bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II study of amrubicin, a new active drug in refractory or relapsed small-cell lung cancer (SCLC): Thoracic Oncology Research Group Trial 0301
Authors: Seto T. , Masuda N. , Takiguchi Y. , Isobe H. , Okamoto H. , Ogura T. , Yokoyama A. , Watanabe K. , Eguchi K.
Published: March 2020

7060

Background: Amrubicin, a totally synthetic 9-aminoanthracycline, is a topoisomerase II inhibitor. The response rate to amrubicin at 45 mg/m2 on days 1–3 in chemotherapy-naive patients with extensive stage SCLC was 75.8% on an intent-to-treat analysis, with major dose-limiting toxicities of neutropenia, anemia, thrombocytopenia, and anorexia. The very high activity of amrubicin as a single agent in this disease led us to carry out the phase II trial reported here, which was designed to determine the antitumor activity and toxicity of amrubicin in previously treated pts with SCLC. Methods: Pts with cytologically or histologically proven SCLC who were previously treated with at least one platinum-based chemotherapy and ECOG PS 0–2 were eligible. They received amrubicin 40mg/m2 intravenously on days 1–3 every 3 weeks. The primary end-point was the response rate, which determined the sample size of 44 pts in the sensitive cases and 15 pts in the refractory cases, respectively. Secondary objectives were to determine the progression-free survival, overall survival, and 1-year survival rate. Results: In total, 60 pts consisting of 44 sensitive cases and 16 refractory cases with median age 67 years (range 52–79) and 46 out of 60 male were enrolled. The median treatment cycles were 4 (1–8). Grade 3/4 hematological toxicity per patient (pt) was neutropenia (83%), thrombocytopenia (20%) and anemia (33%). Febrile neutropenia was observed in 3 pts. Grade 3/4 non-hematological toxicity per pt was pneumonia (3%), anorexia (15%), low Na levels (8.3%), pneumonitis (1.7%) and cerebral hemorrhage (1.7%). No treatment-related death was observed. The overall response rates were 52% (95% CI: 37–68) in the sensitive cases, and 50% (95% CI: 25–75) in the refractory cases. The progression-free survival, overall survival and 1-year survival in the sensitive cases and the refractory cases were 4.0 and 3.2 months, 11.7 and 10.9 months and 48.2 and 37.8%, respectively. Conclusions: Amrubicin has a significant activity in SCLC, particularly in pts refractory to prior chemotherapy, with predictable and manageable toxicities. Further studies to evaluate the survival benefit of amrubicin in this setting are warranted.

No significant financial relationships to disclose.
A phase II, multicenter, randomized clinical trial to evaluate the efficacy and safety of bevacizumab in combination with either chemotherapy (docetaxel or pemetrexed) or erlotinib hydrochloride compared with chemotherapy alone for treatment of recurrent or refractory non-small cell lung cancer
Authors: Fehrenbacher L. , O’Neill V. , Belani C. P. , Bonomi P. , Hart L. , Melnyk O. , Sandler A. , Ramies D. , Herbst R. S.
Published: March 2020

7062

Background: Bevacizumab is a recombinant, humanized anti-VEGF MAb. Erlotinib is a potent, reversible, highly selective and orally available EGFR tyrosine-kinase inhibitor. Both compounds have demonstrated a survival benefit in the treatment of NSCLC: bevacizumab when added to chemotherapy in the first line setting, and erlotinib when given alone in the 2nd/3rd line. In addition, a single arm phase I/II study of the combination of bevacizumab and erlotinib has shown encouraging survival and response rate data, with a favorable safety profile (Sandler et al, PASCO 2004). Methods: A multicenter, randomized phase II trial was conducted to evaluate the safety of combining bevacizumab with chemotherapy (docetaxel or pemetrexed), or with erlotinib; and to make a preliminary assessment of the efficacy of combining bevacizumab with chemotherapy or erlotinib relative to chemotherapy alone, as measured by progression-free survival. All patients had histologically confirmed non-squamous NSCLC and had experienced disease progression (clinical or radiological) during or following one platinum-based regimen for advanced stage disease. Randomization was on a 1:1:1 basis to docetaxel or pemetrexed plus placebo (arm 1) v docetaxel or pemetrexed plus bevacizumab (arm 2) v bevacizumab plus erlotinib (arm 3). Patients remained in the treatment phase of the study until documented radiographic or clinical disease progression or through 52 weeks of study treatment. Results: Between August 2004 and November 2005, 120 patients were randomized and treated. To date, there have been 68/85 required PFS events; arms 1 and 2 therefore remain blinded. Demographics from the first 85 patients for arms 1 & 2 v 3 are as follows: median age 65 v 68;% male/female 64/36 v 44/56; ethnicity % white/black/asian/other 83/12/2/3 v 74/15/4/7; % ECOG PS 0/1/2 46/52/2 v 50/50/0; % adenocarcinoma/BAC&BAC-like/Other 67/7/26 v 69/8/23; % current/previous/never-smoker 15/71/14 v 11/74/15. Conclusions: Efficacy and safety results will be presented at the meeting.

