Extensive-stage Disease Small Cell Lung Cancer Research Articles

1791P Thoracic radiotherapy plus maintenance durvalumab after first-line carboplatin and etoposide plus durvalumab in extensive-stage disease small cell lung cancer (ED-SCLC): A multicenter single-arm open-label phase II trial (SAKK 15/19)tle

1791P Thoracic radiotherapy plus maintenance durvalumab after first-line carboplatin and etoposide plus durvalumab in extensive-stage disease small cell lung cancer (ED-SCLC): A multicenter single-arm open-label phase II trial (SAKK 15/19)tle

The value of serum TRAP1 in diagnosing small cell lung cancer and tumor immunity.

This study set out to investigate the clinical significance of serum tumor necrosis factor receptor-associated protein 1 (TRAP1) in diagnosing small cell lung cancer (SCLC) with different clinical stages, and to compare the diagnostic efficiency with neuron-specific enolase (NSE), carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9). Besides, to analyze the role of serum TRAP1 in tumor immunity. A total of 91 patients with SCLC, 99 patients with non-small cell lung cancer (NSCLC), 102 patients with pulmonary nodules (PN), and 75 healthy people were included. The concentrations of serum TRAP1 was detected by enzyme-linked immunosorbent assay (ELISA). NSE, CEA, and CA19-9 were detected by chemiluminescence. The results showed that level of TRAP1 in Group SCLC was lower than other three groups (P < 0.01), whereas NSE in SCLC was significantly higher than the others (P < 0.01), and the levels of CEA and CA19-9 were higher than healthy people and PN patients (P < 0.01). There was a significant difference in TRAP1 levels between patients with limited-stage disease SCLC (LD-SCLC) and extensive-stage disease SCLC (ED-SCLC) (P < 0.0001). The sensitivity and specificity of TRAP1 in diagnosing LD-SCLC were 0.964 and 0.560, respectively, and the area under the curve (AUC) was 0.819. The sensitivity and specificity in diagnosing ED-SCLC were 0.810 and 0.868, respectively, and the AUC was 0.933, which showed high diagnostic value. The AUC of these two groups can be increased to 0.946 and 0.947 in combination of four biomarkers, effectively improving the diagnosis rate of SCLC. Our findings have revealed that serum TRAP1 has high diagnostic value for SCLC and high diagnostic sensitivity for LD-SCLC. It is a potential biomarker for SCLC. Combined detection can effectively improve the diagnosis rate of SCLC. TRAP1 may be secreted into the circulation by mature immune cells and participates in tumor immunity as a carrier of tumor antigens.

Combination of chemotherapy and immune checkpoint therapy by the immunoconjugates-based nanocomplexes synergistically improves therapeutic efficacy in SCLC

Although the etoposide and carboplatin (EP) combination strategy has been the first-line chemotherapy, patients with extensive-stage disease small-cell lung cancer (SCLC) still have poor survival outcomes. Our retrospective analysis revealed that 46 patients with SCLC only achieved medium overall survival (OS) of 11.6 months after treated by EP. Recently, it was demonstrated that combination therapy of PD1/PD-L1 immune checkpoint blocker and EP could significantly improve the OS of SCLC patients. However, the serious treatment-related toxicity leaded to a high rate of treatment-discontinuation or even death. In the present study, we have developed a novel TPP1-conjugated nanocomplex, abbreviated as TPP1NP-EP, which was co-loaded with carboplatin (CBP) and etoposide (VP16). The TPP1 was a PD-L1 targeting peptide and conjugated on the surface of nanocomplex by a matrix metalloproteinase (MMP-2/9)-cleavable peptide linker sequence PLGLAG. For dual-loading of CBP and VP16, the CBP was chemically conjugated with poly(ethylene glycol) (PEG)–poly(caprolactone) (PCL) by pH-sensitive hydrazone bond and the VP16 was physically encapsulated by emulsion-solvent evaporation method. In vitro and in vivo experiments demonstrated an excellent anti-tumor effect of TPP1NP-EP on SCLC and improved safety. In conclusion, the present study has provided a promising strategy for treatment of malignant SCLC.

The efficiency and safety of immune checkpoint inhibitors in the treatment of small cell lung cancer: a meta-analysis.

