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Charles M Rudin
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ES 09 - Recent Progress in the Management of Small Cell Lung Cancer (ID 518)
- Event: WCLC 2017
- Type: Educational Session
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:David S Ettinger, Kenneth Obyrne
- Coordinates: 10/18/2017, 14:30 - 16:15, Room 501
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ES 09.01 - Genomics and Translational Research (ID 7619)
14:30 - 14:50 | Presenting Author(s): Charles M Rudin
- Abstract
- Presentation
Abstract not provided
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MA 05 - Immuno-Oncology: Novel Biomarker Candidates (ID 658)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Yoichi Nakanishi, P. Mitchell
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 303 + 304
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MA 05.02 - STK11/LKB1 Loss of Function Genomic Alterations Predict Primary Resistance to PD-1/PD-L1 Axis Blockade in KRAS-Mutant NSCLC (ID 10367)
15:50 - 15:55 | Author(s): Charles M Rudin
- Abstract
- Presentation
Background:
The genomic landscape of primary resistance to PD-1 blockade in lung adenocarcinoma (LUAD) is largely unknown. We previously reported that co-mutations in STK11/LKB1 (KL) or TP53 (KP) define subgroups of KRAS-mutant LUAD with distinct therapeutic vulnerabilities and immune profiles. Here, we present updated data on the clinical efficacy of PD-1/PD-L1 inhibitors in co-mutation defined KRAS mutant and wild-type LUAD patients and examine the relationship between genetic alterations in individual genes, tumor cell PD-L1 expression and tumor mutational burden (TMB) using cohorts form the SU2C/ACS Lung Cancer Dream Team and Foundation Medicine (FM).
Method:
The cohorts included 924 LUAD with NGS (FM cohort) and 188 patients with KRAS non-squamous NSCLC (SU2C cohort) who received at least one cycle of PD-1/PD-L1 inhibitor therapy and had available molecular profiling. Tumor cell PD-L1 expression was tested using E1L3N IHC (SU2C) and the VENTANA PD-L1 (SP142) assay (FM). TMB was defined as previously described and was classified as high (TMB-H), intermediate (TMB-I) or low (TMB-L).
Result:
188 immunotherapy-treated (83.5% nivolumab, 11.7% pembrolizumab, 4.8% anti-PD1/PD-L1 plus anti-CTLA-4) pts with KRAS-mutant NSCLC were included in the efficacy analysis. The ORR differed significantly between the KL (8.8%), KP (35.9%) and K-only sub-groups (27.3%) (P=0.0011, Fisher’s exact test). KL LUAC exhibited significantly shorter PFS (mPFS 1.8m vs 2.7m, HR=0.53, 95% CI 0.34-0.84, P<0.001, log-rank test) and OS (mOS 6.8m vs 15.6m, HR 0.53, 95% CI 0.34 to 0.84, P=0.0072, log rank test) compared to KRAS-mutant NSCLC with wild-type STK11. Loss-of function (LOF) genetic alterations in STK11 were the only significantly enriched event in PD-L1 negative, TMB-I/H compared to PD-L1 high positive (TPS≥50%), TMB-I/H tumors in the overall FMI cohort (Bonferroni adjusted P=2.38x10[-4], Fisher’s exact test) and among KRAS-mutant tumors (adjusted P=0.05, Fisher’s exact test) . Notably, PD-1 blockade demonstrated activity among 10 PD-L1-negative KP tumors, with 3 PRs and 4SDs recorded. In syngeneic isogenic murine models PD-1 blockade significantly inhibited the growth of Kras mutant tumors with wild-type LKB1 (K), but not those with LKB1 loss (KL), providing evidence that LKB1 loss can play a causative role in promoting PD-1 inhibitor resistance.
Conclusion:
Loss of function genomic alterations in STK11 represent a dominant driver of de novo resistance to PD-1/PD-L1 blockade in KRAS-mutant NSCLC. In addition to tumor PD-L1 status and tumor mutational burden precision immunotherapy approaches should take into consideration the STK11 status of individual tumors.