[Table: see text]
EGFR mutations detected by high-resolution melting analysis (HRMA) as a predictor of response and survival in non-small cell lung cancer (NSCLC) patients treated with gefitinib
Authors: Takano T. , Ohe Y. , Furuta K. , Tsuta K. , Nomoto K. , Matsuno Y. , Fukui T. , Sekine I. , Kunitoh H. , Tamura T.
Published: March 2020

7075

Background: Recent studies have shown that EGFR mutations, mainly deletions in exon 19 (DEL) and L858R, are associated with gefitinib sensitivity in patients (pts) with NSCLC. We established a new easy method, using high-resolution melting analysis (HRMA), for detecting DEL and L858R mutations even from small biopsy or cytology samples, and evaluated the significance of EGFR mutations in NSCLC on a larger scale. Methods: Among 364 advanced or recurrent NSCLC pts treated with gefitinib between Jul 2002 and Dec 2004, HRMA was performed in 207 pts from whom specimens were available. DNA extracted from the archival tissue or cytology samples not subjected to microdissection was analyzed to detect DEL and L858R using HR-1 (Idaho Technology), an HRMA device. To validate this method, the results were compared with direct sequencing data obtained from microdissected tumor cells from surgical specimens in 66 pts. Results: Tissue/cytology/both samples were analyzed in 91/77/39 pts. EGFR mutations were detected in 85 (41%; DEL/L858R: 49/36) of the 207 pts. In the comparison with direct sequencing, consistent results were obtained from all of the 66 tissue samples, while false negative results were obtained in 2 of the 28 cytology samples. EGFR mutations were seen more frequently in women (54% vs. 31%; P = .001), never-smokers (53% vs. 32%; P = .002), and pts with adenocarcinoma (44% vs. 11%; P = .007). CR/PR/SD/PD was observed in 2/64/11/8 pts with EGFR mutations and in 0/10/23/89 pts with wild-type EGFR. The response rate (78% vs. 8%), time to progression (median, 9.1 vs. 1.6 months) and overall survival (median, 19.9 vs. 9.1 months) were all significantly superior in pts with EGFR mutations (P < .0001). Minor response and/or long SD (>6 months) was observed more frequently in SD pts with EGFR mutations than in those with wild-type EGFR (91% vs. 26%; P < .001). Among the pts with EGFR mutations, the response rate was significantly higher in the pts with DEL than in those with L858R (86% vs. 67%; P = .037). Conclusions: HRMA is a practical and precise method to detect DEL and L858R mutations. EGFR mutations strongly predict a better response and longer survival in NSCLC pts treated with gefitinib.

No significant financial relationships to disclose.
Topotecan: Weekly intravenous (IV) schedule similar to standard 5-day IV schedule as second-line therapy for relapsed small cell lung cancer (SCLC)—A Minnie Pearl Cancer Research Network phase II trial
Authors: Shipley D. L. , Hainsworth J. D. , Spigel D. R. , Gray J. R. , Barton J. H. , Switzer A. , Nicolau M. , Marsland T. , Joseph G. , Greco F. A.
Published: March 2020

7083

Background: Topotecan IV weekly produces significantly less myelotoxicity than the standard 5-day IV schedule and appears as active as the 5-day schedule in patients (pts) with relapsed ovarian cancer. Topotecan 5-day IV schedule is the standard for second-line therapy for sensitive relapse SCLC. Methods: The primary endpoints of this phase II trial were to determine the response rate and toxicity of topotecan IV weekly as second-line therapy in patients with sensitive relapse (SR) and resistant relapse (RR) SCLC. Topotecan 4mg/m2 IV over 30 minutes for 12 consecutive weeks was planned. Dose modifications were made based on toxicity. Pts were evaluated for response after 4 weeks; at least 3 weekly treatments were required to be evaluable. Results: A total of 103 pts (59 SR; 44 RR) were enrolled: 56 men, 48 women; age range 42–86 (median 65); performance status 0=18, 1=69, 2=16, 3=1. 47 pts with SR and 34 pts with RR were evaluable for response by WHO criteria. For SR, 3 pts had partial response (6.4%, 95% CI 1.3%-17.5%), 17 pts had stable disease (7 had minor responses with tumor shrinkage of 39%, 27%, 21%, 20%, 20%, 7%, and 3%, respectively). Using RECIST criteria 5 pts had PR (13%, 95% CI 6%-25%). For RR, 1 pt had a CR (3%, 95% CI 0.1%-15.3%), 6 pts had stable disease (2 had minor responses with 36%, 5% tumor shrinkage). Grade 3/4 neutropenia/thrombocytopenia was seen in 17 and 22pts, grade 3 infection 6 pts; grade 3/4 fatigue 16 pts. There was 1 treatment-related death. Median and 1-year survival for all patients was 4.5 months (SR = 5.6 months; RR 3.2 months, p = 0.05) and 19% (SR = 22%; RR = 10%). There was no difference in survival for PR versus stable pts, and PR/stable had 1-year survival of 46% compared to PD of 9% (p < 0.0001). Conclusions: Topotecan IV weekly has similar activity to the standard 5-day IV schedule in SR SCLC, and considerably less myelotoxicity. These data support the weekly schedule for standard therapy of SR SCLC, and further study of weekly topotecan as a component of combination therapy for SCLC.

[Table: see text]
Safety and pharmacokinetics (PK) of AMG 706, panitumumab, and carboplatin/paclitaxel (CP) for the treatment of patients (pts) with advanced non-small cell lung cancer (NSCLC)
Authors: Blumenschein G. , Sandler A. , O’Rourke T. , Eschenberg M. , Sun Y. , Gladish G. , Salgia R. , Alden C. , Herbst R. S. , Reckamp K.
Published: March 2020

