bluuebunny/crossref_metadata_2025 huggingface dataset:
Intraoperative sentinel lymph node identification using novel receptor binding agent (technetium-99m neomannosyl human serum albumin, 99mTc-MSA) in stage I non-small cell lung cancer
Authors: Kim H. , Kim S. , Kang D. , Yong H. , Lee S. , Jeong J. , Choi Y.
Published: August 2020

7588

Background: In order to simplify synthesis and labelling procedures and to improve the biological properties, we developed a novel mannose receptor-binding agent, Technetium-99m neomannosyl human serum albumin (99mTc-MSA). This study was designed to test the reliability and feasibility of sentinel nodes identification using this new radioactive agent in stage I non-small cell lung cancer. Methods: A total dose of 1mCi of 99mTc- MSA in 0.2ml was administered in one shot at the peri-tumoral region under the chest CT or bronchoscope guidance 3 hours before surgery in the CT room. Dynamic whole-body SPECT lymphoscintigraphic image was obtained at 30 min after injection and static thoracic SPECT lymphoscintigraphy images were acquired at 1 and 2 hour after injection. During operation, the radioactivity of the lymph nodes was counted with a handheld gamma probe before (in vivo) and after (ex vivo) dissection. Lymph nodes with an ex vivo radioactive count more than 5 times the radioactivity count of the resected lung tissue were identified as sentinel nodes. The correlation between the in vivo and ex vivo results was examined. All harvested lymph nodes were examined histologically. Results: Thirty patients (20 men, 10 women; mean age, 62.6±9.40 years) who were candidates for lobectomy with mediastinal lymph node dissection for stage I non-small cell lung cancer were enrolled consecutively. Sentinel nodes could be detected from 30 minutes to 5 hours after the injection of 99mTc-MSA on lymphoscintigraphy. The mean number of dissected lymph nodes per patients was 20.7±1.30 (8∼41). Among 30 patients, sentinel lymph nodes could be identified in all patients (100%). The mean number of sentinel lymph nodes identified was 2.4±1.04 stations (range, 1∼5) per patient. No false-negative sentinel lymph nodes were detected in any of the 8 patients with N1 or N2 disease (0%). The relationship between in vivo and ex vivo results for mediastinal sentinel lymph nodes showed concurrence in 25 of 30 patients (83.3%). Conclusions: The results of this clinical trial showed that 99mTc-MSA had promising properties for sentinel nodes identification in non-small cell lung cancer.

No significant financial relationships to disclose.
Phase II study of the histone deacetylase inhibitor belinostat in thymic malignancies
Authors: Giaccone G. , Rajan A. , Carter C. , Kelly R. , Berman A. , Spittler J. , Espinoza-Delgado I. , Lee M. , Trepel J. , Loehrer P.
Published: August 2020

7589

Background: Thymic malignancies are rare tumors. Chemotherapy is used for advanced disease. There is no established role of second-line therapy in patients with refractory or recurrent disease. Belinostat is an HDAC inhibitor with activity in cutaneous and peripheral T cell lymphoma and is being investigated in several solid tumors. One prolonged minor response (31 m) was seen in a phase I study of this agent in a patient with thymoma. Methods: Patients with recurrent thymoma or thymic carcinoma, progressing after platinum-based chemotherapy were eligible. They were also required to have measurable disease, PS 0–2 and normal organ functions. Belinostat was given iv at 1.0 g/m2 on days 1–5 of a 21-day cycle until disease progression or intolerable side effects. Correlative markers of activity in blood and tumor were performed. Results: From December 07 to December 08, 22 patients have been accrued from 2 institutions; 12 patients were males, median age 52 (23–72), 14 thymomas and 8 thymic carcinomas, mean number of prior regimens 3.5 (1–10), 16 prior tumor resection and 3 myasthenia gravis. A median of 4 cycles have been given (1–15+). Treatment was well tolerated, with nausea being the most common side effect and well controlled with prophylactic antiemetics. 21 patients are evaluable for response: 2 had a partial response (9+, 9+ m), 13 stable disease (3–11+ m) and 6 progression. No responses were seen in 8 evaluable patients with thymic carcinomas. Acetylated lysine and tubulin were analyzed in lymphocytes and monocytes by multiparameter flow cytometry. An increase of protein acetylation (2–10 fold) over baseline was observed at 1 hour post-infusion on day 3 of the first cycle in all patients analyzed. Other correlative markers are being investigated. Conclusions: The thymoma cohort has been expanded to the second stage of the study. Belinostat has activity in patients with recurrent or refractory thymoma.

No significant financial relationships to disclose.
Tumor survivin expression in locally advanced non-small cell lung cancer (NSCLC) patients treated with platinum-based chemoradiation followed by surgical resection
Authors: Fidler M. J. , Seba A. , Farlow E. C. , Basu S. , Kaiser-Walters K. , Steker D. , Coon J. , Kim A. W. , Bonomi P. , Faber L. P.
Published: August 2020

7595

Background: Recently tumor molecular markers have shown promise as prognostic and predictive indicators for survival in early and advanced stage NSCLC patients (pts.) treated with chemotherapy. The objective of this study was to correlate immunohistochemistry (IHC) markers of pre-treatment biopsies in locally advanced NSCLC patients treated with concurrent platinum based chemoradiation followed by surgical resection. Methods: This is a retrospective study that included stage III NSCLC pts who had adequate pre-treatment tumor specimens and were treated with platinum based chemotherapy regimens and concurrent thoracic radiation (40 Gy). Thirty three pts had sufficient pre-treatment tissue for IHC and were identified from a surgical database. Cells were stained by IHC for frequency (0–4) and intensity (0–4) of ERCC1, PTEN, and survivin and analyzed by log-rank and multivariate Cox PH regression for potential relationships to pathologic complete response (pCR), time to recurrence (TTR), and overall survival (OS). Results: Characteristics of 33 pts: 15 females; median age 61; 17 adenocarcinoma, 10 squamous(sq), 5 undifferentiated, 1 adeno-sq. Median OS was 23 months (mo) (5.9–140), and median TTR was 14.7 mo (3.5–121). Following chemoradiation, 9 patients had pCR. pCR was associated with improved TTR, p < .027. ERCC1 and PTEN were not significantly related to OS, TTR, or pCR. High nuclear survivin frequency (>2) was associated with worse OS, HR 0.4, p< .045 and lower nuclear survivin intensity (<4) was marginally associated with pCR, p< .10. Conclusions: In this exploratory analysis, higher survivin expression was associated with worse prognosis in locally advanced NSCLC patients treated with chemoradiation followed by surgery. These results suggest that additional studies of survivin are warranted in NSCLC and that adding survivin inhibitors to chemoradiation is a reasonable strategy for locally advanced NSCLC with high survivin expression.

