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David P Carbone
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EP1.12 - Small Cell Lung Cancer/NET (ID 202)
- Event: WCLC 2019
- Type: E-Poster Viewing in the Exhibit Hall
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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EP1.12-38 - Retrospective Analysis of Immunotherapy Utilization in Advanced Small Cell Carcinoma at an Academic Cancer Center (Now Available) (ID 2520)
08:00 - 18:00 | Author(s): David P Carbone
- Abstract
Background
Small-cell carcinoma (SCC) is an aggressive neuroendocrine carcinoma which commonly originates in the lung (SCLC). In contrast to non-small cell lung cancer (NSCLC), immunotherapy (IO) utilization has been limited for SCLC. Nivolumab was approved as a single agent in 2018 for third-line therapy. In 2019, the IMpower133 trial led to approval of first-line chemo-IO (atezolizumab plus carboplatin and etoposide) for extensive-stage SCLC. Despite these approvals, there is limited data about experience utilizing IO in SCC outside of clinical trials, including patterns of care, survival, and incidence of brain metastases. We therefore conducted a retrospective review of IO utilization at an academic cancer center in the United States.
Method
Institutional pharmacy database was used to perform an unstructured data collection of medical record numbers based on SCC diagnosis and IO treatment codes between January 1, 2008 and October 1, 2018 at The Ohio State University Medical Center. Patient data was then abstracted from the electronic medical record. Variables included demographics, co-morbidities, stage, metastatic sites (including brain), treatment history (including chemotherapy, IO and radiation), and treatment response. Survival from the start of IO to death and median overall survival (OS) from diagnosis to death were calculated.
Result
Forty patients, 17 women and 23 men, were eligible for evaluation. The median age was 64 years (30-91 yo); 36 patients were current/former smokers. At diagnosis, most were extensive-stage (65%). Common metastatic sites at diagnosis included brain (20%), bone (35%) and liver (33%). Overall, 22 patients (55%) developed brain metastases over the course of disease. Median line of IO was 2nd line (range 2nd-5th line); nivolumab-ipilimumab was the most common regimen (43%), followed by nivolumab (38%), then pembrolizumab (20%). Patients received an average of 4 cycles of IO (range 1-35). Nine patients were treated on clinical trial. Median survival after IO was 4.2 months and median OS of 17.3 months. Median survival for patients with brain metastases was 2.2 months vs. 10.3 months without (P=.01). Most patients had no durable response to IO; however, responses were observed in 7 patients (1 CR, 6 PR) and 8 patients had stable disease.
Table 1: Treatment Summary Treatment
Patients – no.
Chemotherapy – any line
Carboplatin
28
Cisplatin
15
Etoposide
40
Topotecan
19
Irinotecan
23
Paclitaxel
11
Gemcitabine
1
Immunotherapy
Nivolumab-ipilimumab
17
Nivolumab
15
Pembrolizumab
9
Radiation Therapy
Radiation (non-CNS site)
36
Radiation (CNS)
24
Type of CNS radiation
Prophylactic Cranial Irradiation
8
Whole brain radiation (therapeutic)
16
Gamma knife/stereotactic radiation
6
This retrospective review describes our experience utilizing IO in advanced SCLC at our academic institution. Although treatment patterns are changing with first-line IO, this data reflects the variability of patient responses. Several patients had prolonged responses, indicating potential areas of further investigation. This data will also be used to evaluate IO activity in CNS disease.
