bluuebunny/crossref_metadata_2025 huggingface dataset:
Malignant pleural mesothelioma (MPM) in elderly patients: A multicenter survey.
Authors: Grosso Federica , Botta Mario , Zucali Paolo Andrea , Pasello Giulia , La Spina Chiara Maria , Roveta Annalisa , Perrino Matteo , Beretta Giordano D. , Polo Valentina , Santoro Armando , Favaretto Adolfo G. , Ceresoli Giovanni Luca
Published: March 2020

7082

Background: The incidence of malignant pleural mesothelioma (MPM) in elderly patients (pts) is increasing in Western countries. Elderly pts with MPM are under-represented in clinical trials, and there are no specific guidelines for their management. The aim of this study was to perform a retrospective survey on this patient population in four Oncology Departments with high MPM accrual and expertise. Methods: The clinical records of elderly pts (≥70 years old) with MPM referred to the participating centers from January 2005 to November 2011 were reviewed. For each patient, age and gender, histology, Eastern Cooperative Oncology Group Performance Status (ECOG-PS), Charlson Comorbidity Index (CCI) and treatment modalities were collected. The study endpoint was overall survival (OS). Results: Out of a total of 610 cases, 210 elderly pts were identified (34% of the whole MPM population observed in the study period). Pts characteristics were: median age 75 yrs (range 70-92), M/F 132/78, epithelial/non-epithelial histology 140/70, ECOG-PS 0/1/2/unknown 130/67/9/4. CCI was 0 in 128 pts (61%), ≥4 in 59 pts (28%). Treatment was multimodality therapy including surgery in 16, chemotherapy in 153 (73%) and best supportive care only in 41 pts (19%). Chemotherapy was mainly pemetrexed-based. Median OS was 11.3 months. Non-epithelial histology, age ≥75 yrs and the presence of comorbidities (CCI ≥1, p=.003; CCI ≥4, p<0.0001) were significantly correlated to a shorter OS. Conclusions: Pemetrexed-based chemotherapy is feasible in selected elderly pts with MPM. Comorbidity is a significant prognostic factor, and should be carefully considered in patient selection. Prospective dedicated trials in elderly pts with MPM selected according to comorbidity scales are warranted.
Outcomes of sarcomatoid malignant pleural mesothelioma, a distinct clinical entity.
Authors: Gattoni Elisabetta , Grosso Federica , Roveta Annalisa , Libener Roberta , Degiovanni Daniela , Mancuso Maurizio , Piccolini Ezio , Ferretti Gabriele , Botta Mario , Betta Pier Giacomo
Published: March 2020

7084

Background: Sarcomatoid malignant pleural mesotheliomas (SMPM), accounting for 10% of MPM, are resistant to chemotherapy (CT) with median survival in the range of 6 months. Here we report on clinical outcome of a large series of SMPM patients treated at our Oncological Department, located in a particularly asbestos-polluted area in Piedmont (Italy). Methods: Patients consecutively diagnosed, treated and included in our MesoDB between 1993 and 2010 were considered for this study. Clinical and pathological data, treatments, response to CT and outcomes were analyzed for the present study. Diagnosis was always confirmed by the same expert pathologist. Results: Data of 672 patients were considered for the analysis. Among these, 53 (8%) were diagnosed with SMPM (17F/36M). Median age was 67,6 years. Asbestos exposure was occupational certain in 12, possible in 15, domestic in 3 and environmental in 23. The predominant symptom at diagnosis was thoracic pain in 34 patients (64%), followed by dyspnea in 16 (30%), fatigue and weight loss in 2 and palpable mass in 1. The predominant radiological finding at diagnosis was diffuse pleural thickening in 23 patients (43%), pleural effusion in 14 (26%), pleural effusion and pleural thickening in 10 (19%), localized mass in 4 (8%), unknown in 2 (4%). Forty-eight patients received first line CT with the following regimens: carboplatin/cisplatin and pemetrexed in29, pemetrexed in 8, cisplatin and raltitrexed in 3, cisplatin and gemcitabine in 3, gemcitabine in 2, doxorubicin based combination in 3 patients. The median number of cycles was 4. Overall response rate to first line CT was as follows: 11 SD (21%), 31 PD (58%) and 6 (11%) patients were not evaluable for response. Median progression free survival was 3.3 (95%CI 2.6-4.1) months. Eleven patients received a second line CT and no responses or disease stabilization was observed. Median OS was 7.6 months. Conclusions: This large series of SMPM suggests that standard CT has only negligible impact on the prognosis, underlying a highly unmet clinical need. SMPM patients should be treated within phase I-II studies with investigational agents. Research should focus to a deeper knowledge of tumor biology and to the identification of druggable targets.
Phase II study of amrubicin (AMR) combined with carboplatin (CBDCA) for refractory relapsed small cell lung cancer (SCLC): North Japan Lung Cancer Group 0802.
Authors: Saito Ryota , Inoue Akira , Sugawara Shunichi , Oizumi Satoshi , Maemondo Makoto , Okudera Koichi , Suzuki Toshiro , Usui Kazuhiro , Harada Masao , Morikawa Naoto , Hasegawa YUkihiro , Ishimoto Osamu , Sakakibara Tomohiro , Asahina Hajime , Nukiwa Toshihiro
Published: March 2020

