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P. Meldgaard
Moderator of
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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: 9
- Moderators:P. Meldgaard, E. Felip
- Coordinates: 9/08/2015, 10:45 - 12:15, Four Seasons Ballroom F3+F4
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ORAL17.01 - First-Line Icotinib Versus Cisplatine/Pemetrexed Plus Pemetrexed Maintenance in Advanced NSCLC Patients with EGFR Mutation (ID 742)
10:45 - 12:15 | Author(s): Y. Shi, L. Wang, B. Han, W. Li, P. Yu, Y. Liu, C. Ding, X. Song, Z. Ma, X. Ren, J. Feng, H. Zhang, G. Chen, N. Wu, X. Han, C. Yao, Y. Song, S. Zhang, L. Ding, F. Tan
- Abstract
- Presentation
Background:
Clinical studies with anti-EGFR agents demonstrate that EGFR TKIs play critical roles in the treatment of non-small cell lung cancer, especially in patients with positive EGFR mutation. Icotinib is an oral, selective EGFR TKIs. Phase 3 study showed that icotinib is non-inferior to gefitinib in treating unselected or EGFR-mutated advanced NSCLC patients as second-line therapy but better safety profile, which provide a rationale to examine icotinib in first-line setting. The objective of this study is to evaluate progression-free survival (PFS), overall survival (OS) and safety of icotinib in chemotherapy naïve NSCLC patients with EGFR mutation.
Methods:
In this phase 3, open-label, randomized study (CONVINCE, NCT01719536), 285 patients (pathologically confirmed NSCLC, positive 19/21 EGFR mutation, treatment naive) will be 1:1 randomized to receive oral icotinib (125 mg, three times daily) or cisplatine (intravenous [IV], 75 mg/m2, day 1) plus pemetrexed (IV, 500 mg/m2, day 1), patients achieving disease control after 4-cycle chemotherapy continue to receive single pemetrexed (IV, 500 mg/m2, day 1) as maintenance therapy until progression. Randomization will be stratified by performance status (0-1/2), smoking status (smoker/non-smoker), disease stage (IIIB/IV), and mutation type (19/21). A total of 228 events would provide 90% power to detect an HR for PFS of 1 at 2-sided significance level of 0.05. Response will be reviewed by both investigator and independent data monitoring committee using Response Evaluation Criteria In Solid Tumors (RECIST version 1.1). Progression Between January, 2013 and August, 2014, 285 patients were randomized and treated at 18 centers from 13 cities in China. The data cut-off was planned at October, 2015 when 228 PFS events were observed in full analysis set (80% maturity). Final results were expected on December, 2015.
Results:
Not applicable
Conclusion:
Not applicable.
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ORAL17.02 - Randomized Trial of Gefitinib with and without Pemetrexed as First-Line Therapy in East-Asian Patients with Advanced NS NSCLC with EGFR Mutations (ID 1319)
10:45 - 12:15 | Author(s): Y. Cheng, H. Murakami, P. Yang, J. He, K. Nakagawa, J.H. Kang, J. Kim, T. Puri, M. Orlando, X. Wang, S. Enatsu, J.C. Yang
- Abstract
- Presentation
Background:
Pemetrexed (P) is the standard of care for non-squamous non-small cell lung cancer (NS NSCLC), whereas epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib (G), are the standard of care for advanced NSCLC with EGFR mutations. Clinical and nonclinical studies have demonstrated synergistic effects of EGFR TKIs and P. Based on these observations, the efficacy and safety of G+P was compared with G monotherapy in patients with NS NSCLC positive for activating EGFR mutations.
Methods:
The primary objective of this randomized, multicenter, open-label, parallel-arm, phase 2 East-Asian study was to assess whether G+P prolongs progression-free survival (PFS) versus G alone. Secondary endpoints included overall survival (OS), overall response rate, disease control rate, time to progressive disease, duration of response, and treatment-emergent adverse events (TEAEs). Eligible patients had stage IV NS NSCLC with activating EGFR mutations, were chemonaïve, and had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1. Patients were randomized in a 2:1 ratio (G+P:G). Dosing schedule was concurrent G (250 mg/day) and P (500 mg/m[2] every 3 weeks) in the G+P arm and G monotherapy (250 mg/day) in the G arm. Treatment continued until progression or unacceptable toxicity. The primary endpoint was analyzed after 144 events, which provided 70% power at a 1-sided 20% significance level, assuming a true hazard ratio (HR) of 0.79.
Results:
Between February 2012 and August 2013, 191 patients were randomized and treated (G+P: N=126; G: N=65). Patients were mostly female (64.4%) with a mean age of 62 years; most were never-smokers (67.0%), had confirmed stage IV disease (84.8%), and ECOG PS of 1 (68.6%). Overall, 55.0% had exon 19 deletions, 39.3% had exon 21 L858R mutations, and 5.8% had other activating EGFR mutations. Baseline characteristics were balanced between treatment arms. Patients in the G+P arm received 96.3% and 92.9% of the planned mean dose of G and P, respectively; patients in the G arm received 97.9% of the planned mean dose of G. Median PFS for G+P (15.8 months) was significantly longer than for G (10.9 months); HR=0.68; 95% confidence interval 0.48, 0.96; 1-sided P=0.014; 2-sided P=0.029. OS data are immature and will be reported at study completion. The incidence of grade 3/4 study drug-related TEAEs was significantly higher for G+P (42.1%) than for G (18.5%); P=0.001. The most common study drug-related TEAEs for G+P were diarrhea (44.4%), aspartate aminotransferase increased (41.3%), and dermatitis acneiform and alanine aminotransferase increased (38.1% for each), and for G were diarrhea (47.7%), dermatitis acneiform (43.1%), and dry skin (35.4%). The proportion of treatment discontinuations due to TEAEs was 16.7% in the G+P arm and 9.2% in the G arm; 2 patients (G+P arm) died due to study drug-related adverse events.
Conclusion:
The combination of G+P led to a significant improvement in PFS compared with G monotherapy for East-Asian patients with EGFR mutation-positive NS NSCLC, and met the primary study endpoint. The incidence of grade 3/4 study drug-related AEs was higher for G+P than for G. ClinicalTrials.gov identifier: NCT01469000.