No significant financial relationships to disclose.
Epidermal growth factor receptor inhibitors as second-line treatment in advanced non-small cell lung cancer: A meta-analysis
Authors: Cruz M. C. , Tan M.
Published: August 2020

7597

Background: Overall survival in lung cancer remains poor despite availability of chemotherapy, which is limited by its toxicity and drug resistance. Advancement in research resulted to the development of targeted therapies, specifically epidermal growth factor receptor (EGFR) inhibitors. Results of clinical studies on survival benefits of EGFR inhibitors were conflicting although beneficial improvements in the quality of life and adverse effects were consistently demonstrated. The aim of our study is to determine the overall survival benefit of EGFR inhibitors alone or in combination with chemotherapy in second-line treatment of advanced non-small cell lung cancer (NSCLC). Methods: We did a meta-analysis of all randomized controlled trials involving patients with advanced NSCLC who failed at least one prior chemotherapy and were given EGFR inhibitor alone or in combination with chemotherapy compared to placebo or chemotherapy, with overall survival as an outcome. Pre-planned subgroup analysis was done on studies comparing EGFR to placebo and chemotherapy.Results: Five of the six trials included were analyzed for overall survival involving 4482 patients. Treatment with EGFR tyrosine kinase inhibitor (TKI) showed a trend towards significant survival benefit (RR=0.96, 95% CI 0.93–1.00, p=0.04) compared to placebo or chemotherapy. Preplanned subgroup analysis demonstrated significant survival benefit with EGFR-TKI versus placebo (RR=0.92, 95% CI 0.86–0.97, p=0.003) but comparable efficacy with chemotherapy (RR=1, 95% CI 0.96–1.06, p=0.84).Conclusions: Second-line treatment with EGFR-TKI demonstrated significant survival benefit versus placebo and comparable survival effect to chemotherapy. Further research should be done to identify patients’ characteristics associated with good treatment response.

[Table: see text]
Diagnostic reproducibility of squamous cell carcinoma (SC) in the era of histology-directed non-small cell lung cancer (NSCLC) chemotherapy: A large prospective study
Authors: Grilley-Olson J. E. , Hayes D. N. , Qaqish B. F. , Moore D. T. , Socinski M. A. , Yin X. , Wilkerson M. D. , Leslie K. O. , Travis W. D. , Funkhouser W. K.
Published: August 2020

8008

Background: Morphology remains the best biomarker for chemotherapy selection in NSCLC. Both bevacizumab and pemetrexed (in first line) are FDA indicated for non-SC histology only, making precise diagnosis key, although data are few on the reproducibility of their categorization. The standard of care, consensus-based World Health Organization diagnostic classification system, Ed. 4 (WHOC) includes 44 diagnostic categories (DC), does not include immunohistochemical (IHC) data, and is not independently validated. In this study, we estimate the reproducibility of SC versus non-SC classification to be only moderately precise. Methods: Pathologists (P) assigned WHOC diagnoses to virtual H&E slides from an incident surgical cohort of 96 primary lung tumors. At a power of 80% we estimated 24 P reviewing 48 slides each would allow for a reproducibility measure in the clinically useful range kappa=0.7, standard error=0.09. In addition to the 44 DC, we also considered the reproducibility of a simplified 10 category system and a chemotherapy-directed 2 class system. Results: 12 self-identified “lung experts” (E) and 12 community (C) P scored slides based on the 44 possible WHOC DC totaling 222 pathologist-pairs and 7130 slides-pairs. P rated confidence in their choices as: high 53%, somewhat 38%, and not confident 8%. 92% of slides were rated as having sufficient quality. Distribution of DC included SC 30% and adenocarcinoma 36%. Conclusions: To our knowledge this is the largest study ever performed of the WHOC, the only one to consider all 44 DC and to distinguish E vs C P. Although this model tests the reproducibility of the WHOC, not clinical lung cancer diagnoses, it shows that reproducible diagnosis of SC based on H&E morphology alone is inadequate. In the era of histology guided therapy, it highlights the need for strict diagnostic criteria and confirmatory IHC stains in the diagnosis of SC.

[Table: see text]

No significant financial relationships to disclose.
A phase II study of BIBW 2992, a novel irreversible dual EGFR and HER2 tyrosine kinase inhibitor (TKI), in patients with adenocarcinoma of the lung and activating EGFR mutations after failure of one line of chemotherapy (LUX-Lung 2)
Authors: Shih J. , Yang C. , Su W. , Hsia T. , Tsai C. , Chen Y. , Chang H. , Terlizzi E. , Shahidi M. , Miller V. A.
Published: August 2020