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MA11 - Immunotherapy in Special Populations and Predictive Markers (ID 135)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:Frank Griesinger, Lecia Sequist
- Coordinates: 9/09/2019, 14:00 - 15:30, Hilton Head (1978)
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MA11.11 - STK11/LKB1 Genomic Alterations Are Associated with Inferior Clinical Outcomes with Chemo-Immunotherapy in Non-Squamous NSCLC (Now Available) (ID 2898)
14:00 - 15:30 | Author(s): David P Carbone
- Abstract
- Presentation
Background
Addition of pembrolizumab (P) to platinum-doublet chemotherapy [carboplatin (or cisplatin) and pemetrexed (CP)] prolongs overall survival and is a standard of care (SOC) for the 1st line treatment of metastatic EGFR/ALK wild-type (wt) non-squamous non-small cell lung cancer (mnsNSCLC). Despite widespread use of the CPP regimen, molecular determinants of clinical benefit from the addition of P to CP remain poorly defined. We previously identified genomic alterations in STK11/LKB1 as a major driver of primary resistance to PD-1/PD-L1 blockade in mnsNSCLC. Here, we present updated data on the impact of STK11/LKB1 alterations on clinical outcomes with CPP chemo-immunotherapy from a large retrospective multi-institution international study.
Method
620 pts with mnsNSCLC and tumor genomic profiling encompassing STK11/LKB1 from 21 academic institutions in the US and Europe were included in this study. Clinical outcomes were collected for two distinct patient cohorts: a) 468 pts treated with first-line CPP (or >1st line following FDA-approved TKIs) that were alive for 14 days thereafter and b) 152 STK11/LKB1-mt pts that received CP prior to regulatory approval of CPP.
Result
Among 468 CPP-treated pts, STK11/LKB1 genomic alterations (N=118) were associated with significantly shorter PFS (mPFS 5.0m vs 6.8m, HR 1.45, 95% CI 1.11 to 1.91; P=0.007) and shorter OS (mOS 10.6m vs 16.7m, HR 1.46, 95% CI 1.04 to 2.07; P=0.031) compared with STK11/LKB1-wt tumors (N=350). The likelihood of disease progression as BOR to CPP differed significantly between the two groups (29.5% vs 17%, P= 0.006). Similar results were obtained when limiting the analysis to EGFR and ALK-wt tumors (N=435) (mPFS 5.0m vs 6.9m, HR 1.48, 95% CI 1.12-1.95, P=0.006 and mOS 10.6m vs 16.7m, HR 1.45, 95% CI 1.02-2.05, P=0.036). Importantly, in pts with STK11/LKB1-mt mnsNSCLC, addition of pembrolizumab to CP did not result in significant improvement of PFS (mPFS 5.0m vs 3.9m, HR 0.82, 95% CI 0.63 to 1.07, P=0.14) or OS (mOS 10.6m vs 9.1m, HR 0.93, 95% CI 0.67 to 1.30, P=0.69) compared to CP alone.
Conclusion
In mnsNSCLC, STK11/LKB1 alterations define a subgroup of pts with inferior clinical outcomes with CPP and lack of benefit from the addition of pembrolizumab to CP chemotherapy. Novel therapeutic strategies are required to establish effective antitumor immunity in STK11/LKB1-mutant NSCLC.
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MA17 - Molecular Mechanisms and Therapies (ID 143)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Biology
- Presentations: 1
- Now Available
- Moderators:Eloisa Jantus-Lewintre, Hongbin Ji
- Coordinates: 9/09/2019, 15:45 - 17:15, Melbourne (1991)
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MA17.02 - Identify Vulnerable Pathways and Improve Treatment Outcomes in LKB1-Deficient Lung Tumors (Now Available) (ID 2067)
15:45 - 17:15 | Author(s): David P Carbone
- Abstract
- Presentation
Background
The LKB1 tumor suppressor is inactivated in about 20% of non-small cell lung cancers (NSCLC) by mutations. Cancer cells with LKB1 deficiency exert complex effects on signal transduction and transcriptional regulation, which may cause these cells more susceptible to certain therapies comparing to cells with intact LKB1 function. Phenformin, an antidiabetic medicine from the biguanides class, has shown activities against NSCLC. Phenformin as a single agent has been shown to reduce tumor burden and prolonged survival in Kras;Lkb1 compound mutant mice but not Kras;p53 mice, suggesting specific activities in tumor with LKB1 deficiency. Currently patients with unresectable locally advanced NSCLC are treated standardly with concurrent chemoradiotherapy followed by checkpoint inhibitor, durvalumab. In this project, we test treatment sensitivity to radiotherapy and/or phenformin in lung cancer cells with intact or deficient LKB1.
