bluuebunny/crossref_metadata_2025 huggingface dataset:
Usefulness of 18FDG-positron emission tomography (FDG-PET) for early prediction of erlotinib (Eb) treatment outcome in non-small cell lung cancer (NSCLC) patients: Results of a pilot study
Authors: Soto Parra H. J. , Ippolito M. , Tiseo M. , Cosentino S. , Ardizzoni A. , Latteri F. , Pumo V. , Cordio S. , Bordonaro R. , Spadaro P.
Published: August 2020

7568

Background: FDG-PET could be useful for early evaluation of tumor response to tyrosine kinase inhibitors (TKI). Glucose metabolic activity seems to closely reflect response to epidermal growth factor receptor (EGFR) TKI in vivo and in vitro (Su H et al, Clin Cancer Res 2006;12:5659–67). Thus, we attempted to assess the clinical value of FDG-PET for early prediction of tumor response to Eb an EGFR-TKI. Methods: Pts with NSCLC stage IV in progression after at least one line of chemotherapy and PS 0–1 were treated with Eb (150 mg orally once daily). FDG-PET was performed on days 0 and 2, after administration of 3 daily doses. FDG uptake was evaluated as the maximum standardized uptake value in the tumor (SUVmax). SUVmax was divided by SUV of the background region (liver) to produce the tumor:nontumor ratio (TNT). FDG-PET responses were evaluated by quantitative changes on TNT and classified according to the EORTC PET study group. PET response were compared with radiographic tumor response (RECIST criteria) assessment based on CT scan at baseline and on day 45. Results: From May 2007, 27 pts were enrolled and 23 were evaluable (4 not-evaluable: 2 BAC PET negative, 2 violations). FDG-PET revealed a metabolic partial response (PR) in 8 pts; subsequent CT scan assessment evidenced 4 PR and 4 long lasting stable disease (SD), respectively. Seven pts had metabolic progressive disease (PD) at PET scan and 8 had SD, all of them presented PD at CT scan. Metabolic PR was associated with a longer median progression-free survival (152 vs 45 days, p = < 0.0001) and longer overall survival (323 vs 128 days p=0.15). For radiological PD pts who presented metabolic SD or PD, survival time was respectively 220 and 117 days. EGFR gene mutation, gene copy number and protein expression are ongoing. Conclusions: FDG-PET using changes on TNT can very early predict (already 2 days after initiation) Eb treatment outcome. Particularly, pts with early metabolic PD are unlikely to benefit from Eb. Therefore, evaluation of the early metabolic response holds promise for assessment of pts selection. The two different behavior of FDG-PET observed on refractory pts, deserve biomolecular analysis for understanding mechanism of resistance.

No significant financial relationships to disclose.
FDG-PET/CT imaging for staging and definition of tumor volumes in radiation treatment planning in non-small cell lung cancer
Authors: Xu Y. , Ma S. , Yu D. , Wang J. , Zhang L. , Di X.
Published: August 2020

7574

Background: 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) /computed tomography (CT) has a potential improvement for staging and radiation treatment (RT) planning of various tumor sites. But from a clinical standpoint, the open questions are essentially the following: to what extent does PET/CT change the target volume? Can PET/CT reduce inter-observer variability in target volume delineation? We analyzed the use of FDG-PET/ CT images for staging and evaluated the impact of FDG- PET/CT on the radiotherapy volume delineation compared with CT in patients with non-small cell lung cancer (NSCLC) candidates for radiotherapy. Intraobserver variation in delineating tumor volumes was also observed. Methods: Twenty-three patients with stage I-III NSCLC were enrolled in this pilot study and were treated with fractionated RT based therapy with or without chemotherapy. FDG-PET/CT scans were acquired within 2 weeks prior to RT. PET and CT data sets were sent to the treatment planning system Pinnacle through compact disc. The CT and PET images were subsequently fused by means of a dedicated radiation treatment planning system. Gross Tumor Volume (GTV) was contoured by four radiation oncologists respectively on CT (CT-GTV) and PET/CT images (PET/CT-GTV). The resulting volumes were analyzed and compared. Results: For the first phase, two radiation oncologists outlined together the contours achieving a final consensus. Based on PET/CT, changes in TNM categories occurred in 8/23 cases (35%). Radiation targeting with fused FDG-PET and CT images resulted in alterations in radiation therapy planning in 12/20 patients (60%) by comparison with CT targeting. The most prominent changes in GTV have been observed in cases with atelectasis. For the second phase was four intraobserver variation in delineating tumor volumes. The mean ratio of largest to smallest CT-based GTV was 2.31 (range 1.01–5.96). The addition of the PET data reduced the mean ratio to 1.46 (range 1.12–2.27). Conclusions: PET/CT fusion images could have a potential impact on both tumor staging and treatment planning. Implementing matched PET/CT reduced observer variation in delineating tumor volumes significantly with respect to CT only.

[Table: see text]
PET-CT compared to invasive mediastinal staging in non-small cell lung cancer (NSCLC)
Authors: Darling G. , Maziak D. , Inculet R. , Gulenchyn K. , Driedger A. , Ung Y. , Miller J. , Gu C. , Evans W. , Levine M.
Published: August 2020