8013

Background: EGFR mutations are associated with exquisite sensitivity to EGFR TKIs in NSCLC. A phase II trial evaluating the efficacy of BIBW 2992 (Tovok), a novel, potent, irreversible, dual EGFR and HER2 TKI with preclinical activity in cell lines harboring activating (H3255, IC50=0.7 nM) and resistant (H1975, IC50=99 nM) EGFR mutations, is reported. Methods: Objective response rate is the primary endpoint of this 2-stage trial. Based on 16 or more unconfirmed PRs in an interim analysis of the first 40 2nd line patients (pts) completing 1 course (28 days), accrual will continue to a total of 120 1st and 2nd line pts (expected completion of accrual by May 2009. Data on 2nd line pts only are presented). Eligible pts have stage IIIB/IV lung adenocarcinoma, EGFR mutation in exons 18–21 (tested by direct sequencing), measurable disease, ECOG PS 0–2 and adequate end organ function. Pts receive 50 mg BIBW 2992 qd until progression. Tumor assessments are performed every 4 weeks for 12 weeks, then every 8 weeks. Results: Since Oct 2007, samples from 289 pts (222 from Taiwan and 67 from the US) have been sequenced. 100 had detectable EGFR mutations including del19 (n=39), L858R (n=45) and others (n=16). 69 pts have started treatment. The trial was moved to stage 2 after 21 of the first 38 treated pts had objective response at 28 days. Of 55 evaluable 2nd line pts, 29 (53%) had PR, and 23 (42%) had SD. Median follow up is 5.1 months. Most common related AEs were diarrhea and skin-related AEs, reported in 87% and 88% of pts, respectively. 27 pts (42.9 %) had dose reduction to 40 mg and 7 pts (11%) to 30 mg but only 1 pt permanently discontinued due to AEs. Diarrhea and rash were main causes of dose reduction. Conclusions: In the 2nd line setting, BIBW 2992 shows efficacy in NSCLC harboring EGFR activating mutations. Diarrhea and skin disorders, the most frequently observed AEs, are manageable with supportive care and dose reduction. Updated response and disease control rates and preliminary progression-free survival data will be presented. An international Phase III trial program investigating BIBW 2992 in NSCLC, LUX-Lung, is now recruiting.

[Table: see text]
Italian multicentric trial comparing chemotherapy with or without low-dose interleukin-2 (IL-2) in advanced non-small cell lung cancer: Results from a phase III randomized study
Authors: Ballardini M. , Ridolfi L. , Bertetto O. , Santo A. , Naglieri E. , Lopez M. , Recchia F. , Lissoni P. , Fumagalli L. , Ridolfi R.
Published: August 2020

8019

Background: Non small cell lung cancer (NSCLC) is associated with an IL-2-dependent cell-mediated immunodeficiency, and lymphocyte count is considered an independent prognostic factor as it seems to correlate with overall survival. A phase III randomized Italian multicentric trial was conducted to evaluate the efficacy of subcutaneous low-dose IL-2 added to standard CT on overall survival (OS) in advanced NSCLC patients. Methods: Histologically/cytologically confirmed stage IIIb or IV non operable NSCLC patients with measurable disease, ECOG PS 0–2, age 18–70 years and adequate bone marrow, renal and liver function were eligible for the study. Randomization was stratified by center, ECOG PS, stage of disease and percentage of weight loss. All patients received gemcitabine (1000mg/m2) on days 1 and 8 + cisplatin (100mg/m2) on day 2 every 21 days for a maximum of 6 cycles (CT arm). In the CT+IL-2 arm, patients also received low-dose subcutaneous IL-2 3,000,000 IU/die on days 3–5; 9–11; 15–17. The study had 90% power to detect a 20% absolute increase in 1-year OS with 120 patients per arm. Results: From June 2000 to October 2004, 241 patients were randomized (arm A/B: 127/114). At a median follow up of 32 months, 1-year OS was 45% for the CT+IL-2 arm vs. 51% for the CT arm (p=0.456 logrank). Median progression-free survival was 6.6 months in the CT+IL-2 arm vs. 6.9 months in the CT arm (p=0.573, logrank). Conclusions: The study did not show any relevant difference in clinical outcome by the addition of IL-2 to CT. Safety and subgroup analyses are ongoing to verify the efficacy of IL-2 as a function of clinical and biological characteristics of patients and tumors. Future studies to investigate the role of T-regulators in chemoimmunotherapy strategies, unknown when the study was originally planned, could be conducted.

No significant financial relationships to disclose.
Paclitaxel/gemcitabine versus paclitaxel/vinorelbine in advanced non-small cell lung cancer (NSCLC): A phase III randomized study
Authors: Kosmidis P. A. , Timotheadou E. , Koutras A. , Pentheroudakis G. , Christodoulou C. , Dimopoulos A. M. , Bafaloukos D. , Samantas E. , Pectasides D. , Syrigos K.
Published: August 2020

8038

Background: Paclitaxel and vinorelbine (PV) have shown synergism of cytotoxic effect in vitro (Cancer Invert, 2000, 18(8): 804-5). This combination was compared prospectively to the paclitaxel/gemcitabine (PG) regimen in non-operable NSCLC. Methods: 415 stage IIIb wet and IV chemotherapy-naïve for metastatic disease patients with PS 0–1 were randomized to paclitaxel 200mg/m2 on day 1 plus either gemcitabine 1gm/m2 (Group A) or vinorelbine 25mg/m2 (Group B) on days 1 and 8 every 3 wks as first line chemotherapy. Results: A total of 398 out of 415 patients were eligible for analysis on the intent to treat basis (group A: 196, group B: 202). All patient and disease characteristics were well balanced. Overall response rate (RR) was 27% for group A and 24% for group B (P=0.57). Median progression free survival (PFS) was 5.2 months (m) (95% CI, 4.4 - 5.9) and 4.7m (95% CI, 4.1 - 5.3) for groups A and B respectively (P=0.51). Median survival (OS) was 11.5m (95% CI, 9.5 - 12.6) and 9.3m (95% CI, 7.7 - 10.9) for groups A and B respectively (P=0.25). Grade 3/4 neutropenia was worse (P<0.001) in group B. Febrile neutropenia and severe infections were more prominent (P<0.001, P=0.005 respectively) in group B. Conclusions: Although RR, PFS, OS are similar in both groups, toxicity is significantly worse in group B and therefore further investigation of PV is of no value.

