bluuebunny/crossref_metadata_2025 huggingface dataset:
Class III beta tubulin expression and benefit from adjuvant cisplatin/vinorelbine chemotherapy in operable non-small cell lung cancer: Analysis of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) study JBR.10
Authors: Reiman T. , Lai R. , Ding K. , Winton T. , Butts C. , Mackey J. , Dabbagh L. , Seymour L. , Tsao M. , Shepherd F. , Seve P.
Published: March 2020

7051

Background: Biomarkers may be useful to select patients who will benefit from a particular chemotherapy regimen. High class III beta tubulin (bTubIII) expression in advanced NSCLC is known to correlate with reduced response rates and inferior survival with the anti-microtubule agents vinorelbine or paclitaxel. JBR.10 demonstrated a 12% and 15% improvement in 5-year recurrence-free (RFS) and overall survival (OS) respectively with the addition of cisplatin and vinorelbine following resection of stage IB-II NSCLC. We sought to determine the impact of bTubIII on patient outcome and benefit from adjuvant chemotherapy in the JBR.10 trial. Methods: We performed an immunohistochemical assay for bTubIII on primary tumor tissue available from 265 of the 482 patients in JBR.10. A validated, numerical bTubIII score was assigned by two observers based on the intensity and frequency of tumour cell staining. Tumours were classified as bTubIII “low” or “high” based on the median score. We examined the prognostic impact of bTubIII in patients treated with or without chemotherapy, and the survival benefit from chemotherapy in low versus high bTubIII subgroups. Results: High bTubIII expression was associated with poorer RFS (HR = 1.9, p = 0.01) in patients treated with surgery alone, but not in patients treated with adjuvant chemotherapy (HR = 1.1, p = .75). In the low bTubIII subgroup, the improvement in RFS with chemotherapy was non-significant (HR = 0.78, p = 0.4), while the improvement in RFS with chemotherapy was significant in the high bTubIII subgroup (HR = 0.45, p = 0.002). With Cox regression, the interaction between bTubIII status and chemotherapy treatment in predicting RFS did not reach statistical significance (p = 0.15). Results for OS were similar. Conclusions: Chemotherapy appeared to overcome the negative prognostic impact of high bTubIII expression. Greater benefit from adjuvant chemotherapy was seen in patients with high bTubIII expression. This is contrary to what has been seen in the setting of advanced disease; possible reasons for this difference are being explored.

No significant financial relationships to disclose.
A prospective randomized phase III, double-blind, placebo-controlled study of thalidomide in extended-disease (ED) SCLC patients after response to chemotherapy (CT): An intergroup study FNCLCC Cleo04 - IFCT 00–01
Authors: Pujol J. L. , Breton J. L. , Gervais R. , Tanguy M. , Quoix E. , David P. , Janicot H. , Depierre A. , Gameroff S. , Maraninchi D.
Published: March 2020

7057

Background: This study aimed at determining whether or not thalidomide prolongs survival of patients (pts) suffering from SCLC. Methods: Eligibility consisted of previously untreated ED-SCLC, age <70 years, PS ≤2, weight loss <10% and, for women, post-menopausal status. Pts were registered in the study and received two courses of PCDE given 4 weeks apart with G-CSF primary prophylaxis recommended. Afterwards, pts who experienced a response were randomized to receive four additional cycles of PCDE plus thalidomide, (400 mg daily) or placebo. The planned accrual was 200 randomised pts in order to detect a 20% survival improvement. Results: The study was shortened with final analysis performed taking into account 119 registered pts (low accrual). There were 4 toxic-deaths (3.3%). Tumour assessment performed after the first two CT courses demonstrated 11 complete responders and 86 partial responders (81.4% overall response rate). Among these pts, 92 were randomly assigned, 49 in the thalidomide group and 43 in placebo group. The 5 remaining pts were not randomised due to poor recovery from previous CT. Pre-study pts’ characteristics did not differ between the two groups. The planned six cycles of PCDE were delivered to an equal proportion of pts in both groups (75.5% versus 74.4%). Mean ± SD exposure duration to thalidomide was 4.5 months ± 2.7 and to placebo 5.1 ± 2.4 (NS). Reasons for withdrawal differed between the two groups with toxicity as main reason for thalidomide (55.3% versus 35%) and disease progression as main reason for placebo (43% versus 62%; p = 0.06). In Cox model of overall survival within the 9 months following randomisation, pts allocated to the thalidomide group had the longest survival (HR of death for pts in the thalidomide group: 0.48 [95% CI: 0.24–0.93]; p = 0.03; median survival from randomisation: 11.7 versus 8.7 months for thalidomide and placebo groups respectively); Conclusion: Thalidomide prolongs survival of pts with SCLC after response to CT. This study is a clue in favour of angiogenesis process as therapeutic window in SCLC therapy. Supported by the French League against Cancer.

No significant financial relationships to disclose.
Randomized phase III study of carboplatin and paclitaxel versus vincristine, doxorubicin and cyclophosphamide chemotherapy in intermediate and poor prognosis small cell lung cancer: Preliminary results
Authors: Baka S. , Mullamitha S. , Ashcroft L. , Nagel S. , Board R. , Lorigan P.
Published: March 2020