Small cell lung cancer (SCLC) is highly invasive and fatal, sensitive to chemotherapy and radiotherapy but prone to relapse, with a poor overall survival rate. It is particularly urgent for SCLC patients to receive effective follow-up treatment. In the past 20 years, there has been no breakthrough in clinical treatment of SCLC. Currently, clinical studies on immunotherapy for SCLC with extensive stage disease (ED) have achieved good efficacy, bringing new hope for the treatment of small-cell lung cancer. PD-1 inhibitors used to treat small cell lung cancer include Pembrolizumab and Nivolumab. PD-L1 inhibitors mainly include Atezolizumab and Durvalumab. Other PD-1/PD-L1 inhibitors, such as Avelumab, are currently being tried for SCLC and the results have not yet been published. This study is to evaluate the efficacy and safety of immunotherapy in patients with ED SCLC. A literature search of the PubMed, Embase, and Cochrane Library databases were performed. Two reviewers independently screened the literature, extracted the data, and evaluated the risk of bias of the included studies. RevMan 5.3 software was used for meta-analysis. Four studies involving 1,981 patients with ED SCLC were included. Both overall survival (OS) [hazard ratio (HR) =0.80, 95% confidence interval (CI) (0.68, 0.95), P=0.009] and progression-free survival (PFS) [HR =0.82, 95% CI (0.75, 0.90), P<0.00001] were longer in the immunotherapy group than in the chemotherapy group. The incidence of total treatment-related adverse events in the immunotherapy group were lower than those in the chemotherapy group [relative risk (RR) =1.050, 95% CI (1.010, 1.080), P=0.007], and the differences were statistically significant. Immunotherapy has better efficacy and safety than chemotherapy for the treatment of ED SCLC.

Effect of metformin in the prognosis of patients with smallcell lung cancer combined with diabetes mellitus.

The prognosis for small-cell lung cancer (SCLC) is very poor, so a new therapeutic strategy and new drugs are imperative. The aim of this study was to examine the effect of metformin on the prognosis of patients with SCLC combined with diabetes mellitus (DM). From 2005 to 2013, 32 patients (4 female and 28 male) with SCLC combined with DM were included in this retrospective study at the Zhejiang Cancer Hospital, China. All patients were diagnosed with SCLC by pathological analysis and had received more than 4 cycles of chemotherapy. Metformin was used in 12 patients. Seventeen patients had limited-stage disease (LD) and 15 patients had extensive-stage disease (ED). Patients with LD SCLC were administered thoracic radiotherapy. The follow-up deadline was January 27, 2016. At that point, 4 patients were alive, 21 patients had died, and 7 patients did not participate in follow-up examinations. In patients with SCLC combined with DM using metformin, a complete response (CR) was observed in 4 patients, a partial response (PR) in 6 patients, a stable disease (SD) in 1 patient, and a progressive disease (PD) in 1 patient, whereas in patients who did not use metformin, CR was observed in 2 patients, PR in 15 patients, SD in 2 patients, and PD in 1 patient (p = 0.384). There was no difference in the median survival time (MST) between patients using metformin and those who did not (12 vs 13 months; p = 0.784). There was a trend toward prolonged MST in patients with LD SCLC using metformin compared with those who did not use metformin (58 vs 29 months; p = 0.084). There was no difference due to the use of metformin observed in MST of patients with ED SCLC (12 vs 13 months; p = 0.396). Metformin use may have a prognostic benefit in patients with SCLC combined with DM. This combination is promising and further clinical trials are required.

Phase 1/2 study of veliparib (V) combined with carboplatin (Cb) and etoposide (E) in patients (pts) with extensive-stage disease (ED) small cell lung cancer (SCLC) and other solid tumors: Phase 1 results.