7086

Background: AMR, a new anthracycline agent, has achieved some promising results for advanced SCLC both in the first-line and the second-line setting. However the efficacy of AMR alone against refractory relapsed SCLC was relatively low in previous studies. This study was conducted to evaluate the safety and efficacy of the combination of AMR plus CBDCA in patients with refractory relapsed SCLC. Methods: Patients with advanced SCLC who relapsed within 90 days after the completion of first-line chemotherapy received AMR (30 mg/m2, day1-3) and CBDCA (AUC 4.0, day 1) every 3 weeks. The primary endpoint of this study was overall response rate (ORR), and secondary endpoints were progression-free survival (PFS), overall survival and toxicity profile. Assuming that ORR of 45% in eligible patients would indicate potential usefulness while ORR of 20% would be the lower limit of interest, with alpha = 0.10 and beta = 0.10, at least 24 patients were required. Results: From September 2008 to May 2011, 30 patients were enrolled from 10 institutions. One patient was excluded because of ineligible histology. Patient characteristics were: Male/Female 26/3; median age 67 (range 50-81); Performance status 0/1/2 9/16/4. The median number of treatment cycles were 4 (range 1-7). The objective responses evaluated by RECIST were: CR 0, PR 10, SD 14, PD 5. The ORR was 34% and the disease control rate was 83%. Median PFS was 3.5 months and median survival time was 7.3 months. Grade 3-4 neutropenia was observed in 23 patients (79%) and grade 3-4 thrombocytopenia was observed in 7 patients (24%). One patient (3%) suffered from grade 3-4 febrile neutropenia. Other grade 3 non-hematological toxicities such as infection, interstitial lung disease, hyponatremia, hypoglycemia, were observed in 7 patients (24%). No treatment related death was observed. Conclusions: This is the first prospective study of AMR combined with CBDCA for refractory relapsed SCLC, which was effective and well tolerated. Further investigation of this treatment is warranted.
Genome-wide association study of survival in small cell lung cancer patients treated with irinotecan and cisplatin chemotherapy.
Authors: Han Ji-Youn , Shin Eun Soon , Lee Yeon-Su , Kim Sook-Young , Hong Seung-Hyun , Kim Jin Young , Lee Jin Soo
Published: March 2020

7089

Background: The prognosis of patients with extensive-disease small-cell lung cancer (ED-SCLC) remains poor. Despite a high initial response rate to chemotherapy, most patients die from rapid recurrence. We conducted a genome-wide analysis study (GWAS) to examine whether germline genetic variations are prognostic factors in ED-SCLC patients treated with irinotecan and cisplatin (IP) chemotherapy. Methods: We prospectively collected blood samples from 139 patients who participated in two phase II studies of IP chemotherapy as first-line therapy and conducted a GWAS using overall survival (OS) as the endpoint. Germline DNA was genotyped using the Affymetrix 5.0 or 6.0 array sets. Associations between OS and single nucleotide polymorphisms (SNPs) were investigated using multivariate Cox regression analysis. Adjustments for age, performance status (PS) and gender were made. We selected most promising SNPs with p<1×10−6 in the GWAS allelic association analyses. Results: A total of 426,019 SNPs were genotyped and 343,530 SNPs passed quality control (HWE, p<10-7, minor allele frequency>1%). We found 7 SNPs showing a significant association with OS. Patients harboring rs16950650 CT, rs7186128 AG or GG, rs17574269 AG, rs8020368 CC, rs4655567 CC, rs2166219 TT and rs2018683 TT genotypes showed shorter OS compared to patients with control alleles. Hazards ratios of death for each risk variants were 30.2 (95% CI, 8.3-109.0, p=2.1X10-7), 2.5 (95% CI, 1.7-3.5, p=3.8X10-7), 7.6 (95% CI, 3.4-16.6, p=4.5X10-7), 3.4 (95% CI, 2.1-5.5, p=3.5X10-7), 4.9 (95% CI, 2.7-9.0, p=3.1X10-7), 5.8 (95% CI, 2.9-11.7, p=8.4X10-7) and 7.8 (95% CI, 3.4-17.7, p=8.0X10-7), respectively. Among these SNPs, rs4655567, rs8020368, rs2018683 and rs17574269 were significantly associated with a refractory relapse. In multivariate logistic analysis including age, gender and PS, rs8020368 CC genotype showed higher risk of refractory relapse than patients with TT or TC genotype (HR=14.9 [95% CI, 1.9-114.8], p=0.010). Conclusions: This exploratory GWAS identified several candidate SNPs that might predictive for the outcome of patients with ED-SCLC receiving IP chemotherapy.
Incidence of venous thromboembolism in lung cancer and its effect on survival.
Authors: Mozayen Mohammad , Tesfaye Anteneh A. , Sarangi Manas ranjan , Talluri Jyothsna , Katato Khalil
Published: March 2020

7102

Background: Lung cancer is a major risk factor of venous thromboembolism (VTE). The incidence of VTE in different histological patterns of lungs cancer and its impact at the disease outcome is not well studied. We aim to evaluate the incidence rate of VTE in lung cancer and its effect on survival. Methods: Patients (pts) with lung cancer diagnosis from cancer database of community hospital were reviewed. Pts’ medical records were checked for VTE over 3 years after diagnosis. Pts’ demographics, pathology, TNM stage and overall survival were studied. Development of VTE was primary outcome and 3 year overall survival was the secondary outcome. Results: A total 2,164 pts with lung cancer between 1995 and 2008 were included. Median age of the study population was 70 years. Males were 53%, African Americans were 7%. 200 pts (9%) were diagnosed with VTE. Out of 1783 pts with non-small cell lung cancer (NSCLC), 176 pts (9.9%) had VTE whereas out of 381 pts with small cell lung cancer (SCLC) 24 pts (6.3%) had VTE (p=0.015). Among NSCLC pts, 13.5% of pts with adenocarcinoma had VTE, whereas 6.6% of pts with squamous cell carcinoma had VTE (p<0.05). The incidence of VTE in stages I, II, III, IV of all pts were (8.4%, 7.3%, 13%, 7.5%) (p=0.007) respectively. In NSCLC, three years overall survival of pts with and without VTE was 22% and 24% respectively (p=0.34). In SCLC, three years overall survival of pts with and without VTE was 21% and 11% respectively (p=0.09). Conclusions: There is a higher incidence of VTE in non-small cell lung cancer than in small cell lung cancer. Among the NSCLC, VTE’s incidence was higher in adenocarcinoma than squamous carcinoma. VTE maybe higher at advanced stages (stage III) in both NSCLC and SCLC combined. There was no significant difference in the 3 years overall survival of lung cancer patients with and without VTE.
A phase (Ph) I/II study of belinostat (Bel) in combination with cisplatin, doxorubicin, and cyclophosphamide (PAC) in the first-line treatment of advanced or recurrent thymic malignancies.
Authors: Thomas Anish , Rajan Arun , Khozin Sean , Szabo Eva , Carter Corey Allan , Guha Udayan , Manu Michell , Berman Arlene W , Kunst Tricia , Piekarz Richard , Schrump David S. , Giaccone Giuseppe
Published: March 2020