7059

Background: The combination of paclitaxel and carboplatin has been found to be effective in lung cancer and well tolerated. Method: This is a phase III randomized trial of paclitaxel and carboplatin (PC) versus vincristine, doxorubicin and cyclophosphamide (CAV) chemotherapy in limited or extensive stage disease patients but with a prognostic score in the intermediate or poor prognosis range.The aim of the study is to determine the one year survival rate, the objective response rate and toxicity. Patients were randomized to: four cycles of PC (paclitaxel 200mg/m2 by IV 3 hour infusion), followed by carboplatin (AUC of 6) by IV injection, 3-weekly or four cycles of CAV (cyclophosphamide 750mg/ m2, doxorubicin 40mg/ m2, vincristine 1.3mg/ m2 by IV injection) every 3-weeks. Thoracic radiotherapy was considered for appropriate patients. Results: 219 patients (110 for CAV and 109 for PC) patients were randomized. Pre-treatment characteristics were well balanced for stage, performance status, and age. There was significantly more grade 3/4 neutropenia in the CAV arm than the PC arm, 67% vs 38% (p < 0.005), whereas the PC arm, had more grade 3/4 thrombocytopenia (19% versus 8% p = 0.012). The PC arm had more grade 2 and 3 neuropathy. 56% grade 3 and 4 infections were observed on CAV arm and 35% on the PC arm (p < 0.005). Hospitalization required for severe neutropenia and infections was less with PC, compared to CAV (146 days for IV antibiotics compared to 308 days for CAV, p < 0.005). Response rates for CAV and PC were 59% and 61% respectively. One-year survival rates for the CAV arm was 6% and 13% for the PC arm. The intention to treat analysis concluded that there is statistical difference on the overall survival time in favor of PC (P = 0.014). Median survival was 94 days (CAV) and 154 (PC). Conclusions: CAV chemotherapy in SCLC patients is associated with higher risk of neutropenic sepsis than taxane based PC chemotherapy with no significant difference on the response rate. The overall survival was better for the PC arm. Final results will follow.

No significant financial relationships to disclose.
A randomized double-blind phase IIa dose-finding study of ZD6474 in Japanese patients with NSCLC
Authors: Nakagawa K. , Kiura K. , Shinkai T. , Eguchi K. , Ohe Y. , Yamamoto N. , Tsuboi M. , Yokota S. , Fukuoka M. , Jiang H.
Published: March 2020

7067

Background: ZD6474 is a once-daily oral therapy that selectively inhibits key signaling pathways in cancer by targeting vascular endothelial growth factor receptor (VEGFR)-dependent tumor angiogenesis, and epidermal growth factor receptor (EGFR)- and RET-dependent cancer cell proliferation and survival. ZD6474 was evaluated as monotherapy in an ongoing randomized, double-blind, parallel-group, Phase IIa, dose-finding, multicenter study in Japan. Methods: Patients with locally advanced or metastatic (stage IIIB/IV) or recurrent non-small-cell lung cancer (NSCLC), after failure of one or two platinum-based chemotherapy regimens, were eligible for this study. Patients were randomized to receive ZD6474 100, 200 or 300 mg/day in a 1:1:1 ratio, with stratification according to sex, histology (adenocarcinoma vs other histology) and smoking status (smoker vs non-smoker). Tumor response was assessed every 4 weeks for the first 24 weeks of treatment and then every 8 weeks until progressive disease (PD) or withdrawal due to any reasons other than PD. The primary objective was the objective response rate, as evaluated by RECIST. Secondary objectives included disease control rate, tolerability and safety. Adverse events (AEs) were assessed using CTC version 3.0. Results: A total of 53 patients (34 males/19 females, median age 60 years [range 30–78], 35 adenocarcinomas and 33 smokers) with a WHO PS status of 0 (n = 20) or 1 (n = 33) were recruited from eight centers between December 2004 and September 2005. Among 53 patients, 6 partial responses (PR; 11%, 2 males/4 females, 6 adenocarcinomas, 2 smokers/4 non-smokers) have been confirmed and disease control (PR or stable disease≥ 8 weeks) has been observed in 27 patients (51%). The most common AEs were rash and diarrhea, and asymptomatic QTc prolongation was also observed. One patient died due to drug-related interstitial lung disease. Conclusions: In this ongoing trial, ZD6474 has demonstrated antitumor activity as monotherapy in patients with refractory NSCLC, with 11% experiencing a PR and 51% having disease control. The tolerability profile of ZD6474 was consistent with that seen previously.

[Table: see text]
Molecular analysis of NSCLC patients with acquired resistance to gefitinib or erlotinib
Authors: Pao W. , Balak M. N. , Riely G. J. , Li A. R. , Zakowski M. F. , Ladanyi M. , Miller V. A.
Published: March 2020

7078

Background: We previously reported that in 2 of 5 non-small cell lung cancer (NSCLC) patients with acquired resistance to the tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, tumors biopsied after disease progression contained a second site mutation (T790M) in the epidermal growth factor receptor (EGFR) kinase domain, in addition to a primary drug-sensitive mutation (exon 19 deletion (del) or exon 21 point mutation (L858R)) (Pao et al, PLoS Med ‘05). No patients had KRAS mutations, which are associated with primary resistance to these TKIs. We sought to determine the frequency of second site EGFR kinase domain and KRAS mutations in tumors from patients with acquired resistance to TKIs, administered either as monotherapy or with chemotherapy. Methods: 18 patients with NSCLC who responded to either TKI alone (n = 14) or TKI plus chemotherapy (n = 4) and then progressed were re-biopsied. Genomic DNA samples from tumors were examined for EGFR (exons 18–24) and KRAS (exon 2) mutations. Results: Sequence analysis was successfully performed on tumors from 17 patients. The T790M EGFR mutation was detected in 6 of 13 (46%, 95% CI 19–75%) on TKI monotherapy, and in 0 of 4 (0%, 95% CI 0–53%) on TKI plus chemotherapy. In one autopsy case, the T790M mutation was detected in 5 of 5 sites, which all harbored the same exon 19 del. No other EGFR or KRAS mutations were detected. Conclusions: Secondary EGFR T790M but not KRAS mutations are commonly associated with acquired resistance to TKI monotherapy. More patients are being studied, and we are trying to elucidate determinants of acquired resistance in the absence of T790M mutations. New therapies are needed to treat and/or suppress the development of acquired resistance to gefitinib or erlotinib. Support: Joan’s Legacy, DDCF, K08-CA097980, R21-CA115051.

