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Misako Nagasaka
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EP1.01 - Advanced NSCLC (ID 150)
- Event: WCLC 2019
- Type: E-Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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EP1.01-67 - Molecular Profiling of K-Ras and Its Subtypes in NSCLC Patients with Liver Metastasis (Now Available) (ID 2802)
08:00 - 18:00 | Author(s): Misako Nagasaka
- Abstract
Background
Non-small cell lung cancer (NSCLC) tend to have a poor prognosis in the presence of liver metastasis. Molecular profiling of NSCLC has played a major role in identifying a number of oncogenic targets that have led to novel targeted therapies. KRAS is a frequently mutated gene in NSCLC, occurring in approximately 30% of lung adenocarcinomas and most commonly manifesting as the transversion mutations G12C, G12V, G12A. there are presently no targeted therapies approved for KRAS-mutant NSCLC. Immunotherapy has emerged as a standard of care for first-line treatment of advanced NSCLC, specifically through targeting the programmed cell death protein-1 (PD-1/PD-L1). Given the aggressive nature of KRAS-mutant NSCLC with liver metastases and the lack of approved therapies targeting the KRAS pathway, checkpoint blockade immunotherapy may represent an impactful primary therapeutic option for these patients.
Method
The CARIS database from 2016 - 2018 was queried and patients with NSCLC were identified. PD-L1 antibody 22c3 ≥1% was considered positive. PD-L1 expression as well as k-ras and TP53 mutation status were analyzed and correlation between different variables were identified using ANOVA
Result
We identified 361 patients with NSCLC having Liver metastasis. Median age was 67. Gender distribution was equal (51.4% males, 49.7% females). Of the 361 patients, we identified 74 patients with mutated K-ras. Thirty nine out of the 74 patients had PD-L1 expression (52.7%). Twenty one patients had the G12C sub-type (28%) with 14 patients (66%) having positive PD-L1 expression.Of the 287 patients with wild type K-ras, 115 patients had PD-L1 positive expression (40%) with no statistical significance (P=0.134) in comparison to the k-ras mutant population.We also studied 2237 K-ras mutant patients without liver metastases where 882 patients had the G12C subtype (39.4%). On the other hand, only 21 patients were positive for G12C k-ras subtype out of the 74 k-ras mutant patients with liver metastases.Among patients with liver metastases, adenocarcinoma was the most common histological subtype (223 patients), Carcinoma NOS was the second common histological subtype (61 patients).Patients with no liver metastasis had median age of 68. Gender distribution was equivocal.
Conclusion
Patients with k-ras mutant G12C subtype were associated with more frequent PD-L1 expression and less occurrence of liver metastases.
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MA23 - Preclinical Models and Genetics of Malignant Pleural Mesothelioma (ID 353)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Mesothelioma
- Presentations: 1
- Now Available
- Moderators:Ramon Palmero Sánchez, Raphael Bueno
- Coordinates: 9/10/2019, 14:30 - 16:00, Copenhagen (1980)
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MA23.05 - A Phase II Trial of Nintedanib in Recurrent Malignant Pleural Mesothelioma (MPM) (Now Available) (ID 943)
14:30 - 16:00 | Author(s): Misako Nagasaka
- Abstract
- Presentation
Background
Background: Malignant pleural mesothelioma (MPM) is a disease that is resistant to chemotherapy and there remains an unmet need for better therapeutic options. Nintedanib (BIBF 1120) is an oral multikinase inhibitor impacting VEGF, FGF, PDGFR, and other kinase activity such as TGFß signaling pathways. VEGF, FGF, and TGFβ are commonly expressed in MPM. We conducted a phase II trial in patients with recurrent MPM after platinum-based chemotherapy.
Method
Methods: Patients (pts) with MPM previously treated with platinum-based chemotherapy, performance status (PS) 0-1, adequate organ function, and no contraindications to anti-angiogenic therapy were eligible for treatment. Nintedanib 200 mg twice per day was administered until disease progression or unacceptable toxicity. The primary endpoint was the 4-month progression-free survival (PFS). A two-stage design was used and >4 pts had to have a PFS of ≥4 months to proceed to the second stage.
