bluuebunny/crossref_metadata_2025 huggingface dataset:
SATURN: A double-blind, randomized, phase III study of maintenance erlotinib versus placebo following nonprogression with first-line platinum-based chemotherapy in patients with advanced NSCLC
Authors: Cappuzzo F. , Ciuleanu T. , Stelmakh L. , Cicenas S. , Szczesna A. , Juhasz E. , Esteban Gonzalez E. , Molinier O. , Klingelschmitt G. , Giaccone G.
Published: August 2020

8001

Background: Erlotinib (E), a small-molecule EGFR TKI, is proven to extend survival versus placebo (P) in 2nd/3rd-line advanced NSCLC. The phase III SATURN study (BO18192) was initiated to evaluate E as maintenance therapy after standard 1st-line platinum-based chemotherapy (CT) in advanced NSCLC. Methods: Patients with no evidence of disease progression after 4 cycles of CT were randomized to receive either E 150 mg/day or P until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) in all patients and the co-primary endpoint was PFS in EGFR immunohistochemistry-positive (IHC+) patients. Results: A total of 1,949 patients entered the CT phase, of whom 889 were randomized to E (n=438) or P (n=451). Median age was 60 years for both arms. Baseline characteristics for E and P arms (%): male/female: 73/27 and 75/25; adenocarcinoma + BAC/squamous-cell/other: 47/38/15 and 44/43/13; stage IIIB/IV: 26/74 and 24/76; Caucasian/Asian/other: 84/14/2 and 83/15/2; ECOG PS 0/1: 31/69 and 32/68; current/former/never smoker: 55/28/18 and 56/27/17. PFS (by investigator assessment; confirmed by independent review) was significantly prolonged with E versus P in all patients (HR 0.71 [95% CI 0.62–0.82]; p<.0001) and in EGFR IHC+ patients (HR 0.69 [95% CI 0.58–0.82]; p<.0001). Subgroup analyses will be reported. Response rate was 12% with E versus 5% with P. Disease control rate (complete response + partial response + stable disease >12 wks) was 40.8% with E versus 27.4% with P (p<.0001). OS data are not yet mature. E was well tolerated: the majority of treatment-related adverse events (AEs) were grade 1/2. AEs reported in ≥10% of all patients were rash (60% with E versus 9% with P) and diarrhea (20% with E versus 5% with P); again, most were grade 1/2. Only 2.3% of patients receiving E had a serious treatment-related AE and 2.8% withdrew due to a treatment-related AE. Conclusions: The SATURN study met its primary and co-primary endpoints with high statistical significance. Erlotinib in the 1st-line maintenance setting is well tolerated, and significantly improves disease control and delays progression versus placebo across patient subgroups.

[Table: see text]
Multicenter prospective trial of customized erlotinib for advanced non-small cell lung cancer (NSCLC) patients (p) with epidermal growth factor receptor (EGFR) mutations: Final results of the Spanish Lung Cancer Group (SLCG) trial
Authors: Massuti B. , Morán T. , Porta R. , Queralt C. , Cardenal F. , Mayo C. , Camps C. , Majem M. , Tarón M. , Rosell R.
Published: August 2020

8023

Background: The purpose of the study was to evaluate the efficacy of erlotinib and the feasibility of screening for EGFR mutations in advanced NSCLC p (chemonaive or relapsed after 2 prior chemotherapy regimens). Methods: Exon 19 deletions and L858R mutations in tumor and paired serum DNA were assessed in one central laboratory, using three different techniques. Results: From April 2005 to December 2008, 2507 p were screened. EGFR mutations were detected in 358 p; 217 were entered on the trial: 158 (72.8%) female; 148 (68.2%) never-smokers; 176 (81.1%) adenocarcinoma; 134 (62.3%) exon 19 deletion, 83 (37.7%) L858R mutation; 112 (51.6%) first-line, 104 (48.4%) second-line. Response in 139/197 evaluable p (70.6%); complete response (CR) in 24 p (12.2%). Odds ratio for response: 3 for p with exon 19 deletion (P=0.001). Time to progression (TTP): 14 months (m). Median survival (MS): 27 m. MS according to response shown in table. Cox model for TTP showed that male gender (hazard ratio [HR], 2.3; P=0.001), L858R mutation (HR, 1.8; P=0.008), and mutated EGFR in serum (HR,1.6; P=0.03) had a negative impact. Conclusions: A multicenter study of customized erlotinib, using a central screening laboratory, is feasible and shows the outstanding benefit to p for selecting erlotinib treatment based on EGFR mutation status. The SLCG has initiated a randomized trial of first-line erlotinib vs chemotherapy.

[Table: see text]

No significant financial relationships to disclose.
Randomized phase II study of erlotinib (E) or intercalated E with carboplatin/paclitaxel (CP) in chemotherapy-naive advanced NSCLC: Correlation of biomarker status and clinical benefit
Authors: Hirsch F. R. , Dziadziuszko R. , Varella-Garcia L. , Franklin W. , Bunn P. , Kabbinavar F. , Wacker B. , Rusk J. , Richardson K. , Camidge D. R.
Published: August 2020