Method
Human lung cancer cell lines described below were used in (1) clonogenic survival assays as well as (2) generating tumor xenograft on nude mice for tumor growth delay experiments. A549, HCC15 and Calu-1 cell lines obtained from ATCC were cultured in RPMI1640 containing 5% FBS, without antibiotics. A549 cells (LKB1 deficient, TP53 WT and KRAS mutated) or HCC15 (LKB1 deficient, TP53 mutated and KRAS WT) were transfected with empty vector or WT LKB1 or LKB1-K78I plasmids; Calu-1 (LKB1 WT, KRAS mutated and p53 deleted) transfected with empty vector or LKB1 CRIPR KO were generated as described previously.
Result
A549 cells with transfected WT-LKB1 were significantly more resistant to ionizing radiation (IR) induced cell kill (8.7% survival at 8 Gy) comparing to cells transfected with empty vector (3.7%) or kinase-dead LKB1 genes (4.2%). Similarly, HCC15 cells with transfected WT-LKB1 are significantly more resistant to IR induced cell kill (7.5%) comparing to cells transfected with empty vector (4.1%) or kinase-dead LKB1 genes (3.4%). Calu-1 cells harbor WT LKB1, and it is significantly more resistant to IR induced cell kill (8.3%) comparing to their counterpart with LKB1 KO (Calu-1 transfected with LKB1 CRIPR KO) (4.1%). When A549 cells were pretreated with 30 μM phenformin prior to, during and after IR, there was no change in survival in cells transfected with WT LKB1; however there was significant further reduction in survival in cells transfected with empty vector (LKB1 deficient). Xenograft tumors were generated in nude mice with A549 cells with the above genetic alterations. There was significant further tumor growth delay in those with A549 with deficient LKB1 comparing to those with A549 with WT LKB1 gene add-back. This tumor growth delay was further enhanced when these mice were treated with oral phenformin prior to, during and after IR treatment, confirming the in vitro experimental results.
Conclusion
Human lung cancer with deficient LKB1 are more sensitive to ionizing radiation in vitro and in vivo. This was regardless of the TP53 or KRAS mutation status. A549 cells with deficient LKB1 were also more sensitive to phenformin treatment. Phenformin treatment further sensitized LKB1 deficient lung cancer cells to IR. This suggested that LKB1 can serve as a predictive biomarker to triage patient treatments.
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MS02 - What Molecular Screening for Which Patients? (ID 65)
- Event: WCLC 2019
- Type: Mini Symposium
- Track: Targeted Therapy
- Presentations: 1
- Now Available
- Moderators:Rosario Garcia Campelo, Santiago Ponce
- Coordinates: 9/08/2019, 10:30 - 12:00, Vienna (2016)
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MS02.01 - Platform Selection in an Era of Increasing Numbers and Types of Relevant Biomarkers (Now Available) (ID 3446)
10:30 - 12:00 | Presenting Author(s): David P Carbone
- Abstract
- Presentation
Abstract
30 years ago, the selection of therapy for lung cancer patients was simple, with only a few choices available, and very little personalization beyond that which can be defined by standard light microscopy and physical exam. The treatment of lung cancer patients today has greatly improved with the discovery of features of tumors and patients that enable the selection of specific targeted and immunotherapy approaches resulting in substantially improved quality and quantity of life. Selection of the appropriate therapeutic based on these features makes huge differences in the lives of these patients, and many studies are now showing that starting with the matched therapy improves survival over switching to it after trying “one size fits all” therapy.