7575

Background: In patients with NSCLC, preoperative staging tests including mediastinoscopy (M) are important in defining which patients are surgical candidates. 18FDG PET-CT is useful in identifying patients with mediastinal disease not evident by CT. Alternatively, M may not be required if PET-CT is negative. We have previously reported reduced rates of unnecessary thoracotomy (T) in the PET-CT arm of a trial which compared staging with PET-CT versus conventional imaging (bone scan and CT liver and adrenals) in patients with clinical stage I, II, or IIIA NSCLC being considered for surgery (J Clin Oncol 26 May 20 suppl: abstr 7502). Methods: In this analysis, we determined the accuracy of PET-CT in mediastinal staging compared to invasive surgical staging either by M alone or by M and T. Patients in the PET-CT arm had invasive mediastinal staging either by M or mediastinal nodal sampling at T. PET-CT was considered positive if N2 or N3 nodes exhibited increased 18FDG uptake. Results: M was performed in 81 of 143 patients in the PET-CT arm; the remainder had mediastinal nodal staging at T. Combining M with T, the sensitivity and specificity of PET-CT were 0.70 [95% CI: 0.48–0.85] and 0.94 [95%CI: 0.89–0.97], respectively. Of 21 patients with a positive PET-CT, 7 did not have tumor. The positive predictive value (PPV) and negative predictive value (NPV) were 0.67 [95% CI: 0.45–0.83] and 0.95 [95% CI: 0.90–0.98], respectively. The results for PET-CT versus M alone were: sensitivity, 1.0 [95% CI: 0.76–1.0]; specificity, 0.88 [95%CI: 0.79–0.94]; PPV, 0.60 [95%CI: 0.39–0.78]; NPV, 1.0 [95% CI: 0.94–1.0]. Based on PET-CT alone, 7 patients would have been denied T if PET-CT abnormalities had not been evaluated with invasive mediastinal staging. Conclusions: Mediastinal abnormalities on PET-CT should be confirmed by invasive mediastinal staging because of the risk of a false positive test. Patients should not be denied potentially curative therapy based on PET-CT alone. If PET-CT is negative in the mediastinum, the likelihood of occult metastatic disease in the mediastinum is very low and invasive staging may not be required depending on the clinical context.

No significant financial relationships to disclose.
A multicenter phase II study of pemetrexed (P), cisplatin (C), and bevacizumab (B) in patients (pts) with advanced malignant mesothelioma (MM)
Authors: Dowell J. , Taub R. , Lan C. , Xie Y. , Dunphy F. , Blake V. , Kindler H.
Published: August 2020

7578

Background: Vascular endothelial growth factor (VEGF) is a key growth factor for MM. In pre-clinical models, anti-VEGF antibodies inhibit MM proliferation. Standard chemotherapy for MM, pemetrexed + cisplatin, yields a response rate of 41%, progression-free survival (PFS) of 5.7 months (mo) and median overall survival (OS) of 12.1 mo. We added the anti-VEGF antibody B to PC in an ongoing phase II multi-center study in MM pts. Methods: Eligible pts have unresectable, histologically-confirmed MM, no prior chemotherapy, and PS 0–1. Pts receive C 75 mg/m2, P 500 mg/m2 and B 15 mg/kg Q21 days for 6 cycles, then B Q21 days until progression. CT scans are obtained Q 2 cycles. Primary endpoint: Progression-fere survival (PFS). Correlative studies include IHC for the VEGF/KDR complex and PCR for simian virus 40 (sv40) T antigen. Results: 43 pts enrolled at 4 centers from 3/06 to 12/08; currently, 34 are evaluable for PFS and 36 for toxicity. Pt characteristics: male 88%; median age 66 (range 24–81); histology: epithelial 62%, sarcomatoid 15%, biphasic 20%, unknown 3%; site of origin: pleural 85%, peritoneal 12%, tunica vaginalis 3%; PS 0 32%, PS 1 68%; thrombocytosis (>400) 32%. Cycles administered 229 (median 4, range 1–18). Grade 3/4 toxicity (%pts): neutropenia 8%; anemia 0%; thrombocytopenia 3%; thrombosis 11%; hypertension 8%; vomiting 8%; mucositis 6%; CVA 3%; proteinuria 0%; perforation 0%. Partial response: 41%, stable disease: 35%. Median PFS: 5.6 mo (95% CI: 4.1, 7.2). Median OS 11.5 mo (95% CI: 9.4, 24). Conclusions: These data suggest that the addition of B to PC does not improve PFS when compared with historical controls of PC in advanced MM pts. Correlative studies evaluating the VEGF/KDR complex and sv40 T antigen are pending.

[Table: see text]
Precision pulmonary trans-arterial chemoembolization (PPTACE) plus percutaneous RFA for unresectable lung neoplasms: Initial experience in twelve cases
Authors: Gadaleta C. , Catino A. , Rubini G. , Ranieri G. , Fazio V. , Gadaleta-Caldarola G. , Vinciarelli G. , Armenise F. , Gaudiano A. , Mattioli V.
Published: August 2020

7593

Background: The study aimed to evaluate the feasibility and safety of precision pulmonary arterial chemoembolization (PPTACE) followed by percutaneous RFA in patients with unresectable lung neoplasms Methods: From November 2007 to October 2008, twelve patients (5 male, 7 female, median age 57) and 20 nodules were treated in 14 sessions. Patients had lung metastases from the following tumors: uterine cancer (2), colorectal carcinoma (7), breast carcinoma (1) and two patients had primary unresectable NSCLC. Median diameter of neoplasms was 2 cm. Both RFA and pulmonary TACE were performed under general anesthesia. Two patients underwent two sessions of treatment due to bilateral disease. After subclavian vein puncture and mapping of arterial vascularization of the segment including the tumoral nodule, antiblastic agents loaded on microspheres (Hepasphere, 50–100 micron in diameter) were selectively perfused in a subsegmental sector. Doxorubicin was used in 3 sessions, as well as mitomycin C, while irinotecan was administered in six cases and cisplatin in one case (one session was performed only with microspheres). Percutaneous CT-guided RFA of lung nodules was performed 2–7 days after PPTACE. Pretreatment work-up included: contrast-enhanced CT-scan, (18-F)Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (18F-FDG PET/CT) and Ventilation Lung Single Photon Emission Tomography (VL-SPET). Results: The treatment was well tolerated; pneumothorax, requiring chest- tube placement, occurred in two sessions (14%). Technical success was achieved in all treated nodules. In all cases, the impedance during RFA decreased from 30 to 50%, with an increase of the delivered energy (expressed by Watts). Morphological response showed a necrotic area, without contrast-enhancement at CT scan, including the neoplasm plus a large safety zone. VL-SPET showed a wide area without ventilation in lung parenchyma submitted to PPTACE and extending over it; the changes on alveolar ventilation detected by VL- SPET after PPTACE could explain the better heat conduction during RFA. Conclusions: Lung RFA after pulmonary TACE is feasible and safe. These preliminary data deserve further investigation.