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ORAL17.03 - Biomarkers for Efficacy in JO25567 Study Evaluating Erlotinib plus Bevacizumab versus Erlotinib in Advanced NSCLC with EGFR Mutation (ID 306)
10:45 - 12:15 | Author(s): S. Atagi, M. Nishio, K. Goto, Y. Hosomi, T. Seto, T. Hida, K. Nakagawa, H. Yoshioka, N. Nogami, M. Maemondo, S. Nagase, I. Okamoto, N. Yamamoto, T. Yamanaka, Y. Igawa, K. Tajima, M. Fukuoka, N. Yamamoto, K. Nishio
- Abstract
- Presentation
Background:
Bevacizumab (B), an anti-vascular endothelial growth factor (VEGF) monoclonal antibody has been proven to provide additional efficacy benefit in combination with platinum-based chemotherapy for 1[st] line therapy of non-squamous non-small cell lung cancer (NSCLC). In JO25567 study, we observed that bevacizumab in combination with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, erlotinib (E) also provided additional 6.3 months median progression free survival (PFS) in advanced EGFR mutation-positive non-squamous NSCLC. To try to understand this additional effect of bevacizumab, we investigated the predictive biomarkers related to angiogenesis comprehensively in JO25567 study. Clnical trials registry number: JapicCTI-111390
Methods:
We evaluated the biomarkers in blood and tissue samples. All samples were collected before E+B or E treatment in JO25567 study. Angiogenesis related ligands and soluble receptors in serum were analyzed by multiplex, bead-based suspension array. Single nucleotide polymorphisms (SNPs) or variable number of tandem repeats (VNTR) of angiogenesis related genes were analyzed by direct sequencing or electrophoresis after PCR for blood sample. VEGF-A concentration in plasma were analyzed by Immunological Multi-Parametric Chip Technique (IMPACT) assay. Messenger RNA of genes related to angiogenesis in tumor tissue were quantitated by multiplex TOF-mass spectrometry (MassARRAY). Immunohistochemistry of neuropilin and exploratory proteomics analysis were planned for surgically resected tumor tissues. PFS were used as an efficacy variable of prediction. Multivariate Fractional Polynomial (MFP) and Subpopulation Treatment Effect Pattern Plot (STEPP) were used for biomarker screening.
Results:
One hundred fifty-two patients were treated with E+B or E in JO25567 study. We analyzed 26 ligands or soluble receptors in 134 serum samples. Follistatin and leptin were identified as potential biomarkers by MFP. The interaction p-value with adjustment of covariates for biomarker and efficacy was 0.0168 for follistatin and 0.0049 for leptin. STEPP suggested that high follistatin related to limited bevacizumab efficacy and low leptin related to higher bevacizumab efficacy. SNPs could be analyzed in 135 blood samples. In 12 SNPs and 1 VNTR of 8 genes, no gene related to bevacizumab efficacy. Plasma samples were collected from 105 patients. Median VEGF-A concentration of E+B group and E group were 18.0 pg/mL and 18.8 pg/mL respectively and was one sixth or more lower than previously reported breast and gastric cancers. Hazard ratio of E+B comparing with E for was 0.23 (95% CI: 0.09-0.60) for low plasma VEGF and was 0.56 (95% CI: 0.26-1.25) for high plasma VEGF. This trend was not consistent with previously reported studies. We analyzed mRNA expression from 24 surgical resected tumors and no predictive value was observed. Because of limited number of surgically resected tumors obtained, we couldn’t proceed exploratory proteomics analysis nor evaluate predictive value of neuropilin expression.
Conclusion:
In this comprehensive predictive biomarker analysis, follistatin and leptin in blood were identified as potential biomarker candidates for E+B therapy.
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ORAL17.04 - Discussant for ORAL17.01, ORAL17.02, ORAL17.03 (ID 3333)
10:45 - 12:15 | Author(s): L.V. Sequist
- Abstract
- Presentation
Abstract not provided
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ORAL17.05 - Clinical Outcomes in Patients with Non-Small-Cell Lung Cancer (NSCLC) Harboring Rare Epidermal Growth Factor Receptor (EGFR) Mutations (ID 534)
10:45 - 12:15 | Author(s): P.M. Domingues, T. Montella, M. Zukin, C. Baldotto, C. Ferreira
- Abstract
- Presentation
Background:
The most described EGFR mutations are deletions in exon-19 and L858R in exon-21. They constitute approximately 50-90% of total EGFR mutations. Their clinical characteristics and sensitivity to EGFR tyrosine kinase inhibitors (EGFR-TKI) are well-known, given that they are described as classic/sensitizing mutations. Recently, despite the lower frequency G719X in exon-18, T790M and insertions in exon-20, and L861Q in exon-21 were described as uncommon EGFR mutations with known clinical significance having distinct features and EGFR-TKI sensitivity. Meanwhile, several other mutations have been reported and characterized as novel mutations. However, the characteristics and clinical benefit of EGFR-TKI in patients with these rare mutations remains unclear. This study aims to describe the epidemiology and the clinical outcomes of patients with rare EGFR mutations.
Methods:
We retrospectively analyzed 287 patients with advanced NSCLC tested for EGFR mutations at the Brazilian National Cancer Institute from May-2011 to May-2014. Del 19 and L858R were described as classic EGFR mutations (CM). All other EGFR mutations, excluding uncommon mutations with known clinical significance (G719X, T790M, insertions in exon-20, and L861Q), were considered rare EGFR mutations (RM). All samples were formalin-fixed paraffin embedded (FFPE). The best response was considered as the best outcome the assistant physician registered in the medical chart. Time for Treatment Failure (TTF) was considered from the beginning of the treatment until suspension by the medical staff. Overall Survival (OS) was measured from diagnosis to death.