Result
Results: Twenty pts. were enrolled. The median age was 70 yrs. (32-81), 90% were male, and 80% were PS=1. The histology was 70% epithelioidal, 5% sarcomatoid, 10% biphasic, and 15% unknown. 15% had prior bevacizumab. The median follow-up is 16.4 mo. A median of 2 treatment cycles (range 1-18) were delivered. There were no responses but 40% had stable disease. The median PFS was 1.8 mo. (95% CI: 1.68, 3.55) and the PFS rate at 4 mo. was 13%. The median OS was 4.2 mo. (95% CI: 2.53, 8.74) and the OS rate at 4 mo. was 55%. Toxicities were usually grade 1-2 and included diarrhea, fatigue, edema, transaminase elevation, anorexia, nausea, vomiting and dyspnea.
Conclusion
Conclusions: The activity of nintedanib in previously treated MPM pts. was modest. The trial did not meet the primary PFS endpoint. However, there was a small subset of pts. that had prolonged stable disease for >4 months thus potentially deriving some clinical benefit from treatment.
Supported by Boehringer Ingelheim.
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P1.16 - Treatment in the Real World - Support, Survivorship, Systems Research (ID 186)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Treatment in the Real World - Support, Survivorship, Systems Research
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.16-27 - Risk Factors Associated with a Second Primary Lung Cancer (SPLC) in Patients (Pts) with an Initial Primary Lung Cancer (IPLC) (ID 607)
09:45 - 18:00 | Presenting Author(s): Misako Nagasaka
- Abstract
Background
The risk for development of a SPLC after treatment of an IPLC is around 1% to 2% per pt per year. The aim of this study was to characterize the risk factors associated with the development of a SPLC.
Method
Pts registered in the Karmanos Cancer Institute Tumor Registry diagnosed with an IPLC between 2000 and 2017 were included in this study. Pts with an IPLC who later developed a SPLC were matched for age, histology and stage to pts with an IPLC who did not develop a SPLC. SPLC was defined as a second lung cancer with a different pathology or if the same pathology, anatomically, molecularly, or chronologically distinct. Six variables including: stage at IPLC, histology, family history, surgery as a primary treatment for IPLC, and smoking history (determined by pack years, and continued tobacco use after first diagnosis) were reviewed. Logistic and Cox regression analyses were performed to determine the relationship of these characteristics with the development of a SPLC, and their association with overall survival (OS).
Result
121 pts with IPLC who later developed an SPLC were identified and compared to 120 pts with IPLC who did not develop a SPLC. Logistic regression analyses did not show that stage at first diagnosis, histology, family history, smoking history, and continued tobacco use after first diagnosis to be relevant for increased risk of SPLC (Table 1). Pts who were primarily treated with surgical resection had a significantly higher probability of developing a SPLC (Odds Ratio, 0.24; 95% CI, 0.12 to 0.48; p<0.001, see Table 1). Pts who did not have surgical resection as their primary mode of treatment for IPLC had a significantly higher hazard of death than those who received surgical resection (Hazard Ratio, 3.02; 95% CI, 1.99 to 4.57; p<0.001).
Conclusion
Based on our findings, pts who had surgical resection for an IPLC were found to have improved OS and a higher possibility of developing a SPLC. Stage at first diagnosis of IPLC, histology, family history, smoking history and continued use of tobacco after first diagnosis did not correlate with increased risk for SPLC. These results warrant further investigation and if confirmed could have an impact on surveillance recommendations post resection of initial lung cancers.
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P2.01 - Advanced NSCLC (ID 159)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.01-100 - Spectrum of EGFR Exon 20 Insertion Mutations and Co-Occurring Genetic Alterations in Patients with Non-Small-Cell Lung Cancer (ID 2538)
10:15 - 18:15 | Author(s): Misako Nagasaka
- Abstract
Background
Epidermal growth factor receptor (EGFR) exon 20 insertion mutations are associated with a low response rate to approved EGFR tyrosine kinase inhibitors (EGFR-TKIs) and short progression-free survival. Pre-clinical studies have shown differences in the affinity of EGFR exon 20 insertion mutations for EGFR-TKIs, suggesting that the location of the insertion within the C-helix may play an important role in determining EGFR-TKI sensitivity. Several EGFR-TKIs designed to target EGFR exon 20 insertion mutations are in clinical development. Comprehensive genomic profiling has allowed for identification of co-occurring genomic alterations, which may help us identify additional pathways that may drive disease progression and drug resistance.