No significant financial relationships to disclose.
Comparison of gefitinib and docetaxel in patients with pretreated advanced non-small cell lung cancer (NSCLC): Meta-analysis from four clinical trials
Authors: Shepherd F. A. , Douillard J. , Fukuoka M. , Saijo N. , Kim S. , Cufer T. , Sellers M. V. , Armour A. A. , Kim E. S.
Published: August 2020

8011

Background: Four open-label, randomized trials evaluated gefitinib (G) vs docetaxel (D) in unselected patients with pre-treated advanced NSCLC: INTEREST (Lancet 2008; 372: 1809), V-15–32 (J Clin Oncol 2008; 26: 4244), ISTANA (J Clin Oncol 2008; 26: Abs 8025), SIGN (Anticancer Drugs 2006; 17: 401). Reported here is a meta-analysis using the patient data from each of these trials. Methods: The meta-analysis compared efficacy of G (250 mg/day) and D (75 mg/m2 [V-15–32 60 mg/m2]) using appropriate analysis populations from INTEREST (1466 patients randomized), V-15–32 (489), ISTANA (161) and SIGN (141). Meta-analyses (unadjusted and adjusted for covariates) were performed by Cox proportional hazards for OS and PFS, and by logistic regression for ORR. Results: G demonstrated similar OS and PFS and superior ORR to D in the primary analyses. Secondary analyses demonstrated similar results. Conclusions: Results were consistent with those of the individual studies. Given the similar/superior efficacy demonstrated by G, its favorable tolerability profile, quality of life benefits and oral administration, G has a favorable benefit-risk profile compared with D in a broad pre-treated advanced NSCLC patient population.

[Table: see text]

[Table: see text]
Randomized phase II study of three doses of the integrin inhibitor cilengitide versus docetaxel as second-line treatment for patients (pts) with stage IV non-small cell lung cancer (NSCLC)
Authors: Manegold C. , Vansteenkiste J. , Cardenal F. , Schütte W. , Woll P. , Ulsperger E. , Rüter B. , Picard M. , Eckmayr J. , von Pawel J.
Published: August 2020

8014

Background: Cilengitide (EMD 121974) is the most advanced compound in clinical development of a new class of oncology drugs, the integrin inhibitors. Integrins (heterodimeric transmembrane receptors) play key roles in cell interactions. Cilengitide selectively inhibits the cell-surface integrins αVβ3 and αVβ5 on activated endothelial cells during angiogenesis and on tumor cells. Methods: Multicenter, open-label, randomized, phase II study in 140 pts with relapsed stage IV NSCLC. Pts received 1 of 3 cilengitide doses (240 [n=35], 400 [n=35], or 600 [n=36] mg/m2) twice weekly or docetaxel 75 mg/m2 (n=34) once every 3-week cycle for 6 months. Responding pts could continue cilengitide for up to 1 year. Primary endpoint: progression-free survival (PFS). Results: Median age (range) was 60 (33–80) years; 94 pts were male (67%); 83% of pts had KPS ≥80%. Median PFS (95% CI) was 54 (43–64), 63 (53–66), 63 (42–67), and 67 (61–123) days for cilengitide 240, 400, 600, and docetaxel 75 mg/m2, respectively. Median OS (95% CI) was 173 (81–197), 117 (92–209), 181 (90–326), and 194 (135–298) days, respectively. One-year survival rate (95% CI) was 13% (1–24%), 13% (0–26%), 29% (12–37%), and 27% (10–43%), respectively. Survival was similar with cilengitide 600 mg/m2 and docetaxel 75 mg/m2: median OS 181 versus 194 days and 1-year survival rate (95% CI) 29% (12–37%) versus 27% (10–43%). Five docetaxel pts (15%) had a partial response. Most pts (98%) had ≥1 adverse event (AE). Most common AEs were dyspnea (33%), nausea (30%), tumor progression (29%), and cough (23%). Dyspnea and tumor progression were more common with cilengitide than with docetaxel. Grade 3/4 treatment-related AEs were more common with docetaxel (n=13, 41%) than cilengitide 240 (n=2, 6%), 400 (n=4, 11%), or 600 (n=4, 11%) mg/m2. For cilengitide, these were nausea, chest pain, dyspnea, and fatigue. Conclusions: PFS in the docetaxel group was greater than that of cilengitide at all doses. However, cilengitide monotherapy at a dose of 600 mg/m2 showed similar OS to docetaxel and better tolerability. Combination studies with standard chemotherapy and cilengitide are warranted.