7103

Background: Belinostat is a hydroxamic acid histone deacetylase (HDAC) pan-inhibitor with single agent activity in thymic malignancies. PAC has activity against thymic cancers. Synergy between Bel and several chemotherapeutic agents, including P, A, and C, has been demonstrated in preclinical models. Methods: Patients with histologically confirmed, treatment naive advanced thymic malignancies, PS<2, measurable disease, and adequate renal, hepatic and hematopoietic functions were eligible. Ph1 evaluated safety and tolerability of the combination using increasing dose levels (DL) of Bel (1000-2000 mg/m² over 48 h CIVI) and PAC (50/50/500 mg/m² IV/cycle) (3+3 dose escalation schema), administered every 21 days for no more than 6 cycles followed by optional maintenance Bel every 4 weeks. Primary end point of Ph2 is overall response rate (ORR). Results: From March 2010 to January 2012, 13 patients were enrolled [7 thymoma (T), 6 thymic carcinoma (TC); 8 in Ph1 and 5 in Ph2; median age: 49 years (range, 23-76)]. In Ph1, 6 patients were treated at DL1 (Bel 1000 mg/m2+ PAC) and 2 patients at DL2 (Bel 2000 mg/m2+ PAC). Dose Limiting Toxicities were Grade 3 nausea and diarrhea, and Grade 4 neutropenia and thrombocytopenia. Recommended phase II dose (RP2D) was set at DL1. Most common grade 3/4 treatment-related adverse events (AE) were lymphocytopenia (100%), leucopenia (85%), neutropenia (77%) thrombocytopenia (54%), anemia (38%), hypophosphatemia (38%), hypomagnesemia, hypokalemia, elevated AST, prolonged QTc and infusion-catheter related thromboembolic complications (23% each). Outcomes included one complete response (CR; T at DL1), 6 partial responses (PR; 4 T, 2 TC; 4 in Ph1, 2 in Ph2) and 6 stable disease (SD; 2 T, 4 TC; 3 each in Ph1 and Ph2). Four patients previously deemed unresectable underwent surgical resection. Conclusions: Belinostat in combination with PAC has activity in thymic malignancies with a predicable AE profile. ORR was 54% including 33% PR in the TC subgroup. RP2D of the combination has been defined. Accrual to Ph2 part and molecular profiling of patient tumors is ongoing.
Neoadjuvant treatment of primary inoperable or local recurrent thymoma with octreotide LAR to improve tumor resectability.
Authors: Schalke Berthold , Boy Sandra , Hofmann Hans-Stefan , Stroebel Philipp , Marienhagen Joerg , May Christoph , Stuermer Andrea , Marx Alexander
Published: March 2020

7105

Background: The therapeutic outcome for unresectable, locally advanced, malignant thymoma is poor. Most important factor for long-term survival in thymoma patients is complete resection (R0) of the tumor. The study was performed to evaluate the efficacy of octreotide LAR plus prednisone in patients with primary inoperable or local recurrent thymoma to reduce tumor size. Methods: This was an open label, single-arm study in patients with inoperable or local recurrent thymoma. Patients were considered unlikely to achieve R0 resection at enrollment. Octreotide LAR was administered once every 2 weeks in combination with prednisone. Two stages were planned according to Fleming’s one sample multiple testing procedure for phase II clinical trials. The objective of the study was to show that octreotide LAR is effective in this patient population with respect to tumor shrinkage. Response was defined as decrease in tumor volume of at least 20% at month 3 as compared to baseline. Results: 17 thymoma patients at Masaoka stage III were recruited. Octreotide LAR showed a response in 15 of 17 patients (88.24%) at week 12. Two patients had discontinued the study before week 12 due to unsatisfactory therapeutic effect or adverse events. At Week 12, 5 patients (29.41%) operable for radical resection. 10 patients (58.82%) were not operable for radical resection. 16 of 17 patients (94.12%) experienced adverse events (AEs). The most frequent AEs were gastrointestinal disorders (70.59%), infections and infestations (64.71%), and blood/lymphatic system disorders (41.18%). Conclusions: Octreotide LAR was shown to be effective in patients with inoperable thymoma with respect to tumor shrinkage.Octreotide LAR was generally well tolerated. The reported AEs are in accordance with the known safety profile.
Three-arm randomized phase II study of carboplatin (C) and paclitaxel (P) in combination with cetuximab (CET), IMC-A12, or both for advanced non-small cell lung cancer (NSCLC) patients who will not receive bevacizumab-based therapy: An Eastern Cooperative Oncology Group (ECOG) study (E4508).
Authors: Hanna Nasser H. , Dahlberg Suzanne Eleanor , Kolesar Jill , Hirsch Fred R. , Ramalingam Suresh S. , Schiller Joan H.
Published: March 2020