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OA 08 - Neuroendocrine Carcinoma: Translational (ID 667)
- Event: WCLC 2017
- Type: Oral
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:David S Ettinger, S. Zöchbauer-Müller
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 311 + 312
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OA 08.06 - Exploratory Analysis for Predictors of Benefit of PARP Inhibitor Therapy in Extensive Stage Small Cell Lung Cancer: ECOG-ACRIN 2511 Study (ID 10321)
11:55 - 12:05 | Author(s): Charles M Rudin
- Abstract
- Presentation
Background:
Veliparib, a potent inhibitor of Poly (ADP) ribose polymerase (PARP) enzyme potentiates standard chemotherapy against small cell lung cancer (SCLC) in preclinical studies. The combination of veliparib (V) with cisplatin/etoposide (CE) doublet as first-line therapy of extensive stage SCLC (ES-SCLC) showed significant signal of efficacy with adjusted PFS HR: 0.63 1-sided p=0.01. There was strata by treatment interaction indicating different efficacy benefit in patient subsets (adjusted treatment HR comparing CE+V: CE: 0.34; 80% CI: 0.22 - 0.51; 1-sided p<0.001 for male patients with high tumor burden versus adjusted HR: 0.81 80% CI: 0.60 - 1.09; 1-sided p=0.18 for other patients subsets). We explored clinical and tissue-based biomarkers as predictors of benefit from this treatment strategy.
Method:
Post-hoc analysis of clinical data was conducted to identify clinical differences in patients who derived significant benefit from the experimental therapy. Clinical differences were compared between patients in the control and experimental arms within the patient stratum with significant clinical benefit. Similarly, comparison was performed between the strata. Archival tissue samples collected from patients with ES-SCLC enrolled and treated on E2511 study was employed for biomarker analysis using immunohistochemistry to assessSLFN11 and DNA-PK expression. The study has 88% power to detect a PFS hazard ratio of 0.5 comparing biomarker positive to negative patients using a one-sided 0.025 level logrank test.
Result:
There was an imbalance between control and experimental arms in the Male/abnormal LDH stratum (in strata) with respect to Age: p=0.006; malignant pleural effusion: p=0.095 and T stage: p=0.02. Median PFS was 5.1 mos on CE (95% CI 4.1-6.1) vs. 6.2 mos on CE+V (95% CI 5.9-8.8); HR=0.32, p=0.002 (unadjusted); median OS on CE was 8.8 mos (95% CI 6.6-11.1) vs. 9.5 mos on CE+V (95% CI 7.8-12.8); HR=0.76, p=0.39. Mutivariable analysis controlling for these imbalances still showed a benefit of veliparib (HR=0.26, p=0.001). Comparison of “in strata” group (N=46) to the “not in strata” group (N=82) showed significant imbalance in pleural effusion (p=0.058); elevated AST (p=0.0099) and bilirubin (p=0.0447). Median PFS was identical at 5.9 mos for both groups while median OS was 10.7 mos (95% CI 8.9-13.2) for “not in strata” subsests vs. 8.8 mos (95% CI 7.8-10.8) for “in strata” with a HR of 1.57 (p=0.027) comparing “in strata” to “not in strata”. Outcome differences based on SLFN11 and DNA-PK expression will be presented at the meeting.
Conclusion:
PFS benefit of PARP inhibitor therapy in extensive stage SCLC patients with elevated LDH and male gender was not associated with any other clinical characteristics.
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OA 10 - Liquid Biopsy for Genomic Alterations (ID 678)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:Adrian G. Sacher, Pasi A Jänne
- Coordinates: 10/18/2017, 11:00 - 12:30, F201 + F202 (Annex Hall)
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OA 10.03 - Liquid Biopsy in the Lung Cancer Clinic: A Prospective Study of Plasma DNA next Generation Sequencing to Guide Matched Therapy (ID 8218)
11:20 - 11:30 | Author(s): Charles M Rudin
- Abstract
- Presentation
Background:
Liquid biopsy for plasma circulating tumor DNA (ctDNA) next generation sequencing (NGS) is now commercially available and increasingly adopted in clinical practice with a paucity of evidence based guidance. We set out to prospectively determine the utility of plasma ctDNA NGS in the lung cancer clinic.
Method:
Patients (pts) with advanced NSCLC who were driver unknown or resistance mechanism unknown were eligible. Pts were enrolled prospectively at Memorial Sloan Kettering (NY, USA) and Northern Cancer Institute (Sydney, Australia). Peripheral blood was collected in Streck tubes (10-20mL) and sent to Resolution Bioscience (Bellevue, WA) for targeted NGS of extracted DNA using a bias corrected hybrid capture 21 gene assay in a CLIA laboratory with unique reads at 3000x and sensitive detection at variant allele frequency above 0.1%. Clinical endpoints included detection of oncogenic drivers, turnaround time, comparison to tissue NGS when available, and ability to match pts to targeted therapy along with their treatment outcomes.