[Table: see text]
K-Ras mutation (mut), EGFR-related, and exploratory markers as response predictors of cetuximab in first-line advanced NSCLC: Retrospective analyses of the BMS099 trial
Authors: Khambata-Ford S. , Harbison C. , Woytowitz D. , Awad M. , Horak C. , Xu L. A. , Dakhil S. , Hermann R. C. , Lynch T. J. , Weber M. R.
Published: August 2020

8021

Background: This phase III study investigated cetuximab (C) plus taxane/carboplatin (TC) in 1st-line advanced NSCLC. Progression-free survival (PFS) was not significantly different with the addition of C to TC; response rate (RR) was significantly higher; median overall survival (OS) was longer, with a difference (not statistically significant) similar in magnitude to the significant OS improvement from FLEX (cisplat/vinorelb±C). Potential patient-selection markers were analyzed, including mut in K-Ras, EGFR mut and gene copy number (GCN), EGFR protein expression, and gene expression profiles. Methods: Chemonaïve patients (pts) with stage IIIB/IV NSCLC (any histology or EGFR expression status) were randomized to TC±C. K-Ras gene exon 2, and EGFR exons 18–21 were sequenced bidirectionally using formalin-fixed paraffin embedded tissue-derived genomic DNA. EGFR GCN was measured by fluorescence in situ hybridization (FISH) and EGFR protein expression by immunohistochemistry (IHC). Exploratory expression profiling studies using Affymetrix GeneChip are ongoing. Analyses were blinded to clinical outcome. The relationships between biomarker status and efficacy were assessed with log-rank tests per study arm for treatment-specific effects, and across the total evaluable population. Results: Samples from 225/676 randomized pts were available; 35/202 (17%) had K-Ras mut, 17/167 (10%) had EGFR mut, 54/104 (52%) were EGFR FISH+, 131/148 (89%) were EGFR IHC+. There were no significant treatment-specific correlations between any biomarker assessed and PFS, OS or RR, except superior OS with TC for the EGFR FISH+ group (P=0.03). With all pts combined, OS was longer in the EGFR mut subset vs wt (P=0.09); PFS was longer in EGFR IHC- pts vs IHC+ (P=0.048). Results from gene expression profiling studies, including EGFR ligands, will be presented. Conclusions: There was no significant correlation between patient response to C and any molecular marker evaluated to date (K-RAS mut, EGFR mut, EGFR IHC, EGFR FISH), exploratory analyses are ongoing. Additional predictive-marker studies are needed to optimize cetuximab therapeutic use in NSCLC.

[Table: see text]
First-line treatment patterns in advanced NSCLC in western Europe (EU), the United States, and Japan including a comparative analysis of younger versus elderly patients
Authors: Vansteenkiste J. F. , Koester M. , Lange M. , Eschbach C.
Published: August 2020

8053

Background: The latest developments in advanced NSCLC are represented by targeted therapy (TT), treatment decisions based on tumor histology, and biomarker research. A patient (pt) case-based survey was conducted in three regions to study current pt characteristics and treatment patterns. Methods: 629 physicians treating stage III/IV NSCLC provided details on up to 10 of their pts. Results: Overall, 3455 EU pts, 895 US pts, and 600 Japanese pts were monitored. This analysis focuses on the 89% of pts with stage IIIb/IV NSCLC. In each region, median age, gender, and occurrence of malignant pleural effusion were comparable but tumor histology differed slightly. Comparative analyses revealed that monotherapy (MT) with either chemotherapy (CT) or TT agents is used significantly more in elderly pts (≥70 yrs) while combination therapy (CT/TT doublets or triplets) is more frequent in younger pts. This is consistent across all regions and histologies (squamous vs non-squamous). In the EU, 48.3% of elderly and 13.6% of younger pts received MT (39.9% vs 15.1% for US pts, 32.0% vs 9.4% for Japanese pts). CT/TT doublets were used predominantly in younger vs elderly pts (72.3% vs 48.1% in the EU, 47.3% vs 36.9% in the US, and 81.7% vs 65.5% in Japan). Triplets were also more widely used in younger vs elderly pts (14.3% vs 3.6% in the EU, 36.3% vs 22.6% in the US, and 6.5% vs 1.8% in Japan). For both age groups, the leading MTs are erlotinib in the EU and US, and gefitinib in Japan but use is higher in elderly pts. Preferred doublets in the EU are platinum+gemcitabine (28.8%), platinum+vinorelbine (13.6%) and platinum+taxanes (13.5%). Platinum+taxanes is predominant in the US and Japan (27.7% and 55.4%, respectively). The triplets, bevacizumab+platinum+taxanes (27.0%) and bevacizumab+platinum+other (3.5%), are also common in the US while these treatments only represent 5.1% and 3.9%, respectively, in the EU. Conclusions: Important regional differences in 1st-line advanced NSCLC treatment exist with triplets being more common in the US only. MT is more frequent in elderly pts and combination therapy is more common in younger pts. This latter finding is consistent across all regions and histological subsets.

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Interim analysis of a phase II trial of 5-azacitidine (5AC) and entinostat (SNDX-275) in relapsed advanced lung cancer (NSCLC)
Authors: Juergens R. A. , Vendetti F. , Coleman B. , Sebree R. S. , Rudek M. A. , Belinsky S. , Brock M. , Herman J. , Baylin S. , Rudin C. M.
Published: August 2020