[Table: see text]
Two-drug gemcitabine-based first-line treatment of elderly patients (pts) with small cell lung cancer (SCLC): The G-STEP program
Authors: Di Maio M. , Gallo C. , Barbera S. , Ceribelli A. , Gamucci T. , Isa L. , Piazza E. , Borsellino N. , Zagonel V. , Gridelli C.
Published: March 2020

7089

Background: Trials testing chemotherapy for elderly pts with SCLC are scanty. Gemcitabine (Gem) is active and well tolerated. The G-STEP program looked for optimal 2-drug combination of G with either vinorelbine (Vin), etoposide (Eto), cisplatin (Cis), or carboplatin (Car). Methods: Extended stage SCLC pts, aged >70 years, PS 0–2, were eligible. Dose of G was 1,000 mg/m2, dd 1&8, every 3 weeks in all the four combinations. As safety data in the elderly were already available for Gem+Vin (Vin dose 25 mg/m2, dd 1&8), a two-stage minimax flexible design was applied with response as end-point: ≥13 responses/30 pts required at 1st stage, with p0=0.40, p1=0.60, α and β=0.10. For Gem+Car, Gem+Cis, Gem+Eto a phase 1–2 Bayesian design to select optimal dose was applied (Thall & Russell, Biometrics, 1998), with 3 possible outcomes for each patient: “active” (response and no unacceptable toxicity [UT]), “inactive” (no response, no UT), or “toxic” (UT independently of response). A response rate [RR] ≥60% and a rate of UT ≤25% were acceptable. Dose levels to explore were: Car: AUC 3.5 / 4 / 4.5, d1; Cis: 50 / 60 / 70 mg/m2, d1; Eto: 60 / 70 / 80 mg/m2, dd 1,2,3. Results: From May 2000 to September 2005, 78 eligible pts were enrolled; median age was 74 years (42% of pts older than 75yrs). In the whole group, median progression-free survival and overall survival were 20.3 weeks (95% CI 17.6 - 24.1) and 33.7 weeks (95% CI 23.7 - 41.6), respectively. Study of Gem+Vin was closed for inactivity after 1st stage with 11 responses / 30 pts (RR 36.7%, 95% exact CI: 19.9–56.1). Gem+Eto arm was closed after 10 pts (5 inactive and 5 toxic) because too high probability (0.994) of inactivity. Gem+Cis arm was closed after 12 pts (2 active, 5 inactive, 5 toxic) because too high probability (0.988) of inactivity. With Gem+Car (December 2005: 2 pts ongoing, 24 analysed: 12 active, 6, inactive and 6 toxic), RR in the 20 pts receiving Car at AUC 3.5 was 60% (95% exact CI: 36.1–80.9). Conclusions: The combination of gemcitabine and carboplatin seems promising for future trials in elderly patients with extended SCLC. The G-STEP program was supported by GIOGER.

No significant financial relationships to disclose.
Compliance with oral topotecan in patients with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC)
Authors: Eckardt J. R. , Ramlau R. , Gervais R. , Shepherd F. , O’Brien M. , Ciuleanu T. , Dharan B. , Wissel P. , Ross G.
Published: March 2020

7092

Background: Compliance with chemotherapy can affect treatment efficacy and patient safety. Selecting an oral chemotherapy regimen with good tolerability in appropriate patients is important. To determine general level of compliance of oral topotecan, a retrospective analysis was conducted on 3 international open-label, multicenter, 2-arm randomized, phase III studies of patients with NSCLC and SCLC. Methods: Patients were randomized to receive oral topotecan d1–5 q21d as follows: Study 387 (Ramlau et al, Proc ASCO, 2005) 2.3 mg/m2/d second-line vs IV docetaxel for NSCLC; Study 389 (Eckardt et al, Proc ASCO, 2005) 1.7 mg/m2/d first-line with cisplatin vs etoposide/cisplatin for extensive-disease SCLC; and Study 478 (O’Brien et al, Lung Cancer 2005) 2.3 mg/m2/d second-line vs best supportive care for SCLC. Oral topotecan was administered to the patient in the clinic on day 1 of each course and the patient was responsible for self-administering the oral capsules the remaining 4 days of dosing. Patient compliance was defined as 100x(sum of number of caps taken across courses)/(sum of number of caps dispensed across courses), where number of caps taken = number of caps dispensed-number of caps returned. Results: Accrual per arm was (387), 414 patients; (389) 389; (478) 71. In the treated population for all three groups, adherence to oral topotecan was high, with >90% of patients recording at least 90% overall compliance (Table). Mean age (% ≥65 years/%PS 2) was (387) 58.8 years (29.2%/14%), (389) 59.7 (32.6%/13%), and (478) 59.8 (33.8%/27%). Median oral topotecan dose intensity (% target) for each course was (387) 87%, (389) 95%, and (478) 98%. The most common reason for dose reductions or delays was hematological toxicity. Conclusions: Oral topotecan can be administered on an outpatient basis with a high degree of patient compliance in the treated population, which included those ≥65 years and those with poor PS.

