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R. Perez-Soler
Moderator of
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MA08 - Treatment Monitoring in Advanced NSCLC (ID 386)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 12
- Moderators:R. Perez-Soler, T. Reungwetwattana
- Coordinates: 12/06/2016, 11:00 - 12:30, Lehar 3-4
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MA08.01 - A Highly Sensitive Next-Generation Sequencing Platform for Detection of NSCLC EGFR T790M Mutation in Urine and Plasma (ID 4637)
11:00 - 11:06 | Author(s): H. Wakelee, V. Melnikova, C.A. Karlovich, S.M. Gadgeel, K. Reckamp, J.W. Goldman, D..R. Camidge, M. Pérol, S. Ou, S.V. Liu, H. Yu, M.A. Socinski, T.M. Mekhail, B. Solomon, R. Natale, G.A. Otterson, V. Papadimitrakopoulou, J. Soria, C. Langer, J.W. Neal, D. Despain, S. Yurasov, J. Litten, M. Raponi, M. Erlander, L.V. Sequist
- Abstract
- Presentation
Background:
Non-invasive genotyping of NSCLC patients by circulating tumor (ct)DNA is a promising alternative to tissue biopsies. However, ctDNA EGFR analysis remains challenging in patients with intrathoracic disease, with a reported 26-57% T790M mutation detection rate in plasma (Karlovich et al., Clin Cancer Res 2016; Wakelee et al., ASCO 2016). We investigated whether a mutation enrichment NGS could improve mutation detection in plasma and urine from TIGER-X, a phase 1/2 study of rociletinib in patients with EGFR mutation-positive advanced NSCLC.
Methods:
The therascreen (Qiagen) or cobas (Roche) EGFR test was used for EGFR T790M analysis in tumor biopsies. Urine and plasma were analyzed by trovera mutation enrichment NGS assay (Trovagene).
Results:
Of 174 matched tissue, plasma and urine specimens, 145 (83.3%) were T790M+ by central tissue testing, 142 (81.6%) were T790M+ by plasma, and 139 (79.9%) were T790M+ by urine. Urine and plasma combined identified 165 cases (94.8%) as T790M+. Of 25 cases positive by ctDNA but negative/inadequate by tissue, 16 were double-positive in plasma and urine, unlikely to be false positive (Figure 1). T790M detection rate was higher for extrathoracic (n=119) vs intrathoracic (n=55) disease in plasma (87.4% vs 69.1%, p=0.006) but not urine (81.5% vs 76.4%, p=0.42). Combination of urine and plasma identified T790M in 92.7% of intrathoracic and 95.8% of extrathoracic cases (p=0.47). In T790M+ patients, objective response rate was similar whether T790M mutation was identified by tissue, plasma or urine: 37.4%, 33.1% and 36.6%, respectively. 4 of 9 patients T790M+ by urine but negative by tissue responded, and 2 of 8 patients T790M+ by plasma but negative by tissue responded.
Conclusion:
Mutation enrichment NGS testing by urine and plasma combined identified 94.8% of T790M+ cases. Combination of urine and plasma may be considered before tissue testing in EGFR TKI resistant NSCLC, including patients without extrathoracic metastases. Figure 1
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MA08.02 - Clinical Research Platform into Molecular Testing, Treatment, Outcome (CRISP): A Prospective German Registry in Stage IV NSCLC AIO-TRK-0315 (ID 5911)
11:06 - 11:12 | Author(s): F. Griesinger, W. Eberhardt, N. Marschner, M. Jänicke, A. Hipper, A. Karatas, M. Sebastian, M. Thomas, P. Schirmacher
- Abstract
- Presentation
Background:
Treatment in non-small cell lung cancer is quickly evolving and new agents make it to the routine practice at a rapid pace. Whether outcome and PRO data generated in clinical trials with often narrow inclusion and exclusion criteria will hold up in the routine practice is of high interest, especially due to the increasing costs of new drugs. Therefore registry data are of ever increasing importance to patients, physicians and reimbursement institutions.
