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R. Soo
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GR 04 - Problems in Advanced Metastatic Disease (ID 18)
- Event: WCLC 2015
- Type: Grand Rounds
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:K. Kelly, R. Pirker
- Coordinates: 9/09/2015, 14:15 - 15:45, 702+704+706
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GR04.02 - Leptomeningeal Carcinomatosis (ID 1845)
14:15 - 15:45 | Author(s): R. Soo
- Abstract
- Presentation
Abstract:
Leptomeningeal disease is a severe neurologic complication that can be seen in up to 5% of patients with cancer and it is more commonly seen in patients with lymphoma, breast cancer, melanoma and lung cancer. It usually presents in approximately 70% patients with metastatic and progressive disease but may also be the first manifestation of cancer in 10% of cases. With improved diagnostic methods and longer survival of patients with advanced stage non-small cell lung cancer (NSCLC), the incidence of leptomeningeal disease has increased. The diagnosis of leptomeningeal disease is usually established by cytological examination of the cerebrospinal fluid (CSF) or by characteristic changes seen on gadolinium enhanced magnetic resonance imaging (MRI). Furthermore MRI provides anatomic information that may be useful in identifying sites for local radiotherapy treatment. Prognosis is generally poor, especially in patients with poor performance status, multiple, serious or major neurological deficits, bulky CNS disease, and CSF block. Factors associated with a better prognosis include good performance status, absence of major neurological deficits, minimal systemic disease, absence of CSF block and the availability of reasonable systemic therapies. Management principles include early diagnosis and achieving systemic control with the aim of preserving or improving neurological status, improving quality of life and prolonging survival, taking into account the burden of systemic disease, intracranial metastasis and the expected prognosis. Currently there is no standard treatment for leptomeningeal disease in patients with NSCLC and options include intra-thecal chemotherapy, systemic chemotherapy, molecular targeted therapy, and radiotherapy. Although the benefit of intra-thecal chemotherapy has not been proven in randomized controlled studies, it is commonly used as it provides local therapy with minimum systemic toxicity and high drug concentrations can be achieved. It has been noted that intra-thecal chemotherapy is ineffective for bulky meningeal disease as intra-CSF agents can only penetrate 2-3mm into such lesions. Retrospective studies in patients with NSCLC harboring sensitizing mutations in the epidermal growth factor receptor (EGFR) gene or rearrangement in anaplastic lymphoma kinase (ALK) gene suggest EGFR or ALK tyrosine kinase inhibitors is an attractive treatment option. Radiotherapy is used to in the treatment of bulky disease and in patients with CSF flow abnormalities. Radiotherapy is also indicated in symptomatic sites and also in the treatment of cauda equine syndrome and cranial neuropathies. Craniospinal irradiation is rarely administered, as it is associated with significant systemic toxicities and leucoencephalopathy. Several case examples will be presented and the clinical presentation, diagnostic assessment and management will be discussed. The role of molecular targeted agents such as the EGFR and ALK tyrosine kinase inhibitors will also be reviewed. The development of novel systemic agents especially molecular targeted agents with improved CNS penetration and anti-tumor activity is urgently required.
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MINI 17 - WT EGFR, Angiogenesis and OMD (ID 131)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:R. Feld, R. Dziadziuszko
- Coordinates: 9/08/2015, 16:45 - 18:15, Mile High Ballroom 4a-4f
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MINI17.05 - Discussant for MINI17.01, MINI17.02, MINI17.03, MINI17.04 (ID 3350)
16:45 - 18:15 | Author(s): R. Soo
- Abstract
- Presentation
Abstract not provided
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MINI 26 - Circulating Tumor Markers (ID 148)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:M. Macmanus, C. Aggarwal
- Coordinates: 9/09/2015, 16:45 - 18:15, 205+207
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MINI26.12 - Circulating Tumor DNA for Noninvasive Monitoring of Non-Small Cell Lung Cancer Patients Receiving EGFR-Targeted Therapies (ID 372)
16:45 - 18:15 | Author(s): R. Soo
- Abstract
Background:
Analysis of circulating tumor DNA (ctDNA) in plasma offers an opportunity to noninvasively monitor tumor burden and identify alternative drivers of disease progression in real-time. However, cancer progression during targeted therapy, such as EGFR-targeted therapies in non-small cell lung cancer (NSCLC), is driven by clonal evolution, and how this impacts the levels of targeted mutations in circulating tumor DNA (ctDNA) for monitoring disease burden is unclear.