7119

Introduction: AMG 706 is an investigational, oral, multi-kinase inhibitor with both antiangiogenic and direct antitumor activity targeting VEGF, PDGF, and Kit receptors. Panitumumab, a fully human monoclonal antibody directed against the epidermal growth factor receptor (EGFr), has shown antitumor activity and acceptable safety in pts with solid tumors. Methods: This is an ongoing, multicenter, dose finding, phase 1b study of AMG 706 with panitumumab and CP in pts with advanced NSCLC. Primary objectives were to assess the safety and PK of AMG 706; secondary objectives included drug exposure and objective response rates. Pts had stage IIIB/IV NSCLC, ECOG score of 0–1, no symptomatic or untreated CNS metastases, and no prior chemotherapy for NSCLC (segments A&C) or ≤ 1 regimen for NSCLC (segment B). AMG 706 was given orally either QD (50 mg or 125 mg) or BID (75 mg) with CP Q3W (P:200 mg/m2; C: AUC = 6 mg/mL · min; Segment A), with panitumumab (9.0 mg/kg Q3W; Segment B), or with CP+ panitumumab (Segment C). AMG 706 was dosed continuously in 21-day cycles (days 3–21 in cycle 1; days 1–21 in cycle 2 and beyond); pts were sequentially enrolled into escalating AMG 706 dose cohorts. Results: As of 9/05, 22 pts were enrolled (10 in A, 12 in B) into AMG 706 dose cohorts of 50 mg and 125 mg QD. In A and B, respectively, 7 and 6 pts were men; median (range) age was 60.5 (60, 74) and 60.5 (55.7, 71.0). One pt in the 125 mg QD cohort in Segment B had grade (gr) 5 pneumonia. Treatment-related adverse events occurring in >5% of all patients are summarized ( table ). Preliminary data showed that AMG 706 PK profiles were similar when administered with CP either 30 min or 48 hrs apart. At 50 mg QD, there was no effect of AMG 706 on the PK of P. Conclusions: Preliminary data indicate that AMG 706 can be combined safely with CP or panitumumab in pts with advanced NSCLC and that there is no effect on the PK of AMG 706 or P. Updated data will be presented.

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Survival update for the phase III study of pemetrexed vs docetaxel in non-small cell lung cancer (NSCLC)
Authors: Demarinis F. , Paul S. , Hanna N. , Chang Yao Tsao T. , Adachi S. , Lim H. L.
Published: March 2020

7133

Background: Results from a large, randomized, phase III study of pemetrexed vs docetaxel as second-line treatment for advanced NSCLC indicated that pemetrexed, a novel multitargeted antifolate, has a median survival time (8.3 months) similar to that of docetaxel (7.9 months) with a more favorable safety profile [JCO 2004;22:1589–97]. This updated analysis reflects data available 23 months after the original analysis, which was performed Jan 2003 (after 519 deaths). Methods: Pts (n = 571) were randomized from March 2001 to Feb 2002 to receive either pemetrexed (500 mg/m2 IV infusion), supplemented with vitamin B12 injections and folic acid, or docetaxel (75 mg/m2 IV infusion) on day 1 of a 21-day cycle. An unadjusted survival analysis was performed and a Cox multiple regression analysis (n = 532) was done to adjust for factors (other than treatment intervention) that affected survival including ECOG performance status (PS), disease stage, and time since last chemotherapy. Percent retention was performed using the Rothmann method. Results: The updated survival analysis (performed after 519 deaths) indicated similar median survival times for pemetrexed (8.3 months; 95% CI: 7.0–9.4) and docetaxel (8.0 months; 95% CI: 6.6–9.3), and comparable hazard ratios (HR) (original 0.99 [95% CI: .82–1.20] vs updated 0.97 [95% CI: .81–1.15]). Percent of docetaxel benefit over best supportive care retained by pemetrexed was similar in both analyses: original 102% (95% CI: 52%-157%) vs updated 106% (95% CI: 68%-163%). Cox multiple regression analysis again showed that the two drugs were similar in survival after adjusting for factors significantly associated with increased survival. Conclusions: These updated survival analyses consistently demonstrate that second-line pemetrexed has similar survival to docetaxel in pts with NSCLC. Given the continued finding of comparable therapeutic efficacy, pemetrexed may be considered a standard second line therapy.

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[Table: see text]
Circulating molecular markers in predicting radiation-induced lung damage
Authors: Zhao L. , Kong F. , Hayman J. , Kalemkarian G. , Arenberg D. , Lysons S. , Curtis J. , Cease K. , Brenner D. , Lawrence T.
Published: March 2020

7144

Background: We hypothesized that circulating molecular markers such as transforming growth factor-beta1 (TGF-β1), interleukin-6 (IL-6), and angiotensin-converting enzyme (ACE) change early during the course of radiotherapy (RT), and that such changes precede RILD after completion of the therapy. Methods and Materials: Patients with stage I-III NSCLC treated with RT (11) or chemoRT (15) (enrolled onto two prospective clinical trials) were included in this study. Serum and platelet poor plasma were obtained prior to (Pre-RT), at 40–50 Gy (during-RT), and at the end of RT (end-RT). The plasma TGF-β1 and IL-6 and serum ACE levels were measured using molecule specific enzyme-linked immunosorbent assays. The endpoints for RILD were ≥ grade 2 radiation pneumonitis (RP) and measures of pulmonary function tests such as forced vital capacity (FVC), forced expiratory volume in the 1st second (FEV1), and diffusing capacity for carbon monoxide (DLCO). The minimal follow-up duration was 3 months. Data is presented as mean ± standard deviation; student t-test was used for significant analysis. Results: Plasma TGF-β1 and IL-6 levels changed remarkably after 40–50 Gy of RT. The mean relative TGF-β1 levels (during-RT over pre-RT) were 1.9 ± 0.9 and 0.9 ± 0.6 in patients with and without RP (p = 0.010), respectively. There were no significant associations between changes of plasma IL-6 and ACE levels and the occurrence of RP. Significant DLCO reduction was observed at 3 months after RT in almost every patient, and such reduction was significantly more remarkable in those who had radiation induced elevation in plasma IL-6 levels (34.8 ± 15.9% versus 15.6 ± 14.5%, p = 0.045). Interestingly, the pre-RT ACE level was significantly associated with changes of FEV1 (p = 0.037) and FVC (p = 0.014): improvement of 13.2 ± 12.0% and 11.0 ± 9.0% versus reduction of 7.6 ± 17.0% and 10.8 ± 17.7% for patients with high versus low levels, respectively. Conclusion: Radiation induced elevation in circulating TGF-β1 and IL-6 levels may be predictive of RILD, while serum ACE level may be associated with decreased risk of RILD.

