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ORAL 16 - Clinical Care of Lung Cancer and Advanced Biopsies (ID 115)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:J.W. Neal, Q. Zhou
- Coordinates: 9/08/2015, 10:45 - 12:15, Mile High Ballroom 2a-3b
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ORAL16.05 - Retrospective Analysis of ctDNA EGFR Mutations in the Phase III, Randomized IMPRESS Study (ID 2106)
11:28 - 11:39 | Author(s): S. Kim
- Abstract
- Presentation
Background:
The majority of patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer respond to first-line EGFR-tyrosine kinase inhibitors (EGFR-TKIs, e.g. gefitinib) but nearly all eventually acquire resistance. The most common mechanism of acquired resistance is a second-site mutation in the EGFR kinase domain, T790M. The phase III, double-blind IMPRESS study evaluated the efficacy and safety of continuing gefitinib plus pemetrexed/cisplatin versus placebo plus pemetrexed/cisplatin in patients with acquired resistance to first-line gefitinib. Study results did not support the continuation of gefitinib after disease progression (by RECIST criteria) when platinum-based doublet chemotherapy is used as second-line therapy. Here we report the results of a retrospective biomarker analysis of plasma circulating free, tumor-derived DNA (ctDNA) from patients in IMPRESS, including T790M profiling, to help understand the IMPRESS clinical trial outcome.
Methods:
Plasma samples for ctDNA isolation were collected at baseline and discontinuation from 151 randomized, non-Chinese patients in IMPRESS (58% of overall IMPRESS population). ctDNA levels of T790M, L858R, and Exon19 deletions were detected using both a quantitative emulsion (BEAMing) digital PCR assay (Sysmex[®]) and a qualitative QIAGEN[®] Therascreen ARMS assay (baseline only). Local EGFR tumor tissue (diagnostic) results were available for 133/151 patients. Mutation concordance rates between tissue and baseline plasma results, and comparisons between the two plasma detection methods, were calculated.
Results:
Baseline ctDNA EGFR mutation results were obtained for >99% (150/151) of patients. Using BEAMing, sensitivity and specificity between baseline plasma EGFR sensitizing mutations and local EGFR tumor tests were 78% (69/89) and 98% (42/43), respectively, for Exon19 deletions, and 82% (31/38) and 97% (91/94) for L858R. The T790M detection rate in baseline plasma samples using BEAMing was 56% (84/150). The Therascreen ARMS assay demonstrated a significantly reduced T790M detection rate of 13% (20/150). Likewise, the sensitivity of the Therascreen ARMS assay with respect to tissue for EGFR sensitizing mutations was also reduced compared with BEAMing: Exon 19: 54% (48/89), L858R: 47% (18/38), though the specificity remained near 100%. In the 97 evaluable plasma samples collected at discontinuation, T790M was detected by BEAMing in 52% (50/97) of patients. When compared with matched baseline plasma, 11 patients had newly acquired T790M mutation at discontinuation while T790M reverted to undetectable in 14 patients. Full plasma profiling data from the complete IMPRESS clinical study population (including 108 patients from China) and correlative analyses of plasma EGFR mutation status with clinical outcome (progression-free survival, overall survival, objective response rate) will be presented.
Conclusion:
In IMPRESS, T790M was detectable with BEAMing digital PCR in the baseline ctDNA samples of 56% of evaluable patients, a rate comparable to similar mutation analyses in this same second-line, EGFR-TKI-failed setting. EGFR mutation detection in plasma using the Therascreen ARMS assay demonstrated comparable specificity to BEAMing but reduced sensitivity. The T790M detection rate afforded by the BEAMing technology will allow for a comprehensive assessment of correlations between clinical outcome in IMPRESS and EGFR mutational status.