Methods:
We collected serial plasma samples from 47 NSCLC patients receiving EGFR-targeted therapy (gefitinib) and hydroxychloroquine, and analysed mutations in EGFR, TP53, PTEN and PIK3CA in plasma by digital PCR and tagged-amplicon deep sequencing (TAm-Seq) of ctDNA.
Results:
We identified the same EGFR mutations in tumor and plasma samples in over 97% of patients, and found that patients with high pre-treatment levels of ctDNA are associated with worse progression-free survival and overall survival. Serial plasma analysis of 32 patients reveals clonal dynamics in ctDNA in response to treatment. In >72% of patients (23/32), EGFR mutations levels increased preceding clinical progression, with the resistant mutation T790M detected in around 50% of these patients (13/23) a median of 6 months before progression became clinically evident. In the remaining 9 of the 32 patients, EGFR-mutant ctDNA levels became uninformative during treatment, and in two patients we identified alternative driver mutations in ctDNA that correlated with progression. In one patient we also showed that the analysis of relative representations of resistant and sensitizing mutations may provide insight to the response to sequential treatment.
Conclusion:
Our results demonstrate the potential of ctDNA for noninvasive stratification and monitoring disease progression in NSCLC patients, and highlight that targeted therapy may drive the selection of alterative mutations. This may impact the representation of the targeted mutations in plasma for assessing disease burden. We therefore propose that effective ctDNA-based monitoring of targeted therapies in oncogene-addicted cancers requires tracking of multiple mutations beyond the targeted genes.
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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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P1.01-003 - Co-Expression of Programmed Death Ligand-1 (PD-L1) and CD3 in Patients with EGFR Mutant NSCLC Treated with EGFR Tyrosine Kinase Inhibitors (TKI) (ID 1163)
09:30 - 17:00 | Author(s): R. Soo
- Abstract
Background:
Recent reports have suggested an association between non-small cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) gene mutations. Other studies have indicated that EGFR signaling can activate PD-L1 expression and immune escape in mutant EGFR driven NSCLC. Furthermore PD-L1 expression is down-regulated by EGFR TKI. In this study, we aim to determine the association between tumoral and immune cell PDL1 expression and clinical characteristics and outcome in EGFR mutant NSCLC patients treated with first line EGFR TKI.
Methods:
Tumors from 90 patients with advanced stage NSCLC with EGFR mutations and treated with first line EGFR TKI were analyzed. Double staining for CD3 and PDL1 was performed by immunohistochemistry. PDL1 expression in tumour membrane, and PDL1 and CD3 expression in tumor and stromal immune cells were segmented and quantified using the Vectra slide imaging system (Perkin Elmer, Waltham, MA).
Results:
The median age of patients was 62 (range 34-88) years, 64 (71%) were female, 69 (77%) were never smokers, and 43 (48%) harbored EGFR exon 19 deletion. Most immune cells were CD3-ve and PDL1-ve in the tumor (median 99%) and stroma (median 86%). PDL1 tumor membrane expression was associated with PDL1 expression in CD3+ve immune in the tumor and stroma. There was no association between PDL1 or CD3 expression with response rate or time to progression.
Conclusion:
This is the first study to characterize PDL1 expression in immune cells in advanced stage NSCLC harboring EGFR mutations. PDL1+ve immune cells are rare in this patient population. PDL1 expression in tumor membrane and immune cells may not be associated with outcome in NSCLC patients harboring EGFR mutations and treated with EGFR TKIs.
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P1.11 - Poster Session/ Palliative and Supportive Care (ID 229)
- Event: WCLC 2015
- Type: Poster
- Track: Palliative and Supportive Care
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.11-002 - The Impact of Gastric Acid Suppressive Therapy on Treatment Outcomes of EGFR Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer (ID 804)
09:30 - 17:00 | Author(s): R. Soo
- Abstract
Background:
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors such as gefitinib and erlotinib are dependent on gastric pH for absorption which may be affected by concomitant gastric acid suppressive therapy (AS) with proton pump inhibitors and histamine 2 antagonists. We sought to determine the effect of gastric acid suppressive therapy on overall survival (OS) in patients treated with EGFR tyrosine kinase inhibitors.
