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David Elashoff
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P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.01-104 - Updated Phase I Results of Carboplatin, Pemetrexed and Exemestane in Postmenopausal Women with Metastatic Non-Squamous NSCLC (ID 14158)
16:45 - 18:00 | Author(s): David Elashoff
- Abstract
Background
Estrogen receptors (ERa, ERb) and aromatase (key enzyme for estrogen synthesis) are expressed in most human NSCLCs. High intratumoral estrogens and elevated aromatase expression in NSCLC predicts poor outcome. In vitro preclinical models show that estrogen stimulates NSCLC gene expression, induces proliferation, and diminishes apoptosis. Furthermore, preclinical NSCLC models demonstrate that antiestrogens or aromatase inhibitors prevent these processes and that the combination of cisplatin and aromatase inhibitors elicits dramatic growth inhibition (Marquez et al., Annals NY Acad Sci. 2009;1155:194). Additionally, depletion of autocrine/paracrine estrogen production hypersensitizes cells to DNA-damaging effects of platinum therapy, thereby providing support for this early phase trial.
a9ded1e5ce5d75814730bb4caaf49419 Method
The primary objective of this phase 1b, open-label, single-center study (NCT01664754) was to evaluate safety and tolerability of escalating doses of exemestane in combination with carboplatin and pemetrexed in postmenopausal women with stage IV non-squamous NSCLC. Key exclusion criteria included untreated CNS involvement, major surgery in prior 4-weeks to therapy, prior/concurrent investigational or standard therapy (with exception of TKI and/or immunotherapy in prior 4-weeks). Patients received escalating doses of exemestane (starting 1-week before chemotherapy) at 25 mg PO daily (Cohort 1) or 50 mg PO daily (Cohort 2) combined with carboplatin (AUC 6 mg x min/mL) and pemetrexed (500 mg/m2) IV q3 weeks for 4 cycles. After 4 cycles, patients were eligible for continued therapy with exemestane and/or pemetrexed. Area under the curve (AUC) was extrapolated using linear trapezoidal methods.
4c3880bb027f159e801041b1021e88e8 Result
Ten patients consented for therapy; 2 patients screen-failed. Three patients completed therapy in Cohort 1, and five patients were treated in Cohort 2. One patient in Cohort 2 exited the trial for alternative therapy after one treatment cycle. The median number of cycles given was 15 (range 1-54). The mean of the maximum serum concentration (Cmax) of exemestane for Cohort 1 was 12.98 ng/mL and for Cohort 2 was 41.38 ng/mL. The AUCinffor the two cohorts was 51.73 and 184.17 ng x h/mL, respectively. The established maximum tolerated dose (MTD) was exemestane 50 mg PO daily with pemetrexed (500 mg/m2 IV q3 weeks) and carboplatin (AUC 6 mg x min/mL IV q3 weeks). No patients were removed from the study for adverse events. Clinical outcome, biomarker and QOL correlates are being collected.
8eea62084ca7e541d918e823422bd82e Conclusion
The combination of carboplatin, pemetrexed and exemestane in post-menopausal women with metastatic non-squamous, NSCLC is safe and well-tolerated. This data supports future clinical trials to establish efficacy with this combination therapy.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P1.11 - Screening and Early Detection (Not CME Accredited Session) (ID 943)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.11-13 - Noninvasive Detection of Early Stage NSCLC EGFR Mutations Using Electric Field Induced Release and Measurement (EFIRM) (ID 11776)
16:45 - 18:00 | Author(s): David Elashoff
- Abstract
Background
The ability of liquid biopsy to detect circulating tumor mutations has proved especially valuable in the treatment of patients with NSCLC since well characterized variants inform small molecule chemotherapeutic options.
EFIRM is a signal amplification technology that allows direct detection of mutations in native plasma and saliva without amplification or sequencing. Previously published work demonstrated a near perfect correlation between biopsy and EFIRM results for the Exon19 del and p.L858R mutations in EGFR in late stage NSCLC patients. In this study we investigated the performance of EFIRM in patients early stage (I and II) NSCLC patients.
a9ded1e5ce5d75814730bb4caaf49419 Method
Plasma samples were collected from 33 healthy controls with biopsy proven benign lung masses and 21 stage I and II NSLC patients with biopsy proven EGFR mutations The samples were immediately centrifuged and frozen. The samples were then blinded and sent for EFIRM analysis.
