bluuebunny/crossref_metadata_2025 huggingface dataset:
AT-101, a small molecule Bcl-2 antagonist, in treatment naïve CLL patients (pts) with high risk features; Preliminary results from an ongoing phase I trial
Authors: James D. F. , Castro J. E. , Loria O. , Prada C. E. , Aguillon R. A. , Kipps T. J.
Published: March 2020

6605

Background: CLL pts with early stage disease are often observed under a “watch and wait” approach. Unmutated immunoglobulin variable-region gene (IgVH); expression of zeta chain associated kinase (ZAP-70); CD38 expression; and cytogenetics abnormalities identify pts with a tendency for early disease progression. Whether pts with these high-risk features may benefit from early intervention warrants investigation in clinical trials. Gossypol, a naturally occurring compound in cotton seeds has been extensively studied in clinical trials and is well tolerated with a favorable safety profile. AT-101, a derivative of R-(-)-gossypol binds to Bcl-2 family proteins and induces apoptosis of CLL cells in vitro. Dysregulated expression of Bcl-2 proteins is critical for CLL leukemogenesis and is an attractive therapeutic target. Methods: We conducted a phase I study to evaluate the safety and tolerability of single agent AT-101 in treatment naïve CLL pts with high-risk features. Clinical activity, pharmacokinetics, and pharmacodynamics were assessed. Results: 7 pts were treated with AT-101 at doses of 20–40mg daily. Pt characteristics: median age 55, median Rai stage II, elevated ZAP-70 (57%), high CD38 (71%), unmutated IgVH (57%), trisomy 12 (43%), and loss of 17p (43%). AT-101 was well tolerated with no grade 4 toxicities, hospitalizations, deaths. Maximum toxicity in 6 evaluable pts was grade III transaminase elevation at week 7, with complete resolution following discontinuation of AT-101. Other most common adverse events, all Grade 1–2 include: elevated transaminases; nausea; fatigue; diarrhea; and hypokalemia. No hematologic toxicity was observed. 5/6 pts had decrease in lymphocyte count, 6/6 had reduction in lymphadenopathy, and 5/5 with palpable spleens had reduction in spleen size. Cmax for 30mg (n=3) and 40mg (n=2) dose of AT-101 was 570ng/ml and 660ng/ml at a Tmax of 4.3 and 4.4 hrs. Tmax correlated with in vivo apoptosis studies revealing maximum leukemic cell apoptosis occurring at 4hrs and poly(ADP-ribose) polymerase cleavage. Conclusions: AT-101 is safe and well tolerated, induces in vivo leukemia cell apoptosis, and may have clinical activity in previously untreated pts with CLL and high risk features.

No significant financial relationships to disclose.
The combination of oxaliplatin, fludarabine (FLU), cytarabine (Ara-c), and rituximab (R) (OFAR) in patients with Richter’s Transformation and FLU-refractory CLL
Authors: Wierda W. , Tsimberidou A. , O’Brien S. , Ferrajoli A. , Faderl S. , Ravandi F. , Cortes J. , Kantarjian H. , Plunkett W. , Keating M.
Published: March 2020

6608

Background: Patients with (FLU-ref) CLL and Richter’s transformation (RT) have a very poor prognosis. Oxaliplatin (OX), a platinum analog with a 1,2-diaminocyclohexamine carrier ligand, has a different activity and side effect profile from cisplatin. OX covalently binds DNA, inducing DNA intra- and inter-strand cross-links. FLU and Ara-c act synergistically to inhibit excision-repair of DNA cross-links, thereby providing the rationale for combining OX, FLU, Ara-c, and R (OFAR). Methods: The phase I portion of a phase I/II study of the OFAR regimen had increasing doses of OX. The OFAR regimen consists of OX 17.5, 20, or 25mg/m2, d1–4; fludarabine 30mg/m2, d2,3; Ara-c 1gm/m2, d2,3; and rituximab 375mg/m2, d3. Courses were given every 4 wks; patients received Neulasta 6mg each course and prophylaxis for tumor lysis, DNA virus’, and PCP. Results: 19 patients enrolled in phase I; 1 received no treatment, 8 had RT, and 10 had FLU-ref CLL. Patients received OX 17.5mg/m2 (3), 20mg/m2 (8), or 25mg/m2 (7). Patients receiving at least 1 course were evaluable for toxicity and could receive up to 6 courses. There were no dose-limiting toxicities, defined as any ≥ G3, non-hematologic, treatment-related toxicity. The major toxicity was hematologic and appeared OX-dose dependent. Neutropenia (G3–4) was experienced by 1/3, 6/8, and 7/7 patients treated at 17.5, 20, and 25mg/m2 OX levels, respectively. Thrombocytopenia (G3–4) was experienced by 2/3, 8/8, and 7/7 of patients treated at 17.5, 20, and 25mg/m2m OX levels, respectively. There were no treatment-related deaths. Five patients continue treatment on the phase I portion, and results will be evaluable, with 3 responders, including 2 complete, in the 7 evaluable patients with RT. Among the 10 FLU-ref patients, there are 5 PRs; treatment continues for 3 of them. Pharmacodynamic analyses demonstrate enhanced killing by OX in the presence of FLU and Ara-c. Conclusions: The OFAR regimen is safe and active for treating patients with RT and FLU-ref CLL. This trial continues to accrue patients to confirm efficacy.