Methods:
Therefore, we have started a prospective, clinical registry for patients with metastatic non-small cell lung cancer. The purpose of CRISP is to set up a national clinical research platform to document representative data on molecular testing, sequences of systemic therapies and other treatment modalities, course of disease in patients with advanced or metastatic NSCLC in Germany not amenable to curative treatment. A particular focus is on molecular biomarker testing of patients before the start of first-line treatment. The data shall be used to assess the current state of care and to develop recommendations concerning topics that could be improved. PRO assessment will provide large-scale data on quality of life and anxiety/depression for real-life patients in routine practice. In addition, two questionnaires (concerning individual quality of life and patient-caregiver communication) will be validated in German patients with metastatic NSCLC. Furthermore CRISP will set up a decentral tissue annotation for future collaborative, investigational scientific biomarker testing.
Results:
This study will be carried out in up to 150 representative cancer centers in all therapeutic sectors in Germany. More than 8000 patients will be recruited and followed up to a maximum of 3 years, respectively until death. The first patients have been included as of December 2015. As of yet, 82 centers have been initiated, 211 patients have been recruited. Preliminary data will be presented at the meeting in terms of molecular test rates, demographic data as well as treatment stratification in the 1[st] line setting.
Conclusion:
The registry CRISP will be the first to present representative real life data, covering all treatment settings of patients with NSCLC in Germany. ClinicalTrials.gov Identifier: NCT02622581 CRISP is supported by Grants from AstraZeneca GmbH, Boehringer Ingelheim Pharma GmbH & Co. KG, Bristol-Myers Squibb GmbH & Co. KGaA, Celgene GmbH, MSD Sharp & Dohme GmbH, Novartis Pharma GmbH, and Pfizer Pharma GmbH.
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MA08.03 - Osimertinib vs Platinum-Pemetrexed for T790M-Mutation Positive Advanced NSCLC (AURA3): Plasma ctDNA Analysis (ID 4733)
11:12 - 11:18 | Author(s): Y.-. Wu, S. Jenkins, S.S. Ramalingam, J. Han, A. Delmonte, T. Hsia, J. Laskin, S. Kim, Y. He, S. Patel, R. Hodge, M. Marotti, V. Papadimitrakopoulou, T. Mok
- Abstract
- Presentation
Background:
AURA3 (NCT02151981) is a Phase III, open-label, randomised study assessing the efficacy and safety of osimertinib, a T790M directed EGFR-TKI, vs platinum-based doublet chemotherapy in patients with EGFR T790M-positive advanced NSCLC, whose tumours progressed on previous EGFR-TKI therapy. Concordance between plasma and tissue testing, and efficacy outcomes by baseline plasma T790M status, were evaluated.
Methods:
Eligible patients were randomised 2:1 to osimertinib 80 mg orally once daily or platinum-pemetrexed (pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 or carboplatin AUC5) every three weeks for up to six cycles. Patients were tumour tissue T790M-positive (by cobas[®] EGFR Mutation Test v2) from a biopsy after disease progression prior to study entry. Blood samples were taken at baseline for retrospective analysis of T790M mutation status by plasma ctDNA using the cobas[®] EGFR Mutation Test v2.
Results:
Concordance data are reported in the table. Within the intent-to-treat (ITT) population (n=419), patients plasma T790M-positive and randomised to treatment (n=172) had markedly improved progression-free survival (PFS) by investigator assessment (IA) with osimertinib vs platinum-pemetrexed: hazard ratio 0.42 (95% CI: 0.29, 0.61); median 8.2 vs 4.2 months. Objective response rate (ORR) by IA was also distinctly improved with osimertinib vs platinum-pemetrexed: 77% vs 39% (odds ratio 4.96 [95% CI: 2.49, 10.15]; p<0.001). This is consistent with the ITT population: PFS hazard ratio 0.30 (95% CI: 0.23, 0.41); p<0.001 (median 10.1 vs 4.4 months); ORR 71% vs 31% (odds ratio 5.39 [95% CI: 3.47, 8.48]; p<0.001). Figure 1
Conclusion:
In plasma T790M-positive patients the clinical benefit of osimertinib was superior to platinum-pemetrexed, consistent with the ITT T790M-positive population selected by tumour tissue test. PFS with osimertinib was similar regardless of selection by tissue or plasma T790M-positive status. Based on these, and AURA Phase II data, routine biopsy testing is recommended for patients with a plasma T790M-negative test where feasible.