Methods:
Patients with advanced stage non-small cell lung cancer harboring EGFR mutations treated with EGFR tyrosine kinase inhibitors were retrospectively identified. Medical records in our single institution were reviewed from 1[st] January 2008 to 30[th] December 2013. Patient clinico-pathological characteristics,use of gastric acid suppressive therapy and the overall survival were obtained. Statistical analysis was performed using chi[2], log rank test and cox regression where indicated
Results:
We identified 191 patients. The median age of patients was 64 years (range: 30-89) ,109 (57.1%) were female, 117(61.3%) were never smokers, 91 (47.6%) harbored EGFR exon 19 deletion and 144 (75.4%) received EGFR tyrosine kinase inhibitors as first line treatment. 55 (28.8%) patients received gastric acid suppressive therapy The groups of patients who received gastric acid suppressive therapy and those who did not receive gastric acid suppressive therapy were similar with regards to gender, smoking status, and type of EGFR mutations, Charlson co-morbidity score and Kanorfsky performance status. Brain metastasis at the time of diagnosis was more frequent in the group who received gastric acid suppressive therapy compared with the group who did not receive gastric acid suppressive therapy (61.8% v 35.3% respectively, p= 0.001). The median overall survival in the total patient population was 13.1 months (95%CI 11.7-15.2 months). On multivariate analysis, presence of visceral metastasis at diagnosis was associated with a worse overall survival (HR: 1.53, 95% CI:1.10-2.13 p value: 0.012). However a Karnofsky performance score of 90-100 was associated with an improved overall survival (HR: 0.69, 95% CI; 0.49-0.97 p value: 0.031). The median overall survival OS in patients with gastric acid suppressive therapy was 11.9 months (95%CI: 9.90-16.94 months) and 14.5 months (95%CI: 11.74-15.95 months) in the group not receiving gastric acid suppressive therapy. (HR: 0.98, 95% CI: 0.69-1.40 p value: 0.934)
Conclusion:
Although the group of patients who were treated with gastric acid suppressive therapy had a numerically poorer overall survival compared to the group who did not receive gastric acid suppressive therapy, this difference was not statistically significant. Based on the our analysis, the use of gastric acid suppressive therapy concurrent with EGFR tyrosine kinase inhibitors in patients with advanced non-small cell lung cancer harboring EGFR mutations did not affect overall survival.
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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: 2
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.01-019 - Effect of EGFR Mutation Status on Graded Prognostic Assessment for Non-Small Cell Lung Cancer and Brain Metastases (ID 1055)
09:30 - 17:00 | Author(s): R. Soo
- Abstract
Background:
The aim of this study is to refine the existing lung cancer graded prognostic assessment (GPA) index by analysing a cohort of patients with non-small cell lung cancer (NSCLC) tested for epidermal growth factor receptor (EGFR) mutation status and newly diagnosed brain metastases.
Methods:
We used the pathology registries of two institutions to identify 259 eligible patients diagnosed with brain metastases secondary to NSCLC between 2006 and 2014. We linked the electronic medical records of these patients to the National Death Registry. Survival is defined as from date of first treatment for brain metastases or date of brain metastases diagnosis for patients on best supportive care till death. We analysed the prognostic factors significant for survival by multivariate Cox regression and recursive partitioning analysis (RPA).
Results:
Significant prognostic factors identified by multivariate Cox regression and RPA were age, Karnofsky performance status (KPS), presence of extra-cranial metastases (ECM), number of brain metastases (BM) and presence of sensitizing EGFR mutations. Patients who were age 70 years old and above (Hazard ratio (HR) 1.47, 95% confidence interval (CI) 1.07-2.01, reference (ref) age < 70 years old); with KPS score 70-80 (HR 2.37, 95%CI 1.69-3.34, ref KPS 90-100); with KPS score < 70 (HR 4.34, 95%CI 2.90-6.51, ref KPS 90-100); ECM present (HR 1.82, 95%CI 1.27-2.62, ref no ECM); having two or more BM (HR 1.40, 95%CI 1.01-1.95, ref less than two BM) and absence of sensitizing EGFR mutations (HR 1.97, 95%CI 1.49-2.61, ref sensitizing EGFR mutations present) were poor prognostic factors. There was a robust separation of survival curves between GPA score 0-1.0 (median survival (MS) 2.1 months), GPA score 1.5-2.0 (MS 6.3 months) and GPA score 2.5-3.0 (MS 14.1 months). The proposed modified GPA index is shown in below table.Proposed modified GPA index
Prognostic factors / score 0 0.5 1.0 Age Group ≥70 years old <70 years old - KPS <70 70-80 90-100 ECM Present - Absent No. of BM ≥2 0-1 Sensitising EGFR mutations Absent - Present
Conclusion:
EGFR mutation status is a significant prognostic factor and should be considered in the design of lung-cancer GPA index. The proposed modified GPA index need to be validated with an independent dataset.