Scientific advances are introducing more and more of these markers every year, and while this is undoubtedly a good thing for our patients, each of them has sensitivity, specificity, and platform issues that need to be defined, and adds a level of complexity to lung cancer management that is unprecedented. Individually, many of these features are rare so that the vast majority of individual assays performed are negative, further adding to clinical frustration. Technology has advanced to allow the testing of hundreds or thousands of gene sequences in a single analysis, but other markers are not simple gene sequence alterations, but rather gene rearrangements, protein expression alterations, and some RNA expression profiles that require testing on different platforms. As a result, optimal tumor profiling can involve several different analyses, can cost a significant amount of money, and take a significant amount of time to return a result in a disease where both time and resources available are scarce. Biopsy adequacy also becomes an issue with multi-platform testing, and the availability of blood-based testing lessens this issue for certain types of testing, but introduces issues of limited sensitivity and scope of analyses.
Layered upon this are the different health care systems and availability of testing platforms found worldwide, each of which has to make hard decisions about doing the best thing for their patients within these local constraints. However, the impact on patient outcomes and the health care system of missing a key tumor feature and the selection of inappropriate and potentially toxic therapy, in a world where a single dose of a drug costs several times the cost of the testing makes cost of testing less of an issue than sample adequacy, speed of results availability, accuracy of results interpretation, and availability of matching drugs.
In this section, the clinical and technical features of the currently available platforms in use and their advantages and disadvantages will be reviewed and compared.
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OA13 - Ideal Approach to Lung Resection and Novel Perioperative Therapy (ID 146)
- Event: WCLC 2019
- Type: Oral Session
- Track: Treatment of Early Stage/Localized Disease
- Presentations: 1
- Now Available
- Moderators:Tomasz Grodzki, Kenji Suzuki
- Coordinates: 9/10/2019, 11:30 - 13:00, Toronto (1985)
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OA13.07 - Neoadjuvant Atezolizumab in Resectable NSCLC Patients: Immunophenotyping Results from the Interim Analysis of the Multicenter Trial LCMC3 (Now Available) (ID 1755)
11:30 - 13:00 | Author(s): David P Carbone
- Abstract
- Presentation
Background
The immune mechanisms dictating response and resistance to PD-(L)1 blockade are not well understood in early stage non-small cell lung cancer (NSCLC). Understanding these mechanisms will be key to improve outcomes and identify the next generation of predictive biomarkers of response to these therapies. Here, we present updated immunophenotyping at time of interim analysis of LCMC3, a multicenter trial of neoadjuvant atezolizumab in resectable NSCLC (NCT02927301).
Method
Patients received 2 cycles of atezolizumab before resection. Tumor, LN biopsies and PB were obtained pre-atezolizumab and at surgery. Paired PB, screening and surgical LN were analyzed using IMMUNOME flow cytometry. Plasma-based cytokine arrays were performed on a subset of patients. Immunophenotypic analyses were correlated with treatment effect, major pathologic response (MPR, primary endpoint) and preoperative treatment-related adverse events (preop-TRAE).
Result
We report on 55 patients with paired PB samples (analyzed within 72h after collection) and completed surgery. We observed preop-TRAE in 32/55 patients (18 grade 1, 13 grade 2, 1 grade 3). CD1c+ and CD141+ myeloid cells (MC) were lower at baseline in patients developing preop-TRAEs, while monocytic M-MDSCs were higher in those patients. Senescent T cells decreased in patients with preop-TRAE and increased in patients with non-preop-TRAE. After treatment, the absolute cell counts of late activated CD4+and CD8+T cells decreased in patients achieving MPR. LN IMMUNOME data, cytokine data and 12-month follow-up (DFS, OS) will be reported.
Preliminary immunophenotyping data from the interim analysis showed significantly lower baseline immunosuppressive cell subsets in patients with preop-TRAE and decreased late activated CD4+and CD8+T cells from PB in patients with MPR.These results, together with additional LN IMMUNOME and cytokine analyses, may improve our understanding of immunophenotypic features associated with outcome, and changes induced by neoadjuvant atezolizumab in early stage NSCLC patients.
