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S. Lee
Moderator of
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ORAL 01 - Chemotherapy Developments for Lung Cancer (ID 88)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 7
- Moderators:G. Blumenschein, S. Lee
- Coordinates: 9/07/2015, 10:45 - 12:15, 401-404
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ORAL01.01 - Randomized Phase III Study of Nedaplatin plus Docetaxel versus Cisplatin plus Docetaxel for Advanced Squamous Cell Lung Cancer (WJOG5208L) (ID 621)
10:45 - 12:15 | Author(s): T. Seto, T. Shukuya, T. Yamanaka, T. Hirashima, T. Kato, Y. Horio, S. Atagi, T. Inoue, Y. Ohsaki, T. Maeda, K. Nishi, T. Sawa, M. Okada, D. Fujimoto, T. Harada, K. Nakagawa, Y. Nakanishi, N. Yamamoto
- Abstract
- Presentation
Background:
Nedaplatin (N) is a second-generation platinum compound with lower nausea/vomiting and nephrotoxicity than cisplatin (C). Nedaplatin plus docetaxel (ND) showed a promising efficacy with acceptable toxicity for advanced squamous cell lung cancer (SqLC) in the previous phase II study.
Methods:
Eligible patients (pts) were those with pathologically proven SqLC with stage IIIB/IV or postoperative recurrence, aged 20-74 years and ECOG PS 0-1. Pts were randomized 1:1 to ND (N 100 mg/m[2] and docetaxel (D) 60mg/m[2] iv, q3w, up to 6 cycles) or C plus D (CD) (C 80 mg/m[2] and D 60mg/m[2] iv, q3w, up to 6 cycles) according to stage, gender and institution. The primary endpoint was overall survival (OS), and secondary endpoints included progression-free survival (PFS), response rate (RR) and adverse events (AEs). Target sample size of 350 provided 90% statistical power to detect a hazard ratio of 0.71 with one-sided type I error of 0.05.
Results:
Between July 2009 and July 2012, 355 pts were randomized. Of 349 for efficacy analysis (ND 177; CD 172), baseline characteristics were well-balanced between two arms. ND had a significantly longer OS (p=0.037, one-sided stratified log-rank test). The OS HR was 0.81 (90%CI, 0.67-0.98) with a median OS of 13.6 months [m] for ND and 11.4 for CD. ND had a longer PFS (p=0.050) with a HR of 0.83 (0.69-1.00) and a median PFS of 4.9 m in ND and 4.5 in CD. RR was 54.5% in ND vs 52.9% in CD (p=0.829). Grade 3 or higher AEs of nausea (4.0% vs 14.3%), fatigue (3.4% vs 10.9%), hyponatremia (13.6% vs 30.3%) and hypokalemia (2.3% vs 8.6%) are more frequent in CD. Grade 3 or higher AEs of neutrophils (82.5% vs 70.3%) and platelets (9.0% vs 0.0%) are more frequent in ND, but there was no difference in grade 3 or higher febrile neutropenia (13.6% vs 15.4%). Treatment related deaths occurred in 4 and 3 pts in ND and CD, respectively.
Conclusion:
ND showed a significantly longer OS as compared to CD with different toxicity profile. ND will be considered as a new standard treatment for advanced or relapsed SqLC. Clinical trial information: UMIN000002015.
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ORAL01.02 - Therapy of Advanced Metastatic Lung Cancers with an Anti-Trop-2-SN-38 Antibody-Drug Conjugate, IMMU-132: Interim Phase II Clinical Results (ID 930)
10:45 - 12:15 | Author(s): R. Camidge, A.N. Starodub, A. Ocean, W.A. Messersmith, A. Bardia, S.S. Thomas, G. Masters, R. Heist, P. Maliakal, S. Govindan, R.M. Sharkey, F.E. Wilhelm, D.M. Goldenberg, M.J. Guarino
- Abstract
- Presentation
Background:
Sacituzumab govitecan (IMMU-132) is a new Antibody Drug Conjugate (ADC) comprising SN-38, the active metabolite of the topoisomerase I inhibitor, camptothecin (irinotecan), conjugated to an anti-Trop-2 humanized antibody at a high drug-antibody ratio (7.6). In vitro and in vivo preclinical data suggest that IMMU-132 delivers up to 136-fold more SN-38 than its parental drug, irinotecan, in a human cancer xenograft. Trop-2 is widely expressed in most epithelial cancers, including non-small and small-cell lung cancers (NSCLC and SCLC).The safety and efficacy of this new ADC is being examined in advanced metastatic lung cancers.