8026

Background: E plus chemotherapy showed no additive effects in NSCLC but preclinical studies suggested that intercalation of E and chemotherapy could give synergy. Clinical studies suggested that EGFR mutations could aid in pt selection. KRAS mutation status of tumors was also evaluated. We conducted a randomized phase II study of E and E intercalated with CP in pts with chemonaive NSCLC. Methods: Stage IIIB/IV EGFR+ NSCLC pts were randomized to E 150 mg/d or CP d1 plus E days 2–15 q21 days (ECP). After 4 cycles, E continued until PD. Tumor tissue was evaluated by IHC (EGFR), FISH (EGFR gene copy number), and PCR amplification followed by DNA sequencing (EGFR and KRAS mutations). Results: Among 143 pts randomized 53% EGFR FISH+; 13% activating EGFR mutations and 8% non-activating EGFR mutations (evaluable samples=114); and 22% KRAS mutations (evaluable samples=130). No pt had both EGFR and KRAS mutations. EGFR-activating mutations were higher among females (19% vs 6% males), adenocarcinoma histology (17% vs 0% others), Asians (45% vs 7% non-Asian), and never smokers (29% vs 7% former and 0% current); KRAS mutations were higher in current smokers (41% vs 27% former and 0% never) and adenocarcinoma histology (22% vs 18% squamous). In the E arm, 6-mo PFS probability for the efficacy evaluable population (n=69) was significantly higher in pts with EGFR activating mutations vs no mutations (89% vs 25%, HR=0.17, P=0.001), numerically higher in pts with EGFR FISH+ vs FISH- (40% vs 22%, HR=0.61, P=0.07), and with KRAS wild type vs mutation+ (38% vs 12%, HR=0.56, P=0.10). Response rates, PFS and OS by type of EGFR/KRAS mutation will be presented. In the ECP arm, 6-mo PFS probability for the efficacy evaluable population (n=68) was numerically higher in pts with EGFR activating mutations (42% vs 29%, HR=0.72, P=0.53), numerically higher in pts with wild type KRAS (32% vs 9%, HR=0.57, P=0.08), and numerically lower in pts with EGFR FISH+ vs FISH- (23% vs 30%, HR=0.93, P=0.78). Conclusions: Activating EGFR mutations correlate with increased 6 mo PFS probability in 1st line therapy with E. EGFR FISH + and absence of KRAS mutation trend towards increased 6 mo PFS rate with E.

[Table: see text]
Irinotecan plus carboplatin versus etoposide plus carboplatin in extensive disease small cell lung cancer: Results of the German randomized phase III trial
Authors: Schmittel A. H. , Sebastian M. , von Weikersthal L. Fischer , Gauler T. , Hortig P. , Fischer J. R. , Link H. , Binder D. , Eberhardt W. , Keilholz U.
Published: August 2020

8029

Background: Superiority of irinotecan over etoposide in combination with cis- or carboplatin was demonstrated in a Japanese and a Scandinavian phase III trial. However, both cisplatin-based North American phase III studies could not detect any difference in efficacy. We report the final results of the German randomized phase III trial comparing etoposide/carboplatin (PE) to irinotecan/carboplatin (IP) in small cell lung cancer (SCLC) extensive disease. Methods: Chemotherapy-naïve extensive disease SCLC patients were randomly assigned to receive carboplatin AUC 5 mg × min/mL either in combination with 50 mg/m2 of irinotecan on days 1, 8 and 15 (IP, Arm A) or with etoposide 140mg/m2 days 1–3 (EP). IP treatment was repeated every 4 weeks, EP every 3 weeks. Response assessment was performed after cycles 2, 4 and 6 and every 3 months thereafter. Toxicity was assessed once weekly. Primary endpoint was detection of progression free survival (PFS), secondary endpoints were overall survival (OS), response rate, and toxicity. Results: A total of 216 patients from 8 centres were randomized. No significant differences in survival or response rate could be detected. Median PFS was 6 months in both arms. Median OS was 10 months (95% confidence interval (CI) 8.3 -11.7) in the IP arm and 9 months (95% CI 7.6 -10.4) in the EP arm. 1 year survival was 37% (95% CI 25.6 - 47.6) and 28% (95% CI 18.2 - 37.4) in the IP and EP arm. 62% of patients in the IP and 63% in the EP arm had a confirmed complete or partial remission according to RECIST criteria. Significant differences in grade 3 and 4 toxicity were observed for thrombopenia (22% IP vs 47% EP) and neutropenia (23% IP vs 61% PE) without differences in the rate of febrile neutropenia. Grade 3 and 4 diarrhea was manageable and as expected significantly more frequent with IP (15%) than with EP (6%). Conclusions: Our phase III trial shows equivalent efficacy of irinotecan when compared to etoposide in combination with carboplatin.

[Table: see text]
Pharmacogenomic analysis from a phase III study of pemetrexed plus carboplatin (PC) versus etoposide plus carboplatin (EC) in chemonaive patients (pts) with extensive-stage disease small cell lung cancer (ED-SCLC)
Authors: Smit E. F. , Socinski M. A. , Mullaney B. P. , Myrand S. P. , Powell E. , Lorigan P. , Kaiser C. , Guba S. C. , Thatcher N.
Published: August 2020

8030

Background: We have reported results of a randomized phase III trial in chemonaive patients with ED-SCLC comparing PC to EC. Study enrollment was closed for futility but pharmacogenomic endpoints were not reported. Here we report the results of immunohistochemistry (IHC) analysis from tumor tissues and single nucleotide polymorphism (SNP) analysis of selected genes implicated in pemetrexed, carboplatin, or etoposide activity. Methods: Proteins studied by validated IHC on Benchmark XT were thymidylate synthase (TS), excision repair cross complementing-1 (ERCC1), glycinamide ribonucleotide formyl transferase (GARFT), and folylpolyglutamate synthetase (FPGS). SNP data from whole blood were genotyped by massArray mass spectrometry from 611 samples. One hundred fifty-eight SNPs were genotyped for TS, FPGS, γ-glutamyl hydrolase (GGH), methylene tetrahydrofolate reductase (MTHFR), folate receptor- α (FR-α), solute carrier 19A1 (SLC19A1) and adjacent regions. Allele frequency and Hardy-Weinberg equilibrium were calculated for each SNP. Results: Of 408 tissue samples (from 908 enrolled pts) available for IHC, 336 samples were assayed for > 1 assay target. The IHC analyses showed improved OS in the EC arm relative to the PC arm for patients with low TSnuclear (12.9 vs 7.5 month, p < 0.001, interaction p value = 0.017). There was no differential treatment effect within the PC arm for low vs. high TS. High vs low ERCC1 levels did not predict outcome following C exposure. GARFT was not associated with outcome by treatment. SNP rs2838952 (adjacent to SLC19A1) was significant for improved OS (HR = 0.590, p = 0.01) in both study arms. SNP rs12379987 (FPGS) was significantly associated with treatment for OS (interaction p value = 0.036). Exploratory analyses found associations between additional SNPs and PFS within and across treatments. Conclusions: Pharmacogenomic analyses of tumor samples show that low TSnuclear expression correlates with OS in the EC arm. Two germline SNPs in regions including FPGS and SLC19A1 were associated with better OS. Further analysis of these pharmacogenomic results is ongoing.