Results:
Of the 287 tested patients, 40 (14%) harbored CM, and 32 (11%) had RM. Only 7 patients harbored uncommon mutations with known clinical significance (1 with G719X and 6 with insertions in exon-20). Of the RM, 18 (56%) were women, 22 (69%) were ever-smokers and only 10 (31%) were never-smokers. RM were associated with smoking as compared to CM (p=0.04). OS was increased in the CM patients (26.4 v 13.4 v 13.7 months,p<0.001; for CM, RM and wild-type, respectively). Sixty patients received EGFR-TKI treatment with 17 harboring RM. Of these 17 RM treated patients, 5 received Erlotinib as first-line, 8 as second/third-line, and 4 as maintenance. When EGFR-TKI was started most patients had PS≤2 (89%). The best response documented was stable disease in 4 (24%) cases. All other 13 (76%) cases had progressive disease. Only three patients received Erlotinib for more than 6 months. Median-TTF was 3.4 months. Median-OS was 17.2 months. In seven cases the mutations have never been described before. In the Erlotinib-treated cohort, RM were associated with worse outcomes (TTF: 13.9 v 3.4 v 3.9 months,p<0.001; OS: 62.9 v 17.2 v 25months,p=0.002; for CM, RM and wild-type, respectively).
Conclusion:
Clinical characteristics of rare EGFR mutant patients differ from classic EGFR mutant. Rare EGFR mutations also conferred little clinical benefit and short TTF with EGFR-TKI treatment. The TTF and OS in rare EGFR mutations were similar to EGFR wild-type patients. Thereby, in this subset of patients the indiscriminate use of EGFR-TKI should be abandoned.
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ORAL17.06 - Phase I/II Study of INC280 plus Erlotinib in Patients with MET Expressing Adenocarcinoma of the Lung (ID 1064)
10:45 - 12:15 | Author(s): C.E. McCoach, A.M. Yu, D.R. Gandara, J.W. Riess, T. Li, P. Lara Jr., F. Lara, P.C. Mack, L.A. Beckett, K. Kelly
- Abstract
- Presentation
Background:
MET dysregulation is one mechanism responsible for EGFR-TKI (epidermal growth factor receptor-tyrosine kinase inhibitor) resistance in patients (pts) with EGFR mutated lung cancer. INC280 is a potent oral small molecular inhibitor of the c-MET kinase. We conducted a phase I/II study of INC280 plus erlotinib to determine the maximum tolerated dose (MTD), dose limiting toxicity (DLT), pharmacokinetics (PK) and antitumor activity of this combination. Tumor analysis of the EGFR and MET pathways was exploratory.
Methods:
Using a 3 + 3, dose escalation design, INC280 was increased over 5 dose levels (DL) from 100 - 600 mg po bid. Daily erlotinib was given at 100 mg in DL1 and 150 mg in DL 2- 6. DL 6 is a transition cohort from INC280 capsules (600 mg) to tablets (400 mg). Both agents were given for 28 days (1 cycle). Key eligibility included: lung adenocarcinoma with MET expression by a CLIA certified lab, age > 18, ECOG PS of < 2, acceptable organ function, and > 1 systemic therapy for advanced disease.
Results:
18 pts were treated on 6 dose levels. Pt characteristics: median age 59 (range 52-78), M/F (7/11), ECOG 0-1/2 (16/2), MET expression by IHC/FISH/RT-PCR/NGS (6/2/9/1), EGFR mutated tumors (9) and previously treated with erlotinib (12). 17 patients completed at least 1 cycle. One DLT (grade 3 neutropenia) occurred in DL 5 (Table 1). Common drug-related adverse events (AE) of any grade were rash (50%) and diarrhea (45%), fatigue (39%), anorexia and nausea (28% each) and increased alkaline phosphatase, hypoalbuminemia and paronychia (22% each). Drug-related grade 3/4 AE were anorexia, increased amylase or lipase and neutropenia (all 6%). PK analysis revealed that INC280 exhibited a linear PK and no interaction with erlotinib. Of the 17 evaluable patients, 3 (18%) patients had partial responses, 10 (59%) had stable disease, 3 of whom had a minor response (10-29% decrease in target lesion) (Table 1). Eight pts have received treatment for >3 months. Figure 1
Conclusion:
In patients with MET-expressing lung adenocarcinoma, INC280 plus erlotinib is feasible, tolerable and demonstrates anti-tumor activity. The recommended phase 2 doses are INC280 400 mg (tablets) bid plus erlotinib 150 mg daily. Three expansion cohorts have been initiated: 1 - EGFR mutated tumors refractory to an EGFR-TKI, 2 - EGFR-TKI naïve in the first line setting and 3 - WT EGFR that are EGFR-TKI naïve as second or third line therapy. Updated trial results from the expansion cohorts will be presented. NCT01911507
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ORAL17.07 - Mechanisms of Acquired Resistance to AZD9291 in EGFR T790M Positive Lung Cancer (ID 1365)
10:45 - 12:15 | Author(s): G.R. Oxnard, K. Thress, C. Paweletz, D. Stetson, B. Dougherty, Z. Lai, A. Markovets, E. Felip, A. Vivancos, Y. Kuang, L. Sholl, A.J. Redig, M. Cantarini, J.C. Barrett, R.N. Pillai, B.C. Cho, L. Lacroix, D. Planchard, J.C. Soria, P.A. Jänne
- Abstract
Background:
AZD9291 is an irreversible, mutant-selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) developed to have potency against both EGFR-sensitizing mutations and T790M. In the ongoing Phase I study of AZD9291 (AURA, NCT01802632), the response rate in patients with T790M positive lung cancer with disease progression on previous EGFR-TKI was >60%, with a preliminary median progression-free survival of >10 months. The molecular mechanisms underlying acquired resistance to AZD9291 are currently under investigation.
Methods:
Plasma genotyping was performed on patients from AURA who had progressed on AZD9291 if they had detectable T790M pre-AZD9291, as assessed by tumor or plasma genotyping, and if they had plasma collected at progression available for analysis. Cell-free DNA (cfDNA) was extracted from plasma taken at progression. Droplet digital PCR (ddPCR) was performed for EGFR exon 19 deletions, L858R, T790M, and C797S. For further exploration, next-generation sequencing (NGS) of an amplicon panel was performed on available progression cfDNA. Lastly, targeted NGS was performed on available resistance biopsy specimens.