No significant financial relationships to disclose.
Preliminary safety and effectiveness of bevacizumab (BV) based treatment in subpopulations of patients (pts) with non-small cell lung cancer (NSCLC) from the ARIES study: A bevacizumab (BV) treatment observational cohort study (OCS)
Authors: Fischbach N. A. , Spigel D. , Brahmer J. , Garst J. , Robles R. , Chung C. , Wang L. , Sing A. , Lynch T.
Published: August 2020

8040

Background: Phase III trials have shown that bevacizumab (Avastin, BV), an anti-VEGF monoclonal antibody, prolongs progression-free and overall survival in advanced NSCLC pts. To further define clinical outcomes associated with BV treatment among a broader population of NSCLC pts in a real-world setting, the ARIES OCS was initiated. Pt populations in OCSs are often more reflective of pts encountered in practice, permitting examination of treatment benefit and toxicity in subgroups that might be too small for study in traditional randomized controlled trials (RCTs). The NSCLC cohort in ARIES will assess clinical outcomes in the overall cohort as well as subpopulations such as the elderly, pts with poor PS or pts on concurrent anticoagulants (AC). Methods: Pts with advanced NSCLC whose 1st-line therapy includes BV may enroll. 257 sites are enrolling pts; total accrual of 2000 pts is expected. There are no protocol-specified treatments or assessments. Data is collected at baseline (BL) then quarterly, including targeted adverse events (AEs) and BV-related serious AEs. Clinical outcomes will be descriptively summarized by baseline characteristics. Multivariate analyses will be conducted if cohort size is sufficient. Results: As of 9/15/08, 1518 NSCLC pts have enrolled. Median F/U is 7.5 mos. Key BL characteristics: 20% ≥75 yrs; 67% adenocarcinoma; 10% ECOG ≥2; 8% brain metastasis; 5% therapeutic AC. The most common 1st-line chemotherapy regimen was carboplatin/paclitaxel (64%). Key safety outcomes and cohort size of subpopulations are in the Table . Conclusions: The safety of BV in subpopulations of pts in ARIES (elderly pts, pts with ECOG PS ≥2, with brain mets at BL, or on therapeutic AC) is generally consistent with safety results from RCTs. Updated outcomes analyses will be presented at the meeting for >1600 pts and subpopulations.

[Table: see text]

[Table: see text]
Efficacy of pemetrexed-cisplatin (PC) in East Asian patients (pts): Subgroup analysis of a phase III study comparing PC versus gemcitabine-cisplatin (GC) in first-line treatment of advanced non-small cell lung cancer (NSCLC)
Authors: Orlando M. , Lee J. S. , Yang C. , Simms L. , Park K.
Published: August 2020

8045

Background: East Asian ethnicity is a recognized favorable prognostic factor in the treatment of NSCLC in trials with either chemotherapy or EGFR tyrosine-kinase inhibitors (TKIs). In a global phase III study (Scagliotti JCO 2008), superior efficacy of PC was shown for pts with nonsquamous NSCLC, while Asian ethnicity was prognostic in the overall population. The purpose of this analysis is to describe the patient and disease characteristics of the East Asian pts enrolled in this study and assess efficacy according to histology and smoking history. Methods: This retrospective analysis of a large phase III study included only patients enrolled from Korea and Taiwan. For survival and progression-free survival (PFS), Cox-adjusted analyses were used to estimate the hazard ratio and 95% CI, while medians were estimated using Kaplan-Meier method. Results: Results for PFS and response rate showed trends similar to overall survival in East Asian pts, favoring PC therapy in nonsquamous pts. The use of post-discontinuation targeted therapies such as EGFR-TKIs was similar between treatment arms in the overall population and in nonsquamous pts. In East Asian pts, EGFR-TKI use was slightly higher in the GC arm, in both the overall population and in nonsquamous pts. In a further subgroup analysis defined by smoking status, East Asian nonsquamous pts treated with PC had longer survival (not statistically significant). Conclusions: Pt and disease characteristics between the East Asian subgroup and the overall population were similar, with notable differences in the percentage of pts with no smoking history and the greater use of EGFR-TKIs as post-discontinuation therapy. This analysis shows the improved efficacy outcomes for East Asian nonsquamous pts treated with PC is consistent with the previously observed treatment effect of PC on nonsquamous NSCLC.

[Table: see text]

[Table: see text]
Cetuximab combined with either gemcitabine (G) followed by docetaxel (D) or carboplatin/gemcitabine (CP/G) in chemotherapy-naive patients (pts) with advanced non-small cell lung cancer (NSCLC): Safety profile from the ongoing phase II/III GemTax IV trial
Authors: Serke M. , Pilz L. R. , Cicenas S. , Eschbach C. , Fischer J. , Kortsik C. , Schumann C. , Steins M. , Manegold C.
Published: August 2020

8048

Background: The EGFR-targeting antibody cetuximab is undergoing broad clinical investigation in NSCLC. Our randomized trial assesses the safety of cetuximab combined with 2 different chemotherapy (CT) regimens in pts with advanced NSCLC. Phase II results are reported. Methods: Pts with histologically confirmed stage IIIB or IV NSCLC, WHO PS 0–2, and no prior CT received cetuximab 400 mg/m2 loading dose followed by 250 mg/m2 weekly either combined with G 1000 mg/m2 days 1 + 8 for 2 cycles (3qw) followed by D 75 mg/m2 day 1 for 2 cycles (q3w) (arm A) or CP AUC5 day 1 and G 1200 mg/m2 days 1 + 8 for 4 cycles (q3w) (arm B). Maintenance cetuximab was administered until disease progression or unacceptable toxicity. Results: 229 pts evaluable for safety received 1810 infusions of cetuximab combined with CT and 1216 infusions of maintenance cetuximab. 35 pts in arm A received 1–26 cycles (median 4) of maintenance cetuximab and 6 pts received ≥10 cycles; 50 pts in arm B received 1–22 cycles (median 3) and 7 pts ≥10 cycles. Grade 1 or 2 skin reactions related to study medication occurred in 84% of pts in arm A and 77% in arm B. In general, toxicity was more common in pts receiving CP (leukopenia and neutropenia 10%; pneumonia and fever 10%). In arm B, thrombopenia developed in 14% of pts and allergic reactions in 8%. Toxicities requiring clinical intervention are shown below. Updated results will be presented for 320 pts. Conclusions: Cetuximab does not significantly increase CT toxicity in the induction phase and is well tolerated in the maintenance phase. Notably, ∼75% of pts developed skin rash (grade 3/4 in ∼5% of pts).