Methods:
A Phase II clinical trial (ClinicalTrials.gov, NCT01631552) is ongoing in subsets of previously-treated patients with metastatic lung cancer, administering IMMU-132 on days 1 and 8 of 21-day treatment cycles. A phase 1 run-in phase selected 8 and 10 mg/kg weekly dosage as safe for tumor cohort phase 2 expansion. Treatment is continued based on tolerance or until progression, with safety and response assessments made every week and 8-12 weeks, respectively.
Results:
Forty-four lung cancer patients were given IMMU-132 doses at 8 mg/kg (N = 23) or 10 mg/kg (N = 21); 38 patients (18 NSCLC and 20 SCLC) are assessable for efficacy. Patients were heavily pretreated (median of 3 prior lines). Objective tumor responses (all partial responses by RECIST1.1) and median progression-free survival (PFS) are reported below per tumor. These studies are being expanded.
IMMU-132 was well tolerated with limited grade 3/4 toxicities above the 3% threshold per patient. Neutropenia was the only Grade 3/4 toxicity (G3, 14%; G4, 7%) together with hyponatremia (G3, 2%; G4, 2%). Other drug-related G3 toxicities included diarrhea (7%), anemia (5%), leukopenia (5%), hyperglycemia (5%) and atrial fibrillation (5%); no patient developed antibodies to the conjugate.Tumor type Prior lines of therapy: median (range) Objective Response Rate (PR) Median PFS (maturity) in months NSCLC (N=18) 3 (1-8) 33% 5.4 (56%) SCLC (N=20) 2.5 (1-7) 25% 2.4 (70%)
Conclusion:
Repeated cycles of IMMU-132 monotherapy are well tolerated. Objective response rate and progression-free survival data in previously-treated metastatic lung cancer (5.4 months in NSCLC) are encouraging and warrant further evaluation of IMMU-132 in these lung cancers.
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ORAL01.03 - A Randomized Phase 2 Trial of Vintafolide and Docetaxel in Folate-Receptor Positive (FR+) Advanced NSCLC Patients: Final Efficacy Results (ID 1600)
10:45 - 12:15 | Author(s): N. Hanna, E. Juhasz, C. Cainip, O. Gladkov, Ó. Juan Vidal, R. Ramlau, O.J. Vidal, R. Lal, J. Symanowski, R. Clark, W. Harb
- Abstract
- Presentation
Background:
Vintafolide (folic acid-vinca alkaloid conjugate) binds to the folate receptor (FR), which is overexpressed in approximately 80% of patients with NSCLC, including patients with squamous cell and adenocarcinoma. Using the molecular imaging agent 99mTc-etarfolatide for SPECT imaging, the FR status of malignant lesions can be determined. Vintafolide has demonstrated single agent activity in patients with advanced NSCLC whose tumors all expressed FR [FR(100%)] compared to patients not FR(100%) (Edelman et al, 2012).
Methods:
This study randomized patients with advanced NSCLC whose tumors were FR(100%) to vintafolide, vintafolide + docetaxel, or docetaxel. Key eligibility criteria: age ≥18 years; 1 prior systemic therapy for advanced disease; ECOG PS 0-1. Patients underwent [99m]Tc-etarfolatide SPECT screening for FR assessment. Vintafolide (2.5 mg) was administered on days 1, 4, 8, 11 every 21 days and docetaxel (75 mg/m[2]) on day 1 every 21 days. The primary endpoint was progression-free survival (PFS). Pre-specified PFS comparisons were performed for vintafolide vs docetaxel and vintafolide+docetaxel vs docetaxel in all patients as well as those with adenocarcinoma. Significance testing for each PFS analysis was one-sided without adjustment for multiplicity (alpha=0.10). Overall survival (OS) was a secondary endpoint.