Results:
Plasma specimens were available following disease progression on AZD9291 from 40 patients with tumors positive for T790M through tumor (33) or plasma genotyping (7). Twenty-six progression cfDNA specimens were positive for an EGFR-sensitizing mutation by ddPCR, and were deemed eligible for initial resistance analysis. Of these, 12 (46%) had no detectable T790M in plasma despite presence of the EGFR-sensitizing mutation, suggesting overgrowth of an alternate resistance mechanism. Seven patients had detectable C797S on ddPCR (27%), all with detectable T790M; of 14 with detectable T790M at resistance, C797S was only detected with EGFR exon 19 deletions (7/9) and not L858R (0/5, p=0.02). Plasma NGS was performed on 12 cases with acquired resistance that were T790M positive pretreatment. Exon 19 deletion/T790M/C797S were detected in four cases, with two of these harboring two different DNA mutations encoding for C797S. One case lost T790M and exhibited HER2 copy number gain (6.3 copies); a tumor biopsy from a separate case underwent aCGH at Institute Gustave Roussy and was also found to have focal HER2 amplification with loss of T790M. Targeted NGS was performed on resistance biopsies from a total of 10 patients from four centers with T790M positive biopsies pre-AZD9291. Six cases maintained T790M, with three harboring exon 19 del/T790M/C797S. In four cases with loss of T790M, one harbored BRAF V600E and one harbored PIK3CA E545K.
Conclusion:
Complementary genomic analysis of plasma and tumor DNA provides insight into the diverse molecular mechanisms of acquired resistance to AZD9291 in EGFR-mutant lung cancer. Our studies show that a majority of cases maintained T790M at resistance, at times acquiring a new C797S mutation in those with EGFR exon 19 deletion. Loss of T790M at progression may be mediated by overgrowth of cells harboring HER2 amplification, BRAF V600E, or PIK3CA mutations. These data highlight the need for investigation of combination therapies to effectively prevent or treat the complexity of drug resistance in EGFR-mutant lung cancer.
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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)
10:45 - 12:15 | Author(s): J. Soria, S. Kim, Y. Wu, K. Nakagawa, J. Yang, M. Ahn, J. Wang, J.C. Yang, Y.-. Lu, S. Atagi, S. Ponce, X. Shi, R. Taylor, H. Jiang, K. Thress, T. Mok
- 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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ORAL17.09 - Discussant for ORAL17.05, ORAL17.06, ORAL17.07, ORAL17.08 (ID 3334)
10:45 - 12:15 | Author(s): T. Mitsudomi
- Abstract
- Presentation
Abstract not provided
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PC 02 - Pro vs Con: Is There a Role for EGFR TKIs in EGFR Mutation Negative Disease? / Pro vs Con: Whole Exome Sequencing vs. Selected Testing (e.g., ALK and EGFR) (ID 48)
- Event: WCLC 2015
- Type: Pro Con
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 4
- Moderators:S. Thongprasert, Y. Wu, P. Meldgaard, K. Syrigos
- Coordinates: 9/08/2015, 14:15 - 15:45, 205+207
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PC02.01 - Is There a Role for EGFR TKIs in EGFR Mutation Negative Disease? - Pro (ID 2030)
14:15 - 15:45 | Author(s): S.A. Laurie
- Abstract
- Presentation
Abstract:
With the dramatic clinical benefit that can be observed using tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) in patients with non-small cell lung cancer (NSCLC) harbouring activating mutations in EGFR, there has understandably been a focus on the use of these agents in this subset of NSCLC. However, EGFR mutation positive NSCLC represents only approximately 10 – 15 % of all non-squamous NSCLC in non-East Asian patients, and a substantial proportion of East Asian patients do not harbour this mutation. Thus, world-wide, the vast majority of those with NSCLC are so-called “wild-type” for EGFR. For these patients, it is clear from randomized clinical trials that the treatment of choice in the first-line metastatic setting is platinum-doublet chemotherapy. Increasing data suggest that chemotherapy may be preferred in the second-line setting. Is there any role for the use of EGFR TKIs in the wild-type population? Randomized data in which an EGFR TKI is compared to placebo in both the maintenance and refractory settings suggest that there may be. NCIC Clinical Trials Group study BR21 [1] which randomized 731 unselected patients to either erlotinib or matching placebo, was designed and conducted prior to the discovery of activating mutations. Patients had received 1 (50 %) or > 2 (50 %) lines of prior therapy; > 90 % had received a platinum-doublet. An improvement in median survival (6.7 versus 4.7 months [HR 0.70, p < 0.001]) was also associated with a quality of life benefit. This benefit was consistent across subgroups, including in the 50 % of patients with non-adenocarcinoma histology. In a separate analysis of ever-smokers with squamous histology, patients highly unlikely to harbour an EGFR mutation, the magnitude of survival benefit was the same as in the overall study population (median 5.6 versus 3.5 months [HR 0.66, p=0.009])[2]. The SATURN trial [3] randomized 889 patients who had not progressed after 4 cycles of platinum-doublet chemotherapy to either erlotinib or placebo. While of debatable clinical relevance, there was a statistically significant one month prolongation of median survival with the use of erlotinib (HR 0.81, p=0.009). A similar effect was observed in the 44 % of patients with known EGFR wild-type status (HR 0.77, p=0.02). In a pre-planned subgroup analysis [4], a greater magnitude of benefit was observed in those patients whose best response to induction chemotherapy was stable disease (median overall survival 11.9 versus 9.6 months [HR 0.72, p=0.002]), with a similar effect noted in those patients with squamous histology (HR 0.67, p=0.01), and those known to be EGFR wild-type (HR 0.65, p=0.004). Maintenance erlotinib has been shown to not negatively impact quality of life [5], and when used in those with stable disease, to be cost effective [6]. Meta-analyses of placebo-controlled trials of EGFR TKIs in the maintenance setting have confirmed a modest progression-free survival benefit in squamous [7] and known wild-type [8] patients. Multiple trials have compared an EGFR TKI to either docetaxel or pemetrexed in the second-line setting. The TAILOR trial [9], the only trial to prospectively determine and enrol only wild-type patients, showed a clear PFS advantage to docetaxel, and a trend towards improved overall survival. However several other trials that enrolled patients who were unselected with regard to EGFR