[Table: see text]

[Table: see text]
A randomized phase II study of sequential carboplatin/paclitaxel (CP) and gefitinib (G) in chemotherapy-naïve patients with advanced non-small-cell lung cancer (NSCLC): Preliminary results
Authors: Nokihara H. , Ohe Y. , Kawaishi M. , Kato T. , Yamamoto N. , Sekine I. , Kunitoh H. , Saijo N. , Tamura T.
Published: March 2020

7096

Background: G has been shown to exhibit antitumor activity against NSCLC, however, the optimal timing of its administration remains unclear. We conducted a randomized phase II study of CP followed by G or G followed by CP in chemotherapy-naïve advanced NSCLC patients in order to select the candidate arm for a subsequent phase III study. Methods: Chemotherapy-naïve patients with histologically or cytologically confirmed NSCLC, stage IIIB or IV, aged between 20 to74 years, performance status 0–1, were randomized to either Arm A (carboplatin (AUC 6, day 1) plus paclitaxel (200 mg/m2, day 1) every 3 weeks for 4 courses followed by daily G (250 mg/day)) or Arm B (daily G until disease progression followed by CP every 3 weeks for 4 courses). The primary endpoint was overall survival, and the planned sample size for this randomized phase II study was 96 patients (Liu’s selection design for pilot studies on survival). Results: From June 2003 to October 2005, 97 patients were enrolled, and 96 of these patients were treated in this study. Forty-nine patients (males/females: 28/21, median age: 63 years, adeno/non-adeno: 43/6, stageIII/IV: 11/38, smoker/non-smoker: 27/22) were randomized to Arm A and 48 patients (males/females: 28/20, median age: 61 years, adeno/non-adeno: 42/6, stageIII/IV: 11/37, smoker/non-smoker: 28/20) to Arm B. The response rate to CP in Arm A was 32.7% (16/49), and that to G in Arm B was 29.8% (14/47). The median survival was not yet reached, and the 1-year survival rates were 64.5% and 70.5% in Arm A and arm B, respectively. As of January 2006, one patient had died of treatment-related perforative peritonitis and two patients had developed interstitial lung disease. Conclusions: G exhibits similar antitumor activity to CP in chemotherapy-naïve patients with advanced NSCLC. The preliminary survival analysis is proposed to be conducted in April 2006.

No significant financial relationships to disclose.
Phase I/II study of ABI-007 as first line chemotherapy in advanced non-small cell lung cancer (NSCLC)
Authors: Rizvi N. A. , Azzoli C. , Miller V. , Ng K. , Fiore J. , Chia G. , Brower M. , Heelan R. , Hawkins M. , Kris M.
Published: March 2020

7105

Background: ABI-007 is a 130-nm albumin-bound form of paclitaxel. This study was designed to determine (1) the MTD and DLTs of ABI-007 in patients with stage IV chemotherapy-naive NSCLC and (2) the efficacy and safety of ABI-007 at the MTD. Methods: Eligibility requirement included ECOG PS 0–1, adequate organ function and sensory neuropathy ≤ grade 1. No prior chemotherapy for metastatic disease was allowed. Prior EGFR TKI therapy was allowed. ABI-007 was administered on days 1, 8, and 15 every 28 days (IV over 30 min. without premedication). In the phase I portion, 3 dose levels were studied (100, 125 and 150 mg/m2) and in the phase 2 portion, 40 patients were treated at the MTD. Results: 50 patients received ABI-007; the median age was 70 yo and 76% of patients were ≥ 65 yo. No DLTs were observed at the 100 and 125 mg/m2 dose level. However at the 150 mg/m2 dose level 2/6 patients had a DLT (febrile neutropenia and sensory neuropathy, respectively) during cycle 1 such that the MTD was exceeded. The 125 mg/m2 dose level was identified as the MTD and expanded to 40 patients in the phase 2 portion of this study. Toxicity and efficacy data is presented for the phase 2 portion. Ten patients (25%) had received prior neoadjuvant or adjuvant chemotherapy and 5 (13%) had received prior gefitinib or erlotinib. Sensory neuropathy was the most frequent toxicity with grade 2 and 3 toxicity occurring in 8% and 15% of patients. Grade 2 and 3 fatigue was observed in 8% and 13% of patients. Grade 3 and 4 neutropenia occurred in 10% and 3% of patients with no febrile neutropenia observed. Response was assessed by RECIST. One CR and 14 PRs were observed for an overall response rate of 15/40 (38%). The median survival was 10.3 months. Conclusions: The MTD for ABI-007 administered over 30 min. on days 1, 8, and 15 every 28 days was 125 mg/m2. No hypersensitivity reactions were observed and no premedication was given. In the phase 2 portion, a 38% response rate and 10.3 month survival was observed. Non-hematologic toxicities were primarily sensory neuropathy and fatigue. Myelosuppression was minimal and no febrile neutropenia was observed. Further development of ABI-007 in NSCLC is warranted based on the encouraging single agent activity observed in this study.

[Table: see text]
Evolution of statistical methodology and design of phase II/III clinical trials in non-small cell lung cancer (NSCLC)
Authors: Bagai R. K. , Dowlati A.
Published: March 2020

7108

Background: A significant heterogeneity exists in the design and reporting of phase II and III therapeutic clinical trials in NSCLC. This has led to difficulty in interpretation of these trials leading to over- or underestimation of therapeutic efficacy. We set out to investigate the statistical methodology and design reporting of chemotherapeutic trials in NSCLC published in the Journal of Clinical Oncology (JCO) over 20 years. Methods: We identified all phase II and III NSCLC chemotherapy trials published in the JCO from January 1983 to August 2005. All manuscripts were reviewed to evaluate components of statistical design that were reported, including: sample size calculation, power, type I error, single or multiple drug trials, relative response sought in phase II trials and improvement in survival time or response rate sought in phase III trials. Results: One hundred forty eight trials were identified. 52% of studies were phase III and 48% were phase II. The majority (78%) were conducted in advanced stage NSCLC. Sample size calculations were reported for only 58% of phase III studies and 31% of phase II studies. Power was reported in 66% of phase III studies and 13% of phase II trials. Type I error was reported in 47% of phase III studies and 17% in phase II studies. 60% of phase III trials defined endpoints (percentage improvement in survival time, improvement in survival time in months or increase in response rate). 41% of phase II trails defined the target response rate, ranging from response rates of 15% to 70%. The frequency of adequate reporting of statistical design was shown to increase from 31% in 1990–1995 to 64% in 2000–2005 ( table ). Conclusions: Significant heterogeneity exists in trial design and reporting of phase II and III trials in NSCLC. This impacts the ability to adequately interpret these studies. More widespread application of statistical methods in planning and reporting of lung cancer clinical trials are necessary to increase reliability of data.