7516

Background: Pre-clinical evidence supports the clinical investigation of inhibitors to the insulin-like growth factor receptor (IGFR) and the epidermal growth factor receptor (EGFR) alone and in combination with one another in patients (pts) with NSCLC. Methods: Pts w/ chemotherapy-naïve, advanced NSCLC, not eligible for bevacizumab-based therapy, ECOG PS 0/1 were eligible. Pts with uncontrolled or untreated brain mets and/or severe hyperglycemia were ineligible. Pts were randomized to receive: C AUC 6 iv + P 200 mg/m2 iv on day 1 every 3 wks combined with either CET iv weekly (arm A), IMC-A12 iv every 2 wks (arm B), or both (arm C). Patients with non-progressive disease (PD) after 12 weeks of therapy were permitted to continue on maintenance antibody therapy until PD. The primary objective was PFS. Secondary objectives included OS and toxicity. The design required 180 eligible patients and had an 88% power to detect a 60% increase in median PFS for either comparison (arm A vs C or arm B vs C) (1-sided 0.10 level test). Results: Characteristics for arms A (n=39)/B (n=42)/C (n=48): males were 51%/57%/54%; median age was 60, 62, 60; PS 0 49%/52%/60%; stage IV 87%/83%/94%; adenocarcinoma 44%/26%/42%. The study was closed prematurely due to safety concerns after 129 eligible pts were treated. 13 patients died during treatment (A=6; B=2; C=5), including 9 w/in ~1 mo of starting therapy. G3-5 toxicities, all attributions, A/B/C: anemia 16%/7%/13%; neutropenia 27%/29%/42%; febrile neutropenia 7%/5%/4%; thrombocytopenia 7%/10%/13%; pneumonia 9%/2%/6%; hyperglycemia 2%/10%/15%; rash 5%/2%/8%; hyponatremia 2%/5%/17%; thromboembolic events 2%/10%/0%; fatigue 16%;22%/13%. The estimated median PFS and OS for arms A/B/C were 3.4, 4.3, and 4.1 mos and 11.7, 8.6, and 8.4 mos, respectively. Conclusions: Based upon apparent lack of efficacy and excessive premature deaths, this study does not support the continued investigation of C + T + IMC-A12 alone or in combination with CET in pts with advanced NSCLC not eligible for bevacizumab.
Updated overall survival results of WJTOG 3405, a randomized phase III trial comparing gefitinib (G) with cisplatin plus docetaxel (CD) as the first-line treatment for patients with non-small cell lung cancer harboring mutations of the epidermal growth factor receptor (EGFR).
Authors: Mitsudomi Tetsuya , Morita Satoshi , Yatabe Yasushi , Negoro Shunichi , Okamoto Isamu , Seto Takashi , Satouchi Miyako , Tada Hirohito , Hirashima Tomonori , Asami Kazuhiro , Katakami Nobuyuki , Takada Minoru , Yoshioka Hiroshige , Shibata Kazuhiko , Kudoh Shinzoh , Shimizu Eiji , Saito Hiroshi , Toyooka Shinichi , Nakagawa Kazuhiko , Fukuoka Masahiro ,   West Japan Oncology Group
Published: March 2020

7521

Background: WJTOG3405 met its primary endpoint of progression free survival (PFS) (9.2 months (mo.) for G vs. 6.3 mo. for CD, hazard ratio (HR) 0.489, 95% confidence interval (CI): 0.336-0.710). (Mitsudomi et al., Lancet Oncol., 2010). However, the impact on overall survival (OS) was not clear then because of relatively short follow-up period. Methods: Overall survival (OS) was re-evaluated using updated data (data cutoff, 31 July, 2011, median follow-up, 34 months) for 172 patients. Results: Eighty-two events had occurred (48%). Median survival time (MST) for G arm was 36 mo. (95% CI: 26.3 -) which was not significantly different from 39 mo. (95% CI: 31.2 -) for CD arm (HR 1.185, 95% CI 0.767-1.829). Multivariate analysis using Cox proportional hazards model revealed that none of covariates (treatment arm, smoking status, sex, age, postoperative recurrence or IIIB/IV, and mutation type) significantly affected OS. In the G arm, MST of patients with exon 19 deletion (36 mo.) was comparable to that of patients with L858R (35 mo.). In the CD arm, 78 patients (91%) received EGFR-TKI as the 2nd or later line treatment, whereas in the G arm, 52 patients (61%) received platinum doublet. Accordingly, 130 patients received both platinum doublet and EGFR-tyrosine kinase inhibitor (TKI) and 34 patients received EGFR-TKI without platinum doublet in their whole courses of therapy. MST for the former and the latter group were 36 months (95% CI: 31.2-45.7) and 45 months (95% CI: 25.6-), without significant difference. Conclusions: This update OS analysis revealed that G for advanced NSCLC with EGFR mutation offers distinct survival benefit of 3 years. There was no difference in OS whether the first-line treatment was G or CD, in accordance with the precedent studies. The reason why PFS difference was not translated into OS difference is probably due to high cross over rate to EGFR-TKI. However, it was noteworthy that 40% of patients in the G arm could be managed without platinum doublet and yet had similar outcome.
Differential progression-free survival (PFS) to erlotinib according to EGFR exon 19 deletion type in non-small cell lung cancer (NSCLC) patients (p) in the EURTAC study.
Authors: Carcereny Costa Enric , Taron Miquel , Queralt Cristina , de Aguirre Itziar , Capdevila Laia , Cros Sara , Vergnenegre Alain , De Marinis Filippo , Massuti Bartomeu , Reguart Noemi , Ono Mayumi , Buges Cristina , Provencio Mariano , Garrido López Pilar , Viteri Ramirez Santiago , Gasco Amaya , Sanchez Jose Miguel , Cobo Manuel , Drozdowskyj Ana , Rosell Rafael
Published: March 2020

7540

Background: Different exon 19 deletion types have shown different in vitro sensitivity to erlotinib, with the lower IC50 for deletion E746_A750 (ELREA) (Yuza et al. Cancer Biol Ther 2007). This information prompted us to examine outcome according to type of exon 19 deletion in the EURTAC study. Methods: The EURTAC trial (clinicaltrials.gov NCT00446225) randomized 174 p with EGFR exon 19 deletions or L858R mutations to receive erlotinib or chemotherapy. Progression-free survival (PFS) was 9.7 months (m) vs 5.2 m, respectively (P<0.0001). Exon 19 deletions were divided into two groups: ELREA vs non-ELREA deletions. Results: Exon 19 deletions were present in 57 p in the erlotinib arm and in 58 p in the chemotherapy arm. ELREA deletions were found in 41 p (71.9%) in the erlotinib arm and in 38 p (65.5%) in the chemotherapy arm. Non-ELREA deletions were found in 16 p in the erlotinib arm and in 20 p in the chemotherapy arm. There were no differences in p characteristics between treatment arms according to type of deletion. PFS for p with ELREA deletions was 9.4 m in the erlotinib arm and 4.6 in the chemotherapy arm (HR, 0.36; P=0.0004). PFS for p with non-ELREA deletions was not reached in p in the erlotinib arm and was 5.3 m for p in the chemotherapy arm (HR, 0.17; P=0.001). The multivariate analysis identified erlotinib arm (P<0.001) and non-ELREA deletions (P=0.001) as independent markers of longer PFS. Overall survival (OS) for p with ELREA deletions was 17 m in the erlotinib arm and 18.4 in the chemotherapy arm (P=0.575). OS for p with non-ELREA deletions was not reached in the erlotinib arm and 19.5 m in the chemotherapy arm (P=0.216). Response rate (RR) for p with ELREA deletions was 53.6% in the erlotinib arm vs 15.7% in the chemotherapy arm (P=0.004). RR for p with non-ELREA deletions was 68.7% in the erlotinib arm vs 10% in the chemotherapy arm (P=0.001). Conclusions: To date, no biological reason has been identified that can explain the greater sensitivity to erlotinib in p with non-ELREA exon 19 deletions. Our findings indicate the need to define the type of deletion prior to treatment since this information can be helpful in predicting the duration of response.
A randomized, double-blind, placebo-controlled multicenter phase II study of the COX-2 inhibitor apricoxib (A) in combination with either docetaxel (doc) or pemetrexed (pem) in advanced non-small cell lung cancer (NSCLC) patients (pts) selected by urinary PGE-m suppression.
Authors: Edelman Martin J. , Tan Ming Tony , Fidler Mary J. , Sanborn Rachel E. , Otterson Gregory Alan , Sequist Lecia V. , Evans Tracey L. , Schneider Bryan J. , Keresztes Roger , Rogers John S. , Antunez de Mayolo Jorge , Medeiros Michelle , Zaknoen Sara L.
Published: March 2020