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MA08.04 - Discussant for MA08.01, MA08.02, MA08.03 (ID 6975)
11:18 - 11:30 | Author(s): B. Han
- Abstract
- Presentation
Abstract not provided
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MA08.05 - Depth of Response to First-Line EGFR TKI Does Not Predict Survival in EGFR-Mutated NSCLC Patients (ID 4834)
11:30 - 11:36 | Author(s): T. Wu, E.H. Hsiue, J. Lee, J.C. Yang
- Abstract
- Presentation
Background:
The association between depth of response to EGFR TKI and prognosis of EGFR-mutated NSCLC remains unclear. We aimed to assess the correlation between maximal tumor shrinkage and survival in patients treated with gefitinib and afatinib.
Methods:
Patients with advanced EGFR-mutated NSCLC enrolled in first-line gefitinib and afatinib clinical trials between 2005 and 2014 at the National Taiwan University Hospital were reviewed. Patients who had at least one measurable target lesion that shrank during treatment were included. Overall survival (OS) was defined as time from date of enrollment to death or May 30[th], 2016. Correlation between tumor shrinkage and OS was analyzed by Pearson correlation coefficient and Kaplan-Meier method. The influence of high maximal tumor shrinkage (defined as ≥50% tumor shrinkage), age, gender, types of EGFR mutation, central nervous system (CNS) involvement at diagnosis, CNS as site of progression, first-line EGFR TKI (gefitinib or afatinib), and subsequent treatments (chemotherapy, third-generation TKI) on OS was evaluated by a multivariate Cox proportional hazard model.
Results:
A total of 189 trial patients were screened and 91 patients were eligible for analysis (gefitinib n=42, afatinib n=49). The median maximal tumor shrinkage during first-line EGFR TKI treatment was 53% (interquartile range 30.5%). Maximal tumor shrinkage did not correlate with OS in all patients (R[2]=0.0225, p=0.169), and either the gefitinib (R[2]=0.0036, p=0.689) or afatinib (R[2]=0.0625, p=0.085) group (Fig.1A). High maximal tumor shrinkage also did not significantly affect OS (HR 0.86, 95% CI 0.54-1.40, p=0.564) (Fig. 1B). In multivariate analysis, CNS as site of progression (HR 2.96, 95% CI 1.39-6.29, p=0.005) and first-line afatinib (HR 0.51, 95% CI 0.29-0.91, p=0.022) were the only factors that significantly influenced OS.Figure 1
Conclusion:
The depth of response to first-line gefitinib and afatinib was not predictive of OS in patients with EGFR-mutated NSCLC.
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MA08.06 - Impact of Depth of Response (DpR) on Survival in Patients with Advanced NSCLC Treated with First-Line Chemotherapy (ID 4460)
11:36 - 11:42 | Author(s): D. Morgensztern, M. O'Brien, T.J. Ong, M.A. Socinski, P.E. Postmus, A. Ko
- Abstract
- Presentation
Background:
DpR, defined as maximum tumor shrinkage, has emerged as a potential predictor for long-term treatment outcome across multiple tumors, including NSCLC treated with immunotherapy or targeted therapy. This exploratory analysis evaluated whether DpR correlated with survival in patients with advanced NSCLC treated with platinum-doublet chemotherapy in a phase III randomized clinical trial.
Methods:
Patients received first-line nab-paclitaxel 100 mg/m[2] weekly or paclitaxel 200 mg/m[2] q3w, both + carboplatin AUC 6 q3w. The current analysis evaluated DpR as best percent change from baseline in total target lesion length during treatment. For patients with tumor shrinkage, data were grouped into quartiles based on maximum percent shrinkage from baseline (Q1: > 0%-≤ 25%; Q2: > 25%-≤ 50%; Q3: > 50%-≤ 75%, Q4: > 75%) and compared with data from patients with no change or tumor growth (NC/G).