Results:
Over 14 months, 199 FR(100%) patients were randomized and treated (vintafolide: 63; vintafolide+docetaxel: 68; docetaxel: 68). Patient and disease characteristics were well-balanced between arms. The vintafolide+docetaxel arm met the primary endpoint of superior PFS over the docetaxel arm in all patients regardless of histology (17.0% censored; unstratified Cox model hazard ratio [HR] =0.75; unstratified one-sided p-value=0.0696) as well as in the prespecified 133 patient adenocarcinoma subgroup (18.8% censored; HR=0.73; p-value=0.0899). Trends in OS favored the vintafolide+docetaxel arm over the docetaxel arm in all patients (37.7% censored; HR=0.88; p-value=0.2874) and showed the greatest benefit in the adenocarcinoma subgroup (42.8% censored; HR=0.70; p-value=0.1018). The single-agent vintafolide arm was not superior to docetaxel. Vintafolide+docetaxel treatment was associated with more neutropenia (all grades: 77% versus 62%), febrile neutropenia (13% versus 6%), and peripheral neuropathy (34% versus 21%) compared to docetaxel alone.
Conclusion:
The addition of vintafolide to docetaxel resulted in a statistically significant improvement in PFS in FR(100%) NSCLC patients regardless of histology (PFS HR= 0.75) and in the adenocarcinoma subset (PFS HR= 0.73). Additionally, there was a trend towards improvement in OS in all patients regardless of histology (OS HR= 0.88) and in the adenocarcinoma subset (OS HR= 0.70). Vintafolide +docetaxel was generally well tolerated, although rates of neutropenia, neutropenic fever, and neuropathy were higher than with docetaxel alone. Final survival results will be presented at the conference.
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ORAL01.04 - Discussant for ORAL01.01, ORAL01.02, ORAL01.03 (ID 3289)
10:45 - 12:15 | Author(s): M. Boyer
- Abstract
- Presentation
Abstract not provided
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ORAL01.05 - Phase I/II Dose Escalation Study of Immunoconjugate L-DOS47 as a Monotherapy in Non-Squamous Non-Small Cell Lung Cancer Patients (ID 3272)
10:45 - 12:15 | Author(s): D. Kowalski, C. Szczylik, A. Szczesna, R. Ramlau, E. Wiatr, H. Chao, S. Demas, K. Roszkowski-Sliz
- Abstract
- Presentation
Background:
L‑DOS47, a cancer therapeutic designed to exploit the acidic tumour extracellular environment, is a protein conjugate consisting of a urease conjugated to a camelid monoclonal antibody (AFAIKL2) that is targeted to the CEACAM6 antigenic tumour marker. The AFAIKL2 antibody serves as a targeting agent to deliver the enzyme to the tumor sites while the urease enzyme converts urea, an abundant natural metabolite, into ammonia and generates a local pH increase. The combined effect of ammonia toxicity and pH increase is cytotoxic to cancer cells in culture and in xenograft models. This first in human study of L‑DOS47 was designed to define the maximum tolerated dose of multiple doses of L-DOS47 administered intravenously to patients with non-squamous NSCLC when given as a monotherapy.
Methods:
Stage IIIb or IV histologically confirmed non-squamous NSCLC patients (aged ≥18 yrs, ECOG PS ≤2) receive multiple cycles of L-DOS47 during the study treatment period. L-DOS47 is administered once weekly over 14 days followed by 7 days rest in each treatment cycle. Patients are recruited into cohorts and received the same dose of L-DOS47 on Days 1 and 8 of each treatment cycle. Dose levels of L-DOS47 are escalated in further cohorts following a review of safety data by the Trial Steering Committee.
Results:
Thirty-three (33) pts (median age 61, 58% male) were enrolled in the first ten cohorts (dose levels: 0.12, 0.21, 0.33, 0.46, 0.59, 0.78, 1.04, 1.38, 1.84, 2.45 µg/kg) in four Polish centers. L-DOS47 was well tolerated at the dose levels reviewed. No DLTs were reported. Adverse events reported to date were expected for the population under study. None of the patients treated to date have had a partial or complete response as defined by RECIST v1.1. Sixteen (16) patients had an overall response of stable disease after completing two cycles of L-DOS47. One patient in cohort 9 was dosed for 9 cycles without disease progression.