[Table: see text]
Blood-based CHRNA3 single nucleotide polymorphisms (SNPs) and outcome in advanced non-small cell lung cancer (NSCLC) patients (p)
Authors: Rosell R. , Ramirez J. L. , Sanchez-Ronco M. , Isla D. , Moran T. , Cobo M. , Massuti B. , Taron M. , Carbone D. , De Aguirre I.
Published: August 2020

8033

Background: Nicotonic acetylcholine receptors (nAChRs) are associated with resistance to gemcitabine (gem), cisplatin (cis) and paclitaxel in NSCLC cell lines. Three SNPs of CHRNA3, CHRNA5 and LOC123688 increase lung cancer risk. These SNPs may have influenced outcome in p treated in our phase III trial (Cobo et al. J Clin Oncol 2007;25:2747–54). Methods: Stage IV NSCLC p were treated with customized chemotherapy based on ERCC1 mRNA expression. p in the control arm received docetaxel (doc)/cis; p in the genotypic arm with low ERCC1 levels (low genotypic group [LG]) received doc/cis; p in the genotypic arm with high ERCC1 levels (high genotypic group [HG]) received doc/gem. DNA was extracted from lymphocytes, and CHRNA3 (rs1051730), CHRNA5 (rs16969968) and LOC123688 (rs8034191) SNPs were genotyped with the Taqman allele discrimination assay. Results: A significant interaction was found for CHRNA3 and PS (P = 0.02). In p with PS 0, CT p had a better response than both CC (P = 0.01) and TT (P = 0.02) p, and LG p also had a better response (P = 0.01). When the CHRNA3 genotype was added in the multivariate analysis for progression-free survival (PFS), an improvement was observed in the LG in PS 0 p (P = 0.02). PS 0 p in the LG with the CT genotype attained an 84% response, 12.1-month PFS, and 19-month median survival (MS) ( Table ). Conclusions: CHRNA3 genotyping can improve customized chemotherapy based on tumor ERCC1 mRNA in stage IV NSCLC p with PS 0.

[Table: see text]

No significant financial relationships to disclose.
Outcomes for the elderly (≥70 years) from a three-arm phase III trial of gemcitabine in combination with carboplatin (GC) or paclitaxel (GP) versus paclitaxel plus carboplatin (PC) for advanced non-small cell lung cancer (NSCLC)
Authors: Ansari R. H. , Edelman M. J. , Belani C. P. , Socinski M. A. , Obasaju C. K. , Monberg M. J. , Chen R. , Treat J.
Published: August 2020

8052

Background: Approximately 50% of lung cancer patients (pts) are ≥ 70 y, however, this population has been historically underrepresented in clinical trials. Even among pts ≥ 70 y, doublet chemotherapy has been shown to be superior to single-agent therapy (Lilenbaum JCO 2005, Sederholm JCO, 2005), and the efficacy and safety of platinum-based chemotherapy doublets in NSCLC pts ≥ 70 years with good PS have been reported to be similar to those in younger pts (Fossella, ASCO 2003, #2528, Kelly, ASCO 2001, A-1313). The current analysis examined whether any differences were present by age in a three arm trial of GC or GP versus a standard regimen of PC. Methods: 1135 chemonaïve pts with stage IIIB or IV NSCLC were randomized to receive: G 1000 mg/m2 d 1,8 plus C AUC 5.5 d 1; or G 1000 mg/m2 d 1,8 plus P 200 mg/m2 d 1; or P 225 mg/m2 plus C AUC 6.0 d 1. Stratification was based on stage, baseline weight loss, and brain metastases. Cycles were repeated every 21 days up to 6 cycles or disease progression. Clinical results were retrospectively analyzed in by patient age. Results: See Table . Conclusions: In this trial of commonly used regimens for advanced NSCLC, pts 70–74 years of age had significantly longer survival than pts 75–79 years of age. Pts 80+ years of age also had lower survival than the 70–74 year age group, but this difference was not statistically significant. No pts 80+ years of age had brain metastases at study entry. There was no clear pattern with respect to the effectiveness of individual treatment regimens by age group.

[Table: see text]

[Table: see text]
A multicenter phase II study to evaluate efficacy and safety of gefitinib as the first-line treatment for Korean patients (pts) with advanced pulmonary adenocarcinoma harboring EGFR mutations
Authors: Kim D. , Lee S. , Lee J. , Lee M. , Kang J. , Kim S. , Shin S. , Kim H. , Heo D. S.
Published: August 2020

8066

Background: This study (D7913L00056) was designed to prospectively evaluate the efficacy and safety of first-line gefitinib treatment in pts with advanced pulmonary adenocarcinoma harboring EGFR mutations and to explore the molecular factors affecting the efficacy of gefitinib. Methods: Chemo-naïve pts with advanced (stage IIIB/IV/recurrent disease) pulmonary adenocarcinoma underwent direct DNA sequencing of tumor EGFR exons 18, 19 and 21. Pts with EGFR mutations received gefitinib 250 mg/d until disease progression or unacceptable toxicity. The primary end-point was objective response rate (ORR). The protocol planned to accrue 45 pts with EGFR mutations in a single stage. Results: Out of 147 screened pts, 45 pts (31%) had EGFR mutations and received gefitinib. The most common EGFR mutations were in-frame exon 19 deletions (del 19, 29 pts, 64%) and L858R point mutations in exon 21 (L858R, 15 pts, 33%). One patient had atypical mutation of L861Q in exon 21. The ORR by RECIST was 53.3% (95% CI, 38.8 to 67.9) and disease control rate (DCR) including stable disease was 86.7%. Progression free survival (PFS) at 12 months (mo) was 74.6% (95% CI, 58.8 to 85.1). Median PFS was not reached after median 10.1 mo follow-up. Treatment was well tolerated. Six pts experienced grade 3 toxicities including rash, pruritis, and anorexia. No grade 4 toxicities were reported. Subgroup analysis according to the EGFR mutation subtypes was carried out. The ORR and DCR were higher in pts with del 19 than those with L858R (62.1% vs 33.3%; P=0.0705 and 96.6% vs 66.7%; P=0.0062, respectively). All 4 pts with progressive disease had an L858R mutation. No secondary resistant mutations such as T790M were found in those pts. In addition, PFS at 12 mo was significantly better in pts with del 19 than those with L858R (63.2% vs 23.8%, P=0.0034). Conclusions: Gefitinib as the first-line treatment for Korean pts with advanced pulmonary adenocarcinoma harboring EGFR mutations was very effective and well tolerated. Subgroup analysis suggests that the benefit from gefitinib treatment was more prominent in pts with the del 19 mutation.