No significant financial relationships to disclose.
Prevalence of pre-existing conditions and incidence of new medical conditions after diagnosis of non-small cell lung cancer
Authors: Koo L. C. , De Lissovoy G. , Hanna N. L. , Lyidick E. , Lambe M. , Higenbottam T. , Steinberg M. H. , Langmuir P.
Published: March 2020

7152

Background: Patients with non-small cell lung cancer (NSCLC) are likely to have concurrent disease that affects treatment/prognosis. Estimates on the: 1) prevalence of pre-existing co-morbidities provides background information for clinical trials and patients, and 2) incidence of new conditions post diagnosis improves understanding of disease progression, treatment effects, and adverse event reports. Methods: Patients aged ≥66 with a primary diagnosis of NSCLC from 1991–1999 were identified in the SEER- Medicare linked database. ICD-9 codes from medical service claims (≥2) were analyzed to estimate comorbidity rates. Results: In the 12 months prior to NSCLC diagnosis, the prevalence for ischemic heart disease, cardiac dysrhythmias, and heart failure were 14%, 9%, and 8% respectively– indicating a substantial proportion of patients who might be poor candidates for surgery or cardio-toxic treatments. These prevalence estimates are likely to underestimate true prevalence due to the 1-year window of observation. For all 9 medical conditions, the incidence rates for new conditions were as much as 2 to 3 times higher than the prevalence rates for the same comorbidity before diagnosis. Conclusions: NSCLC patients have high prevalence of cardio-vascular conditions prior to diagnosis and many new medical conditions are detected post diagnosis as a result of increased detection, disease progression, and treatment.

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A phase II study of gefitinib as first line treatment for good performance advanced or metastatic non-small cell lung cancer in East Asian patients
Authors: Yang C. , Yu C. , Chen K. , Lin Z. , Kuo S. , Hwang T. , Cheng A. , Yang P.
Published: March 2020

7167

Background: Gefitinib is an effective treatment for chemotherapy-treated nonsmall cell lung cancer (NSCLC) in East Asian patients. There were only limited prospective studies on the use of gefitinib in chemonaive advanced or metastatic NSCLC patients. Methods: Eligibility included histological or cytological proven chemonaive stage IIIB/IV NSCLC, measurable disease, ECOG performance status of 0–2, good organ functions and candidate for platinum-based chemotherapy. Patients were treated with 250mg gefitinib per day. Tumor assessments were performed every two months by RECIST criteria. Responding patients were treated until progression. Patients with stable disease more than 2 months may continue treatment or shift to chemotherapy. The primary objective of this study was overall response rate of patients. Secondary objectives included 1-year progression-free survival, overall survival, and ancillary biomarker studies. Simon’s two-stage design was used to aim at a response rate more than 20%. Forty-four patients were planned in stage one and the study will be terminated if 5 or less patients responded to the treatment. A total of 106 patients are planned. Results: The planned interim analysis on the first 44 patients is reported here. There were 13 male and 31 female, median age was 63 (range 39–86), ECOG performance status of 0/1/2 were 0/40/4. 33 patients were nonsmokers. 39 patients had adenocarcinoma. The side effects of the treatment were mild and well accepted by patients. There were 24/9/10/1 patients with PR/SD/PD/NE. Overall response rate was 54.5% and disease control rate was 75%. The response rates for female / adenocarcinoma / nonsmoker were 58%/59%/61% respectively. The response rates for male / non-adenocarcinoma / smoker patients were 46%/20%/36%. The median time to progression for all patients was 6.3 months. Conclusions: Gefitinib is a very effective treatment for East Asian chemonaive advanced or metastatic NSCLC patients. Although the patients’ number was small, the response rates for patients with one unfavorable predictive factor were comparable to the response rates of patients receiving combination chemotherapy. The response rates and duration for 106 patients will be presented in the meeting.

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Final survival and safety results from a multicenter, open-label, phase IIIb trial of erlotinib in patients with advanced non-small cell lung cancer
Authors: O’Neill V. , Hainsworth J. , Spigel D. , Bloss J. D.
Published: March 2020

7169

Background: Erlotinib is an orally available, reversible inhibitor of the EGFR tyrosine kinase with a proven survival advantage for patients with locally advanced or metastatic NSCLC who have failed one prior chemotherapy regimen. Preliminary data suggest that never smokers respond particularly well, as assessed by both response and survival. Method: This is a phase IIIb, multicenter, open-label trial of erlotinib in patients with advanced NSCLC who have progressed following standard chemotherapy treatment. The trial allowed patients access to erlotinib therapy prior to FDA approval; patients could remain on study up to 9 months following approval. The co-primary objectives were best ORR (as assessed by investigator) and OS associated with erlotinib therapy in this group, and in patient subsets defined by tobacco history. Secondary objectives include evaluating safety; characterization of OS and RR in sub-populations, including histology, sex, ethnicity; duration of time on treatment. Patients and Treatment: Between August and November 2004, 229 patients were enrolled and treated. Erlotinib was given at the standard dose of 150mg once daily. Demographics are as follows: M/F% 60/40; median age 68 (27–90); ECOG PS% 0/1/2/3 25/44/23/7; squamous histology 34%, adenocarcinoma 45%; >1 prior regimen 47%; prior platinum 83%; never smoked 9%. Results: At the time of the final analysis (August 2005), 60% of subjects had died; data are therefore mature. Among the 229 treated subjects, the best ORR was 8.3% (CI: 5.2% - 12.4%). The ORR in never-smokers, previous smokers and current smokers was 28.6% (CI: 13.2% - 50.6%), 6.0% (CI: 3.0% - 10.4%) and 7.3% (CI: 2.0% - 19.0%), respectively. Median overall survival for all patients was 6.3 months (CI: 4.7 - 8.0). Median survival was 5.2 (CI: 4.2 - 7.3) and 6.3 months (CI: 3.6 - 9.2) in previous smokers and current smokers, respectively; and was not reached in never-smokers. Median duration of treatment was 10.6 weeks. One ILD-like event was reported (0.4%). Conclusions: No unexpected safety signals were seen. The observed ORR and survival data are consistent with the findings from the pivotal phase III randomized trial.