Result:
Seventy-six pts were prospectively accrued. Plasma NGS detected an oncogenic driver in 36% (27/76) of pts, of whom 14% (11/76) were matched to targeted therapy; including pts matched to clinical trials for HER2 exon 20 insYVMA, BRAF L597Q and MET exon14. Of the 10 evaluable pts, 10 partial responses were observed. Mean turnaround time for plasma was 6 days (3-12) vs 21 days (16-30) for tissue (P <0.0001). Plasma ctDNA was detected in 60% (46/76) of pts; detection rate was 46% (16/35) if blood was drawn on active therapy and 73% (30/41) if drawn off therapy, either at diagnosis or progression (Odds ratio 0.31, 95% CI 0.12 – 0.81; P=0.02). Of the 25 concurrent tissue NGS performed to date, there was a 96% plasma concordance with tissue and a 60% tissue concordance with plasma for driver mutations.
Conclusion:
In pts who were driver or resistance mechanism unknown, plasma NGS identified a variety of oncogenic drivers with significantly shorter turnaround time compared to tissue NGS, and matched patients onto targeted therapy with clinical benefit. Plasma ctDNA is best detected at diagnosis of metastatic disease or at progression. A positive finding of an oncogenic driver in plasma is highly specific and can immediately guide treatment, but a negative finding may still require tissue biopsy. Our findings provide evidence to support the incorporation of plasma NGS into practice guidelines.
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OA 10.05 - Non-Invasive Molecular Profiling in NSCLC by Targeted and Whole Exome Analysis of Plasma cfDNA (ID 10422)
11:45 - 11:55 | Author(s): Charles M Rudin
- Abstract
- Presentation
Background:
Molecular characterization of tumor can guide the choice of therapy for NSCLC patients. However, tumors are complicated by spatial heterogeneity and sometimes may not be of sufficient quality and quantity for analysis. NGS using plasma cell-free DNA (cfDNA) input may capture temporal and spatial heterogeneity, and enable genomic profiling in patients without adequate available tumor tissue. Targeted gene panels allow for robust detection of known oncogenic drivers, but may not be comprehensive enough to screen for novel biomarkers or mechanisms of acquired resistance. Whole exome sequencing (WES) allows for hypothesis-free biomarker discovery, but may be technically challenging in the setting of limited tumor-derived DNA content in plasma cfDNA. In this study, we aim to develop a workflow to guide the selection of samples for targeted and whole exome sequencing for noninvasive molecular profiling.
Method:
Plasma samples were collected from 20 NSCLC patients receiving a variety of treatment (chemotherapy, targeted therapy, or immunotherapy). Most patients (>70%) had stage III or IV disease at the time of plasma collection. CfDNA was extracted from 3 mL of plasma, and analyzed using low-pass shallow whole genome sequencing (sWGS) and MSK-IMPACT, a hybridization capture-based assay targeting over 400 cancer-related genes. Analysis of matched normal was performed for somatic variant calling.
Result:
Median cfDNA yield per plasma sample was 28ng (range 7 - 236ng). We applied z-score statistics to estimate the levels of tumor-derived mutant allele fractions in cfDNA based on sWGS data. We trained the algorithm using a separate cohort of cfDNA data from >100 patients with metastatic solid tumors to classify samples by mutant allele fraction (MAF) as either low (<5% MAF) or high (>5% MAF) tumor-derived DNA. In the subset of 10 patients with unknown drivers, two were estimated to have MAF >5% in cfDNA, and WES recapture was performed. MSK-IMPACT targeted sequencing identified actionable alterations in a subset of patients who did not have sufficient materials for tissue profiling. WES in cases with high tumor-derived DNA content by sWGS identified alterations in genes outside of the MSK-IMPACT panel.
Conclusion:
Molecular profiling using cfDNA is feasible in lung cancer and may identify actionable alterations to inform treatment decisions in patients without sufficient tissue for molecular characterization. The application of sWGS to estimate the levels of tumor-derived mutant allele fractions in plasma cfDNA samples may help guide selection of the optimal downstream sequencing strategy.
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OA 14 - New Paradigms in Clinical Trials (ID 681)
- Event: WCLC 2017
- Type: Oral
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:Alex Adjei, Eun Kyung Cho
- Coordinates: 10/18/2017, 11:00 - 12:30, Room 311 + 312
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OA 14.05 - Phase 2 Basket Trial of Ado-Trastuzumab Emtansine in Patients with HER2 Mutant or Amplified Lung Cancers (ID 10368)
11:45 - 11:55 | Author(s): Charles M Rudin
- Abstract
- Presentation
Background:
Human epidermal growth factor receptor 2 (HER2, ERBB2) mutation and amplification each occurs in 2% of lung cancers, resulting in receptor dimerization and oncogenic signaling with in vitro sensitivity to trastuzumab. Ado-trastuzumab emtansine is a HER2 targeted antibody drug conjugate linking trastuzumab with the anti-microtubule agent emtansine.