No significant financial relationships to disclose.
Quality of life (QOL) companion to CALGB 9840: A phase III study of paclitaxel (P) via weekly 1 hour (hr) versus standard 3 hour infusion every 3 weeks with trastuzumab in the treatment of patients with/without HER-2/neu-overexpressing metastatic breast cancer
Authors: Naughton M. J. , Gu L. , Wang X. F. , Seidman A. D. , Winer E. , Kornblith A. B.
Published: March 2020

674

Background: This study determined if adding trastuzumab (Herceptin, T) to P modified the QOL of HER-2 non-overexpressors and examined QOL differences between patients treated with weekly versus standard P. Methods: Of the 585 patients treated in CALGB 9840, 394 provided QOL data. Eligibility criteria and main trial results were reported, indicating greater efficacy in weekly versus standard P, but no greater efficacy with T in HER-2 negatives (Seidman AD et al., Proc ASCO 2004, Vol. 22, No 14S, abstract 512). HER-2 non-overexpressors were randomized to 1 of 4 groups: 1) P 175 mg/m2 over 3 hrs every 3 wks; 2) P 80 mg/m2 over 1 hr weekly; 3) P 175 mg/m2 over 3 hrs every 3 wks + T 4 mg/kg load, then 2 mg/kg weekly; and 4) P l 80 mg/m2 over 1 hr weekly + T 4 mg/kg load, then 2 mg/kg weekly, all IV. All HER-2 overexpressors received T and were randomized to group 3 or 4. Patients completed QOL interviews prior to randomization, and at 3, 6, and 9 months. Main outcome measures were the EORTC-C30 with the Breast Module (QLQ-BR23). Data were analyzed using general linear models for repeated measures, with the following covariates: treatment arm, assessment point, patient age, race, education, marital status, performance status, prior chemotherapy, and prior radiation therapy. Results: HER-2 negative patients receiving weekly P with/without T as compared to standard P with/without T reported better global QOL (p=.022) and fewer cancer symptoms (p=.036). No QOL differences were observed among the HER-2 overexpressors. The use of T in the HER-2 negatives, regardless of P schedule, resulted in better role (p=.002) and emotional functioning (p=.039), and fewer arm (p=.045) and breast (p=.033) symptoms than HER-2 negative patients not receiving T. No differences in physical, social, and cognitive functioning were observed across any of these treatment groups. Conclusions: Both weekly P and T improved the QOL of HER-2 negative patients. There were no QOL differences by P schedule among the HER-2 overexpressors. The higher QOL in HER-2 negatives receiving T was unexpected, inconsistent with clinical data, and needs further exploration in the dataset.

[Table: see text]
Eicosanoid modulation in advanced non-small cell lung cancer (NSCLC): CALGB 30203
Authors: Edelman M. J. , Watson D. M. , Wang X. , Kratzke R. A. , Mauer A. M. , Green M. R. , Vokes E. E. , Graziano S. L. , Masters G. A. , Bedor M. M.
Published: March 2020

7025

Background: Increased expression of eicosanoids have been associated with adverse prognosis. Specific inhibitors of key enzymes of two eicosanoid pathways, COX-2 (celecoxib) and 5-LOX (zileuton) have been developed. In vitro, the addition of these inhibitors have demonstrated enhancement of cytotoxic chemotherapy. We hypothesized that the addition of eicosanoid inhibitors to standard chemotherapy of carboplatin (C) and gemcitabine (G) could improve outcome in advanced NSCLC. Methods: Patients (pts) with stage IIIb (pleural effusion)/stage IV NSCLC, PS 0–2, no prior therapy were eligible. All pts received up to six cycles of C AUC 5.5 d1 + G (1000 mg/m2) d1,8. Pts were randomized to three arms: A: Celecoxib (CEL) 400 mg po bid. B: Zileuton (Z) 600 mg qid po, C: CEL and Z at the same doses. CEL and Z were begun on the first day of therapy and continued until progression. In this randomized phase II trial, the objective was to demonstrate a 50% failure free survival (FFS) at 9 months. Serum and tissue samples were required. Results: Between 12/05/03 and 9/30/04, 140 pts were entered and 136 were eligible and treated (A: 44, B: 47, C: 45). M: 86, F: 50; PS 0,1,2 = 38,85,13. Toxicity was primarily hematologic with approximately 70% grade 3/4 toxicity on each arm. Response and survival with 95% CI (see table ). Arm C has superior FFS when compared to combined Arms A+B (p =.054, unstratified log rank test), however, this benefit decreases when adjusted for baseline PS (0 vs, 1,2) and stage (IIIB vs. IV) in a Cox model, p=.15, 2-sided Wald test. There was no difference in terms of OS (p=.96). Serum and tissue were submitted for >90%. Analysis of COX-2 and 5-LOX expression are pending. Conclusions: 1. The combination of C/G + eicosanoid modulators was well tolerated. 2. The trend towards improved FFS in Arm C is intriguing, however, did not achieve the primary endpoint. 3. Correlative studies which may be able to identify pts likely to benefit from this approach are in progress.

[Table: see text]

[Table: see text]
Phase II trial of amrubicin in patients with previously treated small cell lung cancer (SCLC)
Authors: Kato T. , Nokihara H. , Ohe Y. , Yamamoto N. , Sekine I. , Kunitoh H. , Kubota K. , Nishiwaki Y. , Saijo N. , Tamura T.
Published: March 2020

7061

Background: Amrubicin, a totally synthetic 9-amino-anthracycline, has been shown to have excellent antitumor activity as a single agent against previously untreated extensive-stage SCLC. The objective of this study was to assess the efficacy and safety of amrubicin in patients with refractory or relapsed SCLC. Methods: Patients with histologically or cytologically confirmed SCLC, 20 to 74 years in age, performance status 0–2, with a history of receiving first- or second- line chemotherapy were eligible for the study. Amrubicin (45mg/m2/day) was administered on Days 1–3 every 3 weeks for four to six courses. The primary endpoint was the response rate (RR), and planned sample size for this phase II study was 33 patients (Simon’s two-stage minimax design). Results: From June 2003 to January 2005, 35 patients (26 males/9 females, median age, 64 years) were enrolled, and 34 of these patients were treated with the study drug. Four courses or more were administered in 59% (20/34) of the patients, and dose reduction was required in 52% (15/29) of the patients who had received 2 courses or more. Four complete responses and 14 partial responses were observed among the 34 treated patients, yielding a RR of 53% (95% confidence interval: 35.1%–70.2%). The median survival duration in the patients was 8.8 months, and the 1-year survival rate was 26%. Grade 3/4 leukopenia, neutropenia, and thrombocytopenia were observed in 76%, 97% and 38% of the patients, respectively. Febrile neutoropenia occurred in 12 patients (35%), and one patient died from treatment related pneumonia. Conclusion: Amrubicin (45mg/m2/day) was effective in patients with previously treated advanced SCLC, however, severe hematological toxicities occurred in some patients.