[Table: see text]

No significant financial relationships to disclose.
Efficacy and pharmacogenomic correlation of the combination of oxaliplatin and paclitaxel in first line advanced non-small cell lung cancer (NSCLC). Preliminary results of the Spanish Lung Cancer Group (SLCG) 0103 phase II trial
Authors: Garrido Lopez P. , Isla D. , Gil B. , López-Brea M. , Lianes P. , González Larriba J. , Medina B. , Sánchez Ronco M. , Taron M. , Rosell R.
Published: March 2020

7122

Background: Ox is an attractive platinum analogue that has not been fully explored in NSCLC. We tested the combination of ox/pac as first-line therapy in NSCLC. We also assessed single nucleotide polymorphisms (SNPs) in several DNA repair genes (XRCC1 Arg399Gln, XRCC3 Met241Thr, XPD Lys751Gln and XPD Asp312Asn) and correlated the results with outcome in these patients (p). Methods: 68 stage IIIB (pleural effusion) and IV NSCLC p received up to 6 cycles of p 200 mg/m2 on day 1 plus ox 130 mg/m2 on day 2 every 21 days. Response was assessed after the third and sixth cycles. SNPs were determined by TaqMan assay in peripheral blood extracted at baseline Results: p characteristics: median age 62; 82% male; performance status 0, 54.5%; adenocarcinoma 48%; CNS metastases (mets), 15%, liver mets, 17%. 259 cycles delivered. Grade (G) 3–4 toxicity profile: neutropenia 11%; febrile neutropenia 8%; neurosensory (G3) 5%; asthenia (G3) 8%; diarrhea (G3) 5%. Laryngodysesthesia was observed in 1 p. There were 2 deaths due to neutropenic fever. In 52 evaluable p, overall response rate was 48% (PR 46%, CR 2%, SD 6%, PD 21%). Median time to progression was 4.4 months (m) (95% CI, 2.9–5.9 m). Median survival was 7.9 m (95% CI, 5.5–10.3 m). Conclusions: The combination of ox/pac offers similar results to other platinum-based regimens with an acceptable different toxicity profile and without a significant increase in neurotoxicity. Final data on response, time to progression and survival according to SNPs will be presented.

No significant financial relationships to disclose.
Initial results of a phase II study of biweekly pemetrexed and gemcitabine in patients with advanced NSCLC
Authors: Dudek A. , Larson T. , McCleod M. , Schneider D. J. , Dowell J. E. , Ye Z. , Cunneen J. , Monberg M. , Tai F. , Obasaju C. K.
Published: March 2020

7128

Background: Pemetrexed (P), a multi-targeted antifolate, is synergisitic with gemcitabine (G) in preclinical models. A phase I study examining a biweekly schedule established a recommended phase 2 dose of G 1500 mg/m2 followed by P 500mg/m2. Methods: Patients with Stage IIIB (with pleural effusion) or IV NSCLC, ECOG PS of 0 or 1, no prior systemic chemotherapy, immunotherapy, or biological therapy were enrolled. G was infused over 30 minutes, followed immediately by P given intravenously over 10 minutes once on day 1 every 14 days. Cycles were repeated until 12 treatments or progressive disease. All patients received folic acid, vitamin B12 and steroid prophylaxis. Results: Data on 53 patients (29 male, 24 female) are currently available. Median age: 64 (range: 35, 80), ECOG performance status 0:1 = 38%:60%, Stage IIIB:IV = 19%:81%. Three hundred twelve cycles of treatment were administered with 14 dose reductions (26.4%); median number of doses was 5 for both G and P, and median dose intensity was 98.05% for both G and P. Response data included 1 complete response (1.9%), 14 partial responses (26.4%), 24 stable diseases (45.3%), and 10 progressive diseases (18.9%), with a response rate of 28.3% (95% CI: 16.8–42.3%). Patient-based Grade 3/4 hematologic events included febrile neutropenia (9.4%), neutropenia (28.3%), and thrombocytopenia (1.9%). Grade 3/4 non-hematologic events included fatigue (22.6%), dyspnea (7.5%), dehydration (7.5%), diarrhea (5.7%), constipation (3.8%), and pneumonia (1.9%). Preliminary median survival was 7.8 months (95% CI: 6.0–10.8) with 43.4% patients censored and median TTPD was 4.6 months (95% CI: 2.8–6.1). Conclusion: Biweekly G and P appear to be well tolerated in advanced NSCLC. A clinical benefit rate (ORR + SD) of 73.6% indicates activity in patients with advanced NSCLC. The dose intensity for biweekly G and P is higher than a previously reported 6-cycle, 21-day regimen with median dose intensity of 83.2% for P and 82.2% for G (West, et al. Proc ASCO 2005; 7117).