[Table: see text]
A phase II trial of erlotinib monotherapy in pretreated patients (pts) with non-small cell lung cancer (NSCLC) who do not possess active EGFR mutations
Authors: Yoshioka H. , Hayashi H. , Kiura K. , Takigawa N. , Hotta K. , Harita S. , Kamei H. , Bessho A. , Tabata M. , Tanimoto M.
Published: August 2020

8067

Background: Efficacy of gefitinib therapy strongly depends on the presence of active EGFR mutations in Asian NSCLC pts, with objective response rates (ORR) of 71.2% and only 1.1% in active mutant-positive (EGFRmt+) and -negative (EGFRmt-) tumors, respectively [Mok T, ESMO2008]. Recently, the survival advantage of erlotinib, another TKI, is observed even in pts with EGFRmt- tumors (HR=0.74, p=0.09 [Zhu C, JCO2008]), indicating such subpopulation might also benefit from this TKI. The aim of this trial was to evaluate its efficacy and toxicity in Japanese pts with relapsedEGFRmt- tumors. Methods: Primary endpoint was ORR. Patients with EGFRmt--NSCLC previously treated with one to three chemotherapy regimens were enrolled in this trial. The mutation status was assessed by the PCR clamp methods. Erlotinib was administered at a dose of 150mg/day until disease progression or unacceptable toxicities. Results: Thirty pts were enrolled between Jan and Dec 2008. Median duration of erlotinib treatment was 60 days. All pts were assessable for efficacy and safety. Demographics of the pts were as follows: M/F:24/6, Ad/others:20/10, ECOG-PS 0/1/2:7/19/4, and smoker/non-smoker:22/8. Platinum-based regimens were commonly used as the prior chemotherapy. Objective response was obtained in one pt (3.3%; RECIST). Seventeen pts obtained SD (56.7%). Toxicity profiles were almost tolerable with the treatment interruption in 11 pts (median duration; 10 days). Skin rash was common (grades 1, 2 and 3 in 7, 15, and 7 pts, respectively; NCI-CTCAE ver3). One pt developed grade 4 pulmonary embolism, but it seemed due to disease progression. Other 2 pts developed interstitial lung disease (grades 2 and 3 in one pt each). No treatment-related deaths (TRD) occurred. With a median follow-up time of 6.4 months, MST and MPFS time were 8.6 and 2.1 months, respectively. Conclusions: This is a first prospective biomarker study showing that erlotinib therapy for pretreated pts with EGFRmt- tumors seems as almost effective and safe as the standard docetaxel therapy (PR: 5.8%, SD: 42.7%, MST: 7.0 months, MTTP: 2.5 months and TRD: 4.9% [Shepherd JCO2000]).

No significant financial relationships to disclose.
Incidence and outcomes associated with brain metastases (BM) in a three-arm phase III trial of gemcitabine in combination with carboplatin (GC) or paclitaxel (GP) versus paclitaxel plus carboplatin (PC) for advanced non-small cell lung cancer (NSCLC)
Authors: Edelman M. J. , Belani C. P. , Socinski M. A. , Ansari R. , Obasaju C. K. , Monberg M. J. , Chen R. , Treat J.
Published: August 2020

8076

Background: A limited number of randomized phase III studies of advanced or metastatic NSCLC have included a mixed population of patients (pts) with and without BM at presentation. Analyses of pts with lung cancer from the 1970s and 1980s indicated that the incidence of BM at the time of diagnosis was approximately 10%. Methods: 1135 chemonaïve pts with stage IIIB or IV NSCLC were randomized to receive: G 1000 mg/m2 d 1, 8 plus C AUC 5.5 d 1; or G 1000 mg/m2 days 1 and 8 plus P 200 mg/m2 d 1; or P 225 mg/m2 plus C AUC 6.0 d 1. Stratification was based on stage, baseline weight loss, and presence or absence of BM. Cycles were repeated every 21 d up to 6 cycles or disease progression. Pts who developed BM as the only evidence of progression were able to be treated with whole brain radiation and steroids and remained on study. Results were retrospectively analyzed in by presence or absence of BM at study entry. Results: BM rates by subgroup were as follows (%): overall (17.1), nonsquamous (19.3), squamous (6.9), <70 y (21.3), ≥ 70 y (7.1), female (19.2), male (15.7), Caucasian (16.7), African American (18.8%), Hispanic (22.2), PS 0 (12.9), PS 1 (19.7), weight loss <5% (18.3), weight loss ≥ 5% (15.1), and stage IV (19.0). Among pts with (N=194) and without (N=941) BM, response rates=28.9% and 29.1%, median survival = 7.7 mos (95% CI: 6.7, 9.3) and 8.6 mos (95% CI: 7.9, 9.5), and median time to progression = 4.3 mos (95% CI: 3.4, 5.6) and 4.6 mos (95% CI: 4.2, 5.1), respectively. Rates of grade 3 or 4 adverse events were not different among pts with and without BM. Median survival among pts with BM was 7.6 mos for GC (N=66, 95% CI: 6.3, 10.1), 8.2 mos for GP (N=64, 95% CI: 4.6, 10.5), and 7.7 mos for PC (N=64, 95% CI: 6.1, 10.2). Conclusions: 1) The higher incidence of BM (17.1%) observed in this trial may be related to the increasing incidence of adenocarcinoma, or to the increasing sensitivity of imaging modalities. 2) There was no difference in response, time to progression or survival for pts with or w/o BM.