status had a substantial number of wild type patients, and none of these trials demonstrated a difference in overall survival in wild-type patients between an EGFR TKI and chemotherapy. While these were retrospective analyses on only a subset of enrolled patients with available tissue, wild-type patient numbers in many trials approached (and in one exceeded) the number of patients enrolled to TAILOR. Further, unlike other trials, TAILOR prohibited crossover, which may have impacted survival results, particularly for patients with squamous carcinoma in the erlotinib arm. Taken together these trials suggest that a treatment strategy that includes both chemotherapy and an EGFR TKI sequentially, irrespective of order, will lead to a similar length of survival provided patients receive both lines of therapy. In platinum-pretreated patients who are fit it is likely preferred to use chemotherapy and then at progression move on to an EGFR TKI, as the chance of patients receiving both treatments is higher. Additional data to suggest that EGFR TKIs may have activity in wild-type patients comes from several small, randomized phase II trials comparing second-line chemotherapy with the same chemotherapy with intercalated EGFR TKIs. These studies have shown prolonged PFS in patients treated with the combination. What these trials demonstrate is that EGFR TKIs appear to have a modest treatment effect in EGFR wild-type patients. In these days of targeted therapies leading to substantial treatment effects in a variety of tumours with oncogenic drivers, is this magnitude of benefit sufficient? In lung cancer, many other treatments have been adopted for a similar magnitude of benefit. Although objective response rates to EGFR TKIs are low in wild-type patients, they are also low to standard cytotoxic chemotherapies beyond first-line, and it seems possible that there is a larger proportion of patients with stabilization of disease and / or slowing of progression that is clinically relevant. Not all oncologists or patients will feel that a trial is warranted, but an EGFR TKI is a reasonable choice as last-line therapy when the option is no further treatment, or as maintenance treatment in patients with squamous histology following a best response of stable disease to induction platinum-based chemotherapy. EGFR “wild-type” is a heterogeneous, not homogeneous, population, and as with any therapy, only a subgroup of patients will benefit from treatment. However a consistent reproducible biomarker for benefit in the wild-type subgroup has not yet been discovered. EGFR protein expression, gene copy number, Kras status and serum proteomics have all been evaluated with at times conflicting results, due to limited samples and the retrospective nature of the analyses. The development of rash may be a pharmacodynamic predictor of greater efficacy [10]. Additional work is required to determine which wild-type patients may derive benefit from an EGFR TKI, to avoid needless toxicity and improve cost-effectiveness. References 1. Shepherd et al. N Engl J Med 353: 123-132, 2005 2. Clark et al. Clin Lung Cancer 7:389-394, 2006 3. Cappuzzo et al. Lancet Oncol 11:521-529, 2010 4. Coudert et al. Ann Oncol 23:388-394, 2012 5. Juhasz et al. Eur J Cancer 49:1205-1215, 2013 6. Walleser et al. Clinicoeconomics Outcomes Res 4:269-275, 2012 7. Ameratunga et al. Asia-Pacific J Clin Oncol. 10:273-278, 2014 8. Vale et al. Clin Lung Cancer 16:173-182, 2015 9. Garassino et al. Lancet Oncol 14:981-988, 2013 10. Ding et al. Contemp Clin Trials 29:527-536, 2008
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PC02.02 - Is There a Role for EGFR TKIs in EGFR Mutation Negative Disease? - Con (ID 2031)
14:15 - 15:45 | Author(s): L.V. Sequist
- Abstract
- Presentation
Abstract not provided
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PC02.03 - Whole Exome Sequencing vs. Selected Testing (e.g., ALK and EGFR) - Pro (ID 2032)
14:15 - 15:45 | Author(s): I.I. Wistuba
- Abstract
- Presentation
Abstract not provided
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PC02.04 - Whole Exome Sequencing vs. Selected Testing (e.g., ALK and EGFR) - Con (ID 2033)
14:15 - 15:45 | Author(s): Y. Yatabe
- Abstract
- Presentation
Abstract:
Great advantages of next generation sequencing have been published so far, and many new genetic alterations were found with whole genome sequencing. Targeted sequencing using next generation sequencing technique can analyze FFPE small biopsy specimens, but may be equivalent or less than the current selected testing, such as EGFR and ALK testing. Although the targeted sequencing can actually analyze multiple genes, most diagnostic panels include the genes that are frequently altered in cancer generally, thus practically useful genes are limited in terms of lung cancer, such as EGFR, ALK, ROS1, and RET. In contrast, whole exome sequencing is potentially useful, as it can comprehensively examine mRNA expression on tumor cells. In general, mRNA in clinical samples well represents tumor genetic status even with significant dilution with the normal cells, which are less active in transcription. However, it is difficult to perserve high quality RNA with clinical samples, and it is unclear that the whole exome sequencing is constantly clinically applicable for small biopsy specimens. Furthremore, there are some cases that show discrepant results between DNA and RNA based assays. As EGFR transcript is suppressed in SCLC, EGFR mutation cannot be detected with the exome sequencing in SCLC transformed as a resistant mechanism to EGFR-TKI treatment. On the other hand, current selected testing for EGFR and ALK has been confirmed with clinical trials and are adjusted to clinical demands, e.g., short turnaround time and high sensitivity.
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ORAL 37 - Novel Targets (ID 146)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:S.S. Ramalingam, E. Thunnissen
- Coordinates: 9/09/2015, 16:45 - 18:15, Mile High Ballroom 4a-4f
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ORAL37.05 - Prevalence and Clinical Association of MET Gene Amplification in Patients with NSCLC: Results from the ETOP Lungscape Project (ID 444)
16:45 - 18:15 | Author(s): P. Meldgaard
- Abstract
Background:
The reported prevalence of MET gene amplification in non-small cell lung cancer (NSCLC) varies from 0-21% and clinical correlations are emerging slowly. In a well-defined NSCLC cohort of the ETOP Lungscape program, we explore the epidemiology, the natural history of MET amplification and its association with MET overexpression, overall survival (OS), relapse-free survival (RFS) and time to relapse (TTR).
