Editores da série MOC: Antonio Carlos Buzaid - Fernando Cotait Maluf - Carlos H. Barrios

Editor-convidado: Caio Max S. Rocha Lima

ASCO 2014

[ASCO 2014] Câncer de Pulmão

Apoio:

astellas_marca-onco_150x60     Roche_azul_80x45

A equipe do MOC selecionou os abstracts de maior impacto da ASCO 2014. Veja abaixo os destaques em Câncer de pulmão:

Câncer de Pulmão de Células Não Pequenas

Câncer de Pulmão de Células Pequenas

  1. A randomized phase III study of cisplatin (CDDP), etoposide (ETOP) and irinotecan versus topotecan as second-line chemotherapy in patients with sensitive relapsed small-cell lung cancer (SCLC): Japan Clinical Oncology Group study JCOG0605
  2. Comparison of cisplatin- versus carboplatin-based concurrent chemoradiation for limited-stage small cell lung cancer using SEER-Medicare data
  3. Final outcome results of platinum-sensitive small cell lung cancer (SCLC) patients treated with platinum-based chemotherapy rechallenge: A multi-institutional retrospective analysis
  4. Prophylactic cranial irradiation (PCI) has a detrimental effect on the overall survival (OS) of patients (pts) with extensive disease small cell lung cancer (ED-SCLC): Results of a Japanese randomized phase III trial
  5. Randomized phase III trial in extensive-disease small cell lung cancer comparing first-line etoposide to topotecan in combination with platinum
  6. Randomized phase II-III study of bevacizumab in combination with chemotherapy in previously untreated extensive small-cell lung cancer: Results from the IFCT-0802 trial
  7. Randomized trial on thoracic radiotherapy (TRT) in extensive-stage small cell lung cancer
  8. Retrospective evaluation of prophylactic cranial irradiation in patients with limited-stage small cell lung cancer with stereotactic radiotherapy: A multi-institutional study

Mesotelioma

Cancer de Pulmão de células não pequenas

A randomized, double-blind phase 3 trial of adjuvant erlotinib (E) versus placebo (P) following complete tumor resection with or without adjuvant chemotherapy in patients (pts) with stage IB-IIIA EGFR positive (IHC/FISH) non-small cell lung cancer (NSCLC): RADIANT results

Sub-Category: Adjuvant Therapy
Meeting: 2014 ASCO Annual Meeting
Abstract No: 7501
Author(s): Karen Kelly, Nasser K. Altorki, Wilfried Ernst Erich Eberhardt, et al.
Completely resected IB-IIIA NSCLC pts were randomized 2:1 to receive E 150 mg qd or P for 2 years. Pts were stratified according to stage, histology, prior adjuvant chemotherapy, smoking status, EGFR FISH status, and country. The primary endpoint was disease free survival (DFS) in the full analysis set (FAS). Secondary endpoints included overall survival (OS) in the FAS and DFS and OS in the EGFR mutation (EGFR M+) subset (del19/L858R). Hierarchical testing procedure was used. Conclusions: Adjuvant E did not prolong DFS in the overall population. Further investigation in EGFR M+ pts is warranted. The safety profile of E was consistent with that in advanced disease.

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Postoperative chemotherapy as effective as preoperative for N2-positive stage III non-small cell lung cancer

Abstract No: 7533
Author(s): Daniel J Boffa, Jacquelyn Hancock, Amy Moreno, et al.
The National Cancer Database (NCDB) was queried for patients with clinical T1-4N2M0 NSCLC (clinical Stage III – N2) undergoing resection via lobectomy or pneumonectomy between 2003 and 2006. Conclusions: Chemotherapy appears to be similarly effective in stage III NSCLC patients with N2 disease when given before or after resection in the NCDB. This finding, could impact the role preoperative mediastinal staging in operable stage III lung cancer.

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SELECT: A multicenter phase II trial of adjuvant erlotinib in resected early-stage EGFR mutation-positive NSCLC

Abstract No: 7514
Author(s): Nathan A. Pennell, Joel W. Neal, Jamie E. Chaft, et al.
Eligible pts had resected stage IA-IIIA NSCLC harboring a TKI-sensitizing EGFR mutation. Pts were treated with erlotinib 150 mg/day for 2 years after completion of standard adjuvant chemotherapy and/or radiotherapy. With a sample size of 100 pts the study was powered to demonstrate a primary endpoint of 2-year disease free survival (DFS) >85%, compared to a historical control of 76% in resected early-stage EGFR-mutant NSCLC. Conclusions: Pts with EGFR mutation-positive NSCLC treated with adjuvant erlotinib have an improved 2-year DFS compared to historical genotype-matched controls. Recurrences are rare on erlotinib and most occur in the 12m after discontinuation, suggesting longer duration of adjuvant treatment may be beneficial.

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A multinational phase III randomized trial with or without consolidation chemotherapy using docetaxel and cisplatin after concurrent chemoradiation in inoperable stage III non-small cell lung cancer (CCheIN)

Abstract No: 7500
Author(s): Keunchil Park, Yong Chan Ahn, Jin Seok Ahn, et al.
Patients with inoperable stage III NSCLC were randomized to either CCRT alone (observation arm) or CCRT followed by consolidation chemotherapy (consolidation arm). N2 or N3 disease was confirmed by PET and/or pathology. CCRT with D (20 mg/m2) and P (20 mg/m2) was administered every week for 6 weeks with a total dose of 66 Gy of thoracic RT as 33 fractions. In the consolidation arm, patients were further treated with 3 cycles of D and P (35 mg/m2each on day 1 and 8, every 3 weeks). The primary endpoint is progression-free survival (PFS). The secondary endpoints are overall survival, response rate, pattern of failure, and safety. Total target number of patients is 434. This study suggests that consolidation chemotherapy with DP after CCRT with weekly DP in stage III NSCLC does not prolong PFS.