[Table: see text]
Cost-effectiveness of zoledronic acid versus placebo in the management of skeletal metastases in lung cancer patients (LC pts): Comparison across three European countries
Authors: Stephens J. , Kaura S. , Botteman M. F.
Published: August 2020

8081

Background: Zoledronic acid (ZOL) reduces the risk of skeletal-related events (SREs) in LC pts with bone metastases. The present retrospective analysis compared the economic impact of ZOL in LC pts in France, Germany, and the United Kingdom (UK). Methods: Estimated direct costs and quality-adjusted life-years (QALYs) experienced by LC pts with bone metastases receiving placebo (PBO) or ZOL were modeled and compared. Overall survival (OS), SRE incidence, and number of infusions administered were obtained from a 21-mo randomized clinical trial comparing the proportion of pts who experienced an on-study SRE with 4 mg ZOL or PBO every 3 wk (Rosen et al. JCO. 2003). Costs of treatments and SREs were estimated using national reimbursement listings (eg, diagnosis-related groups), private databases, and published literature. Mean number of SREs was calculated by multiplying mean SRE rate by OS for LC pts in the study. For QALYs, OS was multiplied by a utility factor of 0.53. Consistent with similar economic analyses, it was assumed that quality of life (QOL) decreased 20% to 80% (depending on the SRE type) for 1 mo after each SRE experienced. Sensitivity analyses were performed to test the effects of alternate scenarios, with < €30,000/QALY considered cost-effective. Results: During the median OS of 179 days, PBO pts (n = 120) experienced a mean of 2.07 SREs vs 1.32 SREs among ZOL pts (n = 124). QALYs were estimated at 0.352/pt (ZOL pts) and 0.335/pt (PBO pts). Use of ZOL resulted in a net increase of 0.017 QALY/pt vs PBO. ZOL drug-related costs were €1,610, €1,510 and €1,597 per pt in France, Germany, and the UK, respectively. Use of ZOL resulted in reductions in SRE costs of €2,221, €2,031, and €2,014 per pt, respectively. Overall, ZOL saved €598 per pt in France, €521 in Germany, and €417 in the UK. In sensitivity analyses, ZOL was cost-effective under a variety of scenarios (total range, -€98,356 to +€34,052 per QALY). Conclusions: ZOL leads to fewer SREs, better estimated QOL, and lower estimated costs relative to PBO in German, French, and UK LC pts with bone metastases. Use of ZOL in these populations is therefore cost-saving and highly cost-effective.

[Table: see text]
Genetic and proteomic features associated with survival after treatment with erlotinib in first-line therapy of non-small cell lung cancer
Authors: Amann J. M. , Lee J. , Roder H. , Brahmer J. , Schiller J. , Carbone D. P.
Published: August 2020

8089

Background: An improved understanding of molecular features of cancers and cancer patients associated with benefit from targeted therapies could allow the rational personalization of therapies to increase the probability of efficacy and decrease toxicity and cost. Multiple biomarkers have been proposed for predicting benefit after therapy with EGF receptor targeted therapies in first line colon and second line lung cancer therapy. Methods: In this study, we analyzed available tumor and serum samples from ECOG 3503, a single arm phase II study of erlotinib in first line lung cancer, for mutations in Kras and EGFR, as well as the previously described serum MALDI proteomic classifier (Veristrat). Out of 137 enrolled patients, there were 93 serum samples and 43 tumor samples available. Results: Molecular analysis of a subset of tumors from patients enrolled in ECOG 3503 shows that 10/43 (23%) contained Kras mutations and 3/43 (7%) harbored EGFR mutations. Classification of the 93 available sera for the pattern of proteins previously published as associated with survival after treatment with gefitinib identified 68/93 (73%) as predicted to be “good” and 25/93 (27%) predicted to have poor survival. Of the 6 responders with available serum, 5 were classified as MALDI good. Correlation with survival demonstrated a highly statistically significant correlation with MALDI status (p < 0.001), and a marginally significant association of EGFR mutation with survival (p = 0.05), but no correlation with ras mutation status. Median survival was 10.8 months in MALDI good patients and 3.9 in MALDI poor patients. MALDI status was independent of both ras and EGFR mutation status. Conclusions: Thus, in distinct contrast to colon cancer, ras gene mutations do not appear to be associated with survival after first line EGFR-targeted therapy in lung cancer. The previously defined MALDI predictor is potent and highly clinically significantly associated with survival after first line treatment with erlotinib, and is independent of mutations in ras and EGFR in this dataset.

[Table: see text]
Anatomic response correlation with biological response
Authors: Kasymjanova G. , MacDonald N. , Roseman M. , Kreisman H. , Pepe C. , Agulnik J. S. , Gagnon B. , Small D.
Published: August 2020

8092

Background: Chronic systemic inflammation is a well recognized strong adverse prognostic factor in advanced NSCLC. We have previously identified that in stage IIIB/IV NSCLC the presence of elevated C-reactive protein is associated with early progression of the disease and reduction in median survival. Little is known, however, about CRP behavior over time and its correlation with response to chemotherapy and survival. Methods: Newly diagnosed NSCLC with IIIB/IV disease had CRP measured prior to 1st treatment and after 2 cycles of chemotherapy between February 2005 and September 2008. For each measure CRP level was categorized as < 10mg/L or ≥10mg/L. Response was evaluated by chest CT following two cycles of CTX and rated as progression (PD) or freedom from progression (FFP). We investigated the association between change in CRP and response to 2 cycles of CTX, as well as survival. Results: 143 pts were enrolled. Of those, 62 patients had a CRP level <10mg/L and 81 patients ≥10mg/L at the time of diagnosis. After 2 cycles 70% and 72% of pts in each category remained in the same category and 30% and 28% of patients changed category: in 24/81 pts CRP decreased below 10mg/L and in 17/62 pts CRP increased above 10mg/L. Thus, after two cycles 69 pts had CRP <10mg/L and 74 pts ≥10mg/L. The rate of progression after 2 cycles was significantly lower among pts with CRP <10mg/L after 2 cycles of chemo ( Table ). Median survival was 19 (16–22) mo for those with CRP <10mg/L and 9.3 (7.1–11.4) mo for those with CRP ≥10mg/L after 2 cycles (P<0.001). The hazard increased by 66% (HR 1.7) for those pts with CRP increased above cut-off point of 10 mg/L and decreased by 60% (HR 1.6) for pts whose CRP decreased below cutoff point. Conclusions: The presence of an inflammatory state expressed by high levels of CRP either prior to treatment or following 2 cycles of chemotherapy correlates significantly with both first-line chemotherapy response and survival. Normalization of CRP might improve the prognosis of patients in terms of survival and response to chemotherapy.