8530 Background: The majority of SCLC cases are diagnosed as ED, for which there is a poor prognosis and no curative treatment (Tx). V, a potent PARP inhibitor, has been shown in preclinical studies to enhance the antitumor activity of platinum-based agents and E against SCLC. The presented phase 1 dose-escalation (NCT02289690) evaluated V combined with Cb/E. Methods: Pts (≥18 years) with ED SCLC or other advanced/metastatic solid tumors with ≤1 line of prior cytotoxic therapy and ECOG performance score 0/1 were included. This study followed a 3+3 design. V starting dose and schedule were 80 mg BID PO administered on days (D) –2 to 5 in combination with Cb AUC 5 mg/mL•min administered on D 1 and E 100 mg/m2 administered on D 1 to 3 via intravenous infusion in 21-D cycles. V schedules of D –2 to 12 and continuous dosing were also explored. Primary objectives were to establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) for V combined with Cb/E, and to evaluate the pharmacokinetic (PK) interaction between V and E. Results: Thirty-nine pts (n = 24 ED SCLC; n = 15 other solid tumors) with median age of 62 years (range 43–79) received study Tx. Most common adverse events (AEs; ≥40%) were nausea (54%), fatigue (51%), alopecia (46%), and anemia (44%); grade 3/4 AEs (≥30%) were decreased neutrophil count, neutropenia (31% each), and anemia (26%). Dose-limiting toxicity occurred in 1 pt (n = 1 grade 3 fatigue) at V 240 mg BID D –2 to 5. The MTD was not reached; RP2D for V was set at 240 mg BID on D –2 to 12 based on long-term tolerability. Continuous dosing of V 240 mg BID with Cb/E resulted in unacceptable Cb/E dose delays due to hematologic toxicity. Coadministration of V (80 to 240 mg BID) with Cb/E exhibited dose-proportional kinetics with no impact on the E PK. Confirmed responses: ED SCLC 63% (15/24 pts) across all dose levels and in 83% (5/6) at RP2D; other tumor types: 13% (2/15) across all dose levels. Conclusions: V + Cb/E had an acceptable safety profile in pts with ED SCLC, with an RP2D of 240 mg BID D –2 to 12. Coadministration of V with Cb/E had no effect on E PK. Responses were seen across all dose levels. A phase 2 study of V with Cb/E in ED SCLC is ongoing. Clinical trial information: NCT02289690.

Prognostic and predictive value of circulating tumor cells and CXCR4 expression as biomarkers for a CXCR4 peptide antagonist in combination with carboplatin-etoposide in small cell lung cancer: exploratory analysis of a phase II study

SummaryBackground Circulating tumor cells (CTCs) and chemokine (C-X-C motif) receptor 4 (CXCR4) expression in CTCs and tumor tissue were evaluated as prognostic or predictive markers of CXCR4 peptide antagonist LY2510924 plus carboplatin-etoposide (CE) versus CE in extensive-stage disease small cell lung cancer (ED-SCLC). Methods This exploratory analysis of a phase II study evaluated CXCR4 expression in baseline tumor tissue and peripheral blood CTCs and in post-treatment CTCs. Optimum cutoff values were determined for CTC counts and CXCR4 expression in tumors and CTCs as predictors of survival outcome. Kaplan-Meier estimates and hazard ratios were used to determine biomarker prognostic and predictive values. Results There was weak positive correlation at baseline between CXCR4 expression in tumor tissue and CTCs. Optimum cutoff values were H-score ≥ 210 for CXCR4+ tumor, ≥7% CTCs with CXCR4 expression (CXCR4+ CTCs), and ≥6 CTCs/7.5 mL blood. Baseline H-score for CXCR4+ tumor was not prognostic of progression-free survival (PFS) or overall survival (OS). Baseline CXCR4+ CTCs ≥7% was prognostic of shorter PFS. CTCs ≥6 at baseline and cycle 2, day 1 were prognostic of shorter PFS and OS. None of the biomarkers at their respective optimum cutoffs was predictive of treatment response of LY2510924 plus CE versus CE. Conclusions In patients with ED-SCLC, baseline CXCR4 expression in tumor tissue was not prognostic of survival or predictive of LY2510924 treatment response. Baseline CXCR4+ CTCs ≥7% was prognostic of shorter PFS. CTC count ≥6 at baseline and after 1 cycle of treatment were prognostic of shorter PFS and OS.