No significant financial relationships to disclose.
Randomized phase III study of high-dose sequential chemotherapy (CT) supported by peripheral blood progenitor cells (PBPC) for the treatment of small cell lung cancer (SCLC): Results of the EBMT Random-ICE trial
Authors: Leyvraz S. , Pampallona S. , Martinelli G. , Ploner F. , Aversa S. , Rosti G. , Brunsvig P. , Montes A. , Yilmaz U. , Perey L.
Published: March 2020

7064

Background: EBMT has defined in a phase II trial (JCO 1999, 3531) feasibility and activity of high-dose sequential CT for SCLC increasing 3 fold the dose-intensity and significantly the peak-dose and the total dose of CT. Methods: Randomized prospective study aiming to improve the 3-year survival from 12% in the standard (S) to 24% in the high-dose (H) arm, for a total accrual of 340 patients. Limited or extensive ≤ 2 metastatic sites, age ≤ 65 y.o., PS 0–1. Arm S/Arm H: ifosfamide 5 g/m2 d1/2.5 g/m2/d × 4; carboplatin 300 mg/m2 d1/AUC = 5/d × 4; etoposide 180 mg/m2/d. × 2/300 mg/m2/d × 4, every 28 days, for 6 cycles in Arm S. Three cycles were given in Arm H supported by PBPC collected after 2 courses of epirubicin 150 mg/m2/paclitaxel 175 mg/m2. Due to low accrual, a formal stopping rule was introduced with boundaries for early stopping in favour of a difference (O’Brien-Fleming) or of lack thereof (Pocock). The present analysis has been done with 110 deaths. Results: Since June 1997, 145 patients have been accrued (evaluable =140, S = 71, H = 69), median age 53, prognostic factors balanced. Mobilization toxicity ≥ 3: neutropenia 61%, thrombopenia 11%, anemia 7%, infection 6%, mucositis 9% and 2 toxic deaths. Toxicity ≥ 3 among 353 cycles of S and 152 of H respectively: neutropenia 26%/100%, thrombopenia 12%/100%, anemia 8%/69%, infection 1%/15%, fever 11%/72%, toxic death 1/8. Response rate of S and H: 67% (CR 32%)/77% (CR 37%) (p = 0.188). Median follow-up 4.9 years. Progression free survival 8.8 and 12 months (p = 0.737, unadjusted) and median overall survival 15 and 19.1 months (p = 0.659, unadjusted) for S and H respectively. At 3 years, 19% of the patients were alive in both arms. Conclusions: Random-ICE was designed with strong statistical power and shows no evidence that the treatment of SCLC can be improved by increasing the dose-intensity, the peak-dose or the total dose of ICE and that such intensification strategy should probably be abandoned.

No significant financial relationships to disclose.
Analysis of c-erb-1 (EGFR) and c-erb-2 (HER2) expression in bronchial dysplasia: Evaluation of potential targets for chemoprevention of lung cancer
Authors: Merrick D. T. , Kittelson J. , Winterhalder R. , Kotantoulas G. , Ingeberg S. , Keith R. L. , Kennedy T. C. , Miller Y. E. , Franklin W. A. , Hirsch F. R.
Published: March 2020

7070

Background: Lung cancer is preceded by a premalignant phase during which intervention could decrease associated morbidity and mortality. Molecular characterization of factors involved in controlling progression of bronchial dysplasia (BD) will provide markers of premalignant change and identify targets for chemoprevention. Methods: Immunohistochemical (IHC) analysis of EGFR, HER2, Ki67 and MCM2 expression in BD was undertaken in 268 bronchoscopically obtained biopsies from 134 consecutive subjects recruited to University of Colorado protocols as study subjects with prior sputum atypia and >20 pack years tobacco use or FEV1 < 75% predicted or as never- or healthy-smoker controls. IHC on the worst and best histologic biopsies from each subject were scored and linear regression tests were used to determine significance of correlation between marker expression and histology or proliferation. Results: Analysis of biopsies with the most severe diagnosis from each subject showed a linear relationship between increasing marker expression and severity of dysplastic change for EGFR (p < 0.001), Ki67 (p < 0.001) and MCM2 (p = 0.001) but not HER2 (p = 0.102). Increased expression of either EGFR or HER2 was associated with increased expression of proliferation markers Ki67and MCM2, and combined overexpression of these receptors was associated with the highest levels of proliferation. Finally, in a comparison of subjects that were grouped according to the degree of difference between their best and worst biopsy histology, the absence of an associated trend toward increased EGFR expression with increased difference in histology suggested a field effect in the induction of EGFR expression. Conclusions: Our results 1) demonstrate a direct correlation between levels of EGFR expression and degree of BD, 2) suggest a field effect in the induction of EGFR expression in the airways of subjects with BD and 3) indicate a potential synergistic effect on epithelial proliferation in lesions with increased expression of both EGFR and HER2. These findings suggest that EGFR plays a prominent role in the development and progression of BD and could provide a promising target for chemoprevention of lung cancer.