[Table: see text]

No significant financial relationships to disclose.
Correlation of polymorphisms of genes involved in platinum/gemcitabine (P/G)-based metabolism with toxicity and clinical response in patients (pts) with advanced non-small cell lung cancer (NSCLC)
Authors: Tonato M. , Ludovini V. , Pistola L. , Floriani I. , Meacci M. , Chiari R. , Garavaglia D. , Tofanetti F. R. , Flacco A. , Ferraldeschi M. , Crinò L.
Published: August 2020

8093

Background: Selecting patients according to key genetic characteristics may help to tailor chemotherapy and optimize the treatment in NSCLC. Genetic variations in drugs metabolism may affect the clinical response, toxicity and prognosis of NSCLC pts treated with P/G-based therapy. Methods: We evaluated 8 single nucleotide polymorphisms (SNPs) of 6 genes (P53 Arg72Pro (G/C); XRCC3 Thr241Met (C/T); XPD Lys751Gln (A/C); ERCC1 Asn118Asn (C/T); CDA Lys27Gln (A/C), Ala70Thr (G/A), Thr145Thr (C/T) and RRM1 C524T) involved in P/G-based metabolism in a homogeneous population of pts with advanced NSCLC treated with this regime. Genomic DNA was extracted from whole blood samples using the QIAamp DNA estraction kit on Biorobot EZ1 (Qiagen). Polymorphisms were detected with TaqMan-probe based assays using the 7300 Real-Time PCR System (Applied Biosystems, Foster City, CA). Association between SNPs and response, toxicity, progression free survival and overall survival was estimated using logistic regression model, the Kaplan-Meier method, the long-rank test and the Cox proportional hazard model. Results: We performed a retrospective analysis in 192 chemotherapy-naive pts (median age 63 years), including M/F:74/26%; stage IIIb/IV:24/76%; Adeno/Squa/other Ca:42/27/31%; ECOG PS:0–1/2–3:94/6%. Overall response rate was 32.3%, stable disease 25% and disease progression 42.7%. The CDA Thr145Thr T/T genotype significantly correlated with poorer response (partial response in 23.1% of pts versus 42.3% and 34.6% in C/T and C/C genotypes, respectively; p=0.03). The ERCC1 T/T genotype was significantly associated with haematological toxicity (G1–4) (p=0.05) compared to ERCC1 C/C allele. The CDA Thr145Thr C/T genotype was significantly associated with non-haematological toxicity (G3–4) (p=0.02) compared to CDA Thr145Thr C/C allele. The median overall survival (OS) time and progression free survival (PFS) were 12.7 and 4.7 months, respectively. None of the analyzed polymorphisms was related to PFS or OS. Conclusions: These data suggest that genetic polymorphisms in the ERCC1 and CDA genes may modulate the toxicity and response to P/G-based therapy in pts with advanced NSCLC.

No significant financial relationships to disclose.
An open label phase II trial of the Plk1 inhibitor BI 2536, in patients with sensitive relapse small cell lung cancer (SCLC)
Authors: Gandhi L. , Chu Q. S. , Stephenson J. , Johnson B. E. , Govindan R. , Bonomi P. , Eaton K. , Fritsch H. , Munzert G. , Socinski M.
Published: August 2020

8108

Background: BI 2536 is a potent, selective inhibitor of polo-like kinase 1 (Plk1), a regulator of mitotic progression. BI 2536 demonstrated favorable tolerability and antitumor activity in phase I trials. We investigated the antitumor efficacy, safety and PK of BI 2536 in patients (pts) with sensitive relapse SCLC. Methods: This open label single arm phase II study followed a Gehan two-stage design. Primary objective was to determine the antitumor efficacy of BI 2536 in SCLC pts with disease recurrence ≥60 days after completion of first-line chemotherapy. 18 pts had to complete 2 courses to be evaluable for stage 1 analysis. In case of ≥2 partial or complete antitumor responses (RECIST criteria), stage 2 accrual would continue until 40 pts were entered. Patients received 200 mg BI 2536 as a 1h i.v. infusion on Day 1 every 3 weeks. Dose escalation to 250 mg (cycle 3 onwards) was encouraged in pts with <Grade 2 drug related non-hematologic and 60 days after completion of first-line therapy. Of 23 pts, no objective antitumor responses were observed, 7 had stable disease as best response, 14 had progression, 2 were not evaluable. A median of 2 courses were given, up to a maximum of 12 in 1 pt. The PFS rate at 3 months was 25%. Due to the lack of antitumor responses, trial accrual was terminated after stage 1. Overall, BI 2536 was well tolerated. Frequent AEs were neutropenia (48%), fatigue (39%), nausea (30%), anemia, vomiting, constipation (26% each), and thrombocytopenia (22%). Drug related grade 3/4 AEs were neutropenia (13%/26%), grade 3/4 thrombocytopenia (1 pt each), grade 3/4 anemia (1 pt each), grade 4 sepsis (1 pt), Grade 4 ARDS (1 pt) and Grade 3 fatigue (1 pt). PK analyses indicate that BI 2536 has high clearance (>1,000 mL/min) and quickly distributes in multiple compartments in a large volume of distribution (>1,000 L). Estimated elimination half-life was >25 h. Conclusions: BI 2536 was well tolerated in relapsed SCLC pts, but demonstrated no convincing antitumor efficacy after stage I of the study. Therefore, BI 2536 will not be assessed further as a single agent in SCLC.