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OC01 - Opening Ceremony (ID 82)
- Event: WCLC 2019
- Type: Opening Ceremony
- Track:
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/07/2019, 19:00 - 20:30, Barcelona (2005)
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OC01.02 - IASLC Distinguished Awards (Now Available) (ID 3553)
19:00 - 20:30 | Author(s): David P Carbone
- Abstract
- Presentation
Abstract not provided
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-71 - Bone Metastases and Skeletal-Related Events in Patients with Metastatic NSCLC Treated with ICIs: A Multi-Institutional Study (Now Available) (ID 2421)
09:45 - 18:00 | Author(s): David P Carbone
- Abstract
Background
Skeletal-related events (SRE) occur frequently in patients (pts) with metastatic NSCLC (mNSCLC) and confer a poor prognosis. Data on SRE and the effects of bone modifying agents (BMA) in NSCLC pts treated with immune checkpoint inhibitors (ICI) are limited as is the effect of bone modifying agents (BMA) on development of SRE and overall survival (OS). Here we report the incidence, impact on survival, and risk factors for SRE in pts with mNSCLC treated with ICI in a multi-institutional cohort.
Method
We conducted a retrospective study of pts with mNSCLC treated with ICI at our institutions from 2014 to 2017. Overall survival (OS) was calculated from the date of ICI initiation to death from any cause or last follow-up. Cox regression model was used to study the association between OS and baseline bone metastases (BM). The associations between SRE and categorical outcomes were studied using chi-square/Fisher’s exact test. The study was approved by each institution’s ethics review board.
Result
Table 1. Multivariate survival analysis. Parameter Level Hazard Ratio 95% HR Confidence Limits P-value BM at baseline Absent Ref <0.0001 Present 1.847 1.414-2.413 ECOG 0 Ref 0.0006 1 1.494 1.017-2.196 2 1.506 0.969-2.341 3 3.788 1.442-9.949 Histology Adenocarcinoma Ref 0.969 Squamous 1.057 0.786-1.420 Lines of Therapy 1 Ref 0.0007 2 1.580 1.123-2.223 >=3 2.064 1.417-3.005 We identified a cohort of 330 pts: 259 (72%) treated in second line or beyond; 211 (64%) received nivolumab; median age 63.4; median OS 10.4 mo (95% CI: 8.6, 12.5). In our cohort, 124 (38%) pts had BM at time of ICI, and 43 (13%) developed SRE after ICI (median 2.8 months; 19 pathologic fractures, 1 cord compression, 26 palliative radiation, 8 surgery). Patients with BM at ICI had shorter OS after controlling for ECOG, histology, and line of therapy (Table 1; Hazard Ratio 1.847; 95% CI 1.414 - 2.413; p <0.0001) compared to pts without baseline BM. Development of SRE was associated with presence of BM at baseline but not age, histology, or mutation status (EGFR, KRAS, and TP53). The use of BMA was not associated with OS or decreased risk of SRE. The development of new or progression of existing BM (22% of pts) during ICI was associated with a worse prognosis (mOS 7.1 vs 11.6 mo, p=0.017).
Conclusion
Bone metastases and SRE are a significant cause of morbidity in pts with mNSCLC treated with ICI. The presence of BM at baseline was associated with a worse prognosis after controlling for multiple clinical characteristics. In our cohort, the use of BMA was not associated with decreased risk of developing SRE, osseous progression, or survival.