8055

Background: Epigenetic gene silencing mediated through aberrant DNA methylation and histone deacetylation is a key contributor to lung carcinogenesis. Pre-clinical studies suggest that combining inhibitors of DNA methyltransferase (DNMT) with inhibitors of histone deacetylase (HDAC) synergistically induce re-expression of epigenetically-silenced tumor suppressor genes. Clinical studies at our institution combining the DNMT inhibitor, 5AC, with the HDAC inhibitor, entinostat, in hematologic malignancies have shown remarkable clinical activity. We hypothesized a similar effect would be seen in lung cancer. This study aims to assess the response rate and time to progression of 5AC and entinostat in NSCLC. Methods: Patients (pts) include adults with histologically confirmed recurrent NSCLC and progressive disease after ≥1 prior chemotherapy regimen. 40 mg/m2 of 5AC is administered SQ days 1–6 and 8–10 with 7 mg of entinostat PO days 3 and 10 of a 28 day cycle. A standard Simon two stage design is being used. The sample size is calculated with a power of 90% and a two-sided type 1 error allowance of 5%. Stage 1 included 18 pts, with subsequent expansion to a total of 32. Results: 25 pts have enrolled to date. Demographic characteristics include: mean age (range) - 63 (46- 80); M:F - 1:2; 80% former smokers; 80% adenocarcinomas; mean # of previous therapies - 3. One pt. has had a complete response. She remained on therapy for 14 m and came off therapy due to a new nodule which was resected. Molecular analysis suggests a second primary stage I NSCLC. She remains disease free at 20 m. Another man has stabilization of disease (SD) for ≥16 m with marked symptomatic improvement. Another pt had SD for 4 months. The remaining pts have progressed after 2 cycles of therapy. Main toxicities included injection site reactions, nausea/vomiting, constipation, fatigue, and hematologic toxicities. Conclusions: The combination of 5AC and entinostat is safe and well tolerated in advanced NSCLC pts. 2 pts have had durable benefit from treatment, including a complete response. Pharmacodynamic and pharmacokinetic analyses are being conducted to identify characteristics of the subset of pts responding to this novel therapy.

[Table: see text]
The relationship between the responses to prior systemic therapies and the efficacy of subsequent pemetrexed (Pem) therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC)
Authors: Sun J. , Oh D. , Lee S. , Kim D. , Im S. , Kim T. , Lee J. , Kim Y. , Heo D. S. , Bang Y.
Published: August 2020

8061

Background: Pem has been used for pts with previously treated advanced NSCLC. We tried to examine whether the response to prior systemic therapy regimen could predict the efficacy of subsequent Pem therapy. Methods: The medical record of clinical stage IIIB or IV NSCLC pts who received Pem as the second-line or further-line treatment were analyzed retrospectively. Prior systemic therapies were divided into 4 types [gemcitabine based (G), paclitaxel based (P), docetaxel based (D), and EGFR tyrosine kinase inhibitors (I)]. Along with that, patients were classified into two response groups, either responders (partial responses or stable disease for 4 months or more) or non-responders to each type of the prior therapy. Response rate (RR) and progression free survival (PFS) for Pem therapy were analyzed according to the response groups for each type of prior therapies. Results: A total of 247 pts received Pem therapy, and their median PFS was 2.3 months. The number of pts who previously received G, P, D and I, was 159, 120, 110, and 139, respectively. The RR for Pem was higher in responders to G therapy than in non-responders to G (15.0% vs 4.3%, p = 0.02). In addition, median PFS after Pem therapy was longer in responders to G therapy than in non-responders (3.0 vs 1.7 months, p = 0.007). However, the responses to prior P, D, I therapies had no impact on the efficacy of subsequent Pem therapy. By univariate analyses, the variables of the responders to G therapy, female, never-smoker, ECOG performance status 0–1 were good predictive factors for Pem therapy in terms of PFS. By multivariate analysis, only the responders to G therapy had a statistical significance (Hazard ratio = 0.55; 95% CI, 0.37–0.82). Conclusions: The response to the prior gemcitabine based therapy was a predictive factor for subsequent pemetrexed therapy for advanced NSCLC.

No significant financial relationships to disclose.
Analysis of optimal timing of gefitinib in sensitive non-small cell lung cancer (NSCLC) patients: Should we use gefitinib as first-line chemotherapy?
Authors: Kenmotsu H. , Goto K. , Naito Y. , Nishiwaki Y. , Kubota K. , Ohmatsu H. , Niho S. , Yoh K. , Nagai K. , Saijo N.
Published: August 2020

8068

Background: In gefitinib-sensitive NSCLC such as Asian origin, adenocarcinoma, and never/light smoker, the superiority of gefitinib relative to carboplatin/paclitaxel as first-line chemotherapy was recently demonstrated (IPASS). However, the optimal timing of this agent is still controversial. Methods: To assess the optimal timing of gefitinib for sensitive NSCLC, we retrospectively reviewed 720 NSCLC patients treated with this agent at National Cancer Center Hospital East between 2002 and 2008. Results: A total of 190 patients responded to gefitinib monotherapy (response rate 26%) were analyzed in this study. Forty-four patients (23%) were treated with gefitinib as first-line chemotherapy, and 146 (77%) as second or more-line chemotherapy. Patient characteristics (first-line/second or more-line) were as follows: median age (range) 68 (44–82)/64 (33–82); female 84/67%; non-smoker 80/57%; PS0–1 84/74%; adenocarcinoma 93/97%; stage IV 43/54%; recurrence after surgical resection 45/26%. There were some imbalances between the two groups in terms of female (p=0.0296) and recurrence after surgical resection (p=0.0187). Although 64% of second or more-line group received platinum-based chemotherapy in their clinical course, only 27% of first-line group received it. Median follow-up time was 17.2 months. Progression free survival (PFS) from the start of gefitinib was similar between first-line and second or more-line groups (median PFS: 11 vs. 11 months, p=0.3085). However, overall survival (OS) from the start of first-line chemotherapy was significantly longer in second or more-line group (median OS: 23 vs. 33 months, p=0.0298). Conclusions: Even if gefitinib is administered to sensitive patients as first-line or second or more-line chemotherapy, it should have similar efficacy. The significantly longer survival in second or more-line group may be on account of more percentage of patients receiving platinum-based chemotherapy.

