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Yu Shyr
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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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P1.04-17 - Phase I/II Study of Nivolumab and Vorolanib in Patients with Refractory Thoracic Tumors (ID 2443)
09:45 - 18:00 | Author(s): Yu Shyr
- Abstract
Background
Single-agent nivolumab has limited efficacy in thoracic tumors. The antitumor activity of VEGF TKIs is typically attributed to their effect on angiogenesis; however, emerging data suggest these agents can modulate the immune system, especially in the immune suppressive microenvironment. Preliminary results in multiple solid tumors demonstrated clinical benefit when nivolumab was added to anti-angiogenic agents albeit with increased toxicities. Vorolanib was designed to improve the safety profile without compromising efficacy. No dose-limiting toxicities (DLTs) from vorolanib were reported in multiple single-agent phase I trials.
Method
NCT03583086 is an ongoing multi-institutional, phase I/II study of nivolumab and vorolanib in patients with thoracic tumors who have failed at least one prior line of therapy. A standard 3+3 dose escalation design was planned with three doses of vorolanib (200, 300, and 400 mg once-daily) and 240 mg nivolumab every two weeks to determine the maximum tolerated dose. Phase II will evaluate the response rate in five cohorts: PD-1/PD-L1 naïve non-small cell lung cancer (NSCLC), PD-1/PD-L1 primary refractory (defined as progression on PD-1/PD-L1 therapy within 12 weeks), NSCLC patients with acquired resistance (achieved at least stable disease and then progressed) to PD-1/PD-L1, thymic carcinoma, and small cell lung cancer patients who have progressed on prior platinum-based chemotherapy. Exploratory correlatives will assess changes in the innate and adaptive immune responses after treatment.
Result
Phase I enrolled 10 patients (eight NSCLC and two thymic cancers); one patient was not evaluable for DLT and replaced. No DLTs were observed in three patients at the first dose level of 200 mg. Vorolanib was escalated to 300 mg, and elevated ALT (Grade 3) occurred in two of six patients just beyond the DLT period but deemed clinically significant; thus, 200 mg vorolanib with 240 mg nivolumab is being evaluated in expansion cohorts. The most common adverse events were elevated ALT, AST, and lipase, diarrhea, and fatigue; most were Grade 1/2. Grade 4 hyperglycemia and elevated lipase and Grade 3 elevated serum amylase occurred in one patient each. In seven efficacy-evaluable patients (2 immunotherapy naïve NSCLC; 3 NSCLC with prior immunotherapy; 2 thymic cancer), two partial responses were observed (1 PD-1/PD-L1 naive NSCLC and 1 thymic cancer patient); the NSCLC patient was also PD-L1 negative. Three NSCLC patients with prior PD-1/PD-L1 inhibitors had tumor regression; two of these had acquired resistance and the other was primary refractory to prior immunotherapy.
Conclusion
The combination of 200 mg vorolanib and 240 mg nivolumab was generally well tolerated. Clinical activity was observed in both PD-1/PD-L1 naïve patients and those treated with prior immunotherapy. Final phase I results and available phase II data will be presented.
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P2.03 - Biology (ID 162)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.03-58 - Double Primary Lung Cancer and Breast Cancer Is a Distinct Disease Entity (ID 2005)
10:15 - 18:15 | Author(s): Yu Shyr
- Abstract
Background
Double primary lung cancer (LC) and breast cancer (BC) is occasionally observed in clinic. Prior knowledge often attributes increased risks for second primary BC/LC in LC/BC patients to radiation exposure. Our previous study showed that in a 128-patient female Taiwanese double primary LC/BC cohort, 77 (60%) had both cancers diagnosed within 5 years of each other, suggesting the existence of other contributing risk factors. The current study aims to identify characteristics of female double primary LC/BC patients in western-based population.
Method
The double primary LC/BC cohort was identified from the Vanderbilt BioVU database. Vanderbilt BioVU is a de-identified electronic medical record (EMR)-based biorepository that enables longitudinal EMR study and paired genetic data assessment.
Result
A total of 65 patients were identified. Among them, 59 (90.8%) were non-Hispanic Caucasians, 5 (7.7%) were African Americans, and one (1.5%) was an Asian. Twelve (18.5%) had their BC and 5 (7.7%) had their LC diagnosed before age 50. Eleven (16.9%) patients were life-long never-smokers, and among them, 4 (36.4%) had their BC and 2 (18.2%) had their LC diagnosed before age 50. Definite disease diagnostic dates were available in 62 patients. Among these, only 18 (29.0%) received radiotherapy for either LC or BC and had two cancers diagnosed beyond 5 years from each other. Among the 50 patients with available data for BC molecular subtypes, 38 (76.0%) were ER/PR-positive and HER2-negative, 4 (8.0%) were ER/PR-positive and HER2-positive, and 6 (12.0%) were triple-negative. All of the HER2-positive patients were never-smokers; one of them had bilateral BC, another had bilateral LC, and the rest two had strong LC family history. Forty-eight (73.9%) patients in this cohort had family cancer history within their first to third-degree relatives. There were BC in 28 (43.1%), LC in 20 (30.8%), colon cancer in 9 (13.9%), hematological malignancies in 9 (13.9%), gynecological cancers in 6 (9.2%), prostate cancer in 5 (7.7%), pancreatic cancer in 4 (6.2%), gastric cancer in 3 (4.7%), esophageal cancer in 2 (3.1%), glioblastoma multiforme in 2 (3.1%) and kidney cancer in 2 (3.1%) patients, respectively.