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P1.04 - Immuno-oncology (ID 164)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.04-15 - Smoking Status Is Not a Replacement Biomarker for Tumor Mutation Burden in Non-Small Lung Cancer (ID 454)
09:45 - 18:00 | Author(s): David P Carbone
- Abstract
Background
Recent clinical studies suggest tumor mutation burden (TMB) as a promising therapeutic biomarker of anti-tumor immune checkpoint blockade (ICB). Given the causal link between cancer-causing mutations and tobacco smoking, patients with a significant smoking history may respond better to ICB. However, it is not clear if smoking history is an adequate surrogate biomarker for TMB. Here, we sought assess the clinical utility of smoking history in predicting tumor mutation burden.
Method
Publicly available smoking history and DNA somatic alteration data from NSCLC were downloaded from The Cancer Genome Atlas and a large dataset of lung adenocarcinoma tumors published by Imielinski, et al (Cell, 2012) Tumor mutation burden was calculated as the sum of all somatic mutations divided by the exome sequencing coverage. Smoking history was analyzed both as categorical (ever, never, former) and semi-continous variables (pack years). Hypermutancy was defined as greater than or equal to 10 mutations per megabase.
Result
A total of 395 LUAD and 419 LUSC patients were included in this analysis. Smokers had significantly higher tumor mutation burdens than non-smokers; however, in both LUAD and LUSC, there were smokers with low TMB and non-smokers with high TMB. Smoking pack year history (SPY) was weakly positively correlated (Spearman ρ = 0.20, p = 2.5x10-4) in LUAD but uncorrelated (Spearman ρ = -0.026, p = 0.61) in LUSC. Non-smokers and patients without a recorded SPY were excluded from the SPY analysis. We calculated AUCs for predicting hypermutancy in tumors, using variable thresholds of SPY. In LUAD and LUSC, SPY had an AUC of 0.38 and 0.47 in predicting TMB, showing that SPY was not better than random prediction. We also sought to predict TMB from smoking as a binary variable. In LUSC, 8/18 (44%) non-smokers and 253/447 (57%) smokers were hypermutant. In LUAD, 9/61 (15%) non-smokers and 219/391 (56%) smokers were hypermutant. Additionally, we repeated this analysis on matched smoking history and TMB from an independent cohort of 162 LUAD tumors published by Imielinski, et al. Similarly, we found that 1/27 (4%) of nonsmokers and 66/135 (49%) of smokers were hypermutant. In this cohort, the AUC in predicting TMB with SPY was 0·21.
Conclusion
In this study, we investigated the relationship between tobacco smoking and TMB. While the average lung cancer patient with a history of tobacco smoking has a higher TMB than the average never-smoker, there is not a clear relationship between the extent of exposure in pack years and TMB. In general, smoking is not an informative biomarker for TMB, however, non-smokers who develop LUAD are unlikely to have high TMB. This study highlights the value of next generation sequencing for TMB in predicting therapeutic response to ICB.
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P1.10 - Prevention and Tobacco Control (ID 175)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Prevention and Tobacco Control
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.10-11 - Examination of Lifestyle Factors and Associations with Genetic Mutations in Lung Cancer Cases (ID 2545)
09:45 - 18:00 | Author(s): David P Carbone
- Abstract
Background
With the advent of targeted therapy it is extremely useful to know what factors may be associated with specific mutations in order to better target treatment therapies. Few reports have assessed factors related to targeted therapies for lung cancer, especially in the United States. Common driver mutations relevant to lung cancer include EGFR, ROS1, ALK, KRAS and RET. In this report, we examined demographic, clinical and selected lifestyle factors, including age, sex, smoking, body mass index (BMI) and NSAID use and their association with lung cancer specific mutations.
Method
Electronic medical records were reviewed for lung cancer cases (ICD-9: 162.2-9; ICD-10: C34.X) from the Ohio State University James Cancer Hospital from 2013-2018; demographic, clinical and lifestyle data were extracted, including age, sex, smoking, body mass index (BMI), NSAID use, as well as any driver mutations (EGFR, ROS1, ALK, KRAS and RET). Due to the small sample sizes for some of the mutations, they were combined into one overall mutation variable. Logistic regression analysis was performed to assess whether any associations exists between the risk factors and the presence of a mutation. Odds Ratios (ORs) were used to estimate the associations with alpha=0.05.