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ORAL 17 - EGFR Mutant Lung Cancer (ID 116)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:P. Meldgaard, E. Felip
- Coordinates: 9/08/2015, 10:45 - 12:15, Four Seasons Ballroom F3+F4
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ORAL17.08 - Gefitinib/Chemotherapy vs Chemotherapy in EGFR Mutation-Positive NSCLC Resistant to First-Line Gefitinib: IMPRESS T790M Subgroup Analysis (ID 3287)
12:01 - 12:12 | Author(s): S. Kim
- Abstract
- Presentation
Background:
Exon 20 T790M mutation is the most common cause of acquired resistance to first-line epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs). The IMPRESS study (NCT01544179; Phase III, double-blind IRESSA[TM ]Mutation Positive Multicentre Treatment Beyond ProgRESsion Study; Lancet Oncology: in press) reported no statistically significant difference in progression-free survival (PFS; primary endpoint) between gefitinib plus cisplatin/pemetrexed (cis/pem) (G) vs placebo plus cis/pem (P) in patients with acquired resistance to first-line gefitinib (hazard ratio [HR] 0.86; 95% confidence interval [CI] 0.65–1.13; p=0.273; median PFS 5.4 months in both arms) and other secondary endpoints. Among the subgroup analyses performed for IMPRESS, the most noticeable difference was observed by T790M status as tested via plasma circulating free tumor-derived DNA (ctDNA).
Methods:
Patients (age ≥18 years [Japan ≥20 years], chemotherapy-naïve, locally advanced/metastatic NSCLC with an activating EGFR mutation, prior disease progression on first-line gefitinib) from 71 centers (Europe/Asia Pacific) were randomized to G or P (gefitinib 250 mg/day or placebo, plus cis 75 mg/m[2]/pem 500 mg/m[2]). For biomarker analysis, consenting randomized patients provided 10-mL blood samples (at Visit 1 [baseline], 4, 6; then every 6 weeks and at discontinuation) from which to obtain ctDNA. ctDNA levels of EGFR mutations, including T790M, were detected using a quantitative emulsion (BEAMing) digital PCR assay (Sysmex[®]) conducted at a central laboratory (positivity defined as ≥0.02% mutant DNA fraction).
Results:
Data are reported for plasma samples from baseline visits (serial data will be available in the future). Blood samples were available for all 261 randomized patients, of whom T790M status was known for 247 (93.2%): T790M mutation-positive n=142 (57.5%; G=81, P=61) and T790M mutation negative n=105 (42.5%; G=46, P=59). Median PFS for the T790M mutation-positive subgroup was 4.6 vs 5.3 months for G and P, respectively (HR 0.97, 95% CI 0.67 to 1.42, p=0.8829). Median PFS for the T790M mutation-negative subgroup was 6.7 vs 5.4 months for G and P, respectively (HR 0.67, 95% CI 0.43 to 1.03, p=0.0745). See Table for additional study endpoints.
Conclusion:
Following acquired resistance to first-line gefitinib, these data suggest there were two distinct patient populations defined by T790M genotype. For plasma T790M-positive, gefitinib should not be continued when platinum-based doublet chemotherapy is used as second-line therapy. For plasma T790M-negative, continuation of gefitinib in combination with platinum-based doublet chemotherapy may offer clinical benefit, which would require further confirmation in a prospective randomized study.IMPRESS subgroup populations (plasma) T790M mutation-positive N=142 T790M mutation-negative N=105 ORR, % (G vs P) 28.4 vs 39.3 p=0.282 37.0 vs 27.1 p=0.171 DCR, % (G vs P) 81.5 vs 77.0 p=0.5175 93.5 vs 83.1 p=0.0895 OS, HR (95% CI)* 2.16 (1.26, 3.82) p=0.0067 0.83 (0.36, 1.85) p=0.6644 Plasma BEAMing PCR (compared with tumor), % (n/N) Exon 19 Deletions L858R Sensitivity 73.8 (124/168) 81.6 (62/76) Specificity 96.7 (89/92) 95.3 (161/169) Concordance 81.9 (213/260) 91.0 (224/247) *OS immature, follow up ongoing G: gefitinib plus cisplatin/pemetrexed; P: placebo plus cisplatin/pemetrexed ORR, objective response rate; DCR, disease control rate; OS, overall survival
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P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.01-064 - A Phase II Study of Gemcitabine-Cisplatin plus Necitumumab for Stage IV Sq-NSCLC (ID 927)
09:30 - 09:30 | Author(s): S. Kim
- Abstract
Background:
To report the efficacy and safety results from a study of necitumumab (N), manufactured under process D, modified from Process C, used in the pivotal SQUIRE study, in combination with gemcitabine (G) plus cisplatin (C) as first-line treatment in patients with advanced squamous non-small cell lung cancer (Sq-NSCLC). (NCT01788566)
Methods:
This was an open-label, single-arm, multicenter, phase II study in patients with advanced Sq-NSCLC. Patients were enrolled who were aged ≥18 years and had measurable, pathologically confirmed stage IV Sq-NSCLC without prior chemotherapy. Patients had ECOG-PS 0-1, adequate organ function, and life expectancy of ≥12 weeks. Patients received N (800 mg iv, Days 1 and 8) plus GC (G=1250 mg/m² iv, Days 1 and 8; C=75 mg/m² iv, Day 1) each 3-week cycle for up to 6 cycles. Patients with at least stable disease (SD) could continue to receive N alone until progressive disease (PD) or other discontinuation criteria. Primary endpoint was objective response rate (ORR) based on RECIST1.1. Secondary endpoints included overall survival (OS), progression-free survival (PFS), disease control rate (DCR), change in tumor size (CTS; % improvement in lesions), and safety.