Results:
Tumor measurement by independent review (baseline and postbaseline) was evaluable in 959 patients pooled across treatments. The median (Figure) and 1-year OS increased with each quartile vs NC/G (NC/G: 4.8 months and 17%; Q1: 10.4 months and 44%; Q2: 14.5 months and 62%; Q3: 19.3 months and 71%; Q4: 23.5 months and 70%) with HRs for OS vs NC/G of 0.42 for Q1 (95% CI, 0.33-0.53; P < 0.0001), 0.28 for Q2 (0.22-0.36; P < 0.0001), 0.23 for Q3 (0.16-0.31; P < 0.0001), and 0.19 for Q4 (0.11-0.33; P < 0.0001), respectively. Similar findings were observed for all quartiles vs NC/G for age (≥ 70 and < 70 years) and histology (squamous and nonsquamous) in subset analyses (P < 0.05 for all comparisons).
Conclusion:
DpR was associated with increased OS in patients with advanced NSCLC receiving first-line platinum-based doublet chemotherapy, regardless of age or histology. These findings underscore the importance of evaluating quality of treatment response in this patient population.Figure 1
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- Abstract
- Presentation
Background:
Circulating tumor cells (CTCs) have been reported prognostic and predictive in non-small cell lung cancer (NSCLC) and a few of other cancer types. In 1[st] line setting, whether EPCAM[+]CK[+]CD45[-] CTC and/or stem cell-like cKIT[+]EPCAM[+ ]CK[+]CD45[-] CTC enumeration and dynamic changes can be prognostic and/or predictive to standard chemotherapy need further investigation in Chinese patients with NSCLC.
Methods:
A prospective study on the CTC enumeration in advanced NSCLC with 1st line chemotherapy (POLICE) was started by China Thoracic Oncology Group (CTONG). Patients with NSCLC naïve for systemic regimens were enrolled since August 2013. CTCs were detected by Cell Search Platform and identified as positive for EPCAM[+]CK[+]CD45[-] phenotype. CD117 (cKIT) marker was added to test the frequency of stem cell-like cKIT[+]EPCAM[+]CK[+]CD45[- ]CTCs. Primary endpoints were CTC counts and its correlation with first line therapy.
Results:
Totally 180 patients were enrolled. In 174 case total CTC and cKIT[+]CTC positive (cutoff >=1) rates were 38.5% (67/172) vs 14.3% (24/168), 21.8% (31/142) vs 6.3% (9/142), 13.7% (13/95) vs 6.4% (6/94) and 40.4% (38/94) vs 15.0% (13/93) at time-points of baseline, after first-cycle-chemo, after four-cycles-chemo and disease progression. At time immediately after first-cycle-chemo, patients in CTC=0 group got statistically higher ORR (29.0% VS 7.1%, P=0.017) and DCR (74.2% VS 42.9%, P=0.002) than in CTC>=1 group. At time after four-cycles-chemo, patients in CTC=0 group got statistically higher DCR (88.3% VS 58.3%, P=0.026) than in CTC>=1 group. At time either after first-cycle-chemo or after four-cycles-chemo, patients in CTC>=1 group got worse PFS (5.7m VS 4.0m, P=0.025; 6.3m VS 4.0m, P=0.001 ) than in CTC=0 group. At time after first-cycle-chemo, patients in groups cKIT[+]CTC>=1 and cKIT[-]CTC>=1 got worse PFSs (3.1m vs 4.0m vs 5.7m, P=0.001) and worse DCRs (44.4% vs 42.1% vs 73.9%, P=0.009) than in CTC=0 group. For 142 patients categorized into three groups of dynamic CTC decrease (17), CTC unchanged (82), and CTC increase (43), there were significant differences in terms of DCR (71.8% vs 71.6% vs 33.3%, P=0.018) and PFS (5.2m vs 5.6m vs 3.1m, P=0.037).
Conclusion:
In first line setting of advanced NSCLC, at time-points after first-cycle-chemo other than baseline, total CTC or cKIT[+]CTC counts could be predictive for worse DCR or PFS. CTC increase from baseline to after-first-cycle-chemo might be a strong signal for the inefficacy of first line chemotherapy in the NSCLC patients.