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A randomized phase III trial comparing triple weekly usage with weekly usage of paclitaxel in concurrent chemoradiotherapy for patients with locally advanced non-small cell lung cancer

Abstract No: 7545
Author(s): Guangying Zhu, Anhui Shi, Hongmei Lin, et al.
It is a multi-center, randomised, controlled, phase III trail. After 2 to 4 cycles of induction chemotherapy, patients with LANSCLC were randomly assigned to two groups. In group 1, chemotherapy consisted of paclitaxel (15 mg/m2, 3times/week, 270 mg/m2 over six weeks). In group 2, chemotherapy consisted of paclitaxel (45 mg/m2, 1 time/week, 270 mg/m2over six weeks). Radiotherapy consisted of 60-70Gy (2Gy per fraction and 5 fractions per week). Conclusions: The study results showed that triple weekly usage is more safe and effective than weekly usage of paclitaxel with CCRT for patients with LANSCLC.

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A randomized trial of prophylactic cranial irradiation versus observation in patients with fully resected stage IIIA N2 non-small cell lung cancer and high risk of cerebral metastases after adjuvant chemotherapy

Abstract No: 7508
Author(s): Si-Yu Wang, Ning Li, Wei Ou, Xiong Ye, et al.
In this open-label, randomized trial, patients with fully resected stage IIIA N2 NSCLC and high cerebral metastases risk without recurrence after postoperative adjuvant chemotherapy were randomly assigned to receive PCI (30 Gy in 10 fractions) or observation. The primary end point was disease-free survival (DFS). The secondary end points included the incidence of brain metastases, overall survival (OS) and toxicity. Conclusions: In patients with fully resected stage IIIA N2 NSCLC and high risk of cerebral metastases after adjuvant chemotherapy, PCI prolongs DFS and decreases the incidence of brain metastases.

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Final overall survival (OS) results from a phase II study of pemetrexed (Pem) and cisplatin (Cis) with concurrent thoracic radiation (RT) after Pem-Cis induction in patients with unresectable locally advanced (LA) nonsquamous non-small cell lung cancer (NS-NSCLC)

Abstract No: 7539^
Author(s): Silvia Novello, Walburga Engel-Riedel, Monika Serke, et al.
Pts with unresectable Stage IIIA/B NS-NSCLC (AJCC V6) and ECOG-PS 0-1 received 2 cycles of Pem 500/Cis 75mg/m2on Day (d)1, q21d. Pts who did not progress, with no residual neurological toxicity >G2, ECOG-PS 0-1 and lung V20<35% continued with 2 cycles of full dose Pem-Cis + concurrent RT (2Gy/fraction, 66Gy total). All pts received vitamin supplementation/dexamethasone prophylaxis as per Pem label. Pem-Cis induction CT followed by full-dose Pem-Cis and concurrent RT was effective (median OS 26mo), acute and late toxicity was manageable during both induction CT and concurrent CT+RT.

 

All pts (ITT)
N=90

Started concurrent CT+RT
(N=75)

Kaplan-Meier estimate,
months (95%CI)

mPFs

10.6 (8.6, 17.3)

12.5 (9.6, 19.0)

mOS

26.2 (16.7, n.e.)

30.0 (21.3, n.e.)

Tumor response, % (95%CI)

Response rate

60.0 (49.1, 70.2)

72.0 (60.4, 81.8)

Disease control rate

77.8 (67.8, 85.9)

93.3 (85.1, 97.8)

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NEOSCAN: Phase II trial of neoadjuvant chemotherapy for resectable lung cancers with switch to chemo alternative in 18F-FDG PET nonresponders

Abstract No: 7515
Author(s): Mark G. Kris, Matthew David Hellmann, Jarushka Naidoo, et al.
We enrolled pts with clinical stage IB-IIIA NSCLCs (primary tumor >2 cm and SUVmax≥4.5) deemed to be resectable by a thoracic surgeon. All pts had a pretreatment PET. Pts received 2 cycles of cisplatin (or carboplatin) + gemcitabine (squamous) or pemetrexed (adenocarcinoma/other), followed by repeat PET. If PET showed ≥35% decrease in SUVmax, pts continued on platinum-based therapy. Pts with suboptimal response (<35% decrease) were switched to vinorelbine + docetaxel q2 weeks (2 doses = 1 cycle). The primary endpoint was partial metabolic response after 2 cycles of “switch” therapy as assessed by PERCIST (SUVmax decrease ≥30% using the pre-switch scan as new baseline). We powered the study to detect a 30% response rate to “switch” chemotherapy (≥6 responses in ≤25 pts who received vinorelbine + docetaxel). Conclusions: Pts with resectable lung cancers who have a suboptimal PET response to histology-selected, platinum-doublet neoadjuvant chemotherapy can be effectively treated with vinorelbine and docetaxel followed by surgery. We now plan to correlate pathologic response in resected tumors with SUV change.

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Phase II study of cetuximab, pemetrexed, cisplatin and concurrent radiotherapy in patients with locally advanced, unresectable, stage III, non-squamous, non-small cell lung cancer (NSCLC): Results of the IFCT-0803 trial

Abstract No: 7511^
Author(s): Jean Tredaniel, Fabrice Barlesi, Cecile Le Pechoux, Delphine Lerouge, et al
Based on a 2-stage Simon approach, a total of 106 patients were to accrue. An interim analysis of the first 34 patients authorized the continuation of the study. Eligible patients receive thoracic radiation (66 Gy) along with cisplatin (75 mg/m²) and pemetrexed (500 mg/m²) on D1 administered every 21 days for four cycles; weekly cetuximab (400 mg/m²) for the first week, then 250 mg/m²) is added from the first week of therapy for a total of 12 doses. The primary objective is to assess the disease control rate at the 16th week (16W-DCR), one month after the treatment completion. Conclusions: IFCT-0803 trial showed both the feasability and high DCR for radiation, cisplatin, pemetrexed and cetuximab combination, with a tolerable toxicity profile. Our data will be updated at the ASCO meeting, the accrual goal (106 pts) being reached on Jan. 2014.