[Table: see text]
Predicting clinical benefit from EGFR TKIs: Not all EGFR mutations are equal
Authors: Hirsch F. R. , Franklin W. A. , McCoy J. , Cappuzzo F. , Varella-Garcia M. , Witta S. E. , Gumerlock P. , West H. , Gandara D. R. , Bunn P. A.
Published: March 2020

7072

Background: EGFR mutations are associated with better response and in some studies (mainly Asian) also with prolonged survival after gefitinib therapy in patients with advanced NSCLC. Although a number of mutations have been reported, most frequent are exon 19 or exon 21 mutations of the EGFR tyrosine kinase domain.Whether clinical outcomes differ by subtype of EGFR mutation has not been previously reported. Methods: Mutation analysis (as previously described) was performed in 157 of 204 patients with advanced NSCLC treated with gefitinib (250 mg or 500 mg) in 2 study cohorts (Italian study of Iressa Expanded Access Program and SWOG 0126). Fifty nanograms of genomic DNA was isolated from pretreatment tumors, amplified for EGFR exons 19 and 21 by touchdown hemi-nested polymerase chain reaction and sequenced in both sense and antisense directions. Results: EGFR mutations were found in 43 pts (27%). Overall, patients with EGFR mutations had a response rate of 39% versus 7% for those without (p ≤ 0.001), disease control rate of 52% versus 37% (p = 0.14), time to progression of 3 months in both groups and median survival of 13 months versus 11 months (p = 0.14). Patients with exon 19 mutations exclusively (N = 11) had better outcome than those with exon 21 mutations exclusively (N = 31), with response rates of 67% versus 20% (p = 0.02), median time to progression of 15 months versus 2 months, and median survival of 26 months versus 10 months. There was a difference in time to progression (11 months versus 3 months) and overall survival (median 26 months versus 11 months) between patients with and without exon 19 mutations, while no difference was apparent in these outcome measures in patients with and without exon 21 mutations. Sample size provided insufficient power for significance tests of differences in survival outcomes. Conclusions: Not all EGFR mutations are created equal. Mutations in exon 19 are more predictive of response and survival after gefitinib than exon 21 mutations.

[Table: see text]
Mutational analysis of the EGFR gene in lung cancer with acquired resistance to gefitinib
Authors: Mitsudomi T. , Kosaka T. , Endoh H. , Yoshida K. , Hida T. , Tsuboi M. , Tada H. , Kuwano H. , Yatabe Y.
Published: March 2020

7074

Background: Non-small cell lung cancer (NSCLC) harboring activating mutations in the epidermal growth factor receptor (EGFR) gene is usually highly sensitive to EGFR tyrosine kinase inhibitors (TKI), gefitinib or erlotinib. However, it is common to develop acquired resistance to TKI after presenting an initial striking response. It has been reported that secondary mutation of threonine to methionine at codon 790 (T790M) of the EGFR gene is related to this acquired resistance. Methods: We sequenced exons 18–21 of the EGFR gene in 14 NSCLC patients exhibiting acquired resistance to gefitinib following the initial good response. This region of the EGFR gene corresponds with that of the ABL gene where various secondary mutations have been reported in patients with chronic myelogenous leukemia (CML) with acquired resistance to imatinib. To raise sensitivity of the assay, we also subcloned the PCR products into plasmids and sequenced, or we used CyCleave method (real-time PCR combined with fluorescence labeled mutant specific probe) in addition to usual sequencing. We also searched for secondary K-ras mutations. Results: All the 14 patients had activating mutations of the EGFR gene (9 with exon 19 deletions, 5 with L858R). In addition, we found that 7 of 14 patients had a T790M mutation, but there were not any other novel secondary mutations. In these seven patients, T790M mutant bands were smaller than wild-type bands. Patients with T790M tended to be never smoking female, but there was no difference in the period of gefitinib administration by the presence or absence of T790M. We could not detect any T790M in tumors before gefitinib treatment at the sensitivity of 1%. There were no patients with acquired mutation of the K-ras gene. Conclusions: Secondary T790M mutation of the EGFR gene accounted for half of the cases with acquired resistance to gefitinib. Unlike the cases with CML, various kinds of secondary mutations were not likely to exist in the EGFR gene as a mechanism of acquired resistance.

No significant financial relationships to disclose.
Phase II study of irinotecan (cpt-11) and cisplatin (cddp) regimen (IP) with concurrent thoracic radiotherapy (TRT) in limited-stage small cell lung cancer (LS-SCLC)
Authors: Castellano D. , Bartolomé A. , Font A. , Lopez-Martín A. , Diz P. , Lopez-Brea M. , Garrido P. , Lianes P. , Cortés Funes H. , Paz-Ares L.
Published: March 2020

7084

Background: the combination of CPT-11 and CDDP (IP) is an active regimen for SCLC. (Noda et al NEJM ’02, Hanna et al ASCO 2005). We performed a multicenter phase II study to assess the efficacy and toxicity of IP regimen with concurrent TRT in previously untreated LS-SCLC pts. Methods: Eligible pts were required to have histologically confirmed SCLC, measurable disease, no prior therapy, ECOG PS of 0–2, adequate organ functions, and to give informed consent. Treatment consisted of: CDDP 60 mg/m2 D1, I 60mg/m2 IV D1, 8 Q 21D for 4 cycles, and concurrent TRT 2.0 Gy daily to a total of 60.0 Gy, beginning with the 2nd cycle. I was adjusted to 50 mg/m2 at 2nd and 3rd cycles (during TRT). Pts were restaged after 4 cycles. Pts without progression or undue toxicity received 2 additional cycles. PCI (2.0 Gy X 10) was offered to CR pts. The primary endpoints were response rate and OS. Results: Twenty-six pts were included and 25 pts were evaluable for response (median age 62; M/F, 22/4; PS 0/1/2, 9/17; T2–4N0,T2–4N+ 6/20pts). Among 126 cycles administered, the relative dose-intensities of I and CDDP were 80% and 92% respectively. Median number of cycles/pt was 5 (1–6), and 22 pts completed the IP + TRT program. Fifteen pts achieved a CR and 6 pts a PR, for an overall RR of 84%. Median TTP was 12 months. At a median follow-up of 14 months, 19 pts are alive, and estimated median survival is 17 months. Grade 3–4 (NCI-CTC 3.0) toxicity (per cycle) during concurrent therapy included: neutropenia (25%), anemia (3%), thrombocytopenia (3%), diarrhea (10%), vomiting (5%), esophagitis (10%). There were no treatment-related deaths. Two pts required hospitalization during the concurrent therapy due to g3 diarrhea (1 pt) and febrile neutropenia (1 pt). Conclusions: The concurrent regimen of IP + TRT is highly effective in pts with LS-SCLC. The associated toxicity profile is predictable and adequate. Further study is warranted.