[Table: see text]

[Table: see text]
Efficacy and safety of first-line bevacizumab (Bv) and cisplatin/gemcitabine (CG) in elderly patients (pts) with advanced non-small cell lung cancer (NSCLC) in the BO17704 study (AVAiL)
Authors: Leighl N. B. , Zatloukal P. , Mezger J. , Ramlau R. , Archer V. , Moore N. , Reck M.
Published: August 2020

8050

Background: AVAiL, an international, placebo-controlled, phase III trial, evaluated Bv plus CG in pts with previously untreated advanced, non-squamous NSCLC, with performance status 0/1. A retrospective analysis was performed to assess the efficacy and safety of Bv plus CG in the subpopulation of elderly pts (≥65 years [yrs]). Methods: 1,043 pts (age 20–83) were randomized to C 80mg/m2 and G 1,250mg/m2 q3w for up to 6 cycles plus either Bv 7.5mg/kg q3w (Bv 7.5; n=345), Bv 15mg/kg q3w (Bv 15; n=351) or placebo (Pl; n=347). Bv/Pl was administered until disease progression. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), objective response rate (RR) and safety. Efficacy and safety were compared between pts <65 yrs vs ≥65 yrs. Results: Efficacy data were available for 304 pts ≥65 yrs (median age 68), and 739 pts <65 yrs (median age 55). Baseline characteristics were similar between the groups. In the Bv arms, 179 pts (93%) received ≥1 cycle of treatment; 85 (47.5%) completed >6 cycles. Bv-treated pts ≥65 yrs derived an improvement in PFS compared to Pl (Bv 7.5: HR 0.71, p 0.023; Bv 15: HR 0.84, p= 0.25). ORRs were 40%, 29% and 30% for pts ≥65 in the Bv 7.5, Bv 15 and Pl arms. Survival was similar in all treatment arms regardless of age, (pts ≥65 Bv 7.5 HR 0.84; Bv 15 HR 0.88, p=NS). Safety data were available for 284 pts ≥65 yrs and 702 pts <65 yrs. There were no safety signals of concern in older patients. Grade ≥3 toxicities occurred in 84%, 80% and 80% of older pts treated with Bv 7.5, Bv 15 and Pl. Pts ≥65 yrs had no episodes of severe hemoptysis, but in Bv 7.5 and Pl arms, were more likely to have other bleeding, compared to pts <65. The incidence of hypertension and febrile neutropenia were similar in pts ≥65 and <65 yrs. Treatment-related deaths were not increased in Bv-treated pts ≥65 yrs vs pts <65 yrs or in Bv-arms vs Pl. Conclusions: The PFS benefit from Bv-based treatment in the elderly subpopulation is similar to that observed in the overall patient population. No particular safety signals were identified in this population, suggesting acceptable tolerability of Bv in elderly pts in AVAiL.

[Table: see text]
Phase II randomized trial of erlotinib versus vinorelbine in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC) aged ≥70 years in Taiwan
Authors: Chen Y. , Tsai C. , Shih J. , Perng R. , Whang-Peng J.
Published: August 2020

8051

Background: Epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors, such as erlotinib, are effective against NSCLC, especially in East Asian patients. Single-agent chemotherapy, such as vinorelbine, is an appropriate treatment choice for elderly patients. Oral vinorelbine is more convenient for elderly patients than intravenous vinorelbine. The primary objective of this study was to compare the response rate of chemo-naïve, elderly patients with advanced NSCLC treated with daily erlotinib versus oral vinorelbine. Methods: Chemo-naïve Taiwanese patients aged ≥70 years with advanced NSCLC were enrolled and randomized (stratified by histology, smoking status, ECOG performance status, and gender) to receive either oral erlotinib 150mg/day or oral vinorelbine (60mg/m2 on days 1 and 8 of the first cycle and subsequently increased to 80mg/m2 every 3 weeks in the absence of grade 2 adverse events). From February 2007 to July 2008, 116 patients were enrolled. Results: By October 2008, 77 enrolled patients (n = 37 for erlotinib; n = 40 for vinorelbine) had completed 6 cycles of study treatment and were available for efficacy and safety analyses. Objective response rates were 21.6% (8/37) with erlotinib and 12.8% (5/39) with vinorelbine [95% CI -0.09–0.24 for the difference in response rate between arms]. Disease control rate was 70.3% with erlotinib and 56.4% with vinorelbine [95% CI -0.09–0.34 for the difference in disease control rate between arms; p = 0.216). Median time to disease progression was 4.4 months [95% CI 4.1–5.4] with erlotinib, compared with 3.9 months [95% CI 2.4–6.9] with vinorelbine, p = 0.6069. The most common treatment-related toxicities were skin rash and diarrhea with erlotinib, and diarrhea and nausea with vinorelbine. Conclusions: Erlotinib is effective and well tolerated compared with oral vinorelbine in elderly, chemo-naïve, Taiwanese patients with NSCLC. Updated efficacy and safety data will be presented.