7546

Background: Overexpression of COX-2 has been associated with advanced stage and worse outcomes in NSCLC, possibly due to elevated levels of the COX-2 dependent prostaglandin, PGE-2. COX-2 inhibitors in addition to standard therapy has been associated with superior outcome in pts in whom the urinary metabolite of PGE-2, PGE-M is suppressed by the inhibitor. We hypothesized that pts defined by PGE-M suppression would benefit from the addition of apr to doc or pem. Methods: Pts with NSCLC, progressive after one platinum based therapy, PS 0-1, normal organ function, alb ≥2.5, CCr ≥ 45 were eligible for screening. A 5 day run in period with apr 400mg qd was performed. Only pts with a ≥ 50% decrease in urinary PGE-M could actually enroll. Chemotherapy was doc 75 mg/m2 or pem 500 mg/m2 q21 d per the investigator plus apr/placebo (P) 400 mg qd. The primary endpoint was progression free survival (PFS). Results: A total of 109 pts were screened of whom 72 demonstrated ≥50% suppression and enrolled (table). Toxicity was similar between the arms. No improvement in PFS was seen with apricoxib vs. placebo. By chemotherapy assignment: pem/apr vs. pem/P : 103 days vs. 98 (p =.49); doc/apr vs. doc/P: 75 vs. 97 (p=.18). An adverse interaction between baseline PGE-M and doc was seen in survival (p=.026); each unit increase in urinary PGE-M increased the HR by 1.014 (p < 0.038 ) vs. pem (HR =.990, p=n.s.). There was no correlation between baseline PGE-M or magnitude of PGE-M suppression and benefit from apr. Conclusions: 1. Apr did not improve outcome despite patient selection. 2. There was a trend towards an adverse outcome when apr was combined with docetaxel, that was not evident with pemetrexed. 3. Baseline urinary PGE-M may be an adverse prognostic factor for treatment with doc. [Table: see text]
Final results of a randomized, double-blind, phase II study of gemcitabine plus vandetanib or plus placebo in the treatment of advanced (stage IIIB/IV) non-small cell lung cancer (NSCLC) elderly patients (ZELIG study NCT00753714).
Authors: Gridelli Cesare , Novello Silvia , Zilembo Nicoletta , Foa Paolo , Favaretto Adolfo G. , De Marinis Filippo , Genestreti Giovenzio , Crinò Lucio , Grossi Francesco , Caffo Orazio , Ferraù Francesco , Cruciani Giorgio , Brandes Alba Ariela , Galetta Domenico , Barni Sandro , Fasola Gianpiero , Siena Salvatore , Mari Ettore , Iannacone Claudio , Ciardiello Fortunato
Published: March 2020

7550

Background: Vandetanib (V) is a once-daily oral inhibitor of VEGFR, EGFR and RET signaling. Single-agent gemcitabine (G) is a standard of care option for unselected patients (pts) unfit for doublet platinum based chemotherapy. This study assessed the progression-free survival (PFS) benefit of G+V compared to G plus placebo (P) in pts with advanced NSCLC aged ≥ 70 years. Methods: Eligible pts (stage IIIB/IV NSCLC; WHO PS 0-2; all histologies; chemonaïve, aged ≥70) were randomized 1:1 to receive G 1200 mg/m2 i.v. day 1 and 8 of each 21-day cycle, up to 6 cycles plus V 100 mg/day or plus P until progression/toxicity. The primary objective was PFS (80% power to detect a hazard ratio [HR] ≤ 0.667). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Results: Between Oct 2008-May 2010, 124 pts (median age 75 yrs (70-84); 72.6% male; 57.2% WHO PS 0-1; 74.2% past/never-smoker; 58.1% adenocarcinoma; 89.5% stage IV) were randomized to G+V (n = 61) or G+P (n = 63). Baseline characteristics were similar in both arms. At data cut-off (Apr11), 87.9% pts progressed and 73.4% pts had died. PFS was significantly prolonged for G+V (HR=0.729; 95% CI 0.484-1.096; p=0.0417), median PFS G+V=6.0 months, G+P=5.5 months. No differences were seen in ORR (14.8% and 12.7%; p = 0.74), DCR (72.1% and 66.7%; p =0.51), OS (HR=1.024 [95% CI 0.667-1.571] p=0.8960), proportion of pts alive at 1-year G+V=31.1% and G+P=30.2% (p=0.90). Adverse events (AEs) observed for V 100 mg were generally consistent with previous NSCLC studies of V 100 mg. Common AEs (any grade) occurring with a greater frequency in the G+V arm included skin toxicity (34.4% vs 15.9%) and hypertension (9.8% vs 3.2%). Diarrhea and neutropenia were similar in both arms (14.8% and 14.3%; 19.7% and 19.0%). Conclusions: Despite a marginally statistically significant improvement in PFS the study did not met the primary and secondary end points. The combination G+V was well tolerated in this clinical setting.
Randomized phase II trial of carboplatin combined with weekly paclitaxel (CP) and docetaxel alone (D) in elderly patients (pts) with advanced non-small cell lung cancer (NSCLC): NJLCG 0801.
Authors: Sugawara Shunichi , Maemondo Makoto , Harada Toshiyuki , Inoue Akira , Matsubara Nobumichi , Watanabe Kana , Ishimoto Osamu , Sakakibara Tomohiro , Minegishi Yuji , Usui Kazuhiro , Ando Masahiro , Morikawa Naoto , Mori Yoshiaki , Gemma Akihiko , Nukiwa Toshihiro
Published: March 2020