Method:
Patients with advanced HER2 mutant or amplified lung cancers were enrolled into separate cohorts in a basket trial of ado-trastuzumab emtansine, treated at 3.6mg/kg IV every 3 weeks. The primary endpoint was overall response rate (ORR) using RECIST v1.1. A separate cohort included patients with HER2 mutant lung cancers assessed using PERCIST, with pre-treatment 89Zr-trastuzumab PET as correlative imaging. A Simon two stage optimal design was used with type I error rate under 2.7% (and a family wise error rate across baskets under 10%), power of 89%, H0 10%, H1 40%. Other endpoints include progression-free survival (PFS) and toxicity. HER2 testing was performed on tumor tissue by next generation sequencing (NGS), fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC).
Result:
A total of 33 patients were identified by NGS and enrolled. The first HER2 mutant cohort completed accrual of 18 patients with ORR of 44% (8/18 confirmed, 95% CI 22-69%), rejecting null hypothesis. The median PFS was 4 months, and median PFS for responders was 6 months (range 4-11 months). The PERCIST measured HER2 mutant cohort accrued 9 patients, there were 2 confirmed partial responses (PR) in 5 patients evaluated. The HER2 amplified cohort accrued 6 patients, with 3 confirmed PR observed including 1 with concurrent EGFR sensitizing mutation and resistance to erlotinib. Toxicities included grade 1 or 2 including infusion reaction, thrombocytopenia and transaminitis, there were no treatment related deaths. Of the 27 patients in the HER2 mutant cohorts, there were 18 (67%) exon 20 insertions and 9 (33%) point mutations; responders were seen across mutation subtypes (A775_G776insYVMA, G776delinsVC, V659E, S310F, L755P). Concurrent HER2 amplification was observed in 4 of 27 patients by either NGS or FISH. IHC ranged from 0 to 3+ and did not predict response. Of the 6 patients in the HER2 amplified cohort, 2 had concurrent HER2 mutation and 1 had concurrent EGFR L858R mutation.
Conclusion:
Ado-trastuzumab emtansine is active and well tolerated in patients with advanced HER2 mutant or amplified lung cancers as identified by NGS. While cohort expansion is ongoing, this study has met its primary endpoint in patients with HER2 activating mutations. Further development is warranted.
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P1.02 - Biology/Pathology (ID 614)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.02-001 - SLFN11 Expression in Early Stage Non-Small Cell Lung Cancer Predicts Benefit from Adjuvant Chemotherapy with Taxane and Platinum (ID 9987)
09:30 - 09:30 | Author(s): Charles M Rudin
- Abstract
Background:
No predictive biomarker for cytotoxic chemotherapy is approved for clinical use. Schlafen family member 11 (SLFN11) protein is widely reported as sensitizing to DNA-damaging agents. Epigenetically mediated suppression of SLFN11 is associated with poor response to platinum in patients with ovarian and lung cancer. Pre-clinical lung cancer models suggest that SLFN11 expression may be a useful biomarker of response to cisplatin, PARP inhibitors and topoisomerase inhibitors. Tumor expression of SLFN11 is assessed by immunohistochemistry, RNA expression or DNA methylation; no standard method exists. We used mass spectrometry to quantify SLFN11 protein in archived samples of patients with early stage NSCLC treated with taxane plus platinum (TP) and correlated proteomic expression of SLFN11 with survival.
Method:
We obtained archived tissue sections representing 594 patients with lung cancers of multiple subtypes. A board-certified pathologist marked the tumor areas, which were microdissected and solubilized. In each liquefied tumor sample, 60 protein biomarkers including SLFN11 were quantified with selected reaction monitoring mass spectrometry. Patients were stratified by a SLFN11 cutoff of 100 amol/ug, based on the proteomic assay’s limit of quantification. Survival outcomes were assessed with Kaplan-Meier and Mantel-Cox log-rank analyses.
Result:
Among 86 TP-treated early stage NSCLC patients, those with SLFN11 protein levels above the cutoff (n=51) had better progression-free survival (PFS) than patients with SLFN11 levels below the cutoff (HR: 2.26; 95%CI: 1.08-4.72; p=0.052). Similar differences in PFS were found in the subset of patients with NSCLC (n=77) (HR: 2.79; 95%CI: 1.29-6.05; p=0.030). Differences in overall survival by SLFN11 expression were not statistically significant. In a group of untreated patients (n=440), there were no differences in PFS between patients with high and low expression of SLFN11.