A multicenter, randomized, phase 3 trial comparing fixed dose versus toxicity-adjusted dose of cisplatin + etoposide in extensive small-cell lung cancer (SCLC) patients: The Small-cell-lung cancer Toxicity Adjusted Dosing (STAD-1) trial

ObjectivesData supporting the prognostic role of chemotherapy induced haematological toxicity suggest that toxicity-adjusted-dosing (TAD) of chemotherapy might improve treatment efficacy. We tested whether TAD of the cisplatin-etoposide combination might improve the response rate, in previously untreated extensive stage disease (ED)-SCLC patients, as compared with standard fixed-dosing (FD). MethodsPatients with ED-SCLC were randomized to receive either TAD or FD of cisplatin-etoposide as first-line treatment. Primary endpoint was the objective response rate (ORR) according to the RECIST 1.0 criteria, secondary endpoints included progression free survival (PFS), overall survival (OS) and toxicity. ResultsHundred-fifty-eight patients were randomized. Most patients were male, with ECOG-PS 1, without brain metastases and had not received radiotherapy before study entry. Response rate was 54.4 (95%CI: 43.5–64.9%) and 58.2 (95%CI: 47.2–68.5%) in the control and experimental arms, respectively (P=0.75). No significant differences were found in terms of PFS (HR 1.04; 95%CI: 0.74–1.44, P=0.84) and OS (HR1.01; 95%CI 0.71–1.42, p=0.97). Seven patients died on treatment, one in the standard arm and 6 in the experimental arm. The most frequent cause of death was neutropenia with infection and, apart in one, death was not related to dose modification. Severe toxicity was more frequent in the experimental arm (91% vs 60%). ConclusionsIn our population of chemonaïve ED SCLC patients, TAD failed to improve the ORR, PFS and OS over the FD of cisplatin-etoposide as first line chemotherapy and was associated with increased toxicity.

CheckMate 451: A randomized, double-blind, phase III trial of nivolumab (nivo), nivo plus ipilimumab (ipi), or placebo as maintenance therapy in patients (pts) with extensive-stage disease small cell lung cancer (ED-SCLC) after first-line platinum-based doublet chemotherapy (PT-DC).

TPS8579Background: Most SCLC pts present with ED-SCLC. Initial response rates are high, but disease often rapidly recurs or progresses. Outcomes with second-line treatment are poor. No maintenance therapy has been approved for pts who respond to first-line PT-DC. Nivo, a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor, is approved for previously treated metastatic NSCLC in the US and for previously treated squamous NSCLC in the EU based on 2 phase III trials demonstrating superior survival over docetaxel. Nivo monotherapy and nivo + ipi, a fully human IgG1 cytotoxic T lymphocyte antigen-4 immune checkpoint inhibitor, are being evaluated in previously treated pts with advanced or metastatic SCLC in a phase I/II trial (CheckMate 032, SCLC cohort). Nivo (vs chemotherapy) is also being evaluated in relapsed SCLC in a phase III trial (CheckMate 331). From CheckMate 032, preliminary data of nivo and nivo + ipi has shown antitumor activity with durable tumor responses and manageable safety...

464P Comparision of irinotecan/cisplatin with etoposide/cisplatin in North-West Indian population with extensive-stage disease small-cell lung cancer

464P Comparision of irinotecan/cisplatin with etoposide/cisplatin in North-West Indian population with extensive-stage disease small-cell lung cancer

Cisplatin, Etoposide, and Bevacizumab Regimen Followed by Oral Etoposide and Bevacizumab Maintenance Treatment in Patients With Extensive-Stage Small Cell Lung Cancer: A Single-Institution Experience

BackgroundIn the present study we evaluated the efficacy and safety of a cisplatin (P), etoposide (E), and bevacizumab (Bev) regimen followed by maintenance oral E and Bev in patients with extensive-stage disease small-cell lung cancer (ED-SCLC). Patients and MethodsPatients were administered 3-day fractionated P 25 mg/m2 and E 100 mg/m2 on days 1 to 3, every 3 weeks. After 3 PE cycles, all patients whose disease did not progress continued treatment with PE combined with Bev 15 mg/kg on day 3 every 3 weeks. After completion of 3 PE/Bev cycles, patients who did not experience tumor progression continued maintenance treatment with oral E 50 mg on days 1 to 14 every 21 days combined with Bev 3 times per week until occurrence of disease progression or unacceptable toxicity. ResultsAt our institution, 22 patients were enrolled and their median age was 66 years (range, 38-79 years). After completion of induction chemotherapy (3 PE cycles with 3 PE/Bev cycles) the objective response rate was in 17 patients (77.2%) (95% confidence interval [CI], 54.6-92.1). Twenty-one patients received maintenance treatment with oral E and Bev. The 9-month disease control rate was 8 patients (36.3%). Median progression-free survival was 7.8 months (95% CI, 7.0-11.3 months) and median overall survival was 13.2 months (95% CI, 11.8-18.7 months). Grade 3 to 4 neutropenia occurred in 12 patients (54.4%) and 14 patients (63.6%) of patients during cycles 1 to 3 and cycles 4 to 6 of induction chemotherapy, respectively. Severe adverse events during maintenance treatment were rarely observed. ConclusionA PE and Bev regimen followed by oral E and Bev maintenance treatment appears feasible and effective in terms of 9-month disease control rate in patients with ED-SCLC.