[Table: see text]
Randomized phase II study of gefitinib alone or with simvastatin in previously treated advanced non-small cell lung cancer (NSCLC)
Authors: Han J. , Lee S. , Yun T. , Moon Y. , Park I. , Kim H. , Lee J.
Published: August 2020

8057

Background: Statins reduce not only serum cholesterol levels but also mevalonate synthesis by inhibiting HMG-CoA reductase. Mevalonate is a precursor of several cellular major products including dolichol, geranylpyrophosphate (GPP) and farnesyl-pyrophosphate (FPP). Dolichol has a stimulatory effect on DNA synthesis and is linked to several tumor cell proteins. GPP and FPP cause isoprenylation of Ras and Rho those regulate signal transduction of several membrane receptors crucial for cell proliferation, differentiation, and apoptosis, which result in resistance to gefitinib. Thus depletion of mevalonate metabolites may enhance gefitinib activity in NSCLC. This study compared gefitinib alone with gefitinib plus simvastatin in patients with recurrent NSCLC after at least one chemotherapy. Methods: Between May 2006 and September 2008, 107 patients (51% male, 74% adenocarcinoma, 50% never-smoker, 54% more than two prior regimens) were randomly assigned to gefitinib alone (250 mg/d orally, n=53) or gefitinib plus simvastatin (250mg/d and 40 mg/d orally, respectively, n=54). A cycle was considered as 4 weeks of treatment. Therapy was continued until disease progression or intolerable toxicities. The primary end point was to assess response rate. Secondary end points included time to progression and survival. Median follow-up was 10.1 months. Results: Efficacy was similar for gefitinib and gefitinib plus simvastatin groups. Objective tumor response rates (RR) were 31.5% (95% CI, 19.1 to 43.9) and 32.1% (95% CI, 19.5 to 44.7); median PFS were 1.9 and 2.0 months; and median OS were 9.5 and 12.7 months, respectively. In subgroup analysis, gefitinib plus simvastatin showed a trend for higher RR than gefitinib alone in non-adenocarcinoma group (38.5% vs. 7.7%, p=0.08). Adverse events at both arms were generally mild (grade 1 or 2) and consisted mainly of skin reactions. Conclusions: Gefitinib combined with simvastatin did not improved efficacy compared to gefitinib alone in this unselected patient population, but showed a trend for higher efficacy in non-adenocarcinoma patients. Although it is preliminary, gefitinib combined with simvastatin showed slightly increased OS. Updated survival data will be presented.

No significant financial relationships to disclose.
Everolimus, an mTOR inhibitor, in combination with docetaxel for recurrent/refractory NSCLC: A phase I study
Authors: Khuri F. R. , Harvey R. D. , Saba N. F. , Owonikoko T. K. , Kauh J. , Shin D. M. , Sun S. Y. , Browning K. M. , Tighiouart M. , Ramalingam S. S.
Published: August 2020

8060

Background: The mammalian target of rapamycin (mTOR) pathway is a key cell-signaling cascade that is aberrantly activated in non-small cell lung cancer (NSCLC). Everolimus (E), an mTOR inhibitor, is active as monotherapy for advanced NSCLC. Based on preclinical synergy between everolimus and docetaxel (D), we conducted a phase I and feasibility study with the combination. Methods: Patients with stage IIIB/IV NSCLC, progression following prior platinum-based chemotherapy and ECOG performance status (PS) of 0–2 were eligible. Sequential cohorts of patients were treated with increasing doses of D (day 1) and E (PO QD, days 1–19). Treatment cycles (C) were repeated every 3 weeks. A standard ‘up and down’ dose escalation scheme was utilized. The primary endpoint was determination of optimal dose of the two agents that can be administered in combination. Results: Twenty three patients were enrolled. Median age - 62 yrs; Females- 11; ECOG PS: 0–6; 1 -16; # of prior regimens: 1–12, 2–6, ≥3 -5. At dose level 1 (D- 60 mg/m2, E- 5mg), none of 6 patients had DLT. Four out of 12 patients at dose level 2 (D-75 mg/m2, E-5 mg) had fever with gr 3/4 neutropenia during cycle 1. At dose level 3 (D- 75 mg/m2, E- 7.5 mg), 2 of 3 pts had DLT (fever with neutropenia and grade 3 mucositis). Pharmacokinetic (PK) sampling was performed on days 1 (n=14), 8 (n=9), and 15 (n=10) of cycle 1. Mean E half-life (hr) on days 1, 8, and 15 were 9.66 (2–14), 12.6 (2.2–21.1), and 14.8 (2–21.2), respectively. E accumulation occurred and was greater than expected. In contrast to the mean predicted accumulation factor (R) based on AUC of 1.22 (1–1.44), actual R on day 8 and 15 were 1.78 (0.72–3.17) and 1.88 (0.37–3.3) respectively. Among 20 pts. evaluable for response, 1 had a partial response and 10 had disease stabilization. Six patients completed 6 cycles of combination therapy and continued on E as maintenance. Conclusions: The recommended doses of docetaxel and everolimus that can be administered as a combination are 60 mg/m2 and 5 mg PO QD respectively. The PK characteristics of everolimus appear unaffected by co-administration with docetaxel. Promising anti-cancer activity was noted with clinical benefit in 55% of the pts. A phase II study has been initiated with the combination in refractory NSCLC. Supported by NCI 5 P01 CA116676.

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Phase IIb/III double-blind randomized trial of BIBW 2992, an irreversible, dual inhibitor of EGFR and HER2 plus best supportive care (BSC) versus placebo plus BSC in patients with NSCLC failing 1–2 lines of chemotherapy (CT) and erlotinib or gefitinib (LUX- Lung1): A preliminary report
Authors: Yang C. , Hirsh V. , Cadranel J. , Chen Y. , Park K. , Kim S. , Chao T. , Oberdick M. , Shahidi M. , Miller V.
Published: August 2020