No significant financial relationships to disclose.
Dose escalation study of nab-paclitaxel followed by carboplatin as first line therapy in advanced non-small cell lung cancer (NSCLC)
Authors: Hawkins M. J. , Georgy M. , Makhson A. , Cheporov S. , Sergey O. , Yablonsky P. , Bhar P. , Socinski M.
Published: March 2020

7132

Background: Paclitaxel for injection formulated in Cremophor® and ethanol (Taxol®, Cremophor paclitaxel) 225 mg/m2 and carboplatin area under the curve of 6 mg/min·ml (C6) administered every 3 weeks (q3w) has produced an overall response rate (ORR) of 17% in first line patients (pts) with NSCLC with a 1-year survival of 34% [Schiller et al., NEJM, 2002;346:92]. The aim of this phase II study is to obtain clinical experience with a 130-nanometer albumin-bound form of paclitaxel (Abraxane®, ABI-007, nab™ paclitaxel) followed by C6 in NSCLC to determine a dose that approximates the toxicity of Cremophor paclitaxel/C6. Methods: Pts with previously untreated, stage IIIB or IV NSCLC with measurable disease and a life expectancy of over 12 weeks were recruited. In a dose escalation schedule, 4 cohorts (n = 25 each) of successive pts received nab paclitaxel at doses of 225, 260, 300, or 340 mg/m2 as 30-minute IV infusions followed by C6 q3w. The primary endpoints were the ORR (pts with an objective, confirmed complete or partial response) and toxicity. The primary efficacy analysis was based on all pts who received at least 1 dose of nab-paclitaxel and C6. Stable disease (SD) at ≥16 weeks was also assessed. Results: One hundred pts (100% white; 78% male; median age, 63; performance status score: 0 [11%], 1 [89%] were enrolled from 15 March–28 June of 2005. Accrual was completed in each cohort and serious adverse events reviewed prior to accrual at the next dose level. The results for ORR and SD at ≥16 weeks currently available are shown in the Table . The most common toxicities (any grade) were neutropenia, 43%; fatigue, 37%; sensory neuropathy, 37%; nausea, 35%; thrombocytopenia, 33%; anemia, 24%; alopecia, 24%; and vomiting, 21%. Conclusions: The combination demonstrated antitumor activity and was reasonably well tolerated. Mature data will be presented.

[Table: see text]

[Table: see text]
Phase II trial with carboplatin/gemcitabine induction chemotherapy followed by radiotherapy concomitantly with paclitaxel/gemcitabine in stage III non-small cell lung cancer (NSCLC)
Authors: Hirsh V. , Duclos M. , Souhami L. , Del Vecchio P. , Ofiara L. , Faria S. , Ayoub J. , Charpentier D. , Portelance L. , Soulieres D.
Published: March 2020

7139

Background: The optimal combination of concomitant thoracic radiotherapy (TRT) and CT in stage III unresectable NSCLC remains unclear. The role of induction CT with Cb/G regimen, less toxic than Cisplatin/G, has not been established in stage III NSCLC. Methods: Forty-two patients (pts), 41 evaluable, entered this trial between January 2003 and November 2004, 27 males, 14 females, median age 60 (37–70), 19 pts with ECOG PS 0, 22 pts with PS 1, 22 pts with stage III A (N2), and 19 pts with stage III B (N2, N3). They received Cb AUC 5 i.v. on day 1 and G 1000 mg/m2 i.v. on days 1 + 8 every three weeks x 2 cycles, followed on day 50 by TRT, 60 Gy over 6 weeks, concomitantly with P 50 mg/m2 i.v. and G 100 mg/m2 i.v. on days 1 + 8 every three weeks x 2 cycles. Results: After induction CT, partial response (PR) was 73.1% (30 pts), stable disease (SD) 24.4% (10 pts), and 2.5% (1 pt) had progressive disease. After TRT and P/G, 19.5% (8 pts) had CR, 75.6% (31 pts) PR, and 4.9% (2 pts) PD. Median time-to-disease progression was 11.5 months. Median survival has not been reached yet, but surpassed 16.5 months; one-year survival is 71% (29 pts). Twenty three patients are still alive, after minimal follow-up of 13 months. First site of PD was in lungs in 7 pts, in brain 5 pts, in bones 4 pts; 2 pts died without PD, of cardiovascular disease. Toxicity of induction CT was minimal. During TRT and CT, grade 3 neutropenia, thrombocytopenia, and anemia occurred in 8 pts, 3 pts, and 3 pts respectively, grade 4 neutropenia and thrombocytopenia in one pt each. Nine pts received red cell transfusions, one pt platelet transfusion. One patient developed esophageal fistula with grade 4 toxicity, 3 pts had grade 3 esophagitis, 2 pts grade 3 infections, and one pt grade 3 dermatitis and elevation of liver enzymes. Conclusions: This regimen is effective, well tolerated, and appears to be an excellent choice for stage III NSCLC. Sponsored by Eli Lilly Canada.