CA184-156: Randomized, multicenter, double-blind, phase III trial comparing the efficacy of ipilimumab (Ipi) plus etoposide/platinum (EP) versus placebo plus EP in patients (Pts) with newly diagnosed extensive-stage disease small cell lung cancer (ED-SCLC).

TPS7608 Background: Phase III studies have not reported improvement for ED-SCLC beyond EP. Moreover, chemotherapeutic response in SCLC is short-lived, with a median survival of 8–12 months and 5-year survival rates ranging from 1%–2%. Ipi, a fully human monoclonal antibody which binds CTLA-4, augments antitumor immune responses and may potentially improve the clinical benefit of EP. A randomized phase II study of Ipi + paclitaxel/carboplatin (PC) in pts with ED-SCLC showed significant improvement in progression-free survival (PFS) [measured by immune-related response criteria (irRC)] over PC in pts receiving phased Ipi + PC; irRC were derived from WHO criteria to better capture response patterns observed with Ipi. Addition of Ipi trended toward prolonged overall survival (OS) and did not exacerbate PC toxicity; immune-related adverse events were managed using protocol-specific guidelines. This global (~227 sites among 34 countries), multicenter phase III study in pts with ED-SCLC (ClinicalTrials.gov identifier NCT01450761) will determine if adding Ipi to EP increases OS vs EP alone. Methods: Pts with first-line ED-SCLC and ECOG 0-1 will be eligible; pts with a history of autoimmune disease will be ineligible. Pts will be randomized (1:1 to either Arm A or Arm B) to 2 cycles of EP (etoposide [100 mg/m2, IV on Days 1-3 Q3W] and cisplatin [75 mg/m2, IV] or carboplatin [AUC=5, IV] once Q3W), followed by 4 cycles of blinded study drug (Ipi 10 mg/kg, IV in Arm A or placebo in Arm B, Q3W) with 2 concurrent cycles (during cycles 3-4) of EP and Ipi (6 cycles of total therapy). Eligible pts will receive Ipi maintenance therapy Q12W until disease progression or unacceptable toxicity; pts with a complete response will also be eligible for prophylactic cranial irradiation at investigator’s discretion. The primary endpoint is OS; secondary endpoints include OS among pts who receive blinded therapy, immune-related and mWHO PFS, best overall response rate, and duration of response. The trial will also characterize safety, and is estimated to enroll 1100 pts. Clinical trial information: NCT01450761.

Comparing irinotecan/cisplatin with etoposide/cisplatin in patients with ED-SCLC: A meta-analysis of efficacy and toxicity