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Prognostic significance of EGFR FISH and IHC in non small-cell lung cancer patients treated with chemotherapy alone
Authors: Dziadziuszko R. , Holm B. , Skov B. G. , Osterlind K. , Franklin W. A. , Varella-Garcia M. , Bunn P. A. , Hirsch F. R.
Published: March 2020

7193

Background: High EGFR gene copy number by fluorescence in situ hybridization (FISH) predicts response and survival benefit in non small-cell lung cancer (NSCLC) patients (pts) treated with EGFR tyrosine-kinase inhibitors, but its prognostic value remains debated. We aimed to evaluate the association of EGFR FISH, EGFR immunohistochemistry (IHC) and prognosis in NSCLC pts treated with chemotherapy alone. Methods: 85 pts treated with platinum-containing chemotherapy (median follow up of 15 months [range: 2–29 months]) were included in the study. There were 47% females, 35% of pts with performance status (PS) 0, 53% PS = 1 and 12% PS = 2, 6% of never-smokers. Median age was 62 years (range: 41–80 years). Stage I-IIIA was diagnosed in 7%, stage IIIB - 44% and stage IV - 48% pts. Adenocarcinoma was the most common histology (51% pts). EGFR FISH was performed using LSI EGFR SpectrumOrange/CEP 7 SpectrumGreen probe and IHC using DAKO PharmDx kit. Results: FISH results were available in 79 pts (93%), and EGFR FISH-positive tumors (high polysomy or gene amplification) were found in 28 pts (35%). IHC results were available in 81 pts (95%) and 25 pts (31%) were scored as positive (staining index ≥200). Distribution of clinical characteristics did not differ according to either FISH or IHC result. FISH-positive pts had higher EGFR IHC staining indices as compared with FISH-negative pts (median 160 vs. 60, p = 0.005, Mann-Whitney U test). Median survival of FISH-positive pts was 12.6 months vs. 8.1 months in FISH-negative pts (log-rank p = 0.68; HR = 0.88 [95% CI: 0.49–1.59]) and the respective figures for progression-free survival (PFS) were 7.5 vs. 4.9 months, log-rank p = 0.72; HR = 0.91 [95% CI: 0.55–1.51]. Median survival in IHC-positive vs. IHC-negative pts was 6.6 months vs. 9.2 months (log-rank p = 0.44; HR = 1.27 [95% CI: 0.69–2.36]). There was no significant difference in PFS (median of 4.8 vs. 5.3 months, respectively; log-rank p = 0.71; HR = 1.11 [95% CI: 0.64–1.92]). FISH and IHC remained insignificant in a Cox regression survival analysis. Conclusion: In this cohort of NSCLC patients treated with chemotherapy alone, EGFR FISH was associated with EGFR IHC and both features had no statistically significant influence on prognosis.

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Extrapulmonary findings detected in a low-dose spiral computed tomography (sCT) early detection study for lung cancer (LC)
Authors: Ricardi U. , Novello S. , Cardinale L. , Crida B. , Perotto F. , Sperone P. , Borasio P. , Giajlevra M. , Selvaggi G. , Scagliotti G. V.
Published: March 2020

7206

Background: In 2001 a feasibility study testing low-dose sCT as an early diagnosis tool in asymptomatic volunteers at high risk for lung cancer was planned and initiated at our institution with an evaluation at baseline and then annually for 5 years. Subjects & Methods: We enrolled 520 asymptomatic volunteers, 73% males, aged 55 years or older (median age 60 yrs), with at least 20 pack-years of cigarette smoking and no previous cancer. Results: At baseline, one hundred forty-four extra-pulmonary findings (28%) were detected. The more common findings were: radiologically-detected adrenal enlargements (19%); thyroid struma (8%); hepatic abnormalities, like angiomas, cysts, calcifications, steatosis (29%); renal alterations, like cysts, lithiasis, vascular calcifications and one case of stage I renal carcinoma (21%); spleen abnormalities, like cysts, calcifications, accessory spleen (5%); cholelithiasis (4%); pancreatic alterations (1%); thymic nodules (1%); axillary adenopathy (5%); aortic ectasia or aneurysm (5%) and one breast nodule. In 2 cases (renal carcinoma and breast nodule) a surgical resection was performed. All these findings were followed up through a letter to the general practitioner. In 62 subjects the initial findings were considered worth of further imaging investigations or were suggestive for a clinically definite disease (e.g. renal carcinoma). In the remaining 82, mainly based on personal history data, the abnormalities were already known and previously diagnosed. Globally, the cumulative number of extrapulmonary findings from 2nd to 5th year was 275 and the more common findings were: cysts (hepatic 9%, renal 13%), lithiasis (renal 1%, hepatic 5%), thyroid struma 4%, adrenal adenomas 3%, vascular calcifications 37%, aneurysm 3%, vertebral artropathy 2%. Conclusions: Even if early detection of lung cancer will result in a survival benefit, in the cost-effectiveness analyses the additional costs from the detection of extra-pulmonary findings should also be carefully considered because in many cases they may request substantial outpatient clinic admissions and further diagnostic investigations.

No significant financial relationships to disclose.
Correlation between the presence of lectin binding sites of pulmonary adenocarcinoma cells and their metastatic cells
Authors: Thöm I. , Schult-Kronefeld O. , Burkholder I. , Görn M. , Andritzky B. , Kugler C. , Edler L. , Schumacher U. , Laack E. , Bokemeyer C.
Published: March 2020

7212

Background: During tumor progression to metastasis, the aberrant glycosylation of tumor cell membrane glycoconjugates plays a key role. These changes can be detected histochemically by the use of lectins. The aim of the present investigation was to analyze a possible association between the presence of lectin binding sites of pulmonary adenocarcinoma cells and their lymph node and hematogenous metastatic cells. Methods: For this purpose, the expression of HPA-, PHA-L- and UEA-I binding sites were assessed in primary tumors, lymph node metastases and hematogenous metastases of 96 patients with metastatic adenocarcinomas of the lung who underwent surgery between 1999 and 2002. Results: We found a significant positive correlation between the binding of the lectins HPA (p = 0.002), PHA-L (p < 0.00001) and UEA-I (p < 0.00001) to the cells of the primary tumor and to its lymph node metastases. There was positive correlation between the binding of HPA to the cells of the primary tumor and the hematogenous metastases as well. Conclusion: We are the first to demonstrate a positive correlation between the binding of the lectins HPA, PHA-L and UEA-I to the cells of the primary tumor and to its lymph node metastases. Expression of HPA bindig sites is also preserved in the hematogenous metastases in metastatic disease. Our results support the hypothesis that the aberrant glycolsylation of tumor cell membrane glycoconjugates is involved in the metastatic spread of tumors.