[Table: see text]
The use of statins may prolong survival of non-small cell lung cancer patients
Authors: Wang D. , Hanbali A. , Jankowski M. , Duran E. U. , Syed A. , Farhan S. , Chapman R.
Published: March 2020

7149

Background: Hypercholesterolemia is one of the most common morbidities in United States. Statins have been proven as effective cholesterol-lowering agents and have been widely used in this country. They have been reported reducing the incidence and risk of various cancer types. However, the impact of using statins on the survival of patients with diagnosed non-small cell lung cancer is unknown. Methods: Ongoing retrospective study involves a cohort of 1,233 patients with diagnosed non-small cell lung cancer. Patients were identified from the Tumor Registry at Henry Ford Health System between January 1999 and December 2004. To date, the electronic medical records from 407 of the 1,233 cases were reviewed. Statistical analyses were performed and stratified for statin users versus non statin users. Results: Data from 407 patients were included in this analysis. There were 109 patients with hypercholesterolemia, 54 of them were statin users at the time of their non-small cell lung cancer diagnosis. Average age was 70 (range 46–85) years for statin users and 65 (range 29–93) years for non statin users. Median survival of 407 subjects was 9.82 months. After stratifying for statin use, the median survival of statin users was 12.38 months while the median survival of non statin users was 9.75 months, with a p value of 0.012. Conclusion: Though small sample size, this study is the first time ever suggesting a possible survival benefit of statin use in patients with non-small cell lung cancer who have received their standard anti-tumor regimens. Other variables that may contribute to this result will be further clarified and discussed after completing the data collection and analysis of this entire cohort. Based on our preliminary result, a prospective study of co-morbidity management with statins in patients with non-small cell lung cancer is warranted.

No significant financial relationships to disclose.
Randomized phase II study of carboplatin and paclitaxel (CP) versus gemcitabine and vinorelbine (GV) in performance status (PS) 2 patients with advanced non-small cell lung cancer (NSCLC): Preliminary results of West Japan Thoracic Oncology Group 0004
Authors: Kaneda H. , Nakagawa K. , Saito H. , Kashii T. , Iwamoto Y. , Katakami N. , Nakano T. , Kurata T. , Fukuoka M.
Published: March 2020

7151

Background: A platinum-based chemotherapy is a standard treatment in PS 0–1 patients with advanced NSCLC and a non-platinum doublet is an alternative option. However, the role of combination chemotherapy remains to be defined in PS 2 patients with advanced NSCLC. We have conducted a randomized phase II study to compare the efficacy and safety of CP versus GV in PS 2 patients with NSCLC. Methods: Chemotherapy-naive ECOG PS 2 patients with stage IIIB (malignant effusion) or IV NSCLC were enrolled in this study. Patients were randomized to carboplatin AUC 6 and paclitaxel 200 mg/m2 day 1 every 3 weeks or gemcitabine 1,000 mg/ m2 and vinorelbine 25mg/m2 day 1, 8 every 3 weeks. The primary endpoint was 1-year survival rate and secondary endpoint were response rate, toxicity, time to progression and quality of life. Results: A total of 89 patients were enrolled and 86 were eligible: 42 patients (median age 64 years, male/female 31/11, stage IIIB/IV 7/35) in CP and 44 patients (median age 67 years, male/female 33/11, stage IIIB/IV 7/37) in GV. Of 84 patients evaluable for response, one complete response and 11 partial responses were obtained in CP (29.3%) and 9 partial responses in GV (20.9%). As of 12/05, toxicity data were available in 80 patients. Grade 3/4 toxicity in CP and GV included neutropenia 65.8% vs 63.4%, anemia 13.2% vs 31.7%, thrombocytopenia 7.9% vs 12.2%, liver dysfunction 2.6% vs 9.8%, febrile neutropenia 15.4% vs 12.2%, infection 30.8% vs 22%, nausea/vomiting 15.4% vs 2.4%, constipation 23.1% vs 7.3% pulmonary infiltrates 5.1% vs 12.2% and neuropathy 5.1% vs 0%. Conclusions: CP and GV were feasible and effective in PS 2 patients with advanced NSCLC. GV caused more anemia, thrombocytopenia, liver dysfunction and pulmonary infiltrates, while CP produced more nausea/vomiting, constipation and neuropathy. Response and toxicity data in all pts in each arm will be presented at the meeting.

No significant financial relationships to disclose.
Do gender and race influence survival in patients with non-small cell lung cancer brain metastases? An outcomes study utilizing the RTOG RPA class stratification
Authors: Videtic G. M. , Reddy C. A. , Chao S. T. , Rice T. W. , Adelstein D. J. , Barnett G. H. , Mekhail T. M. , Vogelbaum M. A. , Suh J. H.
Published: March 2020

7153

Background: To explore gender, race and their interactions in the setting of NSCLC brain metastases only, a single-institution brain database was analyzed, using the RTOG recursive partitioning analysis (RPA) brain metastases classification. Methods: From 1/82 to 9/04, 831 NSCLC pts with brain metastases were registered. RPA criteria for analysis were: class I- Karnofsky performance status (KPS) ≥ 70, age<65 years, primary tumor controlled, no extracranial metastases; class III- KPS<70; class II- all others. Results: Median follow-up was 5.4 months (m) (range 0–122.9). Median age was 62.4 (range 25–90). Median KPS was 80 (range 20–100). There were 485 males [M] (58.4%) and 346 females [F] (41.6%). 824 pts (99%) were either African-American (AA; n = 142[17%]) or White (W; n = 682[83%]). Pts characteristics were balanced when stratified by RPA class and by treatments. Median survival (MS) in months from time of brain metastasis diagnosis for all pts was 5.8. MS in months by gender [F vs. M] and race [W vs. AA] was: 6.3 vs. 5.5, p = 0.013; 6.0 vs. 5.2, p = 0.08, respectively. By RPA class for gender, MS trends (in months) favored F over M in classes I and II but not III: 17.1 vs. 9.5 (p = 0.11); 6.8 vs. 6.0 (p = 0.09), 2.7 vs. 2.5 (p = 0.42), respectively. By RPA class for gender and race, MS trends (in months) favored AAF over AAM in classes I and II but not III: 30.0 vs. 12.4, p = 0.50; 11.2 vs. 4.6, p = 0.021; 3.2 vs. 3.2, p = 0.64, respectively; and WF over WM in classes I but not II or III: 14.4 vs. 9.5, p = 0.11; 6.6 vs. 6.3, p = 0.38; 2.4 vs. 2.3, p = 0.49, respectively. On multivariable analysis, significant variables were gender (p = 0.041; RR 0.83); RPA class (p < 0.0001; RR 0.28, for I vs. III; p < 0.0001; RR 0.51, for II vs. III). Conclusions: Gender significantly influences NSCLC brain metastasis survival while race trends to significance. MS trends by RTOG RPA class suggest race may interact with genderprimarily in class I but pt numbers limited significance. Further characterization of these factors is warranted.