ObjectiveIrinotecan in combination with cisplatin for extensive-stage disease small-cell lung cancer (ED-SCLC) patients has gained wide interest. Varying results for this treatment underpin the need for a synthesis of evidence. MethodsWe conducted a literature-based meta-analysis to quantify the magnitude of the benefit comparing irinotecan in combination with cisplatin (IP) with etoposide in combination with cisplatin (EP) in ED-SCLC patients. The primary outcome was overall survival (OS) and progression-free survival (PFS); secondary outcomes included overall response rate, 1- and 2-year survival rates, disease control rate and toxicity. ResultsFour trials including 1,541 patients were identified in the analysis. No positive results (P<0.05) were seen: OS (HR=0.85, CI95%=0.71–1.01; P=0.08) with high heterogeneity (Chi2=7.76, df=3 [P=0.05]; I2=61%), PFS (HR=0.91, CI95%=0.74–1.28; P=0.36) with high heterogeneity (Chi2=11.96, df=3 [P=0.008]; I2=75%), overall response rate (OR=1.16; CI95%=0.79–1.70; P=0.45), disease control rate (OR=1.01; CI95%=0.74–1.38; P=0.95), 1-year survival rate (OR = 1.30; CI95%=0.98–1.72; P=0.07) and 2-year survival rate (OR=1.97; CI95%=0.95–4.09; P=0.07). Fewer patients who received IP suffered severe hematologic toxicities (grade≥3), such as neutropenia, thrombocytopenia and leucopenia. However, severe non-hematologic toxicities (grade≥3), such as diarrhea, nausea, vomiting, fatigue, anorexia, and dehydration, were more common among patients who received IP. ConclusionIP does not lengthen the overall survival or progression-free survival compared with EP in patients with ED-SCLC. Fewer patients receiving IP had grade≥3 hematological toxicities of neutropenia, leucopenia and thrombocytopenia, but more had grade≥3 diarrhea, nausea, vomiting, fatigue, anorexia and dehydration.

Biomarker analysis in a phase III study of pemetrexed–carboplatin versus etoposide–carboplatin in chemonaive patients with extensive-stage small-cell lung cancer

Clinical results of a randomized phase III trial comparing pemetrexed-carboplatin (PC) with etoposide-carboplatin (EC) in chemonaive patients with extensive-stage disease small-cell lung cancer (ED-SCLC) resulted in trial closure for futility; biomarker analyses using immunohistochemistry (IHC) and single-nucleotide polymorphisms (SNPs) are described herein. Thymidylate synthase (TS), excision repair cross complementing-1 (ERCC1), glycinamide ribonucleotide formyltransferase (GARFT), and folylpolyglutamate synthetase (FPGS) were investigated using IHC (n=395). SNPs were genotyped for TS, FPGS, γ-glutamyl hydrolase (GGH), methylenetetrahydrofolate reductase (MTHFR), folate receptor-α FR-α, and solute carrier 19A1 (SLC19A1; n=611). None of the IHC biomarkers (folate pathway or ERCC1) were found to be predictive or prognostic in this setting. rs2838952 (adjacent to SLC19A1) had significant treatment-independent association with overall survival (OS; hazard ratio 0.590, P=0.01). Nine GGH-associated SNPs interacted with rs3788205 (SLC19A1) for OS on the PC arm. rs12379987 (FPGS) interacted with treatment for OS (interaction P=0.036). Potential ERCC1 and folate pathway IHC biomarkers failed to predict outcome in either study arm in ED-SCLC. SNPs in regions including FPGS and SLC19A1 and interacting SNPs in GGH and SLC19A1 were associated with differences in OS; however, none of these SNPs predicted for greater survival with PC over EC.

CA184-156: A randomized, multicenter, double-blind, phase III trial comparing the efficacy of ipilimumab (Ipi) plus etoposide/platinum (EP) versus EP in subjects with newly diagnosed extensive-stage disease small cell lung cancer (ED-SCLC).

TPS7113 Background: EP (4-6 cycles) is standard of care 1st-line therapy for metastatic SCLC, and no multinational studies have reported any improvement beyond that reported for EP. Evidence of an ongoing immune response to SCLC tumors suggests that immunotherapy that enhances this immune response to SCLC may enhance the clinical benefit of EP. Ipi, a fully human monoclonal antibody which blocks CTLA-4, augments antitumor immune responses. Because some responses to Ipi may differ from those observed with cytotoxic therapies, immune-related response criteria (irRC) were derived from WHO criteria to better capture response patterns observed with Ipi. A randomized Phase 2 study of Ipi with paclitaxel/carboplatin (PC) in pts with ED-SCLC showed significant improvement in progression-free survival (PFS), as measured by irRC, over PC alone in pts receiving Ipi and PC in a phased regimen (Ipi started after 2 cycles of PC). Furthermore, addition of Ipi did not exacerbate PC toxicity, and immune-related adverse events were managed using protocol-specific guidelines. This multicenter phase III study in pts with ED-SCLC (ClinicalTrials.gov identifier NCT01450761) will determine whether adding Ipi to EP increases OS vs EP alone. Methods: EP consists of 4 cycles of etoposide (100 mg/m2, IV on Days 1-3 every 3 weeks [Q3W]) and cisplatin (75 mg/m2, IV) or carboplatin (AUC=5, IV) once Q3W. Pts will be randomized to receive 4 doses of Ipi (10 mg/kg, IV) in Arm A or placebo in Arm B, Q3W during induction, starting after 2 cycles of EP (phased schedule). Eligible pts will then receive blinded study drug (Ipi in Arm A; placebo in Arm B) Q12W until disease progression or unacceptable toxicity. The primary objective is to compare OS. Secondary objectives are to compare OS in those who receive blinded study drug, compare PFS between study arms, and to estimate best overall response rate and duration of response. First-line ED-SCLC pts with ECOG performance ≤1 will be included. Pts with symptomatic CNS metastases or a history of autoimmune disease will be excluded. The study will randomize 1100 pts at a 1:1 ratio.