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Final results of PX-171–003-A0, part 1 of an open-label, single-arm, phase II study of carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma (MM)
Authors: Jagannath S. , Vij R. , Stewart K. , Somlo G. , Jakubowiak A. , Trudel S. , Schwartz R. , Siegel D. , Kunkel L.
Published: August 2020

8504

Background: CFZ is a novel proteasome inhibitor of the epoxyketone class that exhibits a high level of proteasome selectivityand demonstrates antitumor activity in bortezomib (BTZ)-resistant MM pts in phase I studies. Methods: PX-171–003-A0 was an open-label, multicenter study that enrolled MM pts who relapsed from >2 prior therapies, failed BTZ and at least 1 immunomodulatory agent [thalidomide (THAL) or lenalidomide (LEN)], and were refractory to last treatment [progressing on or within 60 d of last therapy or <25% response to last therapy]. Pts received CFZ 20 mg/m2 IV d 1, 2, 8, 9, 15 and 16 every 28 d for up to 12 cycles (C). Clinical benefit response (CBR) was defined as MR or better. Results: 46 pts were enrolled, including 78% with progression on or within 60 d of last therapy and 22% with no response to last therapy. 39 pts completed at least 1 C of CFZ, had measurable M-protein, and were evaluable for response. Median prior therapies was 5 (range 2–15). 100% of pts received prior BTZ, 91% prior THAL, 89% prior LEN, and 83% prior stem cell transplant (SCT) and all had failed combinations including anthracyclines (80%) and/or alkylating agents (94%). Pts received a median of 3 C (range 1–12); 13 pts completed ≥6 C. CBR was 26% (10/39 eval pts), including 5 pts achieving PR and 5 pts achieving MR. 5 BTZ-refractory pts achieved MR or PR. Median TTP was 6.2 mo, the median DOR for the MR + PR was 7.4 mo. 8/10 pts achieved response during C1. 16 additional pts achieved SD for at least 6 wks. The most common adverse events were fatigue, anemia, thrombocytopenia, nausea, upper respiratory infection, increased creatinine and diarrhea. Peripheral neuropathy occured in < 10% of pts with 1 Gr 3 in a pt with pre-existing Gr 2. Conclusions: Single-agent CFZ achieved a TTP of > 6 mo in relapsed and refractory MM pts who failed available therapies. 26% of patients had at least an MR and median duration of >7 mo with this steroid- and anthracycline-sparing regimen. CFZ toxicities were manageable and importantly, exacerbation of pre-existing PN was rare. The study has been expanded to enroll an additional 250 pts in this unmet medical need population at an escalated dose, and treatment has been extended beyond a year.

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Clinical trial of the novel structure proteasome inhibitor NPI-0052 in patients with relapsed and relapsed/refractory multiple myeloma (r/r MM)
Authors: Hofmeister C. C. , Richardson P. , Zimmerman T. , Spear M. A. , Palladino M. A. , Longenecker A. M. , Cropp G. F. , Lloyd G. K. , Hannah A. L. , Anderson K.
Published: August 2020

8505

Background: NPI-0052 produces rapid, broad and prolonged inhibition of all 3 catalytic activities of the 20S proteasome. NPI-0052 has a non-peptide based structure that appears to result in a unique proteasome inhibition (PI), signal transduction and safety profile. Preclinical data suggest NPI-0052 may demonstrate an improved therapeutic ratio, with significant activity in hematologic and solid tumor malignancies including MM resistant to bortezomib (BZ) and other agents. Methods: This phase I dose escalation study of NPI-0052 was conducted in patients (pts) with r/r MM, including after BZ and/or lenalidomide. Pts were treated with NPI-0052 IV weekly for 3 weeks in 4-week cycles. The dose of NPI-0052 was escalated utilizing a combination of accelerated titration and 3+3 designs. PI and PK were assayed after the 1st and 3rd doses. Results: 17 patients have been treated at doses ranging from 0.025 mg/m2 to 0.6 mg/m2 without reaching a MTD. One patient experienced reversible creatinine elevation associated with progression of light chain nephropathy at 0.075 mg/m2. Drug- related adverse events have consisted principally of mild-to-moderate fatigue, nausea and diarrhea. In this study at dose levels 0.75 and 0.15 mg/m2, the half-life = 0.5 - 5.0 min; clearance = 4.8 ± 5.2 L/min and Vz = 22.6 ± 44.2 L. PI in whole blood demonstrates dose-dependent chymotrypsin-like inhibition up to 26% at 0.075 mg/m2. Of note, 2 patients remained on study for over 6 months and one year with stable disease and no significant toxicity. Importantly, NPI-0052 does not appear to induce peripheral neuropathy or myelosuppression. Conclusions: NPI-0052 was well tolerated in this study with escalation continuing to a recommended phase II dose (RP2D) for r/r MM. The RP2D (0.7 - 0.8 mg/m2), PI and safety profiles of NPI-0052 have been defined in other diagnoses, and appear unique from BZ in spite of up to 100% proteasome inhibition. In this study, NPI-0052 has effects on PD, PK and may potentially confer clinical benefit at doses which are well below the MTD determined in the other trials. Additional trials in MM are being initiated, including with lenalidomide.

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Activity of lenalidomide in a phase II trial for T-cell lymphoma: Report on the first 24 cases
Authors: Dueck G. S. , Chua N. , Prasad A. , Stewart D. , White D. , vanderJagt R. , Johnston J. B. , Belch A. , Reiman T.
Published: August 2020

8524

Background: Novel therapies are needed to improve outcomes in T-cell lymphomas. We report the interim results of a prospective multicenter trial evaluating lenalidomide in T-cell lymphomas. Methods: Patients with relapsed and refractory T-cell lymphomas other than mycosis fungoides were prescribed oral lenalidomide (25mg daily) on days 1 to 21 of each 28 day cycle, with standardized dose reductions for toxicity. Treatment continued until disease progression, death or unacceptable toxicity. The primary endpoint was overall response rate, and secondary endpoints were complete and partial response rates, progression-free and overall survival (PFS, OS), and safety. The two-stage design allows for up to 40 patients. Results: At the time of this interim analysis, 24 patients were enrolled in this study and 23 were evaluable for response. The median age was 65 years. ECOG PS was 0–1 (n=15), 2 (n=7), 3 (n=2). The histology was peripheral T-cell unspecified (PTCL-u, n=10), angioimmunoblastic (n=7), anaplastic large cell (n=5), enteropathic T-cell (n=1) and hepatosplenic gamma/delta (n=1). Median number of prior therapies was 1 (range, 0–4), and three had prior autologous stem cell transplant. Four patients were previously untreated and not candidates for combination chemotherapy. Median time from completion of prior therapy to the start of lenalidomide was 8 months (range, 1–48 months). The overall response rate was 7/23 (30%); all were partial responses. Two patients had stable disease (SD) for ≥3 cycles. Responses were seen in anaplastic, angioimmunoblastic, and PTCL-u histologies. Median PFS was 96 days (range, 8–696 days). Median OS was 241 days (range, 8–696+ days). Among the 9 patients with SD or better, median PFS was 168 days and median OS has not yet been reached with 241–696 days of follow-up. The most common grade 4 adverse event was thrombocytopenia (33.3%). The most common grade 3 adverse events were neutropenia (20.8%), febrile neutropenia (16.7%), and pain NOS (16.7%). Conclusions: In relapsed and refractory T-cell lymphomas, oral lenalidomide monotherapy has clinical activity and toxicity is consistent with the known profile of lenalidomide. Further study of lenalidomide in these diseases is warranted.