No significant financial relationships to disclose.
Compliance of adjuvant chemotherapy in non-small cell lung cancer (NSCLC); No longer an issue
Authors: Aljubran A. , Leighl N. , Pintilie M. , Feld R. , Burkes R. , Shepherd F.
Published: March 2020

7154

Background: Poor compliance has been a common feature in clinical trials of adjuvant chemotherapy for NSCLC with only 48%-69% of patients completing all planned cycles. This may have been due to lack of perceived benefit by patients and physicians and toxicity of the regimens employed. We retrospectively evaluated compliance and toxicity of platinum-based chemotherapy in the two years following the recent reports of successful adjuvant chemotherapy trials for NSCLC. Methods: Following institutional ethics approval, patients who received adjuvant chemotherapy after complete resection of NSCLC between May 2003 and May 2005 were analyzed retrospectively. Patients were identified using an institutional cancer registry. Patient demographics, ECOG status, stage, pathologic subtype and type of surgery were recorded. The number of chemotherapy cycles, delays, dose reductions and change of chemotherapy were all reported. Results: A total of 50 patients were identified. The median age was 62. 38% were stage I, 18% stage II, 30% stage III and 14% had multiple primary tumors of variable stages. 20% were ECOG PS2 and the rest ECOG 0–1. Only 12% had undergone pnemonectomy. 41 patients (82%) started cisplatin /vinorelbine (3 switched to carboplatin because of nephrotoxicity, and one switched to carboplatin/paclitaxel because of fatigue and vomiting). 3 patients received other cisplatin-based combinations. 6 received carboplatin-based treatment (one because of advanced age, one because of cardiac dysfunction and 4 because of preexisting neuropathy). 80% completed all treatment. 40% required dose reduction. 58% required delays in treatment. 6 events of febrile neutropenia were reported in 5 patients. 7 patients required admission. There were no toxic deaths. Multivariate analysis showed no effect of age, gender, extent of surgery or ECOG status on compliance, need for treatment modification or toxicity. Conclusions: Compared to historical trials, adjuvant platinum-based chemotherapy for resected NSCLC is well tolerated and is now accepted by patients and physicians with a high degree of compliance.

No significant financial relationships to disclose.
Determining incidence and predictors of deep vein thrombosis in patients with non-small cell lung cancer
Authors: Levi D. , Tagalakis V. , Cohen V. , Agulnik J. , Kasymjanova G. , Small D.
Published: March 2020

7159

Background: The risk of deep vein thrombosis (DVT) among patients with non-small cell lung cancer (NSCLC) has not been well studied. We conducted a retrospective cohort study of patients with NSCLC to determine the incidence of DVT and characterize predictors of DVT in NSCLC patients. Methods: The pulmonary oncology database of the SMBD-Jewish General Hospital contains prospectively collected clinical data on all lung cancer patients followed in the pulmonary oncology clinic since January 1, 1997. We identified all consecutive patients with a histologically confirmed new diagnosis of NSCLC between January 1, 1997 and December 31, 2004 and determined the occurrence of an objectively defined DVT. Data on age, gender, NSCLC type and stage, Eastern Cooperative Oncology Group (ECOG) performance status, exposure to surgery and chemotherapy, and death was collected and compared among patients with DVT and patients without DVT. Results: Of the 493 NSCLC patients included in the cohort for a total of 634 person-years, 67 (13.6%) patients developed an objectively confirmed DVT. We calculated an incidence rate of 110 cases (95% confidence interval (CI) 80, 130) per 1000 person-years. Risk factors associated with occurrence of DVT were advanced stage (p = 0.0006) and male sex (p = 0.04). A multivariable regression analysis adjusted for recent surgery and performance status showed that advanced stage (Rate ratio 2.55, 95% CI 1.33–4.89) and male sex (Rate ratio 1.75, 95% CI 1.03–2.94) were independent predictors of DVT. Age, type of NSCLC, and chemotherapy did not predict DVT. The risk of dying was 1.7-fold increased (Hazard Ratio 1.73, 95% CI 1.29–2.32, adjusted for age, sex, stage, surgery, performance status, and date of lung cancer diagnosis) among patients with DVT compared to patients without DVT. Conclusions: Our results show a high incidence of DVT in NSCLC patients and that advanced stage and male sex are important predictors of DVT. Moreover, NSCLC patients with DVT have a 1.7 fold increased risk of dying than patients without DVT. Confirmation of our results by prospective studies may provide the necessary evidence for targeted use of prophylactic anticoagulants in NSCLC patients to prevent development of DVT and improve related survival.