A phase II study of second-line bendamustine in relapsed or refractory small cell lung cancer (SCLC).

7094 Background: Bendamustine is an alkylating agent with a nitrogen mustard group and purine-like benzimidazole group. Bendamustine in combination with carboplatin has shown efficacy as first line therapy in extensive stage SCLC with RR 73%, TTP 5.2 months and OS 8.3 months [Köster, et al, JCO 2007]. This study aims to investigate the efficacy and safety of single agent bendamustine as 2nd or 3rd line therapy in patients with extensive-stage disease, small-cell lung cancer (ED-SCLC). Methods: This is an open-label, single-arm, multicenter phase II trial. Eligible patients had previously treated ED-SCLC, up to 2 prior regimens, ECOG performance status 0-2, evaluable/measurable disease, and adequate marrow, renal and hepatic function. Patients with stable treated brain metastases were allowed. Patients were treated with bendamustine (120mg/m2 IV days 1 and 2 every 3 weeks) for up to 6 cycles. Evaluation occurred every 2 cycles. Primary endpoint was TTP; secondary endpoints include RR, PFS, OS, and toxicity. Results: 48 patients were enrolled; 56% were male and 96% were Caucasian. 33 patients were evaluable for response. There was 1 CR, 9 PR, 13 SD (48% disease control rate) and 10 PD. Median TTP was 3.37 months (95% CI 2.30 to 4.47 months). At the time of analysis, 13 patients were alive and with a median overall survival of 4.77 months (95% CI 3.67 to 6.07 months). 5 patients (10.4%) required dose reductions due to AEs, 2 due to fatigue, 1 due to neutropenia, 1 due to pancytopenia and 1 due to pneumonia. Grade 3/4 AEs included fatigue (18.8%), dyspnea (14.5%), infection without neutropenia (12.5%), anemia (8.3%), neutropenia (8.3%), and diarrhea (8.3%). Conclusions: These data indicate that single agent bendamustine appears to be well tolerated and effective in the second or third line setting for patients with SCLC.

Abstract LB-396: Molecular characterization of ED-SCLC: high-resolution SNP 6.0 arrays, mRNA expression, and miRNA arrays from the phase III GALES trial