Result
We identified 892 lung cancer cases in which tumor specimens were examined for mutations. Four types of mutations were identified: EGFR (n=89), ALK (n=19), ROS1 (n=8) and RET (n=12), for a total of 127 cases with mutations compared to 765 without mutations. The mean age for both groups was 65 years, with over 61% of the mutation group being female versus 54% of the non-mutation group). Overall, 84% of cases were white race, with slightly more non-whites in the mutation group (86% versus 83%). Logistic regression analyses revealed that age <50 years (OR=1.9; 95%CI=1.1, 3.6), female gender (OR=2.1, 95%CI=1.4, 3.1), and never smoking (OR=7.5, 95%CI=4.08, 3.5) were significantly associated with increased odds of having a mutation after controlling for other factors. Having a BMI>30 approached significance (OR=1.01, 95%CI=0.99,1.02) but NSAID use (aspirin, ibuprofen and/or acetaminophen) did not show significant associations with the presence of lung cancer mutations in this analysis.
This study revealed significant associations between younger age (<50 years), female gender and never smoking with the presence of driver mutations in lung cancer cases. Previous reports have not assessed the relationship between BMI, NSAID use and lung cancer driver mutations to our knowledge. We also understand the significant limitations in obtaining quality data on NSAID use from the medical charts, and a more in-depth review is being planned. Nevertheless, this report confirms several known predictive factors related to driver mutations, and for the first time shows a lack of correlation with NSAIDs and potentially BMI. Future reports should also aim to assess more diverse populations.
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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): David P Carbone
- 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.
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P2.14 - Targeted Therapy (ID 183)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 2
- Now Available
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.14-10 - Identification of Frequent, Activating HER2 Mutations and HER2 Inhibitor Response and Resistance in Canine Lung Cancer (Now Available) (ID 2583)
10:15 - 18:15 | Author(s): David P Carbone
- Abstract
Background
Naturally occurring primary canine lung cancers share clinical and pathologic features with human never-smoker lung cancer, but their genetic and biologic underpinnings have been unknown. We mapped the genomic landscape of canine lung cancer, discovering somatic HER2 (ERBB2) mutations in ~38% of canine pulmonary adenocarcinomas (cPACs). We describe our genomic findings, effects of HER2 mutations on cell signaling and HER2 inhibitor response/resistance, and results of pharmacokinetic (PK) studies of the HER2 inhibitor neratinib in healthy dogs.
Method
We performed multi-platform genomic analysis of 92 primary canine lung tumors or cell lines. We evaluated HER2 signaling by Western blot. Neratinib and lapatinib responses were assessed in HER2-mutant and wild-type cPAC cell lines in vitro. HER2-mutant cell lines were continuously treated with IC50 neratinib doses to select for drug resistance, then evaluated for resistance mutations. Neratinib tolerability and PK were evaluated in healthy, mixed-breed, middle-aged dogs given a single 6 mg/kg oral neratinib dose with or without maropitant citrate or loperamide. Plasma samples for PK were collected pre-dose and timepoints from 0.5-24h after dosing.
Result
Canine lung cancers exhibited low tumor mutation burden. HER2 was the most commonly mutated gene in cPACs, occurring in ~38%, but was absent from canine adenosquamous or squamous cell carcinomas. HER2 hotspot V659E transmembrane domain (TMD) mutations were most common and comparable to activating TMD mutations in human cancer. HER2 V659E correlated with constitutive phosphorylation of Akt in cPAC cell lines. HER2 V659E lines displayed hypersensitivity to neratinib and lapatinib relative to wild-type lines. Continuous treatment of HER2-mutant cell lines led to rapid development of resistance. Characterization of resistance-driving alterations is ongoing, as are efficacy studies in mouse xenografts. A dose of 6 mg/kg neratinib in healthy dogs showed that neratinib was tolerable and achieved therapeutic levels from IC50 studies. Evaluation of neratinib tolerability and efficacy in dogs bearing HER2-mutant lung cancer is ongoing.