No significant financial relationships to disclose.
Administration of sunitinib to patients with non-small cell lung cancer and irradiated brain metastases: A phase II trial
Authors: Novello S. , Abrey L. E. , Grossi F. , Camps C. , Mazieres J. , Selaru P. , Patyna S. , Torigoe Y. , Chao R. , Scagliotti G.
Published: August 2020

8077

Background: Sunitinib (SU), an oral, multitargeted inhibitor of VEGFRs, PDGFRs, KIT, FLT3, CSF-1R, and RET has promising single-agent antitumor activity in refractory non-small cell lung cancer (NSCLC) (Socinski JCO 2008). Brain metastases (BrMs) occur in ≥25% of NSCLC patients (pts); preclinical data suggest that VEGF signaling is required for the growth of BrMs, and that SU can cross the blood-brain barrier. This study assessed the safety and preliminary efficacy of SU in NSCLC pts with BrMs. Methods: NSCLC pts who had received ≤2 prior systemic therapies and prior whole brain radiation therapy (WBRT) were eligible to receive SU at a starting dose of 37.5 mg with continuous daily dosing (CDD) in 4-wk cycles. Antitumor efficacy was based on overall (RECIST) and intracranial (WHO) tumor assessments. Intracranial disease was assessed by MRI. Safety was assessed by monitoring adverse events (AEs) and health-related quality of life was assessed using FACT/NCCN Lung Symptom Index (FLSI) and Brain Symptom Index (FBrSI). Study termination was to occur when 3 cases of intracranial hemorrhage (ICH) associated with neurologic deficit were noted. Results: To date, 47 pts, including 28 with adenocarcinoma and 10 with squamous cell carcinoma, received SU for a median of 2 cycles (range: 1, 9). The median age of pts was 61 yrs (range: 35, 75), most were male (n=26, 55%), were ever smokers (n=36, 77%) and all had good performance status (ECOG 0/1). In total, 25 pts (53%) experienced non-neurologic grade (G) 3/4 AEs; the most frequent were fatigue/asthenia and dyspnea. Neurologic AEs occurred in 4 pts (9%), including intracranial pressure increased, mental impairment, and gait disturbance (each n=1 and G1) and 1 pt with G3 convulsion and peripheral motor neuropathy. Importantly, no cases of ICH were noted. Stable disease occurred in 7 (19%) of 36 measurable pts. Median PFS was 10.9 wks (95% CI: 6.4,15.4). Median OS was 19.6 wks (95% CI:13.1, NR). Mean change from baseline in FLSI and FBrSI scores did not differ significantly at any time point. Conclusions: Oral SU 37.5 mg on a CDD schedule had a manageable safety profile in NSCLC pts with BrMs. These data support the investigation of SU in combination with agents with known antitumor activity in pts with BrMs.

[Table: see text]
Racial/ethnic disparities in lung cancer stage of diagnosis and survival
Authors: Raez L. E. , Koru-Sengul T. , Allen G. , Clarke J. , Santos E. S. , Hu J. J.
Published: August 2020

8080

Background: There are differences in the treatment outcome of non-small cell lung cancer (NSCLC) patients (pts) between non-Hispanic whites (NHW) and African Americans (AA). Little is known regarding the outcomes of Hispanics (H). Methods: Registry data on 2,696 pts with NSCLC treated during 1999–2006 was obtained. The objective of the study was to evaluate differences in NSCLC survival according to different ethnicities. Chi-square was used to compare distribution of tumor stage. Survival curves were compared using log-rank test for each of the tumor stages. Adjusted hazard ratios (AHR) and 95% confidence intervals (95% CI) were reported based on the results of a multivariate Cox regression model for overall survival (OS) with adjustment for gender, age at diagnosis, and race. Results: Most pts had stage III/IV at diagnosis; majority of the AA or HW presented in advanced stage compared with NHW. Significantly higher proportions of AA and H were diagnosed with stage IV compared to NHW ( Table ). Mean age at diagnosis was 62 yrs (AA 58, H 60, and NHW 66yrs) and it was significantly different among the 3 groups (one-way ANOVA, p<0.0001). AA and H have significantly shorter stage-specific median survival for early stage compared to that in NHW ( Table ). In pts with advanced stages the pattern was similar: AA and H have a significantly shorter median survival than that in NHW. In early-stage pts, significant predictors for OS from multivariate Cox regression model were female gender (AHR=0.65; p<0.001), AA (NHW as the referent group; AHR=2.67; p<0.0001), and H (NHW as the referent group; AHR=2.01; p<0.0001). In late-stage pts, significant predictors for OS were female gender (AHR=0.79; p=0.0002), AA (NHW as the referent group; AHR=1.53; p<0.0001, and H (NHW as the referent group; AHR=1.28; p=0.0006). Conclusions: NHW pts had better OS than H and AA; we will evaluate whether gene expression profiles or presence of EGFR overexpression have an impact on racial/ethnic disparities in the outcome of NSCLC.

[Table: see text]

No significant financial relationships to disclose.
Simulation of survival with first- and second-line non-small cell lung cancer (NSCLC) therapy using a public domain drug-disease modeling framework
Authors: Bruno R. , Lu J. , Sun Y. , Claret L.
Published: August 2020

8087

Background: Modeling and simulation approaches are advocated to support drug development decisions. In this study, we evaluated the ability of a drug-disease model recently developed by scientists at the FDA using data from pivotal studies in NSCLC (Wang et al. http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008–4351b1–00-index.htm ) to simulate survival and tumor response for approved therapies in NSCLC. Methods: The modeling framework comprises a longitudinal tumor size model and a survival model relating change in tumor size at first visit (week 8) and patient characteristics (tumor size and ECOG performance status at baseline) to survival time. The tumor size and survival models were used to simulate change in tumor size at first visit and expected survival in the carboplatin/paclitaxel (CP) arm of the E4599 study (first-line NSCLC, N Eng J Med. 2006;355:2542–2550) and in the erlotinib arm in the BR.21 study (second-line NSCLC, N Eng J Med. 2005;353:123–132). The predictive distributions (95% prediction interval [PI]) of survival times were derived from multiple replicates (500) of 400 CP patients and 500 erlotinib patients with similar characteristics to patients in the original studies. Results: There was a high level of concordance between the results of the simulation and the observed results in the two arms, indicating that the modeling framework successfully predicted survival and tumor response. Expected median survival was 9.8 (95% PI, 8.2–11.8) months (vs 10.3 months observed) for the CP arm and 6.8 (95% PI, 5.3–8.9) months (vs 6.7 months observed) for the erlotinib arm. The median change in relative tumor size from baseline at week 8 predicted by the model was 12.1% for the CP arm and 9.5% for the erlotinib arm. Conclusions: The modeling framework can be used to perform simulations of survival of approved treatments. These results suggest that the model could be used to simulate survival for investigational treatments based on tumor shrinkage data observed in early clinical studies (e.g. phase II) to support end-of-phase II decisions and the design of phase III studies.