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MA08.08 - Discussant for MA08.05, MA08.06, MA08.07 (ID 6959)
11:48 - 12:00 | Author(s): A. Mansfield
- Abstract
- Presentation
Abstract not provided
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MA08.09 - Monitoring Plasma EGFR Mutations during First Line Treatment with EGFR TKIs in NSCLC Patients (ID 4547)
12:00 - 12:06 | Author(s): K. Mohorcic, I. Kern, U. Janzic, N. Turnsek Hitij, M. Rot, T. Cufer
- Abstract
- Presentation
Background:
Genotyping cell free circulating DNA (cfDNA) is a non-invasive method of detecting EGFR mutations (EGFRmu) in plasma and may provide an option to identify patients who progress while treated with EGFR TKIs. The aim of our study was to monitor plasma EGFRmu and identify dynamic case specific changes in plasma EGFRmu during routine treatment of advanced EGFRmu NSCLC patients.
Methods:
Plasma was collected from patients with advanced EGFRmu NSCLC treated with first- or second-generation EGFR TKIs. Plasma EGFRmu were dynamically monitored consecutively at every scheduled visit. Cobas EGFR Mutation Test v1 and v2 (Roche, USA) was used to detect 42 mutations at EGFR gene in exons 18 to 21. Liquid biopsy progression (LBP) was determined as reappearance of EGFRmu in plasma after negativisation during treatment or increase of EGFRmu levels expressed by semi-quantitative index (SQI). Radiologic progression was determined in accordance with RECIST1.1 criteria.
Results:
From May 2014, 23 patients were treated with EGFR TKIs for advanced EGFRmu NSCLC; 20/23 had detectable activating mutations in plasma before any treatment and were therefore included in our analysis. Dynamic changes of plasma EGFRmu during 1[st] line EGFR TKI treatment are shown in Figure 1. Eight patients (40%) experienced RECIST 1.1 progression while on treatment, whereas one patient was inevaluable. In 4/8 patients (50%) LBP appeared at the same time as radiologic progression, in 3/8 patients (37%) LBP appeared before radiologic progression (8w, 14w, 20w before, respectively) and in 1 patient (12%) radiologic progression appeared 6w before LBP. Among patients who did not experience radiologic progression yet, some dynamic changes in cfDNA were also observed, but alterations in the SQI values were much smaller. Figure 1
Conclusion:
Monitoring EGFR mutations in plasma is a feasible and less invasive method in routine clinical practice and could be used as a predictive marker of progression on treatment with EGFR TKIs.
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MA08.10 - Detection of the T790M Mutation of EGFR in Plasma of Advanced NSCLC Patients with Acquired Resistance to EGFR-TKI (WJOG8014LTR) (ID 5377)
12:06 - 12:12 | Author(s): K. Azuma, T. Takahama, K. Sakai, M. Takeda, T. Hida, M. Hirabayashi, T. Oguri, H. Tanaka, N. Ebi, T. Sawa, A. Bessho, M. Tachihara, H. Akamatsu, S. Bandoh, D. Himeji, T. Ohira, M. Shimokawa, N. Yamamoto, Y. Nakanishi, K. Nakagawa, K. Nishio
- Abstract
- Presentation
Background:
NSCLC patients with activating mutations of the EGFR initially respond well to TKIs, but about half such patients develop TKI resistance through acquisition of a secondary T790M mutation. Whereas next-generation EGFR-TKIs have been developed to overcome T790M-mediated resistance, performance of a second tumor biopsy to assess T790M mutation status can be problematic.
Methods:
We developed and evaluated liquid biopsy assays for detection of TKI-sensitizing and T790M mutations of EGFR by droplet digital PCR (ddPCR) in EGFR mutation–positive patients with acquired EGFR-TKI resistance.