7565

Background: Standard first-line chemotherapy for elderly NSCLC pts has been considered as a monotherapy with vinorelbine or gemcitabine globally. However, we have demonstrated the high efficacy of CP for elderly pts in our previous trial (Ann Oncol 2010). Meanwhile, D has been considered as an alternative option for this population in Japan according to the result of WJTOG9904 (JCO 2006). Thus we compared the two regimens to select the proper candidate for future phase III trial. Methods: Eligible pts were aged 70 years or older with newly diagnosed stage IIIB/IV NSCLC; ECOG performance status 0-1; adequate organ function; written informed consent. Pts were randomized to receive carboplatin (AUC 6) on day 1 and paclitaxel (70mg/m2 on day 1, 8, and 15) every 4 weeks or D (60mg/m2 on day 1) every 3 weeks. The primary endpoint was overall response rate (ORR), and secondary endpoints were progression-free survival (PFS), overall survival, and toxicity profile. Assuming that ORR of 40% would be potential usefulness while ORR of 20% would be the lower limit of interest, 40 pts in each arm were required if expect 10% loss to follow up. Results: Between July 2006 and September 2010, 84 pts were enrolled and 41 pts in CP arm and 42 pts in D arm were eligible (median age, 76 years; 75% male; 72% stage IV). Median treatment cycle was 4 in each arm (CP, range 1-6; D, range 1-8). ORRs were 51% (95%CI: 36-66%) and 26% (95%CI: 12-39%) in the CP and D arm, respectively. With a median follow-up of 18.4 months, median PFS were 6.5 and 3.9 months in the CP and D arm, respectively (Logrank, P=0.0027). Grade 3 or severer toxicities were as follows: neutropenia (CP, 56% and D, 79%), anemia (CP, 15% and D, 7%), thrombocytopenia (CP, 10% and D, 0%), infection (CP, 20% and D, 25%). One treatment-related death due to neutropenia, pneumonia, and lethal arrhythmia occurred in D arm but none in CP arm. Conclusions: The platinum doublet CP achieved higher activity with an acceptable toxicity profile for elderly pts with advanced NSCLC compared to monotherapy with D. The superiority of CP to the monotherapy in this trial is consistent with results of recent IFCT-0501 trial (Lancet 2011).
Older patient participation in SWOG lung cancer trials: Comparative analysis from 1993 to 2008.
Authors: Hesketh Paul Joseph , Redman Mary Weber , Unger Joseph M , Moon James , Gandara David R.
Published: March 2020

7570

Background: In 1999, SWOG published a study demonstrating the underrepresentation of patients 65 years and older on clinical trials (Hutchins NEJM). A second report published in 2006 demonstrated increasing proportions of patients > 65 years (31% 1997-2000; 38% 2001-2003) being enrolled into SWOG trials (Unger JCO). Older patient enrollment was still disproportionately low compared to the US cancer population. The current analysis focuses on patients with lung cancer from 1993-2008. Methods: The proportions of enrollment onto SWOG lung cancer treatment trials by age (65-69, 70-79, ≥80 years) and gender were computed for 4-year time intervals between 1993 and 2008; corresponding rates in the US were derived from US Census and National Cancer Institute SEER data. Proportions in the SWOG trials were compared to the SEER proportions using a 1-sample binomial test of proportions. Time trends within SWOG were evaluated using linear regression. Results: The proportion of patients 65-69 was significantly higher than the US population between 1993 and 2004, but was not significantly different after 2004. Proportions of patients on SWOG trials 70-79 years old and ≥ 80 were significantly smaller than the US population. Females were underrepresented from 1993-2004. Between 2005 and 2008 female enrollment was not significantly different from the US population. Conclusions: Currently, the proportion of patients 65-69 years of age and of female gender enrolled in SWOG trials is representative of the general lung cancer population. Although some progress has been made in increasing trial participation of patients > 70, enrollment remains disproportionately low. The disparity is most evident in patients > 80. Continued efforts are needed to increase older patient participation in lung cancer trials. Supported in part by PHS Cooperative Agreement grants awarded by the National Cancer Institute: DHHS, CA32102 and CA38926. [Table: see text]
Prospective randomized phase II trial of oral vinorelbine (NVBo) and cisplatin (P) or pemetrexed (Pem) and P in first-line metastatic or locally advanced non-small cell lung cancer (M or LA NSCLC) patients (pts) with nonsquamous (non SCC) histologic type: NAVoTRIAL01—Preliminary results.
Authors: Bennouna Jaafar , Zatloukal Petr , Krzakowski Maciej Jerzy , Kollmeier Jens , Riviere Alain , Dansin Eric , Serke Monika , Favaretto Adolfo G. , Havel Libor , Malasse Stephanie , Biville-Hedouin Fabienne , Tan Eng Huat
Published: March 2020