Methods:
Resected stage I-III NSCLC, identified based on the quality of clinical data and FFPE tissue availability, were assessed for MET gene copy number (GCN) and expression analysis using silver in-situ hybridization (SISH) and immunohistochemistry (IHC), respectively, on TMAs (MET and centromere-specific probes; anti total c-MET antibody, clone SP44; Ventana immunostainer). MET amplification was defined as MET/centromere ratio ≥2 with average MET GCN ≥4, high MET GCN at two levels as ≥median CGN and ≥5 (irrespective of amplification) and MET IHC+ as 2+ or 3+ intensity in ≥50% of tumor cells. Sensitivity analysis to define the amplification’s thresholds was also performed. All cases were analysed at participating pathology laboratories using the same protocol, after successful completion of an external quality assurance (EQA) program.
Results:
Currently 2709 patients are included in the Lungscape iBiobank (median follow-up 4.8 years, 53.3% still alive). So far, 1547 (57%) have available results for MET GCN with amplification detected in 72 (4.7%; 95%CI: 3.6%, 5.7%) and high MET GCN (≥5) in 65 (4.2%; 95%CI: 3.2%, 5.2%). The median value of average MET GCN per cell is 2.3. IHC MET expression is available for 1515 (98%) of these cases, 350 (23%) of which are MET IHC positive [170 cases (49%) 3+, 180 (51%) 2+]. The median age, for the cohort of 1547 patients, is 66.2 years, with 32.8% women, and 13.5%, 29.7%, 54% never, current, former smokers, respectively. Stage distribution is: IA 23.6%, IB 24.6%, IIA 17%, IIB 12.1%, IIIA 20.9%, IIIB 1.8%, while 52.7%, are of adenocarcinoma and 40.0% of squamous histology. MET amplification and high MET GCN (≥5) are not significantly associated with any histological tumor characteristics or stage (multiplicity adjusted alpha: 0.005). High MET GCN (≥2.3) is less frequent in current smokers (38.3% vs. 55.6% for former or non-smokers, p<0.001). MET amplification and high MET GCN are significantly associated with IHC MET positivity (p<0.001 in all cases). MET amplification is present in 9.7% of IHC MET+ vs 3.1% of IHC MET- patients and high MET GCN (≥5) in 8.6% of IHC MET+ vs 2.8% of IHC MET- patients. MET amplification ranges from 0 to 16% between centers, while high MET GCN (≥5) and (≥2.3) from 0% to 12%, and 11.8% to 98.9%, respectively. MET amplification and both levels of high MET GCN are not associated with OS, RFS or TTR.
Conclusion:
The preliminary results for this large, predominantly European, multicenter cohort demonstrate that MET amplification assessed by SISH prevails in 4.7% of NSCLC, is associated with strong MET expression, and has no influence on prognosis. The large inter-laboratory variability in GCN despite EQA efforts may highlight a critical challenge of MET SISH analysis in routine practice.
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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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P2.01-017 - Genetic Variations in the EGFR Gene Predicts Outcome in Advanced NSCLC Patients Treated with Erlotinib (ID 812)
09:30 - 17:00 | Author(s): P. Meldgaard
- Abstract
Background:
Genetic variations in the epidermal growth factor receptor (EGFR) gene may alter protein expression or function and influence response to tyrosine kinase inhibitors. This study evaluates the role of genetic polymorphisms in the EGFR gene in advanced non-small cell lung cancer (NSCLC) patients treated with erlotinib. EGFR mutation status was known for all patients.
Methods:
Genotypes for -216G>T, -191C>A and 181946C>T in the EGFR gene were retrospectively evaluated by DNA sequencing and polymerase chain reaction in 354 Caucasian patients with advanced NSCLC. Hundred and seven of the patients had a somatic EGFR mutation, and all patients had been treated with erlotinib. Genotypes were correlated with clinical characteristics and outcome. A multivariate analysis was conducted adjusting for clinical relevant factors, including EGFR mutation status, using Cox proportional hazards model. A subgroup analysis was performed based on the EGFR mutation status.
Results:
Patients harboring at least one variant T allele (CT or TT) at position 181946 had a significantly longer median progression-free survival (PFS) (5.6 versus (vs.) 2.9 months; p =0.032) and overall survival (OS) (8.3 vs. 6.7 months; p=0.032) compared to patients with the CC genotype. The result remained significant in a multivariate analysis; PFS, adjusted hazard ratio (AHR)=0.73 (95% confidence interval (CI): 0.55-0.98); OS, AHR=0.72 (95%CI: 0.54-0.97). Patients carrying -216GT or TT genotypes showed a trend to a better clinical outcome compared to those with the GG genotype. The -216GT or TT and 181946CT or TT combined genotypes showed an even more pronounced association with clinical outcome compared to patients with the -216GG and 181946CC genotype (PFS, AHR=0.66 (95%CI: 0.44-0.98); OS, AHR=0.58 (95%CI: 0.38-0.87)). A subgroup analysis demonstrated that the association might be most relevant in EGFR mutation-positive patients; PFS, AHR=0.27 (95% CI: 0.11-0.68); OS, AHR=0.33 (95% CI: 0.13-0.83).
Conclusion:
A combination of 181946C>T and -216G>T polymorphisms in the EGFR gene seems to be a potential predictor of longer PFS and OS in advanced NSCLC patients treated with erlotinib; especially in EGFR mutation-positive patients. A prospective randomized study is wanted to confirm our data.
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 4
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-003 - Two Methods for Developing in Vitro Erlotinib-Resistant Cell Lines Lead to Distinct RTK Shifts, but Both Result in EMT (ID 928)
09:30 - 17:00 | Author(s): P. Meldgaard
- Abstract
Background:
Several studies have investigated resistance mechanisms underlying acquired erlotinib-resistance in vitro. To mimic the in vivo distribution of the drugs, different approaches such as applying gradually increasing doses of erlotinib to the cells or exposing them to a high fixed concentration of the drug have been used. We demonstrate that two different approaches of developing erlotinib-resistant HCC827 cells results in activation of two distinct RTK bypass-signalling pathways. However, despite these differences both cell lines undergo EMT. Our finding suggests that EMT is a common marker of erlotinib-resistance.