Conclusion
Our data showed that female double primary LC/BC is a distinct disease entity, of which hereditary genetic factors may play an important role. In line with our previous study results, radiation exposure may not be the major risk factor for double primary LC/BC. Genomic studies will be of particular importance to unravel the mystery of this unique disease entity.
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P2.04 - Immuno-oncology (ID 167)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 2
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.04-08 - Preliminary External Validation of the Clinical Definitions of Resistance to Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer (ID 2837)
10:15 - 18:15 | Author(s): Yu Shyr
- Abstract
Background
Immune checkpoint inhibitors (ICIs) have become an important component of treatment for patients with advanced stage non-small cell lung cancer (NSCLC). Unfortunately, the majority of patients on ICIs will eventually progress. Based on the results from a meta-analysis review of the current ICI literature, Gillaspie et al developed a clinical radiographic response criterion to classify patients as having innate, acquired resistance or durable response to ICIs. The objective of this study was to validate this categorization using prospectively collected clinical data.
Method
The study population consisted of Stage IIIB and IV, biopsy-proven NSCLC patients from a single institution treated on or off a clinical trial with single agent ICIs in the first, second line or beyond. De-identified tumor data, stage and treatment data long with response to ICIs were collected prospectively into a database. Patients were censored at last date of follow-up if no progression had occurred. Progression-Free survival (PFS) curves and rates were estimated using the Kaplan-Meier method and then compared to the categorization established by the meta-analysis.
Result
From April 2012 to January 2018, 231 patients met criteria for inclusion and analysis. Median age was 65 years, 61% were male and 92% white. Forty-three (18.6%) received ICI in the first line, while the remaining 188 were treated in the second line or above. Analogous to the meta-analysis, our single center data demonstrated three distinct sub-populations of response. PFS curve slopes were evaluated and compared between the proposed classification and our single center experience (Table 1). The slopes of the curves are similar for the Innate, Adaptive or Acquired Resistance and Durable Response categories established in the meta-analysis. Our single-center experience resulted in a slightly steeper slope in the innate response category compared to the clinical trial literature. This may be explained by our cohort including patients who are treated in the third line or beyond whereas most of the meta-analysis trials restricted populations to either first or second line only. A steeper PFS curve would be expected in a more heavily treated population.
Table 1 PFS Slope Meta-Analysis PFS Slope Validation Innate Resistance 12.9 14.0 Aquired Resistance 3.8 3.4 Durable Response 1.2 1.1
Conclusion
This single center assessment of the proposed classification for resistance to immune checkpoint inhibitors in non-small cell lung cancer confirms the three distinct subgroups of response based on a comparison of the PFS curves. A formal statistical validation will be performed and presented. Future studies are planned to include prospectively collected data from additional comprehensive cancer centers within the validation cohort.
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P2.04-50 - Advanced Statistical Approach Tells the Difference: Taylor-Expansion Adjustment for Survival Analyses in Immunotherapy Trials (ID 1781)
10:15 - 18:15 | Author(s): Yu Shyr
- Abstract
Background
The success in immune checkpoint inhibitors (ICIs) has again revolutionized the paradigm in lung cancer therapy, especially among patients without druggable driver mutations. Landmark studies, such as Keynote 010/042 and Checkmate 017/057, showed that patients in the ICI study arm had a better overall survival compared to patients receiving standard chemotherapy. Furthermore, most of the Kaplan-Meier (KM) survival curves crossed within the first 3 to 6 months and the survival curve for ICI study arm showed a long-tail, suggesting the existence of a subgroup that truly respond to ICIs. However, the traditional Cox proportional hazards model does not provide adjustment for treatment responses between true-responders and poor-responders. We hypothesize that hazard ratios (HRs) between the treatments differ from these two subgroups and adjustment is required for survival evaluation in ICI trials.
Method
Overall survivals in Keynote 010, 042, 189, 407 and Checkmate 017/057 three-year updated data served as the real data illustrations in the current study. The Taylor expansion was applied to the adjustment of HRs derived from the traditional Cox model. Comparisons between the adjusted and the crude HRs were made and the differences in the proportion of patients with long-term survival obtained by the adjustment approach were also inferred.
Result
Our results showed that when the adjustment approach was applied, the adjusted HRs for the ICI poor-responders compared to the chemotherapy control became statistically non-significant. Furthermore, the proportion of patients with long-term survival differed significantly between ICI true-responders and chemotherapy control. The pattern was observed in all four ICI monotherapy studies with crossing survival curves in the initial 3-6 months (Table 1).
Conclusion
The results suggested that the traditional Cox model might not be the optimal method for survival analyses in ICI trials and adjustment is necessary. The differences between the adjusted and the crude HRs may be very significant.