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Phase II study of induction chemotherapy with carboplatin, paclitaxel, and bevacizumab followed by surgery in patients with stage III nonsquamous non-small cell lung cancer: The Tokyo Cooperative Oncology Group trial (TCOG1002)

Abstract No: 7542
Author(s): Toshihiko Iizasa, Ichiro Yoshino, Sakae Okumura, et al.
This study was a multicenter phase II trial (TCOG 1002). After staging N status by endobronchial ultrasonography or positron emission tomography, patients with stage III non-squamous NSCLC received induction chemotherapy with carboplatin (AUC6), paclitaxel (200mg/m2), and bevacizumab (15mg/kg) twice every 3 weeks, followed by carboplatin (AUC6) and paclitaxel (200mg/m2) 3 weeks later. Surgery was then performed. The primary endpoint was overall response rate. Conclusions: Induction chemotherapy with carboplatin, paclitaxel, and bevacizumab followed by surgery is safe and feasible in patients with stage III non-squamous NSCLC. Our results indicate that further studies are warranted to confirm the safety and efficacy ofthis treatment regimenin stage III non-squamous NSCLC.

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Role of PET scan in predicting response to neoadjuvant chemotherapy and long-term outcomes for stage II lung cancer

Abstract No: 7574
Author(s): Ankit Bharat, Brandon Guenthart, Valerie W. Rusch, et al.
Clinical stage II NSCLC (7th ed. AJCC) patients that underwent NAT between 1995 and 2010 were identified using a prospectively maintained database. All patients underwent clinical staging using CT scan and PET scan, with or without invasive lymph node staging. Chemotherapy regimen was unchanged during the study period. Conclusions: In patients with clinical stage II NSCLC, surgery after NAT was associated with low perioperative mortality and good long-term survival. Patients with a >50% reduction of SUV had a significant improvement in long-term survival.

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START2: Tecemotide in unresectable stage III NSCLC after first-line concurrent chemoradiotherapy

Abstract No: TPS7608
Author(s): Suresh S. Ramalingam, Paul Mitchell, Johan F. Vansteenkiste, et al.
Tecemotide is an antigen-specific cancer immunotherapy targeting the mucinous glycoprotein MUC1, which is overexpressed and aberrantly glycosylated in a number of cancers including non-small cell lung cancer (NSCLC). The START study evaluated tecemotide after first-line concurrent or sequential chemoradiotherapy (CRT) for unresectable stage III NSCLC (Butts et al, Lancet Oncol 2013). Though the primary endpoint was not achieved for the overall patient population, the predefined subset of 806 patients treated with concurrent CRT showed improved overall survival (OS; adjusted HR 0.78, 95% CI 0.64–0.95; p=0.016). The pivotal phase III study START2 intends to confirm these results in patients having had initial concurrent CRT. Methods: START2 is a global, randomized, double-blind placebo-controlled phase III trial investigating tecemotide in patients with unresectable stage III NSCLC with stable disease or objective response after first-line concurrent CRT completed 4–12 weeks before randomization. Concurrent CRT is defined as ≥2 cycles of platinum-based chemotherapy that overlaps with radiotherapy (total tumor dose ≥60 Gy, single fraction dose ≥1.8 Gy); any other therapy for NSCLC constitutes an exclusion criterion. Patients will be stratified by response to CRT (stable disease or objective response) and region (North America and Australia; Western Europe; Rest of World), and randomized (1:1) to tecemotide (806 μg lipopeptide) or placebo. One low dose of i.v. cyclophosphamide (300 mg/m2) or saline will be given 3 days prior to the first dose of tecemotide or placebo, respectively. Eight weekly subcutaneous injections will be given initially, followed by 6-weekly injections until disease progression or discontinuation. The primary endpoint is OS time. Secondary endpoints are: time to symptom progression (Lung Cancer Symptom Scale), progression-free survival, time to progression, and safety. Approximately 1002 patients will be enrolled. Sample size was calculated for a hazard ratio of 0.77 corresponding to an increase in median OS from 20 to 26 months in the placebo/tecemotide arm, respectively, a power of 90%, and 1-sided significance level of 2.5%.

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A multicenter randomized phase II trial of erlotinib with and without hydroxychloroquine (HCQ) in TKI-naive patients (pts) with epidermal growth factor receptor (EGFR) mutant advanced non-small cell lung cancer (NSCLC)

Abstract No: 8088
Author(s): Joel W. Neal, Heather A. Wakelee, et al
EGFR-TKI naïve pts with metastatic or recurrent EGFR mutant NSCLC were randomized to E (150 mg daily) with or without HCQ (1,000 mg daily). Tumor assessments were performed every 8 weeks until disease progression. With a sample size of 76 pts, the study was powered for a primary endpoint of improvement in 9-month progression free survival (PFS) from 50% in the E arm compared with 77% in the EQ arm. Conclusions: EQ did not improve 9 month PFS compared with arm E. OS numerically favored the E arm, which may reflect imbalances between the arms. Despite strong preclinical evidence, hydroxychloroquine does not appear to delay the development of resistance to erlotinib in pts with EGFR mutant NSCLC.

