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Sylvia Vania Alarcon
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P01 - Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics (ID 227)
- Event: WCLC 2020
- Type: Posters
- Track: Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P01.08 - Evaluation of Long-Term Pemetrexed Responders in a United States Cohort (ID 3679)
00:00 - 00:00 | Presenting Author(s): Sylvia Vania Alarcon
- Abstract
Introduction
Non-small cell lung cancer (NSCLC) is the leading cause of cancer death1. Pemetrexed, an inhibitor of thymidylate synthase, is approved first line in combination with platinum-based chemotherapy for patients with locally advanced and metastatic non-squamous NSCLC2,3. It is also utilized in the metastatic setting in combination with pembrolizumab followed by pembrolizumab and pemetrexed maintenance therapy.
Results from Keynote-010 suggest a subset of patients who have long-term benefit from maintenance pembrolizumab4,5. This prompted an evaluation of long-term responders to pemetrexed maintenance alone for patients for whom pembrolizumab was contraindicated.
Our investigation describes our institution’s experience with maintenance pemetrexed with the hope of identifying clinical characteristics of patients with NSCLC that may predict long-term pemetrexed responders at a academic medical center in the United States.
Methods
We retrospectively reviewed records of patients with metastatic, non-squamous NSCLC treated at Dana-Farber Cancer Institute, Boston, MA between January 2010 to December 2019 who received pemetrexed as a single agent or in combination with provider’s choice of platinum chemotherapy without progressive disease. Those who received bevacizumab or immunotherapy were excluded. Two cohorts were identified according to time on therapy: 12 to 18 months, and 18 months or more. Demographics and clinical characteristics to evaluate predictive factors were collected. Comparisons for categorical variables used chi-square tests and Fisher exact when cell sizes were too small. Since number of metastases was ordinal, we employed the Mantel-Haenszel test. We used the Wilcoxon rank sum test to compare continuous age across the 2 groups. All analyses were conducted with SAS 9.4 (Carey, NC) and a p-value <0.05 was considered significant.
Results
1235 patients were screened and of those patients, 73 met criteria. 28 (38%) of patients received pemetrexed for less than 18 months, while 45 (62%) of patients remained on therapy for more than 18 months. The majority (63%) were female, white (90%), smokers (81%), with adenocarcinoma (96%), single site of metastases (49%), and ECOG 0-1 (95%). 55% of patients harbored a somatic mutation. Seven patients (9.5%) remained on therapy for over two years. When comparing variables between the two cohorts, there were no differences identified (Table 1).
Conclusion
In this retrospective cohort, were unable to identify any specific clinical predictors of long-term response. Results did seem to be independent of standard clinical factors and somatic mutation status. Continued focus on this area may provide clinical benefit if there are identifiable clinical or biological factors that identify patients who may achieve a long-term response to pemetrexed.
References:
1. National Cancer Institute. SEER Fact Sheets. Lung and Bronchus Cancer. https://seer.cancer.gov/statfacts/html/lungb.html. Accessed 2/15/2018
2. NCCN clinical practice guidelines in oncology. Non-small cell lung cancer. Version 2.2020.
3. Alimta [package insert]. Indianapolis, IN: Eli Lilly and Company; 2004.
4. Herbst RS et al. Lancet. 2016; April 387:1540-1550.
5. Herbst RS et al. Ann Oncol. 2018; 29: x42-x43
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P72 - Tumor Biology and Systems Biology - Basic and Translational Science - Tumor Microenvironment (ID 211)
- Event: WCLC 2020
- Type: Posters
- Track: Tumor Biology and Systems Biology - Basic and Translational Science
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P72.05 - From OR to Lab: Optimized Protocol for Functional Immune Profiling of Freshly Resected Human Non-Small Cell Lung Carcinoma (NSCLC) Specimens (ID 1625)
00:00 - 00:00 | Presenting Author(s): Sylvia Vania Alarcon
- Abstract
Introduction
We have previously reported on clinical and preclinical variables affecting success for generating patient-derived organotypic tumor spheroids (pDOTS) to study immune checkpoint blockade ex vivo in mesothelioma. More recently, we have invested in the creation of a common pipeline to deliver on T-cell banking, pDOTS generation, and physical tumor neoantigen identification from surgical NSCLC specimens. Here we report on further optimization from logistics in the operating room to lab processing to deliver optimally preserved samples for downstream functional analysis of NSCLC tissue.
Methods
Seven surgical NSCLC cases from St. Elizabeth’s Medical Center, Boston, MA under an IRB approved protocol were followed. Prior to surgery, medical records were reviewed for pathology and neoadjuvant chemotherapy administration. Warm ischemia defined as time from clamping of the pulmonary artery or tissue removal to the placement of specimens in culture media on ice. Cold ischemia defined as time from tissue placed in culture media to the beginning of tumor dissociation in the lab. Warm and cold ischemia times were recorded. An improved protocol for tissue dissociation with transfer of newly released spheroids to ice-cold media with serum to keep time in digestion enzymes under 3 minutes was implemented concomitant with flash freezing of a separate piece of tissue on dry ice. Analysis of spheroids at baseline was performed using 4-color immunofluorescence to characterize tumor and immune content and its viability whereas bulk tumor was analyzed by flow cytometry and Poisson detection mass spectrometry.
Results
Study group included 7 cases with the following patient demographics and tissue characteristic: patient average age was 67 (range 51-81) years; gender distribution was balanced with 4 females (57%) and 3 males (43%); stage distribution included 2 (29%) cases from stage I and II each, and 3 (43%) cases from stage III; 4 (57%) cases had adenocarcinoma and 3 (43%) – squamous cell carcinoma tumor histology. The average time of warm ischemia was 15 minutes (range 10- 20 min). Mean time for removal of tissue in the OR to the beginning of processing in the lab was 45 minutes (range 30-60 min). All samples generated sufficient viable material for pDOTS studies, T-cell and tumor banking. Samples from 4 treatment-naïve patients showed an average baseline viability for tumor cells at 66% (range 40-95%). For 3 patients with NSCLC who received prior chemotherapy (platinum/etoposide) and radiation therapy, average baseline viability decreased to 43% (range 30-60%). While the number of CD8 T-cells (CD8s) showed markedly variability based on treatment (chemotherapy/other: 5, 6 and 48 CD8s/well vs naïve: 53, 40, 31, 130 CD8s/well) viability of cytotoxic lymphocytes was unaffected by pretreatment status and ranged from 80 to 90% for both groups.
Conclusion
Our study demonstrates that functional analysis of live tumor tissue requires attention to optimize tissue procurement, limit duration of tissue ischemia, maintenance of maximal cell viability, and the unique challenges to incorporate fresh tissue analyses into standard working operating procedures. While challenging, the barriers to developing functional assays from live tumor tissue are not insurmountable.