Results:
Patients (N=61), median age 65 years, heavy metastatic disease burden; approximately 70% of the patients had metastases to ≥ 2 organ systems. Efficacy results, including an ORR of 48.1% are shown in the Table. Survival and PFS findings were similar to those reported in the SQUIRE study in the GC+N arm (SQUIRE results: median OS of 11.5 months, 1-year survival rate of 47.7%, and median PFS of 5.7 months). Median duration of treatment was 12 weeks (4 cycles) for G and C and 16 weeks (5 cycles) for N; the median relative dose intensity was 85% for G and 93% for C and N. Twenty-eight (46%) patients continued on single-agent N (median: 4 cycles). Skin reactions (n=49; 80.3%) and hypomagnesemia (n=21; 34.4%) were the most commonly reported adverse events of special interest (AESIs, all grades). AESI ≥ Grade 3 were skin reactions (n=8; 13.1%), thromboembolic events (n=7; 11.5%), hypomagnesemia (n=6; 9.8%), and hypersensitivity/ IRR (n=3; 4.9%). There were 27 deaths (20 due to PD and 7 due to AEs [5 had no causal relationship to study drug]) at the time of data cut-off.Table. Efficacy Results
N=61 ORR*† (CR+PR), n (%) [95% CI] 26/54 (48.1)† [34.34–62.16] CR 0 PR, n (%) 26/54 (48.1)† SD 18 (29.5) PD 9 (14.8) Not evaluable 1 (1.6) Not assessable 7 (11.5) DCR CR+PR+SD, n (%) [95% CI] 44 (81.5)† [68.57–90.75] Median OS, months (95% CI) 11.7 [7.59–NA] 1-year survival rate, % (95% CI) 47.6% [30.20–63.08] Median PFS, months (95% CI) 5.6 [3.68–6.87] Median CTS, (%) 42.1 *Assessed by investigators †Patients who had a post-baseline radiological assessment, n=54
Conclusion:
The efficacy results and the safety profile, with N manufactured under process D, are consistent with what is expected for this combination as first-line therapy of patients with metastatic Sq-NSCLC.
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P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.01-012 - Clinical Implications of Isolated Bone Failure without Systemic Disease Progression During EGFR-TKI Treatment (ID 1201)
09:30 - 09:30 | Author(s): S. Kim
- Abstract
Background:
Bone metastasis and skeletal-related events (SREs) such as pathologic fracture and spinal cord compression are common in advanced lung cancer. This study was aimed to investigate the characteristics of disease progression focused on SREs during EGFR-TKI treatment.
Methods:
We retrospectively reviewed the medical records of 3,085 Korean patients with advanced non-small cell lung cancer who were treated with gefitinib or erlotinib between 2004 and 2014. SRE associated with aggravation of bone metastasis was termed ‘bone failure (BF)’. BFs were classified into 2 categories according to the presence of accompanying disease progression of preexisting cancer lesions in extra-skeletal organs; isolated bone failure (IBF) versus non-IBF.
Results:
The incidence of SREs during EGFR-TKI treatment was 4.7% (146/3085). Among them, 60 patients experienced IBF without aggravation of disease in extra-skeletal organs. IBF was more frequent in clinical benefit group (responders and stable ≥ 6 months) than in non-clinical benefit group (53.5% vs 13.3%; P < 0.001). Adenocarcinoma histology and clinical benefit from EGFR-TKI were independent risk factors for IBF (adenocarcinoma: adjusted hazard ratio [HR] 10.283; 95% confidence interval [CI] 1.148 – 92.121; P= 0.037, clinical benefit from TKI: adjusted HR 9.463; 95% CI 3.027 – 29.584; P < 0.001). The time from the start of EGFR-TKI to the occurrence of SRE was significantly longer in IBF than that in non-IBF (9.8 vs 5.2 months; P= 0.054). Moreover, patients with IBF exhibited longer survival time from the initiation of TKI (20.1 vs 7.7 months; P = 0.008) and from the occurrence of SRE (9.2 vs 1.9 months; P = 0.006). Multivariate analysis showed that IBF was one of independent prognostic factors for better survival although the statistical significance was marginal (adjusted HR 0.492; 95% CI 0.237 – 1.021; P = 0.057).