Abstract Background Extensive-stage disease, small-cell lung cancer (ED-SCLC) is a lethal disease with poor clinical outcomes given current systemic therapy options. The objective of this study was to examine potential prognostic factors identifiable through genome-wide characterization methodologies to enhance our current understanding of ED-SCLC and gene networks involved in ED-SCLC. Methods Patient samples obtained within the framework of a randomized Phase III trial (n=908) were successfully assayed for copy number variations (CNVs, n=92), exon array gene expression (n=73), and miRNA array (n=92). The CNV data were adjusted to account for degraded nucleic acids from formalin-fixed, paraffin-embedded samples, and copy number was estimated using the Partek® genomics suite. Unsupervised clustering analysis of exon array data was performed to detect groups of samples with similar expression profiles. Cluster stability was assessed by using bootstrapping procedures, and its association with survival was studied. For miRNAs, which were expressed in &amp;gt;75% of samples, a rank-based correlation analysis was performed between the miRNA expression and mRNA expression. A Cox-regression model was built to calculate miRNAs’ association with survival time. Results A SNP array analysis revealed CNVs at chromosomes 3p, 4q, 5q, 10q, 13q, and 17p, which was in accordance with previous reports. Novel changes at other chromosomal sites are being analyzed. Cluster analysis of expression data suggests the presence of 2 distinct molecular subtypes within the ED-SCLC patient samples examined in this analysis. A significant difference in progression-free survival (PFS) was observed (log rank, p ≤ 0.009); the median PFS for patients belonging to cluster 1 was 5.2 months versus 3.5 months for patients assigned to cluster 2. Cluster 1 showed high expression of genes associated with antiapoptotic pathways through NFKB, I-KB, IRAK1 and IRAK2; Gn-Rh signaling and downstream MAPK induction; and EGR1 factor signaling cascades, including c-Jun and c-Fos. Cluster 2 showed high expression of genes associated with DNA damage repair including ATM, MSH2, BRIP1, Rad50, and MRN complex; and G2/M checkpoint arrest through ATM phosphorylation and cyclin-B induction. Several miRNAs were associated with improved survival, including miRNAs from the miR7 and miR320 families. Conclusions This analysis of ED-SCLC patient samples, which used multiple genomics platforms, confirmed several known aberrations and identified novel markers not previously described with ED-SCLC outcomes. Two clusters of patients with distinct molecular profiles and outcomes were revealed, and miRNAs associated with improved survival outcomes were identified. While these data are exploratory and ongoing, confirmation of these observations may lead to advances in profiling and targeting important genes integral to SCLC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-396. doi:1538-7445.AM2012-LB-396

A multicenter phase II study of belotecan, new camptothecin analogue, in patients with previously untreated extensive stage disease small cell lung cancer

Belotecan (Camtobell, CKD602) is a new camptothecin derivative antitumor agent that belongs to the topoisomerase inhibitors. The aim of this phase II study was to evaluate the efficacy and safety of single agent belotecan in patients with small cell lung cancer (SCLC). Patients with previously untreated extensive stage disease (ED) SCLC were entered into the study. Belotecan was given by daily intravenous infusion at 0.5 mg/m 2/day for 5 consecutive days, every 3 weeks. 62 patients were enrolled in this study. The overall response rate to chemotherapy on an intention-to-treat basis was 53.2%. The median overall survival was 10.4 months, the median time to progression 4.6 months, and the 1-year survival rate 49.9%. The most common toxicity was hematologic. Grade 3/4 neutropenia occurred in 71.0% of patients and grade 3/4 thrombocytopenia 12.9%. Non-hematologic toxicity of grade 3 or 4 was low. The results suggest that belotecan is relatively active and well tolerable as single agent in patients with ED SCLC. Further investigations with platinum or other active agents are needed.

Prognostic factors differ by tumor stage for small cell lung cancer

An analysis of 14 small cell lung cancer (SCLC) trials was performed to improve the current understanding of potential prognostic factors for overall survival (OS) and progression-free survival (PFS) in groups of patients with limited-stage disease SCLC (LD-SCLC) and extensive-stage disease SCLC (ED-SCLC) separately. Data on 688 patients with LD-SCLC and 910 patients with ED-SCLC were included. Clinical and laboratory factors were tested for their prognostic significance using Cox regression models that were stratified by protocol. Recursive partitioning and amalgamation (RPA) analyses were used to identify prognostic subgroups. Poorer performance status (PS) led to worse OS and PFS in the ED-SCLC group but not in the LD-SCLC group. The prognostic impact of PS was strong for men but weak for women in the ED-SCLC group (interaction P value <.012 for OS and PFS). Other negative prognostic factors included increased age and men for the LD-SCLC group and increased age, men, increased number of metastatic sites at baseline, and increased creatinine levels for the ED-SCLC group. In patients with the ED-SCLC, RPA analyses identified 5 subgroups with different prognosis based on baseline PS, creatinine levels, sex, and the number of metastatic sites. The current pooled analysis identified baseline creatinine levels and the number of metastatic sites as important prognostic factors in patients with ED-SCLC in addition to the well established factors of sex, age, and PS. There was a significant interaction between sex and PS within the ED-SCLC group, suggesting that PS is highly prognostic in men but has no significant impact in women. Within the LD-SCLC group, only age and sex were identified as important prognostic factors. RPA analyses confirmed many of these findings.

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)

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 &gt; 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 &lt; 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]