No significant financial relationships to disclose.
Prognostic significance of clinical features and Akt activation in the survival of patients with bronchioloalveolar carcinoma (BAC)
Authors: Ballas M. S. , Tsurutani J. , Steinberg S. , Robertson M. , Egilsson V. , Dennis P. A.
Published: March 2020

7217

Background: Lung cancer is the leading cause of cancer related mortality in the world. BAC is a subset of NSCLC that has recently gained attention because of enhanced efficacy of epidermal growth factor receptor (EGFR) inhibitors in this population. Prognostic features for BAC have not been well defined. Because activation of Akt is a poor prognostic factor for other types of NSCLC, and because changes in Akt may predict outcome for EGFR inhibitors, we assessed the prognostic significance of clinical features and Akt activation in patients with BAC. Methods: 46 cases of BAC were classified according to WHO 2001 criteria. Akt activation was assessed using immunohistochemistry. Associations between ordered Akt levels and other dichotomous parameters were evaluated using an exact Cochran-Armitage test for trend. Survival was analyzed by the Kaplan-Meier method, and hazard ratios (HR) were determined based on Cox proportional hazard models. Results: Tissues from 45 patients were analyzed. Age and histology (mucinous vs. non-mucinous) were not associated with survival. Akt activation was observed in 63% of cases, but was not associated with differences in survival. Complete clinical data (except smoking) were available for 43 patients, and smoking history was available for 31 patients (8 never-smokers, 23 smokers). Cox model analysis revealed that male gender (HR 2.24, 95% CI 1.07–4.71, p = 0.032) and advanced stage (III or IV) (HR 2.17, 95% CI 1.004–4.71, p = 0.049) were associated with a worse prognosis. A model limited only to the 31 patients with smoking data demonstrated that smoking alone (HR 6.89, 95% CI 1.49–31.88, p = 0.013) was associated with a worse prognosis. Conclusions: These studies identify gender, stage, and especially smoking status as potentially important prognostic features for BAC. Akt was not prognostic. Given that the recent NSCLC clinical trials with erlotinib and gefitinib that showed varying survival benefit did not stratify by smoking status and BAC, it is possible that these characteristics could have affected the clinical outcomes. Investigators studying EGFR inhibitors should consider stratifying by smoking status and BAC to determine if there are subsets of patients who could benefit most from these therapies.

No significant financial relationships to disclose.
A phase II, multicenter study of bendamustine HCl plus rituximab in relapsed indolent B-cell and mantle-cell non-Hodgkin’s lymphoma (NHL)
Authors: Williams M. E. , Cohen P. , Tulpule A. , Van der Jagt R. H. , Herst J. A. , Bessudo A. , Lemieux B. , Schwartzberg L. S. , Oliver J. W. , Robinson K. S.
Published: March 2020

7528

Background: Bendamustine HCl, a novel alkylating hybrid agent, has single-agent activity in multiple hematologic and solid tumors. In vitro data have demonstrated the multifunctional mechanisms of bendamustine by which cell death occurs via both apoptosis and mitotic catastrophe. Bendamustine has shown activity in NHL cell lines that are refractory to conventional alkylator chemotherapies. The combination of bendamustine and rituximab has shown a synergistic effect on NHL cells. The efficacy and safety of bendamustine in combination with rituximab in patients with relapsed NHL were evaluated. Methods: This phase II, multicenter study enrolled adult patients with relapsed, indolent, rituximab-sensitive B-cell or mantle-cell NHL. Patients received rituximab 375 mg/m2 IV on day 1 and bendamustine 90 mg/m2 IV on days 2 and 3 of a 28-day cycle for 4 to 6 cycles. An additional dose of rituximab 375 mg/m2 IV was given 1 week prior to the first cycle of bendamustine and 4 weeks after the last cycle. Results: The intent-to-treat population included 67 patients (57% males; median age, 60 years) with indolent NHL (81%) or mantle-cell NHL (16%) (data not available [3%]). A total of 81% of patients had stage III/IV disease. Patients had relapsed from a median of 1 prior therapy; 37% had prior treatment with rituximab. In the 57 evaluable patients, the overall objective response rate (ORR) was 87% (complete response [CR], 33%). The ORR for the 9 evaluable mantle-cell NHL patients was 89% (CR, 33%). For all patients, the median duration of response and progression-free survival had not been reached after a median follow-up of 3.7 months (range, 0–14.2 months). This therapy was well tolerated. Most commonly reported nonhematologic toxicities were grade 1/2 gastrointestinal events, with nausea being the greatest (38%). The primary grade 3/4 hematologic toxicity was neutropenia (29%), with 1 event of sepsis. Conclusions: Bendamustine in combination with rituximab was well tolerated and produced high response rates in patients with relapsed indolent and mantle-cell NHL. These results suggest bendamustine in combination with rituximab provides a potential benefit over single-agent rituximab therapy.