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P2.01-094 - Phase II Trial of Tepotinib/Gefitinib vs Cisplatin/Pemetrexed in T790M-/c-Met+ NSCLC (ID 2105)
09:30 - 17:00 | Author(s): R. Soo
- Abstract
Background:
The recommended phase II dose of the highly selective c-Met inhibitor tepotinib (MSC2156119J) for use in combination with gefitinib was confirmed as 500 mg/day in the phase Ib part of the current trial, in which patients with gefitinib-resistant locally advanced/metastatic c-Met-positive NSCLC were treated with tepotinib plus gefitinib. This trial demonstrated that the combination regimen is well tolerated and has evidence of antitumor activity that may be associated with c-Met-positive tumor status. These observations suggest that c-Met inhibition may have a role in EGFR tyrosine kinase inhibitor-resistant NSCLC and that a phase II trial is warranted.
Methods:
The design of the phase II part of a phase Ib/II trial (NCT01982955) is described. Asian adults with histologically or cytologically confirmed, gefitinib-resistant locally advanced/metastatic NSCLC other than predominantly squamous histology and ECOG PS 0/1 are eligible. Patients must have tumors with documented activating mutations of EGFR. Tumor tissue obtained between documentation of acquired resistance to gefitinib and enrollment must be available. Tumors must be confirmed as being c-Met positive (2+/3+ c-Met protein overexpression by immunohistochemistry using CONFIRM anti-total c-MET [SP44] rabbit MAb [Ventana] or c-Met gene amplification on IQ FISH [Dako] [c-Met:CEP7 ratio ≥2 or <2.0 with >15 c-Met signals/cell in >10% of cells or clusters in >10% of tumor cell nuclei]). EGFR mutation status will be assessed centrally using the therascreen[®] EGFR RGQ PCR Kit (QIAGEN). Patients will be enrolled into different parts of the trial based on tumor T790M status. Patients with c-Met-positive, T790M-negative NSCLC (n=136) will be randomized to tepotinib 500 mg/day p.o. + gefitinib 250 mg/day q3w or cisplatin 75 mg/m[2] + pemetrexed 500 mg/m[2] q3w for up to 6 cycles. Patients with c-Met-positive, T790M-positive NSCLC (n=15) will be treated with tepotinib 500 mg/day p.o. + gefitinib 250 mg/day q3w. The primary objective is to determine whether progression-free survival (PFS) in patients treated with second-line tepotinib combined with gefitinib is superior to that of pemetrexed + cisplatin in patients with c-Met-positive, T790M-negative advanced NSCLC and acquired resistance to first-line gefitinib. The two T790M subgroups will be analyzed separately. An interim analysis of the randomized part of the study is planned when 50% of PFS events have occurred in both arms. Secondary objectives are to evaluate: the safety and tolerability tepotinib combined with gefitinib; the efficacy of tepotinib combined with gefitinib; the antitumor activity of tepotinib combined with gefitinib in patients with c-Met-positive, T790M-positive tumors; and patient-reported outcomes.
Results:
not applicable
Conclusion:
This randomized phase II trial will provide the first evidence regarding whether tepotinib has a role in the treatment of Asian patients with gefitinib-resistant, c-Met-positive, T790M-negative NSCLC.
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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: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-068 - PD-L1 Expression in Tumor Infiltrating Immune Cells Determined by Digital Imaging Is Associated with Poor Survival in NSCLC Patients (ID 1138)
09:30 - 17:00 | Author(s): R. Soo
- Abstract
Background:
Programmed Death-Ligand 1 (PD-L1) has emerged as a potential prognostic marker and as an effective target for therapeutic inhibition in cancer. Using digital slide imaging, we evaluated the clinical, molecular and survival associations of PD-L1 expression in non-small cell lung cancer (NSCLC) according to cell type (tumor and immune cell) and tissue localization (tumor and stroma).