7575

Background: NVBo+P is considered as a standard treatment (trt) in M or LA NSCLC. The recent approval of Pem+P as front line chemotherapy (CT) for non-SCC demonstrates that today, histology could become a “new guidance” to treat patients (pts). Phase III trial (Scagliotti. JCO 2008) showed efficacy of Pem+P in patients with non-SCC pts. Moreover, the higher chemosensitivity of non-SCC is recognised and reported with other chemotherapies (Ardizzoni.JNCI 2007). In GLOB 3 study, NVBo+P also showed better survival in adenocarcinoma (11.7m) than in SCC (8.9m) (Tan.Ann of Oncol 2009). This trial was set up to assess the efficacy of NVBo+P compared to Pem+P for pts with non-SCC histological type. The primary end-point was disease control rate (DCR) including overall response rate (ORR) and stable disease (SD). Methods: Pts were randomised to receive NVBo 80 mg/m² D1D8 (60 at Cycle 1) + P 80 mg/m² D1 q3w or Pem 500 mg/m² + P 75 mg/m² D1 q3w. After 4 cycles of trt, for pts showing a disease control, single agent as continuation maintenance (CM) was proposed until progression or toxicity. Given that Pem+P is now considered as a reference trt in non-SCC, pts were randomised on a 2/1 basis and stratified according to stage (IIIB - IV - relapse), non-SCC confirmed by histology or cytology, gender, smoking status and centre. Results: From 10/09 to 02/11, 153 pts were randomised to receive NVBo+P (102 pts) or Pem+P (51 pts). The efficacy between the 2 arms is similar: The ORR/DCR (Recist 1.1) after 4 cycles of trt are 26%/75% in the NVBo arm (100 eval pts in ITT population) and 24%/78% in the Pem arm (50 eval pts in ITT population). At the end of December 2011, 7 patients are still treated in CM: 5 pts in the NVBo arm and 2 pts in the Pem arm. Conclusions: The 2 CT regimen, NVBo+P or Pem+P have a similar efficacy in terms of ORR/DCR for pts with advanced non-SCC NSCLC. These results appear to be in line with the published data. As the analysis is currently in progress, final results including safety data, PFS and OS will be presented during the meeting.
NGR-hTNF plus chemotherapy as first-line therapy of non-small cell lung cancer (NSCLC).
Authors: Gregorc Vanesa , Zilembo Nicoletta , Grossi Francesco , De Pas Tommaso M , Rossoni Gilda , Pietrantonio Filippo , Rijavec Erika , Giovannini Monica , Citterio Giovanni , Lambiase Antonio , Bordignon Claudio
Published: March 2020

7581

Background: NGR-hTNF (asparagine-glycine-arginine human tumor necrosis factor) is a selective vascular targeting agent able to improve intratumoral chemotherapy uptake. Methods: Chemo-naive, stage IIIb-IV NSCLC patients (pts), stratified by histology (nonsquamous or squamous) and PS (0 or 1), were randomized to cisplatin 80 mg/m2/day(d)1 plus either pemetrexed 500 mg/m2/d1 (nonsquamous) or gemcitabine 1,250 mg/m2/d1+8 (squamous) every 3 weeks (q3w) up to 6 cycles with (arm A) or without (arm B) NGR-hTNF 0.8 μg/m2/d1 q3w until progression. Progression free survival (PFS) was primary end point of this phase 2 trial (β=20%, α=20%, HR=0.62, and n=102). Secondary end points included adverse events (AEs), response rate (RR) and overall survival (OS). Results: 59 pts were assigned to arm A and 57 to arm B. Baseline characteristics in arm A/B were: median age 62/63; male 34/37; PS 1 21/21; squamous 15/15; nonsmokers 14/12; EGFR mutations 5/5. For the nonsquamous group, 281 cycles (mean 6.5; range 1-18) were given in arm A and 190 (mean 4.7; range 1-6) in arm B, while for the squamous group, 88 (mean 6.3; range 1-19) in arm A and 48 (mean 3.7; range 1-6) in arm B. Most common grade 3/4 AEs were neutropenia 14% vs 17% and fatigue 7% vs 11% in arm A and B, respectively. No grade 3/4 AEs related to NGR-hTNF or bleeding in pts with squamous histology were noted. Median follow-up was 12.4 months. In the whole study population, median (m)PFS was 5.8 vs 5.7 months (HR=0.95), RR was 23% vs 19%, and 1-year OS was 62% vs 62% in arm A and B, respectively. In the nonsquamous subset, a trend toward longer mPFS in arm A compared to arm B was noted in pts with a PS of 1 (6.7 vs 4.6 months, respectively), nonsmoking history (6.2 vs 3.4), younger age (6.5 vs 3.4), and EGFR mutations (7.2 vs 3.3). In the squamous subset, mPFS was 5.1 vs 3.9 months (HR=0.71) and mOS was 14.2 vs 10.8 months (HR=0.73) in arm A and B, respectively. In these pts, ORR was 36% in arm A and 23% in arm B, while median changes from baseline in target tumor size after 2, 4, and 6 cycles were -29%, -45%, and -41%, respectively in arm A, and -18%, -22%, and -14%, respectively in arm B. Conclusions: Regardless of histology, NGR-hTNF can be safely given with standard chemotherapy, showing tolerability and hint of activity in squamous NSCLC.
Expression of folate pathway regulators and pemetrexed (pem) activity in patients (pts) with advanced non-small cell lung cancer (NSCLC).
Authors: Gianoncelli Letizia , Toschi Luca , Canal Barbara , Lo Russo Chiara , Rubino Luca , Finocchiaro Giovanna , Giordano Laura , Destro Annarita , Garassino Isabella M.G. , Cavina Raffaele , Siracusano Licia , Roncalli Massimo , Carbone Antonino , Santoro Armando
Published: March 2020

7585

Background: Thymidylate synthase (TS) expression has been reported to predict pem activity in pts with advanced NSCLC. Besides TS, pem inhibits multiple enzymes of the folate pathway including dihydrofolate reductase (DHFR), glycinamide ribonucleotide formyltransferase (GART) and aminoimidazole carboxamide ribonucleotide formyltransferase (AICAR). Aim of present study was to investigate whether these or other biomarkers influence pem activity in NSCLC pts. Methods: Advanced pretreated NSCLC pts who received at least two cycles of single agent pem were considered eligible if they had available tumor tissue to assess at least one of the proposed biomarkers. TS, DHFR, GART and AICAR protein expression was assessed by immunohistochemistry (IHC) in FFPE tumor samples. Pts were grouped as IHC+ and IHC– according to staining intensity. Additionally, presence of EGFR and KRAS mutations was investigated. Results: Ninety-six pts were included in the study. The majority of subjects was male (72%), smokers (93%), with adenocarcinoma (72%). Response rate (RR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) were 12%, 47%, 2.3 and 9.5 months, respectively. Most pts resulted TS-(72%), AICAR-(82%), DHFR+ (68%), GART- (61%). EGFR and KRAS mutations were identified in 15% and 25% of assessable cases. None of the biomarkers was significantly associated with pts characteristics (gender, histology, smoking status), nor with RR or DCR. GART- pts experienced longer PFS when compared with the GART+ group (HR 0.56, p=.052), while no difference was observed according to TS, DHFR and AICAR status. A significantly longer OS was observed for TS- (HR 0.52, p=.012), GART- (HR 0.50, p=.037) and AICAR- (HR 0.40, p=.028) pts. No significant difference in the distribution of EGFR mutant pts receiving EGFR TKIs after pem failure was observed between IHC+ and IHC- groups. Conclusions: Low TS, GART and AICAR protein expression predicts significantly prolonged survival in single agent pem-treated pts with advanced NSCLC. The lack of PFS difference according to TS and AICAR status suggests prognostic rather than predictive relevance for these biomarkers.
Weekly nab-paclitaxel in combination with carboplatin as first-line therapy in elderly patients (pts) with advanced non-small cell lung cancer (NSCLC).
Authors: Socinski Mark A. , Langer Corey J. , Okamoto Isamu , Hon Jeremy K. , Hirsh Vera , Dakhil Shaker R. , Page Ray D. , Orsini James M. , Zhang Hui , Renschler Markus F.
Published: March 2020