Method
Formalin-fixed paraffin-embedded (FFPE) samples from patients with non-small cell lung cancer (NSCLC) were profiled by targeted next-generation sequencing (NGS) using Caris Molecular Intelligence (Caris Life Sciences, Phoenix, AZ). Mutations and copy number variations (CNV) were assessed for each gene included in the NGS panel. Gene amplification (including low amplifications) was defined as gene copy number ≥ 4 and copy number loss as gene copy number < -1.4.
Result
Among the 1,556 patients with EGFR mutations, 104 (6.7%) patients were found to harbor an EGFR exon 20 insertion mutation. There were 70 (67.3%) females and 34 (32.7%) males with a mean age 62 (± 11.5 years). 61 (58.7%) samples came from primary lung sites and 43 samples (41.3%) came from metastatic sites. The main histological types were: adenocarcinoma 89 (85.5%), acinar adenocarcinoma 6 (5.7%), papillary adenocarcinoma 5 (4.8%), adenocarcinoma with bronchoalveolar features 1 (1%), squamous cell carcinoma 1 (1%) and carcinoma not otherwise specified 2 (2%). The most common exon 20 insertion mutation was A767_V769dup (25%), followed by S768_D770dup (13%), H773_V774insAH (5%) and H773dup (5%). The most common pathogenic mutations (including presumed pathogenic) included TP53 (51%), followed by CTNNB1 (6%), PIK3CA (4%), PTEN (3%), SMAD4 (3%), and CHEK2 (2%). Of the 104 cases, CNVs were available from 54 patients. Among these patients, commonly amplified genes included CDK4 (11%), EGFR (9%), MDM2 (9%), FOXA1 (7%), and HMGA2 (6%). Copy number loss was observed with CDKN2A (7%), CTNNB1 (2%), ATR (2%), BRCA2 (2%), and FANCL (2%).
Conclusion
The diverse spectrum of EGFR exon 20 insertion mutations shows molecular heterogeneity of this rare type of EGFR mutations. The presence of co-occurring genomic alterations that may promote tumor progression and drug resistance suggests that combination approaches may be necessary to overcome resistance to EGFR-TKI therapy in some patients with an EGFR exon 20 insertion mutation.
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P2.01-14 - Phase 3 Trial of Sitravatinib Plus Nivolumab vs Docetaxel for Treatment of NSCLC After Platinum-Based Chemoimmunotherapy (ID 614)
10:15 - 18:15 | Author(s): Misako Nagasaka
- Abstract
Background
Sitravatinib is a tyrosine kinase inhibitor (TKI) that targets multiple closely-related receptor tyrosine kinases (RTKs), including the split RTKs VEGFR-2 and KIT as well as the TAM (TYRO3, AXL, and MER) RTKs. Inhibition of the split RTKs may reduce immunosuppressive regulatory T (Treg) cells and myeloid‑derived suppressor cells (MDSCs) within the tumor microenvironment (TME), while inhibition of TAM RTKs may, in addition to promoting depletion of MDSCs, repolarize tumor associated macrophages towards the M1 phenotype that is associated with secretion of pro-inflammatory cytokines. Given these pleiotropic immune‑stimulating effects, sitravatinib may augment the antitumor immune response of nivolumab in patients (pts) with non-small cell lung cancer (NSCLC). An ongoing Phase 2 study demonstrates clinical activity of this combination in pts with metastatic non-squamous NSCLC after progression on a checkpoint inhibitor (CIT).
Method
This randomized, open-label, Phase 3 study (N=664) compares the efficacy and safety of sitravatinib in combination with nivolumab vs docetaxel in pts with advanced non-squamous NSCLC who have radiographically documented disease progression on or after platinum-based chemotherapy in combination with CIT. Pts are randomized (1:1) to receive sitravatinib administered orally once daily in continuous 28-day cycles at 120 mg combined with nivolumab IV at 240 mg every 2 weeks or 480 mg every 4 weeks vs treatment with docetaxel 75 mg/m2 IV every 3 weeks. Patients will be stratified based on duration of previous CIT treatment, ECOG performance status, and presence of brain metastases at baseline. Key eligibility criteria include duration of treatment of CIT for at least 4 months, discontinuation of prior treatment with CIT < 90 days prior to the date of randomization, and absence of symptomatic or uncontrolled brain metastases. The primary endpoint is Overall Survival (OS). Key secondary endpoints include safety and tolerability, ORR, PFS, PROs, and PK. OS will be analyzed using Kaplan-Meier methods and the stratified log-rank test to estimate and compare the median OS between the two treatment arms with 95% CI. An IDMC will be established to review safety at regular intervals and to review efficacy data at the planned interim analysis for futility and possible sample size adjustment based on OS.