Methods:
Tumor samples from 199 NSCLC patients were stained for PD-L1 by immunohistochemistry (IHC) and quantitatively assessed using the Vectra slide imaging system for PD-L1 tumor membrane expression (TME), PD-L1 positive (+) tumor immune cell density (TICD) and PD-L1+ stroma immune cell density (SICD). Assessment of gene mutation and anaplastic lymphoma kinase rearrangement were performed using the AmpliSeq Cancer Hotspot V2 assay and IHC, respectively.
Results:
High PD-L1 TME correlated with larger tumor size, squamous cell histology and poor differentiation. PD-L1+ TICD was associated with male gender and wild-type EGFR. Univariate analysis revealed that stage (p=0.001), PD-L1 TME (p=0.007) and PD-L1+ TICD (p=0.006) were associated with worse survival. Iterative p-value analysis indicated the optimal thresholds for PD-L1 TME were 30 (p=0.003, 73% of cases) or 160 (p<0.001, 7%), while for PD-L1+ TICD they were 6.9% (p=0.022, 33%) or 20% (p=0.001, 5%). In multivariate analysis, stage (p=0.018), PD-L1 TME≥160 (p=0.040) and PD-L1+ TICD≥6.9% (p=0.015) were independently associated with survival.
Conclusion:
PD-L1 Tumor Membrane Expression (TME) and PD-L1+ Tumor Immune Cell Density (TICD) expression determined by digital analysis have prognostic value in NSCLC.
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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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P3.01-011 - Antitumor Activity of Tepotinib plus Gefitinib in Asian Patients with Met+ EGFRm+ NSCLC (ID 763)
09:30 - 17:00 | Author(s): R. Soo
- Abstract
Background:
c-Met abnormalities are key in resistance to EGFR TKIs in EGFRm+ NSCLC patients (pts). The highly selective c-Met inhibitor tepotinib (MSC2156119J) had promising activity in a phase I trial in pts with advanced solid tumors. We report phase Ib data from a trial evaluating tepotinib + gefitinib in pts with Met+ NSCLC (NCT01982955).
Methods:
Asian adults with locally advanced/metastatic NSCLC, Met+ status (2+/3+ c-Met protein overexpression by immunohistochemistry using CONFIRM anti-total c-MET [SP44] rabbit MAb [Ventana] or c-Met gene amplification on IQ FISH [Dako] [c-Met:CEP7 ratio ≥2 or <2.0 with >15 c-Met signals/cell in >10% of cells or clusters in >10% of tumor cell nuclei]) and ECOG PS 0/1 were eligible. EGFR mutation status was assessed using the therascreen[®] EGFR RGQ PCR Kit (QIAGEN). A 3+3 design was used for the phase Ib part; planned recruitment was 15-18 pts, who received tepotinib 300 or 500 mg p.o. + gefitinib 250 mg/d q3w. Primary objective: determine the RP2D of tepotinib for use in combination; secondary objectives: pharmacokinetics, safety, antitumor activity.
Results:
14 pts have been enrolled (median age 65 years; male 43%; ECOG PS 0/1 2/12; median prior therapy regimens including an EGFR TKI 3.5). 3 pts received tepotinib 300 mg + gefitinib and 11 tepotinib 500 mg + gefitinib. No DLTs were observed; 4 pts had grade 3/4 treatment-related adverse events (amylase increase [n=3], lipase increase [2], decreased neutrophil count [1]). Best overall response by c-Met status (cut-off Jan 20, 2015) for the 12 evaluable pts is shown in the table. EGFR mutation status for these 12 pts was T790M and L858R mutation (n=2), L858R mutation alone (4), exon 19 deletion (4), no mutation detected using the therascreen[®] kit (2).Best overall response (n) n=12 Partial response Stable disease Progression IHC 2+ 0 5 2 3+ 4 0 1 FISH c-Met:CEP7 ratio >2 1 0 0 ≥5 copies in >50% of cells 3 1 1 Negative 0 3 2 Not valid 0 1 0
Conclusion:
The RP2D of tepotinib in combination with gefitinib has been confirmed as 500 mg/d in pts with advanced NSCLC. The data show evidence of antitumor activity and that response may be associated with c-Met status. The phase II trial will randomize ≈136 pts with T790M-/c-Met+ tumors who have failed first-line gefitinib to tepotinib 500 mg/d + gefitinib or cisplatin/pemetrexed.