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A phase II clinical trial of the CDK 4/6 inhibitor palbociclib (PD 0332991) in previously treated, advanced non-small cell lung cancer (NSCLC) patients with inactivated CDKN2A

Abstract No: 8077
Author(s): Priya Kadambi Gopalan, Mary Colleen Pinder, et al.
The Retinoblastoma pathway is targeted for mutational or epigenetic inactivation in more than 70% of NSCLC. The most common event is loss of CDKN2A expression (p16 protein), usually by hypermethylation, resulting in deregulated CDK4/6 activity and cell cycle progression. Palbociclib is a highly specific CDK4/6 inhibitor and has been shown to inhibit cell cycle progression and promote cellular senescence. Methods: We conducted a phase II, single arm trial of palbociclib in 19 previously-treated patients with recurrent or metastatic NSCLC. Only patients whose tumors were negative for p16 expression by immunohistochemistry were eligible. The primary endpoint was response rate. A Simon’s 2-stage design was employed, with 2 or more responses required to proceed to the second stage. Palbociclib at 125 mg daily was given orally on days 1-21 of a 28-day cycle. Tumors were assessed by RECIST every 2 cycles. Secondary endpoints included overall survival, progression-free survival, toxicity and biomarker analysis. Conclusions: Palbociclib therapy alone was well-tolerated, and stable disease (SD) was achieved in 50% of evaluable patients, suggesting the induction of cellular senescence. PFS was comparable to other second-line chemotherapeutic agents. Molecular predictors of clinical benefit (SD) are currently under investigation.

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A phase II/III randomized trial of two doses of MK-3475 versus docetaxel in previously treated subjects with non-small cell lung cancer

Abstract No: TPS8124
Author(s): Roy S. Herbst, Alfonso Gurpide, Veerle Surmont, et al.
Eligibility stipulates minimum age of 18 years; ECOG performance status of 0-1, and diagnosis of advanced PD-L1-positive NSCLC with documented progression after platinum-containing systemic therapy. Patients are stratified by ECOG performance status, geographic location of the site, and degree of PD-L1 expression and randomized in a 1:1:1 ratio to receive intravenous MK-3475 (2 mg/kg, every 3 weeks [Q3W] or 10 mg/kg, Q3W) or docetaxel (75 mg/m2, Q3W) for 2 years or until disease progression, unacceptable toxicity, intercurrent illness or investigator decision. Response to treatment will be evaluated every 9 weeks by investigators using the immune-related response criteria (irRC) and centrally by RECIST 1.1. Adverse events (AEs) will be monitored throughout the trial. Primary objectives include OS and PFS per RECIST 1.1 in patients with strong expression of PD-L1, and safety, including incidence and time to first Grade 3-5 AE. Secondary objectives include OS, PFS and ORR per RECIST 1.1 in patients with PD-L1 positive tumors. Fifty of approximately 920 pts targeted for accrual have enrolled.

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A phase III, randomized, open-label trial of nivolumab (anti-PD-1; BMS-936558, ONO-4538) versus investigator’s choice chemotherapy (ICC) as first-line therapy for stage IV or recurrent PD-L1+ non-small cell lung cancer (NSCLC)

Abstract No: TPS8128
Author(s): David Paul Carbone, Mark A. Socinski, Allen C. Chen,
Chemotherapy-naïve pts with ECOG performance status ≤1 and without known EGFR mutations or ALK translocations will be randomized 1:1 to nivolumab (3 mg/kg IV Q2W) or ICC, and stratified by tumor PD-L1 expression level (Dako immunohistochemistry assay) and NSCLC histology. Pts randomized to ICC (maximum of six 3-week cycles) will receive gemcitabine 1250 mg/m2 + cisplatin 75 mg/m2, gemcitabine 1000 mg/m2 + carboplatin AUC 5, or paclitaxel 200 mg/m2 + carboplatin AUC 6 (squamous [sq]), or pemetrexed 500 mg/m2 + either cisplatin 75 mg/m2 or carboplatin AUC 6 (non-sq); with optional crossover to nivolumab. The primary objective is to assess progression-free survival (PFS) with nivolumab vs ICC in pts with strong PD-L1 expression. Secondary objectives are objective response rate and overall survival in strongly PD-L1+ pts, PFS in pts with any PD-L1 expression level, and disease-related symptom improvement. Exploratory objectives include safety, correlation of PD-L1 expression with PFS, pharmacokinetics, pharmacodynamics, pt-reported outcomes, and potential biomarkers.

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A prospective, multicenter phase II trial of low-dose erlotinib monotherapy for patients with previously treated non-small cell lung cancer (NSCLC) with activating mutation of epidermal growth factor receptor (EGFR): Thoracic Oncology Research Group (TORG) 0911

Abstract No: 8080
Author(s): Yoshiro Nakahara, Yukio Hosomi, Kazuhiko Yamada, et al.
Eligible patients had advanced EGFRm+ NSCLC with 1 to 3 prior chemotherapy treatments. Erlotinib with the initial daily dosage of 50 mg was administered. Dose was escalated to 150 mg in case of not achieving CR or PR by RECIST criteria at the evaluation after the first 4 weeks of treatment. Erlotinib was continued until disease progression or unacceptable toxicities. The primary endpoint was independent committee-determined objective response rate (ORR) to the low-dose erlotinib, with target ORR of 70% and threshold of 50%. The sample size was calculated to be 40, and the primary endpoint was met if 26 or more patients responded. Conclusions: This trial is the first prospective study evaluating low-dose erlotinib. Although it appeared to have a certain efficacy, the primary endpoint was not met. Because of its low toxicity, it may be worth further evaluation in elderly and/or frail patients.