Conclusion:
IBF without systemic disease progression frequently occurs in patients with clinical benefits from EGFR-TKI treatment and shows the better survival requiring more active 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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P3.01-077 - A Randomized, Phase II Study of Nimotuzumab Plus Gefitinib vs Gefitinib in Advanced Non-Small Cell Lung Cancer After Platinum- Based Chemotherapy (ID 1176)
09:30 - 09:30 | Author(s): S. Kim
- Abstract
Background:
Nimotuzumab is a humanized anti-epidermal growth factor receptor (EGFR) monoclonal antibody. We aim to evaluate the efficacy of dual inhibition of EGFR with nimotuzumab plus gefitinib in advanced non-small cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy.
Methods:
An open label, randomized, phase II trial was conducted in 6 centers; 160 patients were randomized (1:1) to either nimotuzumab (200mg, IV weekly) plus gefitinib (250mg p.o. daily) or gefitinib alone until disease progression or intolerable toxicities. The primary endpoint was progression free survival (PFS) rate at 3 months. Secondary endpoints included PFS, overall survival (OS), overall response rate (ORR) and safety.
Results:
A total of 155 patients (78 in nimotuzumab plus gefitinib, 77 in gefitinib) were evaluable for efficacy and toxicity. Patient characteristics were well balanced in both groups. Majority of patients had adenocarcinoma histology (65.2%) and ECOG performance status 0 to 1 (83.5%). Among 102 patients with EGFR mutation results available, activating EGFR mutation was documented in 27 patients (12/50 in nimotuzumab plus gefitinib, 15/52 in gefitinib). With a median follow-up of 12.1 months, PFS rate at 3 months was 37.2% in nimotuzumab plus gefitinib and 48.1% in gefitinib [HR 1.03; 95% CI, 0.71–1.40; P=0.98]. Median PFS and OS were 2.0 months and 14.0 months in nimotuzumab plus gefitinib and 2.8 months and 13.2 months in gefitinib [HR 1.03, 95% CI 0.71-1.41, P=0.98 for PFS; HR 0.86, 95% CI 0.57–1.30, P=0.47 for OS]. The ORRs were 14.1% in nimotuzumab plus gefitinib and 22.1% in gefitinib, which was not statistically significant (P=0.76). As expected, patients with EGFR mutation showed significantly longer survival than those with wild-type EGFR or unknown EGFR mutation status (10.3 vs. 1.2 vs. 2.7 months, P < 0.001 for PFS; 23.5 vs. 13.5 vs. 10.5 months, P= 0.001 for OS). Combined treatment of nimotuzumab plus gefitinib did not show superior PFS compared to gefitinib alone in patients with EGFR mutation (13.5 vs. 10.2 months in gefitinib alone, P=0.30) and patients with wild-type EGFR (0.9 vs. 2.0 months in gefitinib alone, P=0.90). The median PFS was not significantly different between two treatment arms according to histology (2.8 vs. 2.9 months in gefitinib alone for adenocarcinoma, P=0.64; 1.2 vs. 2.8 months in gefitinib alone for non-adenocarcinoma, P=0.35). Adverse events (AEs) in both treatment arms were mostly grade 1 to 2 and easily manageable. Importantly, combined EGFR inhibition with nimotuzumab and gefitinib did not increase EGFR inhibition-related AEs, such as acneiform rash (32.4 vs. 30.3% in gefitinib alone, P=0.38), diarrhea (30.7 vs. 35.7% in gefitinib alone, P=0.32), and stomatitis (11.5 vs. 13.4% in gefitinib alone, P=0.19). There was no treatment-related death.
Conclusion:
The dual inhibition of EGFR with nimotuzumab plus gefitinib did not show superiority over gefitinib alone for second-line treatment of advanced NSCLC (NCT01498562).