[Table: see text]
Tumor response category for the indicator of prognosis: Analysis of survival data in a Four-Arm Cooperative Study (FACS) for advanced non-small cell lung cancer (NSCLC)
Authors: Watanabe H. , Leki R. , Mori K. , Takada Y. , Nishiwaki Y. , Saijo N. , Fukuoka M.
Published: August 2020

8088

Background: Tumor response, categorized into CR (complete response), PR (partial response), SD (stable disease) and PD (progressive disease), is a surrogate endpoint for survival and could be expected as a possible indicator of the prognosis. To evaluate whether the tumor response category might be used as an indicator of the prognosis, we conducted an analysis of the best overall response and survival data obtained from FACS, a phase III randomized trial comparing four platinum-based regimens for advanced NSCLC. Methods: A total of 602 patients (pts) with advanced NSCLC from 44 hospitals in Japan were registered in FACS. A retrospective review of the FACS database, including the tumor response and survival, was conducted. The tumor response as evaluated by the investigators was applied with and without confirmation of complete or partial responses at the determination of best overall response. Survival was calculated by the Kaplan-Meier method, and differences among prognostic groups were analyzed by Cox regression analysis. Results: Forty-five pts were excluded from the analysis due to nonavailability of sufficient data. The results are shown in the Table . The response categories of CR, PR and SD could not be categorized into prognostic groups, either with or without confirmation. There were, otherwise, two distinct prognostic groups: non-PD (CR, PR and SD) and PD. Conclusions: The disease control rate was a more sensitive indicator of the prognosis than the response rate in pts with advanced NSCLC registered in FACS.

[Table: see text]

[Table: see text]
Consistency between K-ras mutation in peripheral blood and matched tumor tissues detected by PCR-RFLP in Chinese patients with advanced NSCLC and its clinical significance analysis
Authors: Shuhang W. , Bai H. , Zhao J. , Duan C. J. , Yang L. , Wu N. M. , Wang J. Z. , Wang Y. Y. , Zhuo L. M. , Zhuo L. M. , Wang J.
Published: August 2020

8090

Background: To explore the consistency between K-ras mutation in peripheral blood and matched tumor tissues detected by PCR-RFLP and analyze the prognostic effects of K-ras mutation in peripheral blood in Chinese NSCLC patients (pts) treated by epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Methods: Plasma free DNA and matched tumor samples were collected from 264 hospitalized pts in Department of Thoracic Oncology, Peking University School of Oncology between Jan 2005 and Feb 2008. K-ras mutations were detected in coden 12 and 13 of exon 1 by PCR-RFLP and then verificated by sequencing. We compared the mutations in plasma samples and matched tumor tissues which determined an association between K-ras mutation status and clinical outcomes. Results: In 264 pts, K-ras mutation rates in codon 12 and 13 of exons 1 in peripheral blood were 11.36% (30/264) and 0.75% (2/264), also 9.84% (26/264) and 1.13% (3/264) in matched tumor tissues, respectively. Consistency of mutation in codon 12 between in tissues and plasma was 94%(248/264) (Kappa=0.686,P<0.001). Among 107 pts who received EGFR-TKIs treatment, the effective rate(RR), progression-free survival (PFS) and median survival time (MST) in pts with K-ras mutation in plasma DNA were 6.7.%, 2.7 months and 20.5 months, respectively, all which were lower than those of pts with wild type K-ras (32.5%, 23.7 months, 31.5 months; P=0.001, P=0.001, P=0.278, respectively). Conclusions: There is a high consistency of K-ras mutation rate between plasma DNA and matched tumor tissues. K-ras mutation in plasma is able to predict both response and PFS of NSCLC pts with EGFR-TKIs treatment.

No significant financial relationships to disclose.
Validation study of direct sequencing and PCR-invader for detecting EGFR mutations in non-small cell lung cancer (NSCLC)
Authors: Naito Y. , Goto K. , Kenmotsu H. , Nishiwaki Y. , Kubota K. , Ohmatsu H. , Niho S. , Yoh K. , Nagai K. , Saijo N.
Published: August 2020

8094

Background: EGFR mutation is both a predictive and prognostic factor for NSCLC treated with EGFR-TKI. Although new, highly sensitive methods for detecting EGFR mutations are currently available, these methods have not been validated. Methods: To validate direct sequencing and PCR-invader for detecting EGFR mutation, we analyzed 124 NSCLC by both methods concomitantly. Tumor tissues were obtained by surgical resection. Formalin-fixed paraffin-embedded specimens were prepared to analyze EGFR mutation. In direct sequencing, Exon 18, 19, and 21 of the EGFR gene were amplified, and PCR amplification products were sequenced directly (Mitsubishi Chemical Medience Corporation). PCR-invader was performed using the invasive cleavage of probe oligonucleotides to detect 10 mutations including Exon 18, 19, 20, 21 (BML incorporation). Results: EGFR mutations were detected in 51 patients (41%) by direct sequencing and 56 (45%) by PCR-invader. Discordance between two methods was found in 12 patients (10%). Exon 19 deletion was detected in 18 and 22 patients respectively. Exon 21 L858R was detected in 30 and 32 patients respectively. Each mutation in exon 19 deletions or L858R detected by direct sequencing could also be identified by PCR-invader. Overall 45 mutations were concordant by both methods. In two patients who received gefitinib, one patient with wild type by both methods did not respond to gefitinib. On the other hand, the other patient expressing Exon 19 deletion by PCR-invader but regarded as wild type by direct sequencing responded to gefitinib monotherapy. Conclusions: Discrepancy between two methods for detecting EGFR mutation was demonstrated and PCR-invader seems to be more sensitive. Further investigation including other highly sensitive methods is currently underway.