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A randomized, double-blind, multicenter phase 2 trial of denosumab in combination with chemotherapy as first-line treatment of metastatic non-small cell lung cancer

Abstract No: TPS8130
Author(s): David R. Spigel, Fred R. Hirsch, Richard H. De Boer, et al.
~216 pts with untreated stage IV NSCLC will receive 4–6 cycles of standard of care chemotherapy and be randomized (2:1) to denosumab 120 mg or placebo SC Q3W or Q4W plus a loading dose on day 8. ZA or placebo IV may be offered in a blinded manner if requested. The sample size is powered to test the interaction between treatment effect and RANK or RANKL expression under various reasonable scenarios. Pts will receive calcium and vit D daily. Randomization will be stratified based on bone metastasis (yes or no), histology (squamous vs nonsquamous), and region (North America, Western Europe/Australia, rest of world). The primary endpoint is tumor RANK expression correlated with OS. Primary analysis will occur when ~149 deaths have occurred. Eligible pts will have ECOG status 0–1 and radiographically evaluable disease. Pts with known EGFR-activating mutations, EML-4-ALK translocations, or brain metastasis will be excluded. Pt screening and enrollment is planned or underway in ~10 countries.

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A randomized, multicenter, open-label, phase III study of gemcitabine-cisplatin (GC) chemotherapy plus necitumumab (IMC-11F8/LY3012211) versus GC alone in the first-line treatment of patients (pts) with stage IV squamous non-small cell lung cancer (sq-NSCLC)

Abstract No: 8008^
Author(s): Nick Thatcher, Fred R. Hirsch, Aleksandra Szczesna, Tudor-Eliade Ciuleanu, et al.
Pts with pathologically proven stage IV sq-NSCLC were randomized 1:1 to GC (G=1250 mg/m² iv, days 1 and 8; C=75 mg/m² iv, day 1) plus N (800 mg iv, days 1 and 8) (GC+N arm), or GC alone (GC arm) every 21 days for up to 6 cycles. GC+N pts with no progression continued on N alone until progressive disease or intolerable toxicity. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. EGFR protein expression level by immunohistochemistry (H-score) in tumor tissue was an exploratory analysis. Planned sample size was 1080 pts, with 90% power and a 2-sided alpha level of 0.05. Conclusions: The addition of N to GC statistically significantly improved OS, PFS, and DCR. The safety profile of GC+N is acceptable.

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Ceritinib in advanced anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC): Results of the ASCEND-1 trial

Abstract No: 8003^
Author(s): Dong-Wan Kim, Ranee Mehra, Daniel Shao-Weng Tan, et al.
Adult pts with advanced ALK+ cancers received oral ceritinib q.d. After MTD determination, pts were enrolled to expansion groups: ALKi pretreated (PT) NSCLC; ALKi naive NSCLC; non-NSCLC diseases. Results are reported for all NSCLC pts receiving ceritinib at the recommended dose (750 mg/d). Conclusions: Ceritinib 750 mg/d has rapid, durable and high antitumor activity in ALK+ NSCLC pts, regardless of prior treatment with ALKi, providing effective treatment in this pt population.

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Efficacy and safety results from CurrentS, a double-blind, randomized, phase III study of second-line erlotinib (150 mg versus 300 mg) in current smokers with advanced non-small cell lung cancer (NSCLC)

Abstract No: 8046
Author(s): Egbert F. Smit, Radj Gervais, Caicun Zhou, et al.
Pts with stage IIIB/IV NSCLC (failed first-line platinum-based chemotherapy, current smokers) were randomized to receive standard dose erlotinib (150 mg/day; E150) or an experimental dose (300 mg/day; E300) until progression/death/unacceptable toxicity. Pts were assessed every 6 wks. Primary endpoint: progression-free survival (PFS). Secondary endpoints included: overall survival (OS), disease control rate (DCR), and safety. Planned sample size: 300 randomized pts; 277 PFS events needed to show a HR of 0.714 (median PFS improvement from 10 to 14 wks; E300 was expected to provide a longer median PFS v E150) with 80% power (5% 2-sided α). Conclusions: CurrentS, the first and largest trial in active smokers with NSCLC to date, did not show a statistically significant increase in PFS (primary endpoint) when erlotinib was given at 300 mg v 150 mg. OS (secondary endpoint) was not different between the arms. There was a numerical increase in AESIs with the higher dose. PK data will be presented.

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Erlotinib plus bevacizumab (EB) versus erlotinib alone (E) as first-line treatment for advanced EGFR mutation–positive nonsquamous non-small cell lung cancer (NSCLC): An open-label randomized trial

Abstract No: 8005
Author(s): Terufumi Kato, Takashi Seto, Makoto Nishio, et al.
Open-label randomized trial. Patients with stage 3b/4 or recurrent non-squamous EGFR mutation–positive NSCLC, ECOG performance status 0/1, and no previous chemotherapy were randomly allocated to receive EB (E, 150 mg/day; B, 15 mg/kg every 3 weeks) or E (150 mg/day) until disease progression or unacceptable toxicity. The primary endpoint was PFS determined by blinded independent review committee. Secondary endpoints included overall survival, objective response rate (ORR), safety, and quality of life. The planned sample size was 150, with an alpha error of 0.2 and a power of 80% for a target hazard ratio (HR) of 0.7. Conclusions: EB results in significantly longer PFS than E in patients with EGFR mutation–positive NSCLC.

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Final overall survival results of WJTOG 3405, a randomized phase 3 trial comparing gefitinib (G) with cisplatin plus docetaxel (CD) as the first-line treatment for patients with non-small cell lung cancer (NSCLC) harboring mutations of the epidermal growth factor receptor (EGFR)

Abstract No: 8117
Author(s): Hiroshige Yoshioka, Tetsuya Mitsudomi, et al.
Overall survival (OS) was re-evaluated using updated data (data cutoff, 30 Sep, 2013, median follow-up, 59.1 mos.) for 172 patients. Conclusions: This five-year follow-up OS analysis confirmed that G for advanced NSCLC with EGFR mutation offers survival benefit of 3 years. There was no difference in OS whether the initial treatment was G or CD, probably due to high cross over rate.