[Table: see text]
Impact of gemcitabine (G) on the activity of first-line chemotherapy in non-small cell lung cancer (NSCLC): A meta-analysis
Authors: Pappagallo G. L. , Belvedere O. , Vinante O. , Grossi F.
Published: March 2020

7138

Background: A two-drug platinum-based regimen in which cisplatin or carboplatin is combined with a third-generation agent (i.e. paclitaxel, vinorelbine, docetaxel, or G) is the standard first-line treatment for NSCLC patients with good performance status. Encouraging results have recently been reported for nonplatinum regimens composed of two third-generation drugs. Methods: To assess the impact of G on the activity of first-line chemotherapy in NSCLC, we carried out a meta-analysis on data from 4,362 NSCLC patients who were enrolled in 11 randomized trials comparing a G-containing vs. G-free new generation regimens. We constructed 2x2 tables using response to treatment data. For trials with more than one eligible G-free comparator arm, individual comparisons between the G-based treatment arms and each of the comparator arms were analyzed. A general variance-based method was used to estimate the pooled odds ratio (OR) and 95% confidence interval (CI). We assessed for heterogeneity among the trials based on standard methods. Results: Sixteen comparisons contributed to this analysis. G-containing regimens included: G+cisplatin (894), G+docetaxel (565), G+paclitaxel (200 patients), G+vinorelbine (157), G+carboplatin (49). G-free regimens included: vinorelbine+cisplatin (866), carboplatin+paclitaxel (539), docetaxel+cisplatin (494), cisplatin+paclitaxel (439), vinorelbine+carboplatin (159). Comparing G-containing vs. G-free regimens, the OR for progression was 0.867 (CI 95% 0.770–0.977; p = 0.019), with heterogeneity chi-square 11.639 (p = 0.71). No significant difference was observed for complete (OR 0.909, CI 95% 0.556–1.487; P = 0.707) and overall (complete + partial) response (OR 0.987, CI 95% 0.881–1.106; P = 0.819). Conclusions: These data demonstrate that the progression of disease is more likely in patients treated with G-free doublets. Further analyses are required to address whether disease control (objective response + stable disease) is associated with a survival benefit and may therefore be used as a surrogate end point for survival in chemotherapy trials of NSCLC.

No significant financial relationships to disclose.
A phase I study of talotrexin (PT-523) in patients with relapsed or refractory non-small cell lung cancer (NSCLC)
Authors: Rocha Lima C. S. , Orlov S. V. , Garst J. , Manikhas G. M. , Dowlati A. , Quesada J. A. , Andrews C. , Ramirez M. L. , Choy G. S. , Berk G.
Published: March 2020

7142

Background: Talotrexin is a nonpolyglutamatable antifolate which has demonstrated improved antitumor activity in a broad spectrum of cancer models by targeting DHFR to inhibit tumor growth. Talotrexin binds more tightly (15-fold, Ki 0.35 pM) to DHFR than methotrexate (MTX). In lung cancer cell lines, talotrexin inhibits tumor cell proliferation at sub- to low nanomolar concentrations and is more potent than MTX in all cell lines tested. We conducted a dose escalation study of talotrexin administered as a 5-minute infusion on Days 1, 8, on a 21-day cycle. The primary objectives of this study are to determine the maximum tolerated dose (MTD), pharmacokinetic (PK) profile, as well as the safety and efficacy. Methods: Patients with confirmed NSCLC stage III/IV or recurrent/refractory disease, failed two-lines of therapy ± an EGFR TK inhibitor, ECOG PS 0–2, were enrolled. The starting dose was based on a Phase I solid tumor trial. Three patients were treated at each dose level in the absence of a dose limiting toxicity (DLT). Intrapatient dose escalation was allowed. All patients received folic acid and vitamin B12. Safety assessments were performed by standard laboratory and clinical DLT definitions. Responses were assessed based on RECIST criteria. Plasma talotrexin concentrations were analyzed by a LC/MS/MS method. Concentration-time profiles of talotrexin were analyzed by noncompartmental methods using WinNonlin. Results: Eighteen heavily pre-treated patients were enrolled and received a total of 61 cycles (median 3.4, range 1–7) of talotrexin at 5 dose levels (27–270 mg/m2/cycle), Male/Female: 14/4. The tentative MTD is 90 mg/m2/dose, with mucositis being the predominate DLT. Two partial responses and 9 stable diseases were observed. Talotrexin exhibits linear PK profile across the 5 dose levels evaluated. PK data (16 patients), Cmax and AUC0-∞ exhibited linear PK. Overall mean values (± SD) were CL, 1.31 ± 0.31 L/hr/m2, T1/2z, 6.5 ± 1.4 h, Vss 8.9 ± 2.5 L/m2. Conclusions: Talotrexin demonstrated acceptable tolerability with encouraging activity in relapsed or refractory NSCLC patients over multiple cycles of therapy. Phase II studies in NSCLC are planned.

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A prospective phase II study of induction carboplatin and vinorelbine followed by concomitant topotecan and accelerated radiotherapy (RT) in locally advanced non-small cell lung cancer (NSCLC)
Authors: Patel S. H. , Ajlouni M. , Chapman R. , Lu M. , Kim J. , Movsas B.
Published: March 2020

7146

Background: The key limiting factor in combining chemotherapy with accelerated RT is excessive esophagitis. We investigated the toxicity, response rate, and overall survival (OS) with induction carboplatin and vinorelbine followed by concomitant topotecan and accelerated RT in patients (pts) with locally advanced/unresectable NSCLC. Methods: This was a phase II trial using a two stage study design with a planned sample size of forty pts. Stage IIIA or IIIB NSCLC pts with a KPS > 50 were eligible. Initially, pts received induction carboplatin (AUC 5.5) on days 1, 22 and vinorelbine 25 mg/m2 on days 1, 8, 22, and 29. During the concurrent chemoRT, pts received IV topotecan 0.5 mg/m2 on days 43–47, days 57–61, and days 71–75 prior to the morning RT fraction (fx). RT was given in an accelerated fashion at 2 Gy per fx, bid for 5 consecutive days, every other week to a cumulative dose of 60 Gy over a five week period. Results: Thirty-seven pts were accrued of which thirty-five were evaluable. Overall response rate was 71% (14% CR, 57% PR). Six of 35 (17%) pts had stable disease. Four (11%) pts progressed during treatment. At a median f/u of 17.4 months (3–74 mo), the median survival based on Kaplan-Meier estimates, was 18 months. OS at 1, 2, and 3 yrs was 62%, 41%, and 33%, respectively. Actuarial 5-yr OS was 21%. The median time to relapse was 12.2 months (9.1–24.7 mo). Acute RTOG grade 3 or 4 neutropenia, anemia, and thrombocytopenia were 77%, 49%, and 6%, respectively. There were no cases of grade 3 or 4 esophagitis; RTOG grade 3 or 4 pneumonitis occurred in two pts (6%). Conclusions: This combined modality regimen yielded encouraging OS rates with no grade 3/4 esophagitis. Using 4D RT treatment planning, we plan to further evaluate altered fractionation RT and chemotherapy for this group of pts.