Recruitment begins May 2019.
NCT number NCT03906071
Result
Section not applicable
Conclusion
Section not applicable.
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P2.04 - Immuno-oncology (ID 167)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.04-88 - Surgical Outcomes of a Multicenter Phase II Trial of Neoadjuvant Atezolizumab in Resectable Stages IB-IIIB NSCLC: Update on LCMC3 Clinical Trial (ID 1817)
10:15 - 18:15 | Author(s): Misako Nagasaka
- Abstract
Background
The role of immune checkpoint inhibitors in resectable NSCLC remains undefined. We report the updated safety results of the first multicenter trial assessing neoadjuvant atezolizumab (a PD-L1 inhibitor) for resectable NSCLC.
Method
Eligible patients with clinical stage IB-IIIB resectable NSCLC received 2 cycles of neoadjuvant atezolizumab (1200 mg, days 1, 22) followed by surgical resection (day 40±10). Pre- and post-treatment PET/CT, pulmonary function tests (PFT), and bio-specimens were obtained. Adverse events (AE) were recorded according to CTCAEv.4.0. Preoperative treatment-related TRAE (preop-TRAE) and postoperative TRAE (postop-TRAE) defined as AE onset on, or after date of surgery, were analyzed.
Result
Follow-up data to post-surgery visit were analyzed for 101 patients out of planned 180: mean age: 64.6 years; male: 47/101(46.5%); current smokers: 23/101(22.8%); non-squamous histology: 66/101(65.3%); and clinical stages IB(10.9%), IIA(15.8%), IIB(27.7%), IIIA(38.6%), and IIIB(6.9%). Two cycles of atezolizumab were not completed in 5/101(5.0%) patients due to grade 1 or 2 AEs. Surgery was not performed in 11/101(10.9%) patients: 5 demonstrated disease progression, and 6 for ‘other’ reasons. 6/101(5.9%) patients were deemed unresectable. Surgery was delayed (outside of 10-day window) in 10/90(11.1%) patients by an average of 11(1-39) days. Two of these delays were due to TRAEs (hypothyroidism and pneumonitis), 3 were patient-elected delays, 2 were surgeon-related, and 3 for ‘other’ reasons. Intraoperative vascular complications occurred in 2/90(2.2%) and extensive hilar fibrosis was noted in 20/90(22.2%) patients. Overall, there was insignificant mean change in the PFTs pre- vs. post-atezolizumab therapy. Only 3/101(3.0%) patients had treatment-related dyspnea, dyspnea on exertion, or pneumonitis.
Table 1
ConclusionTreatment Related Adverse Events
(TRAE)
Preoperative TRAE
(N = 101)
Postoperative TRAE
(N = 90)
All AEs
Any grade
55 (54.5%)
20 (22.2%)
Grade 1
29 (28.7%)
7 (7.8%)
Grade 2
24 (23.8%)
9 (10.0%)
Grade 3
2 (2.0%)
4 (4.4%)
Grade 4
0
0
Grade 5
0
0
Specific AEs
Dyspnea
1 (1.0%; grade 2)
3 (3.3%; grade 1)
Dyspnea on exertion
1 (1.0%; grade 1)
0
Myalgia
4 (4.0%; grade 1 or 2)
0
Hyperthyroidism
3 (3.0%; grade 1 or 2)
1 (1.1%; grade 1)
Hypothyroidism
0
1 (1.1%; grade 2)
Pneumonitis
1 (1.0%; grade 3)
3 (3.3%; grade 2 or 3)
Transaminitis (AST or ALT)
8 (7.9%; grade 1 or 2)
3 (3.3%; grade 1 or 2)
Post-atezolizumab Change in Pulmonary Function Tests
PFT factor
Mean change (95% Confidence Interval)
FEV1 (N = 72)
-0.6% (-2.6% to 1.3%)
FVC (N = 72)
0.0% (-1.8% to 1.8%)
DCLO (N = 64)
-1.2% (-4.1% to 1.7%)
Treatment with neoadjuvant atezolizumab in resectable stage IB-IIIB NSCLC was well tolerated, with minimal delay to surgery, and few treatment associated AEs. This trial continues to accrue and assess MPR, survival, and other long-term endpoints.