Conclusion
HER2 TMD mutations are common in otherwise low-mutation-burden primary canine lung cancers. They confer constitutive HER2 signaling and HER2 inhibitor response in cell lines. Dosing and tolerability studies in healthy dogs have shown that therapeutically relevant doses are achievable. Study of HER2 inhibitor response/resistance in cell lines and mouse xenografts is ongoing as is clinical evaluation of neratinib activity in dogs with spontaneous lung cancer. These data offer immediate diagnostic and therapeutic opportunities for pet dogs and bear implications for comparative understanding of human never-smoker lung cancers and other HER2-mutant cancers.
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P2.14-19 - Notch3 and β-Catenin Are Frequently Co-Expressed in EGFR Mutant NSCLC (ID 2976)
10:15 - 18:15 | Author(s): David P Carbone
- Abstract
Background
In the USA approximately 15% of the patients with lung adenocarcinoma have tumors associated with “driver” mutations in the EGFR gene that demonstrate major clinical responses to EGFR Tyrosine Kinase Inhibitors (EGFR TKIs). However, despite the fact that these mutations are always “truncal” (present in every tumor cell), and dramatic tumor shrinkage is seen initially in almost all patients, EGFR TKIs are never curative and tumors always recur. Some tumors that develop resistance appear to have pre-existing resistant sub clones, but the majority appear to acquire resistance by mutational target reactivation or bypass mechanisms. In order to develop acquired resistance, a subset of cells must survive at initial stage of therapy (“drug persister cells”, or DPCs) which are known to serve as a reservoir for accumulation mutation rendering drug resistance. We have demonstrated that Notch3 mediated β-catenin activation enables drug persistence, an essential step for the development of drug resistance.
Method
We have conducted tumor protein expression analysis on a tissue micro array (TMA) containing 86 NSCLC tumors obtained before therapy. These TMAs were subjected to IHC analysis to detect the expression of Notch3 and β-catenin signaling which is known to regulate drug persistence. We have also performed cell viability and biochemical assays under various perturbations to study drug persistence mechanisms in EGFR mutant NSCLC cells.
Result
Previously, we have demonstrated that EGFR TKI treatment leads to drug persistence through Notch3 mediated β-catenin activation. Using pre-treatment NSCLC patient tissue micro array (TMA) we identified that there is frequent co-expression of Notch3 and β-catenin (total) proteins in 90% of EGFR mutant NSCLC. We also observed that there are a relatively low proportion (10%) of patients with active β-catenin in these pretreatment samples. This suggests that the EGFR mutant tumors upregulate Notch3 protein expression, but that β-catenin is predominantly transcriptionally inactive before EGFR TKI treatment. We have also identified that Notch3 is a novel transcriptional target of β-catenin which in turn promotes both β-catenin and EGFR stability. These findings suggest that the Notch3 and inactive β-catenin co-expression is characteristic of EGFR mutant tumors, and β-catenin activation at baseline is infrequent. EGFR TKI therapy activates β-catenin signaling in a Notch3 dependent manner, and here we show that both proteins are frequently highly expressed in these tumors.
The concept of DPCs serving as a reservoir for accumulation of mutations that could cause drug resistance is novel. However, signaling pathways that are associated with the activation of drug persistence are not well characterized. For the first-time, our studies demonstrate that Notch3, β-catenin andEGFR regulate each other and EGFR TKI therapy mediated Notch3 activation leads to β-catenin activation which is essential for the maintenance of drug persister cells in a positive feedback loop. By understanding and targeting the Notch3 - β-catenin axis that control DPCs, these studies can develop therapeutics to prevent resistance to EGFR TKI therapy.