No significant financial relationships to disclose.
Erlotinib in patients with advanced squamous cell carcinoma of the lung
Authors: Gúrpide A. , Massutí B. , Pallares C. , Salinas P. , Montes A. , López-Vivanco G. , González Barón M. , Cobo M. , Amador M. L. , Paz-Ares L.
Published: March 2020

7174

Background: Erlotinib is a potent HER1/EGFR TKI that is approved for the treatment as a single agent in 2nd and 3rd line NSCLC. Several phase II studies have shown that adenocarcinoma histology together with female gender, Asian origin, and never having smoked are associated with responsiveness of NSCLC to erlotinib. The purpose of the analyisis we present here was to describe the outcome in a group of patients with squamous carcinoma of the lung treated with erlotinib. Methods: Eligilibility criteria included stage IIIB-IV chemotherapy-naive patients with confirmed NSCLC, PS 0–2, age ≥ 18 years, adequate organ functions, measurable disease and written informed consent. Patients with diagnosis of squamous cell lung cancer that received erlotinib 150 mgr/day p.o until disease progression or withdrawal were the subject of this analysis. Results: From June 2004 to March 2005, 121 patients with histological diagnosis of squamous cell lung cacer from more than 100 different Spanish hospitals were included in the TARGET study. Median age was 66 yrs. All patients in our analysis were Caucasian. 111 patients were male (92%) and 113 (93%) were current smokers or have smoke sometime in their life. 88% of them have stage IV carcinoma and 74% have received previous treatment for metastatic disease. PS 0/1/≥2 18 (15%)/68 (56%)/32 (29%). In the evaluable population for response (69 pts) 5 PR and 0 CR were observed for an overall RR of 7.25%. Clinical benefit defined as CR+PR+SD was 54%. In the ITT populations median TTP was 3.6 months [95% CI 2.7–5.3]. Median OS was 5,7 m [95% CI 4.0–6.7]. Erlotinib was well tolerated.No unexpected toxicities were observed. Conclusions: This subgroup analysis confirms that erlotinib is active and well tolerated in patients with advanced or metastatic squamous cell carcinoma of the lung. Responses were seen in both genders and in patients with or without smoking history. At this moment histology should not be used as the only selection criteria for treatment of patients with NSCLC after failure to chemotherapy.

[Table: see text]
Quantitative RT-PCR analysing expression of gefitinib resistance related genes predicts clinical outcome of non-small cell lung cancer patients treated with gefitinib
Authors: Kakiuchi S. , Yano S. , Ogino H. , Nakamura Y. , Tsuruo T. , Sone S.
Published: March 2020

7181

Background: Gefitinib, an inhibitor of epidermal growth factor receptor-tyrosine kinase, has shown favorable anti-tumor activity to a subset of patients with advanced non-small cell lung cancer (NSCLC). However, gefitinib failed to significantly prolong survival in comparison to placebo in unselected population. Consequently, selection of patients who will benefit from this treatment is clinically important. In the previous study, we identified gefitinib-resistance related genes (GRRGs) by cDNA microarray analyses and reported that the responsiveness of individual patients with NSCLC to gefitinib could be predicted by expression of GRRGs. The goal of this study is to establish clinically adoptive prediction system of clinical outcome of NSCLC patients treated by gefitinib. Methods: Tumors from 30 NSCLC patients treated daily with 250mg of gefitinib were evaluated for the expression of GRRGs by quantitative RT-PCR. Gefitinib response score (GRS) reflecting gene expression was calculated based on weighted vote method and this numerical scoring system was validated by leave-one-out approach and independent test cases. Results: The sensitivity of 15 learning cases (five partial response (PR) cases and 10 progressive disease (PD) cases) were predicted by leave-one-out cross validation with 93.3% (14/15) accuracy. This numerical scoring system correctly predicted responses to the drug in all of nine additional test cases (three PR cases and six PD cases). Notably, this system also could predict two stable disease (SD) cases who successfully controlled by gefitinib more than four months as responder. On the other hand, four patients who had been judged as SD but showed progression of the disease within three months were judged as non-responders. Moreover, gefitinib-treated patients with good signature had a statistically significant improvement in time to progression, and survival compared with patients with bad signature (13.0 vs 1.7 months, P < .0001; 27.7 vs 6.6 months, P = .0007, respectively). Conclusions: Our results suggest that clinical outcome of NSCLC patients treated with gefitinib could be predicted by expression levels of GRRGs determined by quantitative RT-PCR analyses.

No significant financial relationships to disclose.
EGFR mutations and the correlation with gefitinib therapy in Chinese NSCLC—A systematic review based on individual patient data from 5 medical centers in China
Authors: Wu Y. , Zhong W. , Li L. , Zhang L. , Zhou C. , Liu W. , Lin J. , Zhou Q. , Xu C. , Zhang G. , Mok T.
Published: March 2020

7187

Background: EGFR mutations were found to have a significant association with response to gefitinib. To date, information on status of EGFR mutation in Chinese remains scanty. Comprehensive review of existing information on EGFR mutations is essential for treatment selection in Chinese patients with advanced NSCLC. Methods: We published 4 abstracts on EGFR mutation in Chinese patients at the 41st ASCO. We performed an IPD-meta-analysis on the data from the above investigators plus another one. The original individual EGFR mutations (exon 18,19,21) data was collected. Gefitinib was given with 250 mg/d until disease progression. Results: Total 407 cases were into the IPD review. The patient characteristic was male: female = 258:149; adenocarcinoma: other = 259:148; smoker: nonsmoker =178:153. The EGFR mutation rate was 3.05% (124/407). For adeno subgroup the EGFR mutation rate was 42.5% (110/259), non- adeno was 9.5% (14/148). In female the EGFR mutation rate was 41.6% (62/149), male was 24.0% (62/258). Non-smoker was 39.2% (60/153), smoker was 18.5% (33/178). In univariate analysis adeno, smoking, gender was significant predictive factors for EGFR mutation but in logistic regression only adeno is independent correlation factor (p = 0.000, 95% CI 2.078—9.001). Conclusions: The EGFR mutation is more common in no-smoking female adeno patients with NSCLC. The EGFR mutation group has a tendency of response rate to gefitinib compare to the EGFR wild group in NSCLC patients.

[Table: see text]

No significant financial relationships to disclose.