Conclusion:
L-DOS47 monotherapy is well tolerated at dose levels up to 2.45 µg/kg. ClinicalTrials.gov identifier: NCT02340208
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ORAL01.06 - S-1 and Cisplatin versus Docetaxel and Cisplatin in Patients with Untreated Advanced NSCLC: An Randomised, Multicenter, Phase 3 Trial (ID 2734)
10:45 - 12:15 | Author(s): Y. Shi, M. Wang, J. He, J. Chang, B. Han, X. Liu, G. Chen, C. Zhou, J. Liu, H. Pan, C. Huang, S. Zhang, J. Feng, X. Lin, J. Wang, J. Huang, F. Li, S. Qin, Z. Wang, L. Wang, N. Xu
- Abstract
- Presentation
Background:
Platinum-based doublet chemotherapy is the standard chemotherapeutic regimen for treatment-naïve advanced non-small cell lung cancer (NSCLC). S-1, an oral fluoropyrimidine, combined with carboplatin or cisplatin (CDDP) has demonstrated the non-inferiority to the standard platinum doublet chemotherapy in Japanese NSCLC patients. However, its effectiveness in Chinese NSCLC patients is uncertain. The purpose of this study is to compare the efficacy and safety of these chemotherapeutic regimens in Chinese NSCLC patients.
Methods:
We did this randomized controlled study in 21 sites in China. Eligible patients were those aged 18-70 years who was histologically or cytologically confirmed with locally advanced or metastatic NSCLC with no prior radiotherapy, molecular targeted therapy or chemotherapy. Patients were randomized to receive either S-1 orally 80 mg/m[2]/day (40 mg/m[2]2 b.i.d., 80–120 mg/day) with 60 mg/m[2] CDDP on day 8 every 5 weeks (SP) or docetaxel and CDDP (both 75 mg/m[2]) on day 1 every 3 weeks (DP) for up to 6 cycles. Randomisation was stratified by centre, pathological classification, disease stage and gender. The primary endpoint was progression free survival (PFS), analyzed in the full analysis set. The study is registered at ClinicalTrials.jp, number Japic CTI-111479.
Results:
Between March 2011 and November 2012, 246 patients from 21 institutions in China were randomly assigned and received SP or DP treatment (124 vs 122) with 18-month follow-up period from the last patient randomized. In the SP and DP group, median PFS was 5.9 and 5.7 months (HR=0.68; 95% CI, 0.48-0.96) respectively, median overall survival was 19.1 and 14.8 months, respectively (HR=0.84; 95% CI, 0.61-1.14). The most common grade 3 or worse adverse events in both treatment groups were neutropenia 3.3% vs 55.1%, leukopenia 1.7% vs 39.0%, and febrile neutropenia 0.8% vs 5.9%, of 121 patients in the SP group and of 118 patients in the DP group, respectively.
Conclusion:
The efficacy of SP was non-inferior to DP with a better safety profile. SP would be a new standard first-line chemotherapy regimen for Chinese patients with advanced NSCLC.
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ORAL01.07 - Discussant for ORAL01.05, ORAL01.06 (ID 3290)
10:45 - 12:15 | Author(s): J. Spicer
- Abstract
- Presentation
Abstract not provided
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Author of
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MINI 17 - WT EGFR, Angiogenesis and OMD (ID 131)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:R. Feld, R. Dziadziuszko
- Coordinates: 9/08/2015, 16:45 - 18:15, Mile High Ballroom 4a-4f
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MINI17.03 - Prognostic and Predictive Value of the VeriStrat Classifier in Chemo-Naive NSCLC Patients Treated with Erlotinib or Placebo (TOPICAL Trial) (ID 699)
16:45 - 18:15 | Author(s): S. Lee
- Abstract
- Presentation
Background:
National Comprehensive Cancer Network Guidelines recommend using VeriStrat, a blood proteomics test to determine using erlotinib instead of chemotherapy as second-line treatment for patients with non-small cell lung cancer (NSCLC). However, VeriStrat has not been evaluated in a first-line setting within a randomized trial.
Methods:
TOPICAL was a double-blind randomised placebo-controlled trial, for 670 chemotherapy-naive NSCLC patients (stage IIIb/IV) considered unsuitable for chemotherapy, mainly due to poor performance status (ECOG ≥2) or co-morbidities. They were randomized to receive best supportive care plus oral placebo or erlotinib (150mg/day) until disease progression/toxicity. Although there was no overall survival (OS) benefit among all patients, patients on erlotinib who developed first-cycle rash had improved OS, compared to placebo: hazard ratio (HR 0.76), p=0.006; unlike those without rash (HR 1.30, p=0.017). Pre-treatment serum samples were available for 477 of 670 (70%) TOPICAL patients. They were sent as anonymised aliquots to Biodesix for VeriStrat testing.