Methods:
Two HCC827 erlotinib-resistant cell lines were established using either gradually increasing doses of erlotinib (0.01 μM – 5 μM) resulting in erlotinib-resistant HCC827ER cells. Alternatively a fixed concentration of 5 μM generated HCC827HD with erlotinib resistance. Growth of the resistant cell lines was investigated using MTS assay in combination with erlotinib, linsitinib and crizotinib. Phospho-RTK arrays (R&D Systems), qPCR and immunofluorescence were used to characterize the cells.
Results:
Phospho-RTK array analysis revealed that the erlotinib-resistant HCC827ER cells had an increased activation of MET, and copy number analysis demonstrated the activation to be caused by a MET amplification. Furthermore, HCC827ER showed growth inhibition when treated with the MET-inhibitor crizotinib. The other type of erlotinib-resistant cells, HCC827HD, had increased activation of IGF1R and also responded to the IGF1R-inhibitor linsitinib. However, a common feature is that both HCC827ER and HCC827HD gained EMT features. HCC827ER showed increased expression SLUG, SNAIL and ZEB1, whereas HCC827HD showed increased SLUG and TWIST expression. To detect the relevance of MET and IGF1R signalling in accordance to EMT in the two cell lines, we treated the HCC827ER cells with the tyrosine kinase inhibitor crizotinib (MET) and the HCC827HD cells with linsitinib (IGF1R). In both cases, we saw a decrease in EMT-marker transcription after the treatment.
Conclusion:
Our study demonstrates that different approaches to developing erlotinib-resistant cell lines can lead to distinct activation of bypass receptor tyrosine kinase signalling pathways. EMT, however, is induced in both types of erlotinib-resistance. This finding indicates that EMT is a common trait of the phenotype of erlotinib-resistant cells. More research needs to be done to establish the functional role of EMT in erlotinib resistance.
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P2.04-035 - Methods for Evaluating Early Response to Erlotinib Treatment Using FDG-PET/CT (ID 2865)
09:30 - 17:00 | Author(s): P. Meldgaard
- Abstract
Background:
Early evaluation of response to treatment with Fluoro-deoxy-glucose-Positron-Emission-Tomograpy-CT (FDG-PET/CT ) is increasing rapidly, but which method is the ideal to use is not clear. In this study early response (1-2 weeks) evaluation was performed using three different methods and compared to clinical response at three months.
Methods:
Forty-three patients with metastatic pulmonary adenocarcinoma had FDG-PET/CT scans performed prior to erlotinib treatment and after 1-2 weeks of treatment. The scans were evaluated by one experienced nuclear medicine specialist. The scans were evaluated by three different methods using Siemens Syngovia software: Visual evaluation, as according to Hicks et al, % change in SULpeak as according to PERCIST 1.0 , and finally calculating the % change in total tumor glycolysis (TLG) proposed in PERCIST 1.0. The early response was compared to response on CT at 12 weeks and to progression free survival (PFS)
Results:
The results are shown in figure 1. Defining response as “not progression” on CT at 12 weeks (10 in total), visual evaluation identifies 6 correctly, and 5 of 33 non-responders as responders. One patient classified as a responder who had a PFS of 0.9 months, had stopped treatment because of side effects. The SULpeak method identifies the same 6 responders correctly, and 3 of 33 non-responders as responders. TLG change identifies 4 responders correctly and 3 of 33 non-responders as responders. Looking at early progression (16 in total) , visual evaluation identified 6 correctly, The SULpeak method identified 4 correctly, the TLG method identified 2 early progressions correctly. Figure 1 Table 1: Response groups by patient, ordered by PFS (in months) as found by the three methods. 1 partial response, 2 stable disease and 3 progression. “true” progression and response values are highlighted in bold. Division lines in bold separates response and early progression from the middle group as according to PFS and CT. * Not Available, ** treatment stopped early because of side effects .
Conclusion:
Visual evaluation identified more responders and patients with early progression during treatment with erlotinib. The more objective method based on calculation of SUV calculations identified less responders as well as less patients with early progression, suggesting a lower sensibility for this method. This suggests that the 40% cut off in % change used in this study (as suggested by Wahl et al in the PERCIST criteria), and perhaps the 30% cut off used for SULpeak change are too high for very early evaluation.
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P2.04-073 - PD-L1 Expression Is Induced by MET in an Erlotinib-Resistant Cell Line with MET Amplification (ID 833)
09:30 - 17:00 | Author(s): P. Meldgaard
- Abstract
Background:
The programmed cell death receptor 1 (PD-1) and its ligand PD-L1 have proved to be of significant importance in lung cancer. Production of PD-L1 helps the cancer cells evade the immune system by inactivating T-cells. Clinical trials investigating the effect of treating lung cancer patients with monoclonal antibodies targeting the PD-L1 and PD-1 shows promising results. Expression of PD-L1 is associated with epidermal growth factor receptor (EGFR) mutational status. Further, expression can be significantly decreased by targeting EGFR with tyrosine kinase inhibitors (TKIs). In vitro studies suggest that this initial regulation of PD-L1 expression by EGFR occurs through the Erk pathway. Though, currently not much is known about expression of PD-L1 when TKI-resistance develops. We have developed erlotinib-resistant cell lines. The resistant cell line gained a MET amplification. We demonstrate that PD-L1 is increases in the resistant cells and that this increment is induced by MET signalling.
Methods:
The lung cancer cell line HCC827 with a deletion in exon 19 in the EGFR gene, was treated with increasing concentrations of erlotinib over 5 months until resistance developed. MET gene amplification in the resistant cells was confirmed by PCR. The resistant cell line was used for studying the effect of EGFR and MET inhibitors on PD-L1 expression.
Results:
The HCC827 erlotinib-resistant (ER) cell line gained a MET gene amplification, as seen in previous studies. In the initial phase of erlotinib treatment the expression of PD-L1 decreases. As the dose increases and resistance starts to develop the expression of PD-L1 increases. Activation of Erk is intact in HCC827ER as compared to the parental HCC827 cell line; most likely due to the activation of MET. When HCC827ER cells are treated with the MET inhibitor crizotinib, expression of PD-L1 decreases. When erlotinib is combined with crizotinib an additional effect on PD-L1 expression is observed. These results indicate that increased PD-L1 expression in erlotinib-resistant cell lines may be caused by activation of Erk through MET signalling.