4c3880bb027f159e801041b1021e88e8 Result
There were 12 biopsies positive for p.L858R (11 stage 1 and 1 stage II) and 9 positive for Exon 19 del (7 stage 1A, and 2 stage II). Using statistically derived cut-offs to optimize sensitivity and specificity, there were 2 false positives (both for p.L858R) in the controls yielding an overall specificity of 91% for the 2 SNP Mutation assay. The sensitivity was 92% for the p.L858R with only one negative in 12 samples in a patient with stage 1 and 77% for Exon 19 del with 2 negatives in 9 samples in a single patient each for stage 1 and 2.
8eea62084ca7e541d918e823422bd82e Conclusion
The preponderance of patients in this study had stage I NSCLC. The sensitivity of 94% and 77% respectively for the 2 most common mutations is remarkable for patients with Stage 1 lung cancer and a correspondingly low tumor burden and more importantly at a potentially curable stage. We are in the process of improving the technical performance of this assay and adding additional variants to the panel in order to increase clinical utility. These data are promising for the potential use of the EFIRM platform for the purposes of drug selection, disease recurrence, follow-up of indeterminate lung nodules from spiral CT screening programs, and / or population screening.
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P2.09 - Pathology (Not CME Accredited Session) (ID 958)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.09-05 - Evaluation of PD-L1-Stained Tumor Cells via the 22C3 and SP-142 Antibodies in Cohort of Patients Treated on KEYNOTE-001 (ID 12976)
16:45 - 18:00 | Author(s): David Elashoff
- Abstract
Background
Four PD-L1 antibodies have been utilized in NSCLC clinical trials, with an analytical comparison demonstrating a high level of concordance between the percentage of PD-L1–stained tumor cells with three of these antibodies (22C3, 22C3, 28-8, and SP263), but not a fourth, SP-142 (Hirsch et al, JTO 2017). This finding led us to evaluate the relationship between the percentage of PD-L1–stained tumor cells with 22C3 and SP-142, as well as the association between the PD-L1 levels identified by each antibody and clinical outcomes in 28 NSCLC patients treated on KEYNOTE-001.
a9ded1e5ce5d75814730bb4caaf49419 Method
We performed a retrospective analysis of 28 NSCLC patients treated with pembrolizumab on the KEYNOTE-001 trial at UCLA (23pts) or MSKCC (5pts) with data cut-off 12/2017. Patients had PD-L1–stained tumor cell levels assessed by both the 22C3 antibody (Dako), via central evaluation as previously described (Garon et al, NEJM 2015) and the SP-142 antibody (Spring Bioscience) at UCLA in accordance with established methods (Zaretsky et al, NEJM 2016). Survival curves for PFS and OS were estimated using the Kaplan-Meier method and formally compared between groups using the log-rank test. The association between PD-L1–stained tumor cell levels identified by the two antibodies was assessed using the Pearson correlation coefficient.
4c3880bb027f159e801041b1021e88e8 Result
In 61% (17/28) of patients, PD-L1 levels were grouped similarly (either <1%, 1-49%, or >50%) by both antibodies. Specifically, compared to 22C3 staining, SP-142 led to the same grouping for 63% (5/8) pts with >50% staining, 85% (11/13) pts with 1-49% staining, and 14% (1/7) pts w <1% staining. Evaluating the relationship between PD-L1 grouping and clinical outcomes via the SP-142 antibody revealed improved PFS and OS in pts with higher PD-L1 expression levels, while the 22C3 antibody predicted for improved PFS in these patients, but not improved OS [SP142 (PFS,OS): (p=0.0039, p=0.0425)][22C3 (PFS,OS): p=0.0121, p=0.1222). The PD-L1 results from the SP-142 and 22C3 antibodies were strongly associated (r =0.58, p=0.001).
8eea62084ca7e541d918e823422bd82e Conclusion
The PD-L1–stained tumor cell levels in the majority of patients evaluated were similarly grouped into one of three categories (<1%, 1-49%, or >50%) by both 22C3 and SP142. This analysis is limited by small patient number, but suggests that the number of PD-L1–stained tumor cells identified by each antibody is similar and a higher PD-L1 level identified by either antibody predicts for improved clinical outcomes with pembrolizumab.
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