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Female gender is an independent predictor of superior perioperative survival following non-small cell lung cancer (NSCLC) resection
Authors: Park B. J. , Rizk N. , Flores R. M. , Downey R. , Bains M. S. , Rusch V. W.
Published: March 2020

7150

Background: Selecting patients who will benefit from surgical resection of NSCLC, especially following induction therapy, can be challenging. We analyzed our modern experience to determine factors associated with superior operative outcomes. Methods: A retrospective review of a prospectively maintained database of consecutive NSCLC patients who underwent surgical exploration for resection from January 1999 through June 2005 was performed. Factors evaluated included age, sex, co-morbidities, use of induction therapy, previous thoracic operations, extent of lung resection, and in-hospital mortality. Associations between categorical variables were evaluated with a chi-squared test and for continuous variables with an analysis of variance. Multivariate analysis was done with a logistic regression model. Results: A total of 2,524 patients underwent attempt at surgical resection, 1,398 of whom were female (55.4%). One hundred and four (4.1%) patients had exploration only. The majority of patients underwent lobectomy (1,692/2,524, 67.1%), and 6.1% (154/2,524) had a pneumonectomy. Induction therapy was given in 492 patients (19.5%). Univariate analysis showed that male gender (2.4% vs 0.93%, respectively, p = 0.003), presence of cardiac co-morbidity (p = 0.05), poor diffusion capacity (p = 0.003), and greater extent of resection (p = 0.01) were associated with increased in-hospital mortality. Multivariate analysis controlling for gender, age, diffusion capacity, cardiac, and diabetic co-morbidity, as well as prior lung cancer operation, extent of resection and use of induction therapy demonstrated that increased age, decreased diffusion capacity and greater anatomic lung resection were risk factors for higher in-hospital mortality. However, female sex was an independent predictor of lower in-hospital mortality (OR 0.41, p = 0.01). Conclusions: In addition to other previously described predictors of poor surgical outcome, such as advanced age, poor lung function and greater extent of lung removal, we observed that female gender appears to be associated with better in-hospital survival following surgical resection of NSCLC.

No significant financial relationships to disclose.
Lung cancer in patients ≥ 80 years of age: Analysis of the national surveillance, epidemiology and end results (SEER) database
Authors: Owonikoko T. K. , Belani C. , Cai C. , Oton A. , Potter D. , Ramalingam S.
Published: March 2020

7156

Background: Lung cancer is a disease of the elderly with median age at diagnosis of 70 years. In spite of this, the very elderly (patients ≥ 80 years) group has not been well studied. We analyzed the national SEER database to evaluate outcome of the disease in this subgroup. Methods: All patients with primary lung cancer in the national SEER database from 1988–1997 were included, and grouped into those <80 yrs vs. those ≥80 yrs at the time of diagnosis. We compared the 2 groups for stage distribution, 3-yr & 5-yr survival, survival based on histology, sex, race, stage and treatment. The 5-yr relative survival rate, adjusted for the normal life expectancy, was utilized except for the 3-yr survival comparison. The SEER program, Stat 6.1.4, was used for analysis and all p-values were 2-sided. Results: Of the 129,003 cases of lung cancer registered over 10 years, 14,614 (11%) occurred in patients ≥80 yrs. Overall survival at 3 and 5yrs was inferior in the octogenarian group, {11.8% vs. 20% and 8.3% vs. 16.2%, respectively (p < 0.0001)}. The inferior survival was observed in both males and females {7.1% vs. 14.3% and 9.6% vs. 18.9%, respectively (p < 0.0001)} and with non-small cell histology {9.1% vs. 18.3% (p < 0.0001)}. Stage-specific analysis revealed the same trend {24.9% vs. 46.9% - stage I, 19.1% vs. 30.4% - stage II, 3.1% vs. 9.0% - stage III and 1.1% vs. 1.8% - stage IV (p < 0.0001 for all comparisons)}. Irrespective of race, elderly patients fared worse: 6.9% vs. 12.8% in blacks, 8.4% vs. 16.7% in white and 8.4% vs. 16.3% in other racial groups (p < 0.0001 for all comparisons). Although, therapy (surgery or radiation) benefited both groups, treated elderly group performed worse than younger group {4.9% vs. 8.1% (p < 0.0001) and 45% vs. 45.7% (p < 0.02) with radiation and surgery respectively}. However, only 58% of elderly patients received surgery or radiation therapy compared to 80% of patients <80 yrs. Conclusion: In general, very elderly patients with lung cancer have a worse clinical outcome than younger patients. This is irrespective of histology, stage of disease, sex, gender or race. The worse outcome in the elderly may be due to a larger proportion of them not receiving treatment.