Results:
A total of 260 patients was enrolled between November 2014 and March 2015 at 29 centers for this West Japan Oncology Group (WJOG 8014LTR) study. Plasma specimens from all subjects as well as tumor tissue or malignant pleural effusion or ascites from 41 patients were collected after the development of EGFR-TKI resistance. All plasma samples were genotyped successfully and the results were reported to physicians within 14 days. TKI-sensitizing and T790M mutations were detected in plasma of 120 (46.2%) and 75 (28.8%) patients, respectively. T790M was detected in 56.7% of patients with plasma positive for TKI-sensitizing mutations. For the 41 patients with paired samples obtained after acquisition of EGFR-TKI resistance, the concordance for mutation detection by ddPCR in plasma compared with tumor tissue or malignant fluid specimens was 78.0% for TKI-sensitizing mutations and 65.9% for T790M.
Conclusion:
Noninvasive genotyping by ddPCR with cell-free DNA extracted from plasma is a promising approach to the detection of gene mutations during targeted treatment.
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MA08.11 - Monitoring the Emergence of EGFR T790M ctDNA in Urine from EGFR Mutated NSCLC Patients to Predict Response to 3rd Generation Anti-EGFR TKIs (ID 6342)
12:12 - 12:18 | Author(s): B. Woodward, P. Keshavarzian, R. Phillips, S. Pingle, V. Melnikova, M. Erlander, H. Husain
- Abstract
Background:
EGFR T790M mutation occurs in about half of EGFR mutated NSCLC patients with acquired EGFR-TKI resistance. It is currently unknown if switching therapy to a third generation anti-EGFR TKI based on circulating tumor DNA at first detection with urine is superior to switching therapy based on radiographic progression. Herein we demonstrate the identification of T790M in urine months before radiographic progression, patient responses when treated with an anti-EGFR third generation TKIs, clinical cutoffs that may be predictive of benefit, and a novel clinical trial to consider for treatment selection.
Methods:
From 2014 to 2016 a total of 42 patients with EGFR activating mutations were followed at UCSD Moores Cancer Center through multiple lines of therapy. 34 patients had serial urine collection every 4-6wks from time of first visit. Clinical progression was assessed with CT imaging performed every two months.
Results:
Among the 42 patients, 35 patients had metastatic disease (6 with intrathoracic M1a disease and 29 with distant metastasis M1b). Urine volume ranged from 30-100ml. Average time from first line TKI start to urine T790M was 15.7mos (CI 9.6-25.6), time from TKI start to radiographic progression was 21.9mos (CI 10.7-27.0), and time from urine T790M to radiographic progression was 3.6mos (CI 0.9-6.8). All patients with >30 copies/10[5] genome equivalents (GEq) of urine T790M had response to third generation TKIs. In patients who had urine EGFR T790M from 10-30 copies/10[5] GEq, three serial measurements in the 10-30 range predicted response. EGFR T790M copies of less than 10 copies/10[5] GEq did not predict response to third generation inhibitors.
Conclusion:
EGFR T790M can be identified in urine before radiographic progression and quantitative cut-offs can be predictive of response. We are testing this prospectively in a clinical trial with serial ctDNA analyses obtained for resistance monitoring for up to 24 months on first line TKI therapy. Patients who have urine detection of T790M (>30 copies or three serial collections with 10-30 copies/10[5] GEq) at 12 months and before progression are randomized to second line third generation TKI therapy or continuation of the first line therapy until progression. Patients with undetectable urinary T790M or <10 copies/10[5] GEq will continue on the first line therapy past 12 months until progression. Overall survival, progression free survival, and time to progression will be compared between cohorts to validate the early detection of T790M by urine ctDNA and understand the impact of an early switch in therapy based on ctDNA analyses.
Information from this presentation has been removed upon request of the author.
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MA08.12 - Discussant for MA08.09, MA08.10, MA08.11 (ID 6954)
12:18 - 12:30 | Author(s): M. Filipits
- Abstract
- Presentation
Abstract not provided
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Author of
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MA04 - HER2, P53, KRAS and Other Targets in Advanced NSCLC (ID 380)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
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MA04.09 - RICTOR Amplification in Non-Small Cell Lung Cancer: An Emerging Therapy Target (ID 6177)
17:00 - 17:06 | Author(s): R. Perez-Soler
- Abstract
- Presentation
Background:
Comprehensive genomic profiling (CGP) can discover novel therapy targets in NSCLC. Amplification of RICTOR, encoding a component of the MTORC2 complex, has recently been identified as a targetable alteration leading to clinical benefit.