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First-line crizotinib versus pemetrexed–cisplatin or pemetrexed–carboplatin in patients (pts) with advanced ALK-positive non-squamous non-small cell lung cancer (NSCLC): results of a phase III study (PROFILE 1014)

Author(s): Tony Mok, Dong-Wan Kim, Yi-Long Wu, et al.
Between Jan 2011 and Jul 2013, 343 pts with previously untreated advanced non-squamous ALK-positive NSCLCwere randomized 1:1 to receive crizotinib 250 mg PO BID (n=172) or PPC (pemetrexed 500 mg/m2 + either cisplatin 75 mg/m2 or carboplatin AUC 5–6; all IV q3w for ≤6 cycles; n=171). Continuation of/crossover to crizotinib after PD (per independent radiologic review) was allowed for pts randomized to crizotinib or PPC, respectively. The primary endpoint was PFS. Secondary endpoints included ORR, OS, safety, and pt-reported outcomes. Conclusions: First-line crizotinib treatment showed significant improvements in PFS and ORR compared with standard chemotherapy and had an acceptable safety profile. These findings establish crizotinib as the standard of care for pts with previously untreated advanced ALK-positive non-squamous NSCLC.

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Galaxy-2 trial (NCT01798485): A randomized phase 3 study of ganetespib in combination with docetaxel versus docetaxel alone in patients with advanced lung adenocarcinomas

Abstract No: TPS8118^
GALAXY-2 is a randomized (1:1), international, open-label Phase 3 study enrolling patients who received and progressed on 1 prior systemic platinum-based combination therapy for advanced NSCLC of adenocarcinoma histology, were diagnosed ≥6 months before study entry, and whose tumors are negative for both EGFR mutations and ALK translocation (Target Patient Population [TPP]). Patients (N=700 TPP) are prospectively stratified for ECOG PS, total screening LDH, and geographic region (North America and Western Europe vs Rest of World). The primary endpoint is OS in the TPP. Key secondary endpoints include PFS, ORR, DCR, and DOR in the TPP. OS will also be analyzed in 3 subpopulations of the TPP: mKRAS, elevated LDH, and elevated LDH5. Patients in the control arm are treated with docetaxel 75 mg/m2 on Day 1 of a 3-week cycle. In the combination arm, ganetespib 150 mg/m2 is given on Day 1 with 75 mg/m2 docetaxel, and ganetespib 150 mg/m2 alone is given on Day 15 of each 3-week cycle. Two interim analyses for OS will be performed. Tumor tissue and blood samples will be collected for planned translational studies.

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NEJ009 trial: A randomized phase III study of gefitinib (G) in combination with carboplatin (C) plus pemetrexed (P) versus G alone in patients with advanced nonsquamous non-small cell lung cancer (NSCLC) with EGFR mutation.

Abstract No: TPS8131
Author(s): Akira Inoue, Yukio Hosomi, Makoto Maemondo, et al.
This randomized phase III trial was designed to compare the efficacy and safety of G alone with combined regimen with G, C, and P in patients with advanced EGFR-mutated NSCLC. Eligible patients (N=340) have pathologically confirmed stage IIIB/IV NSCLC with activating EGFR mutation including exon 18 G719A, C, or S mutation, exon 19 deletion, exon 21 L858R, or L861Q mutation. Concurrent mutation in exon 20 T790M is ineligible. Patients must have radiologically measurable disease, ECOG PS 0–1 and no prior systemic therapy. Patients will be randomized (1:1) to receive G 250 mg alone once daily or same schedule of G with C (AUC 5.0) plus P (500 mg/m2) on day1, every 3 weeks, up to 4-6 cycles, followed by maintenance P with concurrent G. The primary endpoint is overall survival (OS) and secondary endpoints include progression-free survival, best overall response, toxicity profile, and quality of life. A minimum of 168 OS events is required for 80% power to detect a OS improvement of GCP regimen versus G alone using the intent-to-treat (ITT) analysis population (HR ≤0.7). A significant (0.025 significance level) 2-sided stratified log-rank test for OS at the final analysis will be indicative of a positive study outcome. An interim analysis is planned to assess safety and whether early discontinuation of the trial is required for futility.

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Randomized phase III study comparing gefitinib (G) with erlotinib (E) in patients (pts) with previously treated advanced lung adenocarcinoma (LA): WJOG 5108L

Abstract No: 8041
Author(s): Nobuyuki Katakami, Satoshi Morita, Hiroshige Yoshioka, et al.
Eligible pts were those with pathologically proven LA with stage IIIB/IV (AJCC version 6) or recurrence, previously treated with at least one chemotherapy regimen, evaluable disease, age ≥20 years and ECOG PS 0-2. Pts were randomized 1:1 to E (150 mg, daily), or G (250mg, daily) according to gender, stage, EGFR mutation status, performance status, smoking history, CT line, and institution. Target sample size was 560 based on the assumption that G was not inferior to E in PFS (2 – 4 months, α =0.025 [one sided], β =0.80).Noninferiority was to be concluded if the upper CI limit was < 1.30. The primary endpoint was PFS, and secondary endpoints included overall survival (OS), response rate (RR), disease control rate (DCR), safety, and time to treatment failure (TTF). Conclusions: Noninferiority in PFS between E and G was not demonstrated according to predefined criteria, however, there was no statistically significant difference in PFS.