No significant financial relationships to disclose.
Tanespimycin plus bortezomib in patients with relapsed and refractory multiple myeloma: Final results of a phase I/II study
Authors: Richardson P. G. , Chanan-Khan A. , Lonial S. , Krishnan A. , Carroll M. , Alsina M. , Albitar M. , Berman D. , Kaplita S. , Anderson K.
Published: August 2020

8503

Background: Tanespimycin (Tan) disrupts HSP90, a key molecular chaperone for signal transduction proteins critical to myeloma (MM) growth, survival and drug resistance. Preclinical data show anti-tumor synergy between Tan and bortezomib (Bz) and suggest Tan may be neuroprotective, including reversibility of Bz-induced peripheral neuropathy (PN). A phase I study of single agent Tan in advanced MM showed favorable tolerability and modest activity. Methods: 72 patients (pts) with relapsed/refractory MM received 0.7 - 1.3 mg/m2 Bz as IVB followed by 1-hr infusion of 100 -340 mg/m2 Tan on days 1, 4, 8,11 q 21d, with 42 pts receiving the highest dose of both drugs as part of a phase II expansion. Toxicities were assessed by CTCAE v3 and response by modified EBMT criteria. Results: Of 72 pts, 72% had IgG subtype with a median age of 60 yo. Median time since MM diagnosis was 50 mos with median of 5 (1–15) prior regimens. Prior treatments included stem cell transplant (69%), thalidomide (74%), Bz (69%), lenalidomide (28%) and Hsp90 inhibitors (13%). 58 pts with measurable disease were treated at 1 or 1.3 mg/m2 Bz. Response rates (≥ MR) were 41%, 20% and 14% in the Bz-naive, -pretreated and -refractory pts respectively. In the subgroup with 1–3 prior therapies and who were Bz-naive, the response rate was 56%. Median duration of response (DOR) for all pts with response (n=14) was 10.7 mos, including 3 Bz-refractory pts who had durable PR through mos 12, 22 and 28. 3 other pts remain in response through 24 mos. Of the 72 pts, the most frequent AEs were diarrhea (60%), nausea (49%), fatigue (49%), thrombocytopenia (40%) and AST elevation (28%), which proved manageable with dose reduction and supportive care. Most frequent G3–4 AEs included thrombocytopenia (25%), diarrhea, anemia and fatigue (7% each), as well as back pain and AST elevation (4% each). Only 21% of pts had G1–2 PN; no G3–4 PN was seen. Conclusions: Tan + Bz is active and well tolerated in relapsed/refractory MM, with durable responses in Bz-naive, -pretreated and -refractory pts. Median DOR for the combination compares favorably to Bz monotherapy. Final PFS data will be presented. No severe PN has been observed, consistent with Tan's neuroprotective effect in pre-clinical models. A phase III study of Tan + Bz vs Bz is ongoing.

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Bortezomib, IV cyclophosphamide, and dexamethasone (VelCD) as induction therapy in newly diagnosed multiple myeloma: Results of an interim analysis of the German DSMM Xia trial
Authors: Knop S. , Liebisch P. , Wandt H. , Kropff M. , Jung W. , Kroeger N. , Sezer O. , Straka C. , Fingerle-Rowson G. , Einsele H.
Published: August 2020

8516

Background: Cytoreductive induction followed by HD-MEL and ASCT is considered standard of care for younger patients (pts) with multiple myeloma (MM). The success of this combined procedure partially depends on the efficacy of induction treatment. Bortezomib-containing induction regimens have already been shown to be superior to standard VAD. In order to further improve the efficacy of induction treatment we combined Vel with intravenous (IV) cyclophosphamide (C) and dexamethasone (D). Methods: This trial is an open, prospective, multicenter, uncontrolled phase II/III study with a planned recruitment of 400 pts. The first 30 pts were included in the dose finding study to determine the optimum dose of IV C in conjunction with Vel and D. The following 170 pts up to 60 years of age with untreated MM were enrolled to receive 3 cycles of induction with Vel 1.3 mg/m2 IV d1, 4, 8, 11; D 40 mg/d d1, 2, 4, 5, 8, 9, 11, 12; and C 900mg/m2 IV d1. Primary study objective is response rate (≥ PR) to VelCD according to the EBMT criteria. Results: Data from the first completed 200 pts (mean age: 52 years; 74% stage III) from 36 German centers were analyzed as ITT population. Response rates are given in Table and were documented in 82% of the subjects with 13q-, in 94% with t(4;14) and in 70% with 17p-. SAEs (n=84) occurred in 24.5% of the pts and were related to Vel, C or D in 16%, 14.5% or 9.5% respectively. The mortality rate of 1% is low, 53% of the patients experienced grade 3 + 4 AEs, infections of grade 3 and 4 were reported in 2% and grade 3 paraesthesia occurred in 2%. Conclusions: This interim analysis demonstrates that bortezomib combined with dexamethasone and intravenous cyclophosphamide (VelCD) is a highly effective induction regimen for pts ≤ 60 years with newly diagnosed MM regardless of cytogenetic risk factors.

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[Table: see text]