No significant financial relationships to disclose.
Evaluation of publicly-sponsored lung cancer trials in US: Are experimental treatments better than the control ones?
Authors: Soares H. P. , Djulbegovic B. , Kumar A. , Tanvetyanon T. , Bepler G.
Published: March 2020

7157

Background: Lung cancer is one of the leading causes of cancer deaths in the US. A considerable number of these patients are treated in randomized clinical trials (RCTs). However, how often experimental lung treatments are superior to control treatments is not known. To accurately assess this, three factors have to be taken into consideration: publication rate, methodological quality of trials and the choice of the comparator intervention. Methods: All phase 3 RCTs that were completed to date by 3 National Cancer Institute cooperative groups (ECOG, NCCTG and RTOG) were eligible for the analysis. We identified 50 RCTs enrolling 11,631 lung cancer patients. The methodological quality of the trials was assessed for possible effects of bias and random error on the outcomes of the trials. The possible impact of the choice of a comparator intervention was also assessed. To evaluate the outcomes, we extracted data on survival (OS), disease free survival (DFS), response rate (RR) and treatment-related mortality (TRM). In addition, the final investigators’ preference about experimental or control interventions was used to assess whether experimental treatments were better than controls. Results: In terms of OS, DFS and RR experimental treatments were as likely as control treatments to be successful—Hazard ratio [HR]= 0.96 (99%CI 0.92–1.01)], [HR = 0.98 (99%CI 0.98–1.17)] and [RR = 1.11 (99%CI 0.84–1.46)], respectively. TRM was worse with experimental treatments [HR = 1.61 (99% CI 1.10–2.36)]. Investigators’ preferences for experimental vs. control treatments were 30% and 70%, respectively (p < 0.001). The quality of trials was high. We did not find any evidence that the methodological quality of trials/choice of comparator influenced the results. Conclusions: We found that there is no clear pattern that predicts which treatment will be better. In aggregate, there is about an equal chance for experimental and standard treatments to result in successful outcomes or that the outcomes may not differ between two types of the treatments, although TRM is slightly higher with experimental arms. This is a welcome finding because if one intervention (experimental or control) was consistently better, maintaining randomization will be difficult.

No significant financial relationships to disclose.
Clinical benefit of erlotinib in male smokers with squamous-cell NSCLC
Authors: Clark G. M. , Cameron T. , Das Gupta A.
Published: March 2020

7166

Background: Previous NSCLC trials have suggested female non-smokers with adenocarcinoma are most likely to benefit from treatment with EGFR inhibitors such as erlotinib. Thus, male smokers with squamous-cell carcinoma might be expected to fail treatment with erlotinib monotherapy. Methods: In a double-blind, placebo-controlled study of 731 patients with incurable stage IIIB/IV NSCLC who had failed 1 or 2 prior chemotherapy regimens, patients were randomized in a 2:1 ratio to receive either erlotinib 150 mg or placebo (Shepherd et al NEJM 2005; 353(2):123–132). For a subset of male patients with squamous-cell carcinoma and a history of smoking, median survival was estimated from Kaplan-Meier survival curves. The hazard ratio (HR) for death and corresponding 95% confidence interval (CI) were calculated from a univariate Cox model and statistical significance was described by a log-rank statistic. Results: In the ITT population the adjusted HR for death between the erlotinib and placebo arms was 0.73 (P < 0.001). Among male smokers with squamous-cell carcinoma, overall survival was significantly improved among patients receiving erlotinib (N = 100) compared with patients with similar attributes in the placebo arm (N = 57): HR = 0.66, 95% CI 0.47 to 0.92, P = 0.016. This difference resulted in median survival time of 5.5 months in the erlotinib arm compared with 3.4 months in the placebo arm. Conclusions: Although male smokers with squamous-cell carcinoma have not been considered ideal candidates for treatment with erlotinib, survival benefits were observed in this subset of patients.

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Targeted COX-2 and EGFR TK inhibition in advanced non-small cell lung cancer
Authors: Reckamp K. L. , Czernin J. , Weber W. A. , Dubinett S. M. , Figlin R. A.
Published: March 2020

7179

Background: Prostaglandin E2 (PGE2) activates Erk/MAPK signaling pathway in an epidermal growth factor receptor (EGFR) tyrosine kinase (TK)-resistant manner as a result of cyclooxygenase-2 (COX-2) overexpressed in lung cancer. Because 10% of patients respond to this class of drugs, evaluating agents that may overcome resistance and determining the population of patients most likely to respond is crucial. Imaging tumor metabolism by positron emission tomography with the glucose analog fluorodeoxyglucose (FDG-PET) is an innovative approach for assessing the efficacy of targeted agents. We studied the combination of COX-2 inhibition (celecoxib) and EGFR inhibition (erlotinib) in a phase I trial in advanced non-small cell lung cancer (NSCLC) and added FDG-PET imaging as a potential method for evaluation of early response. Methods: A phase I, dose escalation trial to investigate the optimal biologic dose (OBD) of the combination of celecoxib and erlotinib in pts with refractory stage IIIB/IV NSCLC. FDG-PET was evaluated in selected patients at baseline, week 2 and week 8 of study treatment. Tumor metabolic activity was quantitatively assessed by standardized uptake values (SUV). Changes in SUV were compared to CT imaging at week 8 with response defined by RECIST criteria. Results: Twenty-two subjects were enrolled and 21 were evaluable for the determination of the OBD, toxicity assessment and response. Rash and skin-related effects were the most commonly reported toxicities. Seven patients demonstrated partial responses and five patients developed stable disease. Responses were seen in patients both with and without EGFR activating mutations. The duration of partial response was 24–93 wks. TTP was 83 weeks in one patient with stable disease. A patient evaluated by FDG-PET had a significant decrease in SUV (-45%) at week 2 which corresponded to partial responses by RECIST at week 8. Conclusions: FDG-PET as a measure of tumor glucose utilization appears to be a promising tool for assessing early response to targeted therapies. A randomized Phase II trial is planned comparing erlotinib and celecoxib with erlotinib plus placebo in advanced NSCLC, and evaluating FDG-PET response as a marker of early efficacy. Supported by UCLA Lung Cancer SPORE NCI P50 CA 90388, GLAVAHS CDA and STOP Cancer Award.

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