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REVEL: A randomized, double-blind, phase III study of docetaxel (DOC) and ramucirumab (RAM; IMC-1121B) versus DOC and placebo (PL) in the second-line treatment of stage IV non-small cell lung cancer (NSCLC) following disease progression after one prior platinum-based therapy

Abstract No:  LBA8006^
Author(s): Maurice Perol, Tudor-Eliade Ciuleanu, Oscar Arrieta, et al.
Abstract:
The full, final text of this abstract will be posted online at 7:30 AM (EDT) on Saturday, May 31.

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Sunitinib (S) switch maintenance in advanced non-small cell lung cancer (NSCLC): An ALLIANCE (CALGB 30607), randomized, placebo-controlled phase III trial

Abstract No: 8040
Author(s): Mark A. Socinski, Xiaofei F. Wang, Maria Quintos Baggstrom, et al.
Stage IIIB/IV pts, PS 0-1 with stable/responding disease after 4 cycles of platinum-based therapy were randomized to S (37.5 mg po qd) vs P. Pts were assessed for progression every 6 weeks. PFS and OS were measured from the time of randomization. The trial was designed to have 90% power to detect a 6 week improvement in PFS using a log rank test at a 2-sided significance level of 0.05. Planned accrual was 244 pts. All p values are 2-sided. Conclusions: CALGB 30607 met its primary endpoint by demonstrating a significant improvement in PFS for S switch maintenance therapy in advanced NSCLC. No effect on the secondary endpoint of OS was seen.

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Câncer de Pulmão de células pequenas

A randomized phase III study of cisplatin (CDDP), etoposide (ETOP) and irinotecan versus topotecan as second-line chemotherapy in patients with sensitive relapsed small-cell lung cancer (SCLC): Japan Clinical Oncology Group study JCOG0605

Abstract No: 7504
Author(s): Koichi Goto, Yuichiro Ohe, Takashi Seto, et al.
ETOP and irinotecan are drugs known to exert promising activity in SCLC. A phase II study of weekly chemotherapy using a combination of CDDP, ETOP and irinotecan (PEI), which are known to inhibit both topoisomerase I and II, showed quite favorable outcome in patients with sensitive relapsed SCLC. A phase III study confirming the superiority of PEI over topotecan as second-line chemotherapy in patients with sensitive relapsed SCLC was conducted. Conclusions: The combination chemotherapy with CDDP, ETOP and irinotecan should be considered as the standard second-line chemotherapy for sensitive relapsed SCLC.

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Comparison of cisplatin- versus carboplatin-based concurrent chemoradiation for limited-stage small cell lung cancer using SEER-Medicare data

Abstract No: 7596
Author(s): Ellen Kim, Tithi Biswas, Siran M. Koroukian, et al.
Cases were selected from the population-based SEER-Medicare lung cancer database if the patient’s first cancer was limited stage SCLC diagnosed at age 66-80 in 1992-2007. CCRT was defined with radiation starting within 60 days of the start of the first cycle of cis/carb. Study endpoints were overall survival (OS, time from diagnosis until death) and cause specific survival (CSS, time from diagnosis until death from lung cancer). SAS v9.3 was used to select cases, and R v3.0.2 was used to calculate Kaplan-Meier survival analysis and log-rank tests for significance. Conclusions: Cis vs carb based CCRT had comparable OS and CSS, even though cis group was younger. This suggests that if carb is better tolerated, it should be preferred for limited stage SCLC, though randomized trials are needed.

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Final outcome results of platinum-sensitive small cell lung cancer (SCLC) patients treated with platinum-based chemotherapy rechallenge: A multi-institutional retrospective analysis

Abstract No: 7600
Author(s): Giovenzio Genestreti, Giulio Metro, Hirotsugu Kenmotsu, et al.
We retrospectively collect each institutional data warehouse of platinum-sensitive SCLC treated with platinum/etoposide rechallenge. Primary endpoint was overall survival (OS) from diagnosis and from the rechallenge of chemotherapy (PPS). Secondary endpoints were response rate (RR) and Progression-Free Survival2 (PFS2) yielded by rechallenge. Conclusions: Rechallenge may be an efficacy option in patients with platinum sensitive disease with a PFS1 > 150 days.

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Prophylactic cranial irradiation (PCI) has a detrimental effect on the overall survival (OS) of patients (pts) with extensive disease small cell lung cancer (ED-SCLC): Results of a Japanese randomized phase III trial

Abstract No: 7503
Author(s): Takashi Seto, Toshiaki Takahashi, Takeharu Yamanaka, et al.
From March 2009, pts with ED-SCLC who had any response to first-line platinum doublet chemotherapy were randomized to either PCI (25Gy/10 fractions) or observation (Obs) alone. The patients were required to prove the absence of BM by MRI prior to enrollment. The primary endpoint was OS and a planned sample size of 330 was determined to detect the hazard ratio (HR) of 0.75 at a significance level of 0.05 and a power of 80%. Secondary endpoints included time to BM (evaluated every 3 months by imaging), progression-free survival (PFS), and adverse effects (AEs). Conclusions: PCI after response to chemotherapy had a negative impact on OS in pts with ED-SCLC.

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Randomized phase III trial in extensive-disease small cell lung cancer comparing first-line etoposide to topotecan in combination with platinum

Abstract No: 7519
Author(s): Morten Mau-Soerensen, Olfred Hansen, Bente Holm, et al. Previously untreated pts with ED SCLC were randomized to six cycles of T (topotecan 2.0 mg/m2 IV, day 1-3; cisplatin 50 mg/m2 IV, day 3) or E (etoposide 120 mg/m2, day 1-3; carboplatin IV AUC = 5, day 1) every 3 weeks. Primary end-point was overall survival (OS) and secondary end-points were response, progression-free survival (PFS), and safety. A sample size of 380 pts was estimated to detect an increase in 2-year survival from 7.5 to 15 % (α=0.05, β=0.20.) ClinicalTrials.gov NCT 00812266. Conclusions: No differences in OS or PFS were observed comparing first line E with T in ED SCLC. Significantly more hematological toxicity was noted in the E arm. A biomarker study is planned to identify pts that derive most benefit from either T or E.