8062

Background: No approved therapy exists for NSCLC patients (pts) who have failed chemotherapy (CT) and the reversible epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), erlotinib (E) or gefitinib (G). The efficacy of BIBW 2992 (Tovok), a potent, irreversible inhibitor of EGFR and human epidermal growth factor receptor 2 (HER2) with preclinical activity against the secondary resistance mutation T790M, in pts progressing after initial clinical benefit on E/G is being assessed in this randomized trial. Methods: Pts with advanced adenocarcinoma of the lung (Stage IIIB/IV; ECOG 0–2), who have failed one or two lines of CT (including platinum) and progressed following at least 12 weeks of E or G are randomized in a 2:1 ratio to receive BSC plus either oral BIBW 2992 50 mg qd or placebo until disease progression or unacceptable toxicity. Primary endpoint is overall survival, with progression-free survival, objective response and clinical benefit rate and duration, safety and quality of life being secondary endpoints. Enrollment of 400 pts is planned (HR=0.70, 85% power). An unblinded interim analysis of tumor response and safety by the independent Data Monitoring Committee (DMC) after the first 40 evaluable pts treated with BIBW 2992 will determine continuation to full accrual. Results: From May to November 2008, 145 pts have been randomized and 76 are still on treatment. Demographics (n=145): median age 59 (range: 30–82); female 68%, current/ex-smokers 38%; metastatic disease 91%, ECOG 0–1 92%; Asian origin 68%. 50% had one prior line of CT. Main prior EGFR-TKI was G in Asians (70%) and E in non-Asians (85%). 40% of pts had achieved a PR or CR on previous treatment with E/G. Duration of prior E/G treatment was >24 weeks and >48 weeks in 80% and 40% of pts, respectively. As expected, diarrhea, rash, anorexia, stomatitis, paronychia, nausea and vomiting were the most frequently observed adverse events. Conclusions: The trial is continuing recruitment after DMC review of efficacy and safety and updated demographics and blinded safety data will be reported.

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Efficacy and safety of PF-00299804 (PF299) in patients (pt) with advanced NSCLC after failure of at least one prior chemotherapy regimen and prior treatment with erlotinib (E): A two-arm, phase II trial
Authors: Janne P. A. , Reckamp K. , Koczywas M. , Engelman J. A. , Camidge D. R. , Rajan A. , Khuri F. , Liang J. Q. , O'Connell J. , Giaccone G.
Published: August 2020

8063

Background: Options are limited for pts with NSCLC following chemotherapy and E. PF299 is an oral irreversible small molecule inhibitor of the HER-1,-2, and -4 tyrosine kinases. Based on non-clinical and phase I NSCLC data, this ongoing phase II U.S. trial evaluates PF299 in pts with NSCLC (KRAS wild-type) who have progressive disease after at least 1 prior chemotherapy regimen and after E. Methods: Pts were enrolled by histology: adenocarcinoma (Arm A) and non-adenocarcinoma (Arm B), and received PF299 45 mg QD. Endpoints include objective response rate, duration of response, progression-free survival, survival, safety/tolerability, and pharmacokinetics. Pharmacodynamic endpoints include assessment of serum levels of HER2 and EGFR extracellular domains. Tissue and blood KRAS assays, and EGFR studies on available tissue, are also being performed. Forty-four and 22 response-evaluable pts were planned to be enrolled into Arms A and B respectively. Results: Thirty-four pts with progressive NSCLC (25 female, 14 smoker) have enrolled to date (Arm A: 30; Arm B: 4): median duration of prior E: 11.5 months; median time since E: 2.5 months. Among 20 response-evaluable pts, stable disease (SD) was observed in 9/18 pts in Arm A, and 1/2 pts in Arm B: median duration of SD: 11.5 weeks [range 6+, 32+ weeks]. Observation of disease control included pts who had recently (≤8 weeks) discontinued E; and also pts whose tumor had known EGFR T790M mutations. At time of data cutoff, confirmation per RECIST of 2 partial responses is pending. The most common treatment-related AEs were skin and gastrointestinal disorders, with grade 3 AEs in 19% and 13% of pts, respectively. Two pts experienced grade 4 pulmonary embolus/dyspnea deemed possibly treatment-related, both in the setting of progressive disease. Conclusions: PF299 shows encouraging activity in NSCLC pts after failure of prior chemotherapy and E. The AE profile was predictable and consistent with the prior phase I trial. At submission, enrollment in the adenocarcinoma arm is complete and enrollment in the non-adenocarcinoma arm continues; updated efficacy data and tumor characterization will be presented.

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Phase II trial of erlotinib in chemotherapy-naive women with advanced pulmonary adenocarcinoma
Authors: Jackman D. M. , Cioffredi L. , Lindeman N. I. , Morse L. K. , Lucca J. , Weckstein D. , Huberman M. S. , Lynch T. J. , Johnson B. E. , Janne P. A.
Published: August 2020

8065

Background: This single-arm phase II study explored the role of clinical characteristics (female gender, adenocarcinoma histology, no tobacco within 1 year) in selecting pts for 1st-line therapy w/ erlotinib. Available tissue for EGFR mutation analysis was required to assess its impact on outcomes. Methods: Eligible pts were chemotherapy-naïve women, stage IIIB/ IV, PS 0–2, adenocarcinoma, and w/ available tissue for analysis of EGFR mutation status. Pts received erlotinib 150 mg PO daily until disease progression or unacceptable toxicity. Primary endpoint was response rate (RR). Secondary endpoints included toxicity, time to progression (TTP), overall survival (OS), and impact of EGFR genotype on clinical outcomes. Results: From 11/04 - 12/08, 84 pts were treated. Median age 68 (range 34–88); 59 PS 0, 24 PS 1, 1 PS 2; race: 79 white, 3 Asian, 2 black; 16 pts had BAC or predominant BAC features; smoking status: 35 never, 49 former. Tox: Rash (90%; 21% grade 3) and diarrhea (69%; 7% grade 3) were the most common toxicities. 32 pts developed toxicity grade 3+ felt likely related to erlotinib. 2 deaths may be treatment-related (1 DIC, 1 hepatic failure). There were also 3 pts w/ PE's (1 fatal). Efficacy: Response (n=84): 0 CR, 27 PR (RR 32%), 27 SD, 23 PD. 7 pts not evaluable (5 tox, 1 non-progression death, 1 withdrawn consent). Median TTP was 5.6 months (95% CI 4.1–7.4 mos), and median OS was 22.7 months (95% CI 15.8 - 26.0 mos). At the time of analysis, there were 36 deaths, 16 pts on treatment w/o progression, and 5 pts lost to follow-up. Compared to smokers, never-smokers trended toward improved RR (43% vs 22%, p=.06), w/ improved TTP (HR .59; 95%CI .36-.96) but no improvement in OS (HR 1.15, 95%CI .58–2.27). Genotype had a more obvious impact on outcomes: compared w/ 37 known wild-type EGFR, 33 pts w/ known sensitizing mutations had a higher response rate (70% vs 0), and significantly improved hazard ratios for both TTP (.20, 95%CI .11-.36) and OS (.36, 95% CI .18 - .73). Results will be updated and outcomes for rarer mutations will be reported. Conclusions: Clinical characteristics may help select appropriate pts for first-line erlotinib when EGFR mutation status is unavailable. However, when available, EGFR genotype is superior to clinical phenotype in selecting pts for first-line erlotinib.