Results:
VeriStrat testing classified 52% (250/477) as having good outcomes, 46% (221) poor outcomes, and 6 unknown. In all patients, VeriStrat classification was associated with OS (good vs. poor: HR=0.58, 95%CI 0.47-0.73; P<0.0001) and PFS (HR=0.72; 95% CI 0.53-0.97; P=0.002), after allowing for gender, histology, stage, treatment and first-cycle rash (unadjusted HRs were similar, as were those ignoring rash). In all erlotinib patients, median OS was 4.9 (good) vs. 3.1 months (poor); HR=0.63, 95% CI 0.47-0.85, p=0.002. The corresponding results among all placebo patients were: 5.3 (good) vs. 2.9 months (poor), HR=0.53, 95% CI 0.39-0.73, p<0.001. Similar results were found for PFS: median 3.1 (good) vs. 2.2 (poor) months (HR=0.72; 95% CI 0.53-0.96, P=0.027) for erlotinib patients; and 2.8 vs. 2.4 months for placebo patients (HR=0.72, 95% CI 0.53-0.97, p=0.033). Among all patients, VeriStrat was not predictive: OS HR for erlotinib vs. placebo was 1.02 (95% CI 0.79-1.31) in the ‘good’ group, and 0.86 (95% CI 0.66-1.12) for ‘poor’; interaction p-value=0.38. Corresponding PFS HRs were 0.86 (95% CI 0.67-1.10) and 0.84 (95% CI 0.65-1.10); interaction p-value=0.92. VeriStrat was also not predictive when allowing for first-cycle rash (Table 1). However, among patients who had rash, those with ‘good’ classification had longer OS (p<0.001) and PFS (p=0.001) than those classified as ‘poor’. Figure 1
Conclusion:
Our large randomized trial among NSCLC patients considered unsuitable for chemotherapy shows that VeriStrat status was prognostic for OS and PFS; but it was not predictive for OS nor PFS, in relation to erlotinib vs. placebo as first-line treatment.
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P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-079 - Addition of Hsp27 Inhibitor Apatorsen to First-Line Gemcitabine/Carboplatin in Advanced Squamous Cell Lung Cancer: Design of the Cedar™ Trial (ID 2169)
09:30 - 17:00 | Author(s): S. Lee
- Abstract
Background:
Outcomes remain poor in patients with non-small cell lung cancer (NSCLC) of squamous origin. There are few established therapeutic targets, and benefits of chemotherapy are frequently short-lived, with rapid development of treatment resistance. More effective therapies are urgently required. Substantial preclinical data demonstrate that heat shock protein 27 (Hsp27) affects numerous pathways implicated in cancer progression and treatment resistance. Approximately 70-98% of squamous-cell tumours express Hsp27. Apatorsen (OGX-427) is a second generation antisense oligonucleotide that effectively down-regulates Hsp27 in vitro and in vivo; clinical studies are evaluating apatorsen in lung, bladder, prostate, and pancreatic cancers.
Methods:
The phase 2, UK, investigator led, randomized, open-label trial Cedar trial was initiated in July 2014. Eligible patients have confirmed Stage IIIB/IV squamous cell lung cancer and no prior chemotherapy for advanced disease, with ECOG score of 0-2 and adequate bone marrow, renal, and liver function; patients with known EGFR mutation or ALK rearrangements are excluded. Planned enrollment is 140 patients; randomization (1:1) is stratified by stage and performance status. Patients receive 21-day cycles of gemcitabine (1250 mg/m[2]) and carboplatin (AUC5) or gemcitabine/carboplatin plus apatorsen (600 mg IV/wk, preceded by 3 doses during a 9-day loading period) for up to 6 cycles. Tumor evaluation occurs q6 wks. Patients randomized to apatorsen may continue weekly single agent maintenance until progressive disease (PD), unacceptable toxicity, or withdrawal of consent. The primary efficacy measure is progression-free survival. Secondary efficacy measures include objective response (OR), change in tumour size at 12 wks, clinical benefit rate, duration of OR/clinical benefit, overall survival, and proportion without PD at 12 and 24 wks. Efficacy analyses are intent-to-treat. Adverse events and laboratory results are assessed, and interim safety analyses are planned. Pre-specified subset analyses will characterize the relevance of Hsp27 expression in tumour and blood samples.
Results:
Not applicable.
Conclusion:
Not applicable.