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A humanized antibody against CD40 (SGN-40) is well tolerated and active in non-Hodgkin’s lymphoma (NHL): Results of a phase I study
Authors: Forero-Torres A. , Furman R. R. , Rosenblatt J. D. , Younes A. , Harrop K. , Drachman J. G. , Advani R.
Published: March 2020

7534

Background: CD40 is a member of the TNF receptor family and is widely expressed on hematologic malignancies of B-cell origin. SGN-40 is a humanized antibody against CD40 with effector cell function and mild agonistic activity. Preclinical toxicity studies and efficacy data supported initiation of a multi-institutional phase I study to test the safety, pharmacokinetics, immunogenicity, and efficacy of SGN-40 in patients with relapsed NHL. Methods: Cohorts of 3–6 pts were treated weekly with a maximum dose of 2, 3, or 4 mg/kg/wk SGN-40. A dose escalation schedule is used such that patients receive 1 mg/kg on D1 and D4, 2 mg/kg on D8, and higher doses on weeks 3–5. Responding patients may receive a second cycle. Further dose escalation up to 8 mg/kg is planned. Results: 16 pts have been treated with multiple histologic subtypes: follicular (1), marginal zone (MZL; 1), mantle cell (4), and diffuse large B-cell (DLBCL; 10). One patient (2 mg/kg) developed a reversible Grade 3 unilateral conjunctivitis and ipsilateral loss of visual acuity. No other dose limiting toxicity has been observed up to 4 mg/kg. Preliminary pharmacokinetic data suggest that the antibody has a relatively short half-life, perhaps reflecting a route of elimination or binding that is not saturated at current doses. Two partial responses have been observed at 3 mg/kg (1 MZL, 1 DLBCL) and one partial response has been observed at 4 mg/kg dose (DLBCL relapsed after autologous stem cell transplant with small volume tumor). Conclusions: Using an intra-patient dose escalation schedule, SGN-40 has been well-tolerated at doses up to 4 mg/kg/wk. Further dose-escalation is ongoing to determine the maximum tolerated dose. Three objective responses have been seen, including two in patients with extensively treated aggressive disease. Correlative studies are underway measuring soluble CD40, cytokine release, effect of FcR polymorphisms, and SGN-40-induced immunogenicity. Given the favorable tolerability and activity, phase II studies in NHL are planned.

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CHOP/CHOEP-14 followed by consolidation with alemtuzumab in untreated aggressive T-cell lymphomas (DSHNHL 2003–1): Feasibility and toxicity of a phase II trial of the German High Grade Non-Hodgkin’s Lymphoma Group DSHNHL
Authors: Trumper L. H. , Hohloch K. , Kloess M. , Dührsen U. , Eimermacher H. , Haas A. , Aldaoud A. , Loeffler M. , Schmitz N. , Pfreundschuh M. , Binder C.
Published: March 2020

7538

Background: The clinical course of peripheral T-cell lymphomas (PTCL) is unfavourable. Treatment protocols developed for aggressive B-NHL are employed, with significantly worse outcomes. The MoAb alemtuzumab (CAM) has shown promising activity in T-NHL, although its use may be complicated by severe infections. Methods: In 2003, the DSHNHL group initiated a prospective multicenter phase II trial for previously untreated PTCL. Six cycles of either CHOEP-14 (< 60 y) or CHOP-14 (> 60 y) with G-CSF support are followed by a short consolidation course with CAM, when either a CR or a good PR has been achieved. Inclusion criteria: PTCL-NOS, AILD, intestinal T-NHL, anaplastic large cell T-NHL (ALK negative); age 18–70 y; all IPIs; ECOG PS 0–3. The primary endpoint is feasibility, measured by occurrence SAE and protocol adherence. Secondary endpoints are remission rate, TTF, OS, DFS, tumor control and TRM. CAM is given at a total dose of 133 mg over 4 weeks. Prophylaxis against PCP and herpes infections is mandatory during CAM therapy and is continued until CD 4 cells are > 200/μl. CMV-positive patients are monitored weekly. Results: 35 (of the planned 37) pts have been enrolled, 31 are evaluable. 5/31 pts are still undergoing chemotherapy. 7/31 pts had progressive disease or NC under/after chemotherapy and did not receive CAM. 18 of the 19 pts who achieved a CR/PR (15/4) received CAM. 12 of the CAM pts are in continuous CR, 7 had progressive disease or relapsed. There was no treatment-related death. Of 7 registered SAEs, 3 were related to chemotherapy, 4 to CAM (1 fungal pneumonia, 2 CMV pneumonias, 1 bacterial sepsis after dental procedure). Other CAM side effects were: Herpes Zoster (1), CMV-reactivation (1), grade III-IV neutropenias (2). All pts recovered with appropriate treatment. Conclusion: Preliminary analysis demonstrates that the combination of CHO/E/P-14 followed by a short course of CAM consolidation therapy is feasible without TRM. The adverse effects related to infections can be severe but manageable upon careful monitoring and close follow-up. The phase II trial will close in 4/2006, to be followed by a randomized phase III trial of A-CHOP-14 vs CHOP-14.

No significant financial relationships to disclose.
Adenovirus-interferon γ (TG1042) demonstrates good tolerance and efficacy in relapsing primary cutaneous lymphoma (PCL): Final results of a phase I/II multicentric trial
Authors: Urosevic M. , Gellrich S. , Dreno B. , Schiller M. , Dereure O. , Baudard M. , Bagot M. , Khammari A. , Bleuzen P. , Dummer R.
Published: March 2020

