% (22/24). For PKCβ2, tissues stained negative in 56.5% (13/23), 1+ in 21.8% (5/23), 2+ in 8.7% (2/23), 3+ in 13% (3/23). Median survival was superior for patients whose tumors did not express PKC-beta 2 (0 or 1+) as compared to expressors (median survival 604 days versus 103 days, p<0.001). Conclusions: PKCβ is expressed in NSCLC and mesothelioma. PKCβ1 expression is a favorable prognostic factor in NSCLC, whereas expression of PKCβ2 is an adverse prognostic factor in mesothelioma. Therapeutic targeting of this molecule would be useful for the future.

No significant financial relationships to disclose.
Study of three weekly nab-paclitaxel regimens in combination with carboplatin as first-line therapy in advanced non-small cell lung cancer (NSCLC)
Authors: Hawkins M. J. , Manikhas G. , Makhson A. , Cheporov S. , Orlov S. , Yablonsky P. , Bhar P. , Socinski M.
Published: March 2020

7659

Background: We previously reported that 130-nM albumin-bound form of paclitaxel (ABI-007, nab paclitaxel) 225 - 340 mg/m2 and carboplatin AUC of 6 mg/min·ml (C6), both administered on day (d) 1 every 3 weeks (q3w), produced an objective (PR/CR) response rate (ORR) of 27% in first line patients (pts) with NSCLC with median progression-free (PFS) and overall survivals of 6.0 and >10.3 months respectively [Hawkins et al., ASCO, 2006]. Grade 2 and 3 sensory neuropathy (SN) was 36–56%. The aim of the current study was to obtain clinical experience with weekly schedules of nab- paclitaxel in combination with C6 in NSCLC prior to initiating large scale clinical trials. Methods: 75 Pts with previously untreated, stage IIIB or IV NSCLC with measurable disease and a life expectancy of over 12 weeks were recruited into 3 cohorts (n = 25 each) of successive pts and received nab paclitaxel weekly using 3 different regimens (see table ). Results: Patient Characteristics: 75 pts (100% Caucasian; 84% male; median age, 60; performance status score: 0 [16%], 1 [84%]. Accrual was completed in each cohort and serious adverse events reviewed prior to accrual at the next dose level. The primary efficacy endpoints are provided in the table . Grade 3/4 hematologic toxicities were: neutropenia 32%/35%; thrombocytopenia, 19%/11%; anemia, 24%/3%. The most common non- hematologic toxicities (any grade) were fatigue, 48%; SN, 48%; nausea, 37%; alopecia, 40%; and vomiting, 26%. Grade 2 and 3 SN was 12–28%. Graded toxicity data by regimen will be presented. Conclusions: When combined with C6, the ORR was higher and there was less peripheral neuropathy for weekly nab-paclitaxel compared to our previous experience using q3w administration.

[Table: see text] [Table: see text]