7590

Background: The median age of advanced NSCLC pts in the US is 71 years; yetelderly pts (≥70 years) are generally undertreated, with only ≈30% receiving systemic therapy. Hence, better, more tolerable therapeutic options are needed for this cohort. In a phase III trial nab-paclitaxel (nab-P, 130 nm albumin-bound paclitaxel particles) + carboplatin (C) vs solvent-based paclitaxel (sb-P) + C, significantly improved ORR, the primary endpoint (25% vs 33%, P = 0.005), with a 1-month improvement in OS (P = NS) and improved safety. This analysis evaluated efficacy and safety in pts ≥70 and <70 years old. Methods: Pts with untreated stage IIIB/IV NSCLC and with an ECOG score of 0/1 were randomized 1:1 (stratified by age [≥70 vs <70 years], region, stage, gender, and histology) to C AUC 6 day 1 and either nab-P 100 mg/m2 on days 1, 8, 15 or sb-P 200 mg/m2 day 1 q 21 days. ORR and progression-free survival (PFS) were determined by blinded centralized review. Results: Of the phase III study population, 15% were elderly (156/1052; 74 pts in the nab-P/C and 82 in the sb-P/C arms). Most elderly pts were male (72%), Caucasian (71%), and had stage IV disease (64%). In pts both ≥70 and <70 years old, ORR was higher in the nab-P/C vs sb-P/C arm (≥70: 34% vs 24%, P = 0.196; <70: 32% vs 25%, P = 0.013). In pts ≥70 years old, PFS trended in favor of nab-P/C (median 8.0 vs 6.8 months, HR: 0.687, P = 0.134); OS was significantly improved (median 19.9 vs 10.4 months, HR: 0.583, P = 0.009). In contrast, PFS (6.0 vs 5.8 median months, HR: 0.903, P = 0.256) and OS (11.4 vs 11.3 median months, HR: 0.999, P = 0.988) were similar for both treatment arms in pts <70 years old. Adverse events were similar in pts ≥70 years old vs the entire study population, with less grade 3/4 neutropenia (P < 0.05) and neuropathy (P < 0.05) and increased thrombocytopenia (P = NS) and anemia (P < 0.05) in the nab-P/C vs sb-P/C arms. In pts ≥70 years old, patient-reported FACT-taxane subscales revealed significantly less neuropathy, pain, and hearing loss in the nab-P/C vs sb-P/C arms (P < 0.001). Conclusions: In elderly pts with advanced NSCLC, nab-P/C as first-line therapy was well tolerated and led to improved ORR and PFS, with significantly longer OS vs sb-PC.
Clinical benefit from pemetrexed before and after crizotinib exposure in patients with ALK positive non-small cell lung cancer (ALK+ NSCLC).
Authors: Berge Eamon , Delee Maxon , Lu Xian , Barón Anna E. , Solomon Benjamin J. , Doebele Robert Charles , Camidge D Ross
Published: March 2020

7601

Background: Crizotinib (Criz) produces high response rates and prolonged progression free survival (PFS) in ALK+ NSCLC. Retrospective analyses suggest enhanced sensitivity to pemetrexed (Pem) in Criz-naïve ALK+ NSCLC. Different biological mechanisms of Criz resistance have recently been discovered. Clinical cross-resistance between Criz and Pem has not been previously investigated. Methods: Patients with stage IV ALK+ NSCLC treated in sequence with Pem then Criz (Pem-Criz), or Criz then Pem (Criz-Pem) were identified. Excluding CNS only progression events when no new systemic treated was started, PFS was compared using Cox Proportional Hazards. Correlations between molecular features of ALK positivity and Pem PFS were analyzed using Spearman correlations. Treatment sequence effect was explored using Fisher’s exact test. Results: We identified 19 Pem-Criz and 9 Criz-Pem ALK+ patients. Pem was given as monotherapy in 37% vs. 66%, and as median 2nd vs. 3rd line cytotoxic in the Pem-Criz and Criz-Pem groups, respectively. For the Pem-Criz group,median PFS was 8.9 months with Pem (range: 1-21.5 months), and 14.7 months with Criz (range:2.9+ -27.5 months). For the Criz-Pem group, median PFS was 8.4 months with Criz (range: 2-29 months), and 4.4 months with Pem (range: 0.5-10.5+ months). Patients were more likely to progress on Pem given after Criz than before, but confidence intervals were wide (HR 1.51, 95% CI 0.626-3.66). Neither native or rearranged signal copy number, nor percent cells ALK+ in the tumors correlated with PFS on Pem. Conclusions: Both Criz and Pem appear to be active drugs in ALK+NSCLC given in either order. Numerically, benefit from Pem was less when given post-Criz compared to pre-Criz, however this difference was not statistically significant. Several potential confounders exist in our small dataset (notably differences in line of therapy and use in combo vs. monotherapy). To fully address whether there may be a significant difference in overlap of induced specific drug resistance mechanisms, the clinical effect of Criz/Pem sequencing should be explored in a larger series adjusting for confounding effects.