Methods:
CGP was performed on hybridization-captured, adaptor ligation-based libraries for up to 315 cancer-related genes plus select introns from 28 genes frequently rearranged in cancer on 14,698 consecutive cases of NSCLC, comprising lung adenocarcinoma, squamous cell carcinoma (SCC) or NSCLC not otherwise specified (NOS). Tumor mutational burden (TMB) was determined on 1.1 Mb of sequenced DNA. All classes of genomic alterations (GA) were assessed simultaneously, including base substitutions, indels, rearrangements/fusions, and copy number changes.
Results:
747 (5.0%) NSCLC featured RICTOR amplification (amp). There were 380 (51%) male and 367 (49%) female patients with a mean age of 64.1 years (range 18-88 years). The primary tumor was analyzed in 333 (45%) cases and a metastasis biopsy in 414 (55%) cases. Genes most frequently co-altered with RICTOR amp included TP53 (79.5%) and FGF10 (64.6%), which is located close to RICTOR on chromosome 5 and is frequently co-amplified. Several known oncogenes in NSCLC were mutated at significantly higher rates in tumors with RICTOR amp, including EGFR (22%), MET (8.4%), ERBB2 (7%), as well as FGFR1 (5%), FGFR3 (1.4%), and FGFR4 (1.6%). 42.2% of tumors with RICTOR amp did not harbor additional alterations in KRAS or genes indicated in the NCCN guidelines. KRAS GA were identified in 19.6% of RICTOR amp tumors, compared with 29.8% of all NSCLC, but this difference was not statistically significant. Mean TMB in RICTOR amp tumors was intermediate (14.9 mut/Mb), and is higher than the overall average for NSCLC (9.2 mut/Mb). The number of RICTOR-amplified tumors with high TMB (>20 mut/Mb) was 23%, higher than the rate for non-RICTOR amp NSCLC (12.9%). Examples of patients with RICTOR amplification within late stage NSCLC responding to MTOR inhibitors will be presented.
Conclusion:
RICTOR amplification, when compared to other non-EGFR known drivers of NSCLC, is a relatively frequent clinically relevant GA that has been shown to respond to MTOR inhibitors. The co-occurrence of RICTOR amplification with mutation of known oncogenic drivers suggests a possible mechanism of acquired resistance to therapy that should be explored further. Tumors with RICTOR amp more often have higher levels of TMB than other NSCLC. Further study of RICTOR amp as a therapy target NSCLC in a clinical trial setting appears warranted.
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OA08 - Targeted Therapies in Brain Metastases (ID 381)
- Event: WCLC 2016
- Type: Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:D. Ball, B. Perin
- Coordinates: 12/05/2016, 16:00 - 17:30, Schubert 1
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OA08.04 - Discussant for OA08.01, OA08.02, OA08.03 (ID 7004)
16:30 - 16:45 | Author(s): R. Perez-Soler
- Abstract
- Presentation
Abstract not provided
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OA20 - Immunotherapy and Markers (ID 401)
- Event: WCLC 2016
- Type: Oral Session
- Track: Biology/Pathology
- Presentations: 1
- Moderators:M. Früh, C.S. Baldotto
- Coordinates: 12/07/2016, 11:00 - 12:30, Stolz 2
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OA20.07 - HHLA2, a New Immune Checkpoint Member of the B7 Family, is Widely Expressed in Human Lung Cancer and Associated with Mutational Status (ID 5184)
11:55 - 12:05 | Author(s): R. Perez-Soler
- Abstract
- Presentation
Background:
Immunotherapy with antibodies against B7/CD28 family members, including PD-1, PD-L1, and CTLA-4 has shifted the treatment paradigm for non-small-cell lung carcinoma (NSCLC) with improved clinical outcome. HHLA2 is a newly discovered member of the family. By regulating T-cell function, HHLA2 could contribute to tumor immune suppression and thus be a novel target for cancer immunotherapy. There is limited information and critical need to characterize its expression profile and clinical significance in NSCLC.