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Molecular bases for sensitivity to figitumumab (CP-751,871) in NSCLC
Authors: Gualberto A. , Dolled-Filhart M. P. , Hixon M. L. , Christensen J. , Rimm D. L. , Lee A. V. , Wang Y. , Pollak M. , Paz-Ares L. G. , Karp D. D.
Published: August 2020

8091

Background: Signaling of Insulin like Growth Factors (IGFs) through the IGF type 1 receptor (IGF-IR) induces tumor resistance to cancer therapy. Bioavailability of IGFs is regulated by IGF-binding proteins (IGFBP), of which IGFBP3 is the most abundant. Figitumumab (F) (CP-751,871), a specific IGF-IR inhibitor, has shown phase 2 activity in NSCLC in some histologies (i.e., squamous cell and adenocarcinoma) but not others (i.e, large cell or NOS tumors). Methods: Protein expression of members of the IGF-IR pathway, EGFR and differentiation markers was determined in core biopsies from 230 NSCLC pts, including 52 pts enrolled in F trials. Plasma concentration of IGF-1 and related proteins was determined in 159 NSCLC pts in F trials. Gene expression profiling was conducted in 35 NSCLC cell lines treated with F. Results: Squamous NSCLC had the highest IGF-IR expression (p=0.057). An association with better outcome was seen for E-cadherin expression (HR =0.62, 0.46–0.82 95% CI, p=0.005) and clustering by E-cadherin levels revealed a strong correlation between IGF-IR and EGFR expression in the high E-cadherin group (p<0.001). This subset included 73% of the squamous cell tumors investigated (N=44). Plasma levels of free IGF-1 (fIGF-1) were low and not predictive of response in squamous cell. In contrast, pts with adenocarcinoma had high plasma fIGF-1 levels (p=0.06) that correlated with vimentin expression (Rho=0.732, p=0.06), and both fIGF-1 and vimentin were predictive of F clinical benefit (p=0.03). Large cell/NOS NSCLC expressed the highest levels of vimentin (p<0.001) but had low E-cadherin and IGF-IR expression and low fIGF-1 plasma levels. Analysis of anchorage independent growth in NSCLC cell lines confirmed that F activity is independently associated to IGF-IR overexpression (p=0.02) and IGFBP3 under-expression (p=0.009). Conclusions: IGF-IR overexpression and increased free IGFs/low IGFBP are key independent mechanisms of sensitivity to F in NSCLC of squamous and adenocarcinoma cell histologies.

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Expression levels of total IGF-1R and sensitivity of NSCLC cells in vitro to an anti-IGF-1R antibody (R1507)
Authors: Gong Y. , Yao E. , Arcila M. , Frankel S. , Teruya-Feldstein J. , Zakowski M. , Thomas R. , Ladanyi M. , Pao W.
Published: August 2020

8095

Background: The IGF-1R (IGF receptor type 1) pathway is frequently deregulated in human tumors and has become a target of interest for anti-cancer therapy. We investigated predictive biomarkers of response to an anti-IGF-1R antibody (Ab) in vitro in NSCLC. Methods: We examined the growth inhibitory effects of R1507, a fully-humanized IgG1 anti-IGF-1R monoclonal Ab (Roche), against a panel of 22 NSCLC cell lines using CellTiter Blue assays. Phospho-receptor tyrosine kinase (pRTK) arrays and ELISAs were used to determine the status of IGF-1R and other RTKs. SNP arrays were used to determine IGF-1R copy number. Immunohistochemical (IHC) staining of total IGF-1R was performed with G11 (an anti-total IGF-1R Ab; Ventana) on a tissue microarray (TMA) containing 77 independent NSCLC tumor samples. Staining intensity was scored on a scale of 0 to 3+ by a pathologist (JF). Results: 5 of 22 NSCLC cell lines were moderately sensitive (25–50% growth inhibition) to R1507 alone. ELISA and pRTK array analysis demonstrated that pIGF-1R levels in the presence or absence of serum did not correlate with drug sensitivity. However, 4 of 5 sensitive lines displayed high levels of total IGF-1R vs 1/17 resistant lines (p=0.003 Fisher's Exact). SNP array analysis showed that sensitive lines also harbor relatively higher copy numbers of IGF-1R. There was no correlation with EGFR/KRAS mutational status. 48% of TMA NSCLC tumors had scores of 2+ or greater, while 5% were scored as 3+. Addition of erlotinib or paclitaxel to R1507 led to further growth inhibition in sensitive but not resistant lines. In one EGFR mutant lung adenocarcinoma cell line, R1507 and erlotinib co-treatment induced apoptosis, whereas treatment with either drug alone induced only cell cycle arrest. Apoptosis was mediated, in part, by the survival-related AKT pathway, as pAKT was significantly downregulated by R1507 but not erlotinib. Conclusions: In NSCLC cell lines, high levels of total IGF-1R are associated with moderate sensitivity to R1507. These results suggest a possible enrichment strategy for clinical trials with anti-IGF-1R therapy.

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