7539

Background: Interferons (IFNs), which can offset the Th2 dominance associated with PCL have been successfully used to treat these PCL. Intratumoral (i.t.) injection of TG1042 (a non-replicating recombinant adenovirus with a human IFNγ cDNA insert) induces high local production of IFNγ without severe toxicity associated with systemic delivery. Methods: We undertook a phase I/II multicentric trial of repeated, i.t. injections of TG1042 in patients with advanced primary T cell (CTCL) or B cell (CBCL) CL. One to 3 lesions were injected on day 1, 8, and 15 (a 4-week cycle) and thereafter up to 12 cycles. Immunohistochemistry and quantitative PCR were performed on injected lesions biopsied at baseline and after the 1st cycle. In the phase I, 18 patients were enrolled in 3 successive cohorts at the doses of 3 × 109 viral particles (vp) (n = 3), 3 × 1010 vp (n = 3) and 3 × 1011 vp (n = 12). In the phase II, 18 evaluable patients were planned to be treated at 3 × 1011 vp. Results: To date, enrollment is complete, 39 patients (32 CTCL and 7 CBCL) have been included, 9 of them are still on treatment. Patients received a median of 4 lines of prior therapy. 11 patients were at stage Ib and 16 patients at higher stage. Altogether, 245 injections of TG1042 have been administered. Treatment was well tolerated with 8 grade 3 related adverse events. Injection site reaction and flu like syndrome are the most common adverse events. Histology demonstrates pronounced changes in infiltrate patterns with signs of vasculitis, increased numbers of eosinophils, neutrophils, CD8 and TIA-1+ve cells. CD4/CD8 ratio decreased in most tumors. Transgene-IFNγ mRNA was detected in injected lesions. Gene expression analysis of biopsies and PBMC shows up-regulation of IFNγ genes. Local clinical response has been observed in 17 (including 9 complete responses [CR]) out of 31 evaluable patients. 13 global responses (7 CR) out of 30 evaluable patients have been observed. All 5 evaluable CBCL responded (3 CR). Conclusions: These results demonstrate that TG1042 is well tolerated and presents a potential significant benefit for the treatment of both CTCL and CBCL. A phase II is planned in patients with CBCL to confirm those encouraging results.

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Prospective, randomized, multicentre clinical trial on the use of interferon a 2a plus PUVA versus PUVA monotherapy in patients with cutaneous T-cell lymphoma, stages I and II
Authors: Stadler R. , Kremer A. , Luger T. , Sterry W.
Published: March 2020

7541

To further define the role of IFN in combination with PUVA we conducted this prospective, randomized, multicentre clinical trial, in cooperation with 26 departments of dermatology in Germany and Switzerland, comparing the efficacy and tolerability of the combination of IFN alfa plus PUVA versus PUVA alone. IFN alfa 2a was administered at 9 Mill units three times a week s.c. in the combination arm, photochemotherapy was applied after oral intake of 8-methoxypsoralen (0.6 mg/kg body weight) five times a week during the first weeks, three times a week from weeks 5 to 23, and twice a week from weeks 24 to 48, with escalating doses, beginning with 0.25J/cm2. Of 124 patients randomized in this trial stages I and II, 50 were evaluable in the PUVA arm and 43 in the IFN plus PUVA arm in total 93 patients. Overall 75% of all patients showed a complete remission, 79% in the combination arm and 72% in the PUVA arm. The primary response criteria of this randomized trial protocol as a rate of complete remissions was therefore statistically non significant. However, the total dose of meladinine to reach best response was significantly lower in the combination arm, in the IFN arm only 74% of the meladinine dose and 57% of the UVA dose was necessary to reach a complete remission in comparison to the PUVA arm. The follow-up period was defined was defined on time to progression and documentation maximal 12 months after best response. The medium follow-up duration is 101 weeks, the medium value 123.7 weeks. The Kaplan-Meyer graph analysis showed a significant difference towards the progression-free interval of the IFN PUVA arm (log-rank test; p = 0.0398, 2-sided, Wilcoxen test p = 0.0465). The results are based on 55 documented progressions of 93 patients. The medium progression-free time for the whole group is 63 weeks, for the PUVA arm 53 weeks, and in the combination arm 113 weeks. Based on these findings, we conclude that IFN alfa 2a plus oral photochemotherapy induces a high remission rate with less UVA dose compared to PUVA alone and doubles the progression-free time of CTCL, stages I and II. IFN and PUVA will be the first-line treatment in early CTCL of the EORTC treatment guidelines.

No significant financial relationships to disclose.
Impact of prior autologous stem cell transplant (ASCT) in patients receiving bortezomib or dexamethasone for relapsed/refractory multiple myeloma in the APEX trial
Authors: Vogl D. T. , Stadtmauer E. A. , Richardson P. G. , Sonneveld P. , Schuster M. W. , Irwin D. , Facon T. , Harousseau J. M. , Boral A. , Anderson K. C.
Published: March 2020

7546

Background: The phase 3 international APEX trial demonstrated significantly superior overall survival (OS), time to progression (TTP), and overall response rate (ORR: CR+PR, EBMT criteria) with bortezomib (VELCADE [Vc]) therapy for relapsed myeloma compared with dexamethasone (Dex). ASCT is a common component of initial therapy and may affect the outcome of salvage therapies. Methods: This analysis aimed to evaluate the impact of prior ASCT on the APEX results. TTP, OS, and ORR were analyzed by prior ASCT treatment. Results: Of 669 randomized patients, 451 (67%) had received prior ASCT (median follow-up in survivors was 21.9 months); in this group, Vc led to higher ORR compared with Dex (41% vs 18%, p < 0.001), higher CR rate (8% vs 0.5%, p < 0.001), and longer TTP and OS (see table), the latter despite crossover to Vc of >62% of patients originally assigned to Dex. A subset of 156 (23%) patients had ASCT as their only prior line of therapy (median follow-up in survivors was 20.0 months), with similar superiority of Vc compared with Dex in ORR (48% vs 29%, p = 0.004), CR rate (6% vs 2%, p > 0.05), and TTP. Among 218 (33%) patients with no prior ASCT (median follow-up in survivors was 21.7 months), Vc was also superior to Dex in ORR (32% vs 18%, p = 0.025), CR rate (4% vs 1%, p > 0.05), and TTP. Conclusions: Vc is consistently superior to Dex in ORR, CR rate, and TTP, regardless of prior ASCT status, and OS is superior in patients who had received prior ASCT. Vc is an effective therapy for myeloma relapsing after ASCT. NE = not estimable.

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