Methods:
We performed immunohistochemistry with an HHLA2-specific antibody (clone 566.1) using tissue microarrays constructed from 679 NSCLC tumor tissues, including 392 cases in the discovery set and 287 cases in the validation cohort. We also studied clinico-pathological characteristics of these patients.
Results:
Overall, HHLA2 was not detected in most of normal lung tissue but expressed in 66% of NSCLC across different subtypes. In particular, EGFR–mutated NSCLC was significantly associated with higher tumor HHLA2 expression in both discovery (EGFR vs. WT: 76% vs. 53%, P=0.01) and validation cohorts (89% vs. 69%, P=0.01). In one of the two cohorts, HHLA2 expression was higher in lung adenocarcinoma as compared to squamous and large cell histology, non-Hispanic White vs. Hispanics, and tumors with high tumor infiltrating lymphocyte (TIL) density. In the multivariate analysis, EGFR mutation status and high TIL intensity were independently associated with HHLA2 expression in lung adenocarcinoma.
Conclusion:
HHLA2 is widely expressed in NSCLC and is associated with EGFR mutation and high TILs in lung adenocarcinoma. It is potentially a novel target for lung cancer immunotherapy.
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P2.01 - Poster Session with Presenters Present (ID 461)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.01-056 - Distinct PD-L1 Expression in Different Components of Pulmonary Sarcomatoid Carcinoma and Its Association with MET Mutation (ID 5228)
14:30 - 14:30 | Author(s): R. Perez-Soler
- Abstract
Background:
Pulmonary Sarcomatoid Carcinoma (PSC) is a unique and highly aggressive subtype of non-small cell lung cancer (NSCLC), characterized by a component of sarcoma or sarcoma-like differentiation. It is generally resistant to platinum-based chemotherapy. However, frequent KRAS and the MET exon 14 skipping mutations have been reported in this subtype. Recently, immunotherapy with antibodies against PD-1/PD-L1 has led to clinical benefits in managing NSCLC. Immune biomarker expression of PD-L1 in differential components of PSC and its relationship with other molecular markers has not been defined and thus there is critical need to investigate its expression profile in this deadly disease.
Methods:
We investigated PD-L1 expression by immunohistochemistry (IHC) using tissue microarrays from a cohort of 41 patients with PSC (antibody: PD-L1/CD274 (SP142)). Positive cases were defined as PD-L1 ≥ 1%. The clinical and molecular characterization of these cases was previously reported (PMID: 26215952). Among the 41 cases, 36 had sufficient tumor tissue for PD-L1 assessment, 8 (20%) were identified with MET exon 14 skipping mutation and 6 (15%) were found to have KRAS mutations.
Results:
The PD-L1 expression was positive in 75% (27/36) of cases. Among the positive cases, 78% expressed PD-L1 ≥ 50%, whereas 22% had PD-L1 staining of 1-49%. Interestingly, only 33% (9/27) had PD-L1 expression in both epithelial and sarcomatoid components, whereas the remaining 66% detected PD-L1 in just one component. The PD-L1 expression was statistically different between the two components (P=0.007). Moreover, all 8 patients with MET exon 14 skipping mutation were PD-L1 positive (6 with PD-L1 ≥ 50%), whereas 5 of 6 patients with KRAS mutation expressed PD-L1 (2 with PD-L1 ≥ 50%). The average age at diagnosis was similar between the PD-L1 positive vs. negative groups (71 years). There was a trend of shorter overall survival in patients whose tumors were positive for PD-L1 (671 vs. 985 days).
Conclusion:
In our particular cohort of PSC patients, high PD-L1 (≥ 50%) was expressed in the large majority of cases which favors potential application of immunotherapy in this disease. In addition, it appears that the expression of PD-L1 is different in the epithelial and sarcomatoid components which could affect scoring in practice. Furthermore, the overall positivity of PD-L1 expression in the unique molecular subtype of PSC patients with MET exon 14 skipping mutation indicates potential interplay between the two biomarkers and suggests that exploration of combination MET and immunotherapy in this subtype is warranted.