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Randomized phase II-III study of bevacizumab in combination with chemotherapy in previously untreated extensive small-cell lung cancer: Results from the IFCT-0802 trial

Abstract No: 7505
Author(s): Jean-Louis Pujol, Armelle Lavole, Bertrand Mennecier, et al. Patients with SCLC were enrolled and then received two induction cycles of CT, three weeks apart (cisplatin – etoposide, or cisplatin – cyclophosphamide – epidoxorubicin – etoposide [PCDE]). Responders were randomly assigned 1:1 to receive 4 additional cycles of CT alone or CT plus Bev (7.5 mg/kg) followed by single-agent Bev until progression or unacceptable toxicity. The primary endpoint was response rate (RR) after 4 cycles (i.e. two cycles after randomization). Conclusions: Bev did not increase the proportion of responder patients at cycle 4. This phase II study failed to demonstrate any signal suggesting an outcome improvement in extensive-SCLC. Consequently this trial will not go further the phase 3 part of the program.

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Randomized trial on thoracic radiotherapy (TRT) in extensive-stage small cell lung cancer

Abstract No: 7502
Author(s): Ben J. Slotman, Corinne Faivre-Finn, Harm van Tinteren, et a.
Patients (WHO 0-2) with confirmed ES-SCLC with a response after 4-6 cycles of standard chemotherapy were randomized to receive TRT (30 Gy/10fx) or no TRT. All received PCI. Primary study endpoint was overall survival. Acute toxicity was graded using CTCAE v3.0. The study had 80% power to detect a hazard ratio of 0.76 at 1 year (2-sided 5% signif.). Accounting for 5% dropout before treatment, 483 patients had to be randomized. Analysis was based on intent to treat. Conclusions: TRT improves progression-free survival. Although TRT did not influence the risk of death in the first year, it led to a significant increase in 2-year survival. TRT should therefore be offered to all ES-SCLC patients with a response to initial chemotherapy. This study was supported by grants from the Dutch Cancer Society (CKTO) and Cancer Research UK and supported by the Dutch Lung Cancer Research Group and The Christie NHS Foundation Trust Clinical Trials Unit.

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Retrospective evaluation of prophylactic cranial irradiation in patients with limited-stage small cell lung cancer with stereotactic radiotherapy: A multi-institutional study

Abstract No: 7591
Author(s): Yuichi Ozawa, Minako Omae, Masato Fujii, et al.
The data of all patients with pathologically proven SCLC from 1/1/2006 to 6/31/2013 were collected from 4 designated cancer care hospitals in Japan, all of which were equipped with or had access to SRT, and thoroughly reviewed. LS disease at diagnosis and who were estimated as CR or good PR after the first treatment were enrolled. All possible patients were periodically screened for BM by CT or MRI and patients with BM were preferentially considered for SRT. The effects of PCI and SRT were analyzed by Kaplan-Meier method and Cox proportional hazards model. Conclusions: PCI does not benefit patients with LS-SCLC in conjunction with periodical brain screening and SRT. A prospective study is currently underway.

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Mesotelioma

COMMAND: A phase II randomized, double-blind, placebo-controlled, multicenter study of defactinib as maintenance therapy in subjects with malignant pleural mesothelioma that has not progressed on at least four cycles of pemetrexed/platinum therapy

Abstract No: TPS7611
Author(s): Dean Anthony Fennell, Paul Baas, Hedy Lee Kindler, et al.
A multinational, randomized, double-blind, placebo controlled, clinical trial will determine if defactinib provides superior clinical benefit compared with placebo as a maintenance treatment in patients with MPM following frontline therapy with pem/platinum therapy. Approximately 370 eligible patients with PR or SD following at least 4 cycles of pem/cis or pem/carboplatin will be enrolled. Patients will receive defactinib 400mg BID or matched placebo (1:1). Patients will continue treatment until disease progression. Randomization will be stratified by merlin status (high vs low) as determined by immunohistochemistry on archival tumor tissue. Primary endpoints will include OS and PFS. An adaptive enrichment design at the interim analysis may restrict patients to those with low merlin protein expression if benefit is observed among the subpopulation. Secondary endpoints include patient-reported outcomes, objective response and safety and tolerability. Twenty-eight sites are actively recruiting patients across 8 countries.

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Nintedanib plus pemetrexed/cisplatin followed by maintenance nintedanib for unresectable malignant pleural mesothelioma (MPM): An international, multicenter, randomized, double-blind, placebo-controlled phase II study

Abstract No: TPS7612
Author(s): Giorgio V. Scagliotti, Natasha B. Leighl, Anna K. et al.
A total of 86 pts—at least 18 years of age and with ECOG score of 0 or 1 and histologically confirmed epithelioid orbiphasic MPM — will be randomized in a 1:1 ratio to receive either up to 6 cycles of 1st-line combination pemetrexed (500 mg/m2)/cisplatin (75 mg/m2) on day one administered along with nintedanib (200 mg bid) or placebo from days two to 21. Pts who do not develop progressive disease (PD) will continue to receive maintenance treatment with either nintedanib or placebo until PD. The primary endpoint is PFS. Secondary endpoints are OS and baseline change in forced vital capacity as a measure of pulmonary function. Frequency and severity of adverse events will also be evaluated as a measure of safety. All pts will attend an end-of-trial visit when they discontinue study treatment permanently, and return for follow-up visits until the end of trial, death, or loss to follow-up.

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