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FDG PET/CT (FDG PET) in evaluation of response in patients with multiple myeloma (MM) treated with bortezomib, pegylated liposomal doxorubicin, and dexamethasone
Authors: Pandit-Taskar N. , Comenzo R. L. , Hassoun H. , Hoover E. , Borkar S. , Reidel E. , Cohen A. , Surti C. , Nimer S. D. , Landau H. J.
Published: August 2020

8533

Background: In a high risk population of pts with newly diagnosed or primary refractory MM, we prospectively studied FDG PET imaging to determine the value of PET/CT in assessing therapeutic response. Methods: Forty pts with high-risk MM defined as ISS II, ISS III or presence of extramedullary plasmacytoma have been enrolled on study and treated using a combination of bortezomib, pegylated liposomal doxorubicin hydrochloride (Doxil), and dexamethasone (BDD) for 3 cycles followed by 2 cycles of thalidomide and dexamethasone for patients achieving at least PR. Pts were assessed using serial FDG PET imaging: at baseline (BL), after 3 cycles of BDD and at end of study (EOS). FDG PET response was determined using European Organization for research and treatment of cancer (EORTC) recommendations. MM disease response was assessed according to the International Myeloma Working Group (IMWG) criteria. Results: Median age of pts enrolled was 59 yrs (range 41–80), 62% male, 38% ISS II, 47% ISS III, and 15% ISS I with soft-tissue disease. Thirty-five percent (14/40) had soft-tissue involvement with MM. At completion of protocol therapy, the ORR was 79%, with 44% of pts achieving CR/nCR and 59% ≥ VGPR. Ninety FDG PET scans were performed in 40 pts; 25 pts were evaluable for FDG PET response. The other pts are as follows: 2 had negative FDG PET at BL, 6 were taken off study (5 for toxicity and 1 with CR), 1 FDG PET was unable to be compared due to technical differences and 6 pts have not completed treatment. Seventeen of the 25 pts had PR by FDG PET, 5 had SD and 3 PD; none of the pts had CR. There was little agreement between MM disease response and FDG PET responses (Kappa statistic, 0.05). Three pts with PD by FDG PET, had PR (n=2) or CR (n=1) by IMWG criteria. One had granulomatous disease rather than MM at biopsy. In 1 pt with progression of disease with a progressive skull-based plasmacytoma, FDG PET was scored as PR by EORTC criteria. Conclusions: There was poor agreement between FDG PET response and MM disease response by IMWG criteria. Serial FDG PET did not provide additional information for therapeutic response assessment in pts with newly diagnosed or primary refractory MM.

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Randomized phase II trial on primary chemotherapy with high-dose methotrexate (HD-MTX) alone or associated with high-dose cytarabine (HD-araC) for patients with primary CNS lymphoma (I.E.L.S.G. #20 Trial): Tolerability, activity, and survival analyses
Authors: Ferreri A. J. , Reni M. , Martelli M. , Pangalis G. , Frezzato M. , Cabras G. , Fabbri A. , Corazzelli G. , Zucca E. , Cavalli F.
Published: August 2020

8545

Background: HD-MTX-based chemotherapy (cht) is the conventional approach to primary CNS lymphoma (PCNSL), but superiority of polycht over HD-MTX alone is unproven. A benefit of adding HD-araC to MTX has been suggested. This is a randomized phase II trial comparing HD-MTX monocht versus HD-MTX plus HD-araC as primary cht in immunocompetent patients (pts) with PCNSL. Methods: 79 HIV- pts with newly diagnosed PCNSL, age 18–75 ys, ECOG-PS≤3, and measurable disease were randomly assigned to receive 4 courses (interval 3 weeks) of MTX 3.5 g/mq (control arm; n=40) or MTX (same dose) + araC 2 g/mq × 2/d, d 2–3 (experimental arm; n=39). Cht was followed by whole-brain irradiation. Pts were stratified based on IELSG score and centre irradiation policy for pts >60 ys in complete remission (CR) after cht. CR rate (CRR) after cht was the primary endpoint; planned accrual (α=.05 β=.2) for P0 30% and P1 50% was 39 pts/arm. Results: Median age of the 79 entered pts was 58 ys (range 25–74). No differences in clinical presentation between arms were observed. Two hundred thirty-one (73%) of the 316 planned courses were actually delivered (MTX 71%; MTX+araC 76%). Causes of cht interruption were: progressive disease in 20 MTX and 8 MTX+araC pts, toxicity in 1 MTX and 7 MTX+araC pts and refusal in 2 MTX+araC pts. As expected, neutropenia, thrombocytopenia and infections were more common in MTX+araC arm. All G3–4 non-hematological toxicities were <5%. One MTX pt and 3 MTX+araC pts died of toxicity. CRR was 18% after MTX and 46% after MTX+araC (p=0.006), with an ORR of 40% and 69% (p=0.009), respectively. At a median follow-up of 30 m., 31 MTX and 22 MTX+araC pts experienced failure, with a 3-yr FFS of 21±6% and 38±8% (p=0.01), respectively. No differences in relapse sites or salvage efficacy between treatment arms were observed. Twelve MTX and 20 MTX+araC pts are alive, with a 3-yr OS of 32±8% and 46±9% (p=0.07). Conclusions: This is the first randomized trial on PCNSL with completed accrual. The addition of HD-araC to HD-MTX resulted in significantly better outcome and acceptable toxicity. MTX+araC may be the cht combination used as control arm in future randomized trials.

No significant financial relationships to disclose.