Conclusion:
Our data demonstrates that Erk-dependent PD-L1 expression is increased in cells with erlotinib resistance caused by MET gene amplification. This mechanism might even be general and include several by-pass resistance mechanisms. Our findings suggest that the role of the PD-L1/PD-1 system should also be studied in erlotinib resistant tumors.
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P2.04-076 - Dynamics of Soluble PD-1 during Treatment with EGFR-TKI in Advanced NSCLC Patients (ID 1186)
09:30 - 17:00 | Author(s): P. Meldgaard
- Abstract
Background:
The programmed cell death receptor-ligand pathway (PD-1/PD-L1) is hijacked by tumors in order to evade immune response. Therapy with monoclonal antibodies against PD-1 or PD-L1 in patients with advanced NSCLC has shown promising results in recent clinical trials. Preclinical studies indicate that the PD-L1 expression on tumor cells, and subsequently the PD-L1/PD-1 interaction, is increased when resistance to EGFR-TKI treatment in EGFR mutated NSCLC tumors occur. A soluble form of PD-1 receptor is present in the blood plasma, and can be detected in healthy individuals and in increased amounts in patients with autoimmune diseases and cancer. The dynamics of soluble PD-1 (sPD-1) during treatment and at the point of resistance to EGFR-TKI treatment is unknown. The aim of the present study is to assess the dynamics in plasma of EGFR mutated circulating tumor DNA and sPD-1 longitudinally during treatment with EGFR-TKI, and to study if the level of sPD-1 will increase at the time of resistance to EGFR-TKI treatment.
Methods:
Consecutive blood samples taken before initiation of treatment with erlotinib, during treatment, and at disease progression while on erlotinib from 20 patients with EGFR wildtype and 20 patients with EGFR mutated advanced NSCLC, has been collected, and will be analyzed. The amount of EGFR mutated circulating tumor DNA (in the EGFR mutated patients) and sPD-1 (all patients) will be detected by use of the Cobas® instrument (RMD) and ELISA (R&D systems), respectively. These results will be described and correlated to the clinico-pathological characteristics of the patients.
Results:
Preliminary results show that sPD-1 can be detected in plasma from lung cancer patients. The final results of the analysis will be presented at the conference.
Conclusion:
The present study is to our knowledge the first to describe the dynamics of soluble PD-1 during EGFR-TKI therapy in both EGFR mutated and EGFR wildtype patients treated with erlotinib. The results will elucidate on the role of sPD-1 as a potential biomarker of resistance to EGFR-TKI therapy. The clinical time point of increased sPD-1 in plasma could indicate a “window of opportunity”, in which these patients could be highly responsive to anti-PD-1 or anti-PD-L1 immunotherapy. Such findings have to be further investigated in prospective clinical trials.
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-009 - Evaluation of RT-PCR Methodology for ALK Assessment in Patients with NSCLC in Europe: Results from the ETOP Lungscape Project (ID 1506)
09:30 - 17:00 | Author(s): P. Meldgaard
- Abstract
Background:
ALK rearrangement is documented in 2%-7% of NSCLC, depending on the population studied and detection method used. Although the reverse transcriptase-polymerase chain reaction (RT-PCR) was the first used and published method, fluorescence in situ hybridization (FISH) has become the primary standard diagnostic method. Recently, immunohistochemistry (IHC) has also proven to be a reproducible, faster and sensitive technique. This is one of the first studies concurrently comparing all three techniques in resected lung adenocarcinomas from the large ETOP Lungscape cohort.
Methods:
95 cases from the ETOP Lungscape iBiobank, selected based on any degree of IHC staining (clone 5A4 antibody, Novocastra, UK), were examined by ALK FISH (Abbott Molecular, Inc.; Blackhall, JCO 2014) and central RT-PCR. For the latter, formalin-fixed, paraffin-embedded (FFPE) unstained slides were collected from participating centers. Slides were de-paraffinized, Toluidine Blue stained, and tumors macro-dissected. Tissue digestion and RNA extraction were performed (Qiagen RNeasy FFPE Kit). Using primers described in the literature covering most of ALK known translocations, RT-PCR (Superscript One-Step RT-PCR with Platinum Taq – 40 loops) was performed, followed by capillary electrophoresis in two separate mixes. Co-amplification of B-actin was done to validate the procedure and RNA quality. All tests were duplicated.
Results:
76 of 95 RT-PCR had adequate RNA quality (B-actin co-amplification present). Among these, 18 were FISH positive, 16 were RT-PCR positive, including EML4-ALK V3a/b in 7, V1 in 5, V2 in one, and undetermined variants in 3 cases. 53 of 54 FISH negative cases were also RT-PCR negative (98%). 15 of 18 FISH positives harbored a translocation by RT-PCR (83%). Among the 4 discrepant cases, 2 FISH+/RT-PCR- cases had IHC H-scores of 180 and 260, and 98.3% and 95% of rearranged cells by FISH, probably corresponding to variants not covered by the RT-PCR. One had an IHC H-score of 5, and 16% cells rearranged on FISH, most probably corresponding to a FISH false positive case. The last had an IHC H-score of 200, 13% rearranged cells by FISH, and, thus is defined as a false negative FISH result. Provided IHC is defined as positive by an H-score above 120, all but one case (H-Score 20, FISH and RT-PCR positive) gave concordant results by a combination of FISH and RT-PCR. Overall, using as true negative or true positive the concordant result of two of the methods, the third method is characterized by high specificity and sensitivity with corresponding values of 100/98/100% and 94/94/89% for IHC/FISH/RT-PCR, respectively.
Conclusion:
RT-PCR is a very good tool for sorting discordant IHC/FISH cases, however, we do not recommend using this technique as single method due to the lower sensitivity of RT-PCR, as not all variants are covered, and also due to the limitations with RNA preservation.