Conclusion:
Mass spectrometric evaluation of SLFN11 retrospectively identified responders to platinum-containing chemotherapy and could be used to predict response for platinum-containing therapy and warrants further validation. Multiplexed proteomics can quantitate SLFN11 simultaneously with other therapeutically relevant proteins (eg, HER2, ALK, ROS1) to inform therapy selection at initial diagnosis and upon relapse.
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P1.03 - Chemotherapy/Targeted Therapy (ID 689)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.03-028 - A Phase II Trial of Albumin-Bound Paclitaxel and Gemcitabine in Patients with Untreated Stage IV Squamous Cell Lung Cancers (ID 8556)
09:30 - 09:30 | Author(s): Charles M Rudin
- Abstract
Background:
Therapeutic options for squamous cell lung cancer (SQCLC) patients remain limited. Platinum-based chemotherapies, which have been the standard first-line treatments for nearly 20 years, are associated with ORR=30-40%, median PFS=4-5.7mo, and median OS=9-11.5mo. We previously reported the results of a phase 1/2 trial of albumin-bound paclitaxel (ABP) in 40 patients with untreated stage IV NSCLC, noting an ORR of 30%, median PFS of 5mo, and median OS of 11mo (Rizvi JCO 2008). These data suggest that platinum adds little when coupled to ABP. Conversely, compelling evidence of anti-tumor synergy between gemcitabine and ABP was recently demonstrated by Frese et al. who showed that ABP downregulates cytidine deaminase (which inactivates gemcitabine), leading to increased intratumoral [gemcitabine] (Cancer Disc 2012). Based on these data, we sought to assess the efficacy of ABP + gemcitabine in patients with SQCLC.
Method:
This is a phase II trial of ABP (100mg/m[2]) + gemcitabine (1000mg/m[2]) given on D1, D8, D15 of an every 4 week cycle (A1) in patients with untreated stage IV SQCLC. Patients received up to 6 cycles and were followed thereafter (A1). The primary endpoint is best objective response (RECIST 1.1). The study utilizes a Simon two-stage design with H0=25% (6/17 responses) and H1=45% (16/41 responses). After clearing the first stage, the study was amended to a 3 week cycle (D1, D8 treatment); to allow ABP + gemcitabine until progression; and to allow maintenance ABP to begin after C4 for tolerability (A2). PFS, TTP, and OS were calculated using the Kaplan-Meier method. Patients underwent NGS by MSK-IMPACT for genotype-phenotype correlation.
Result:
N=17 patients (14 evaluable) were treated on A1 and, to date, N=3 patients (2 evaluable) have been treated on A2. Median age=70, female=30%, median KPS=90%, smokers=90%, median pack years=32. Median cycles of therapy in A1=4. Grade ≥3 related AEs included: peripheral neuropathy (5%); diarrhea (5%); elevated ALT (5%); anemia (15%); and decreased neutrophils (25%). Three patients (15%) experienced a related SAE including G3 decreased WBC, G3 diarrhea, and G3 lung infection. There was 1 unrelated death as a result of complications from a G3 mechanical fall. ORR in A1=50% (7/14 PRs). ORR in A2=100% (2/2 PRs). ORR in A1+A2=56% (9/16 PRs). SD=6 (38%) and PD=1 (6%). Median PFS=5.8mo; TTP=6.9mo; OS=13.3mo.
Conclusion:
ABP + gemcitabine has promising efficacy and is relatively well-tolerated, particularly when compared to platinum regimens. Accrual to the study is ongoing and updated data, including NGS correlates, will be presented.
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P2.04 - Clinical Design, Statistics and Clinical Trials (ID 705)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.04-007 - KEYNOTE-604: Phase 3 Randomized, Double-Blind Trial of Pembrolizumab/Placebo plus Etoposide/Platinum for Extensive Stage-SCLC (ID 9040)
09:30 - 09:30 | Presenting Author(s): Charles M Rudin
- Abstract
Background:
Therapeutic options for small-cell lung cancer (SCLC) remain limited, with etoposide/platinum (EP) as the standard first-line chemotherapy regimen. However, patients with extensive-stage (ES)-SCLC experience high relapse rates within months after initial therapy. Pembrolizumab, a humanized monoclonal antibody against PD-1, has shown antitumor activity as monotherapy in heavily pretreated patients with PD-L1–positive SCLC in the phase 1b KEYNOTE-028 study. KEYNOTE-604 (ClinicalTrials.gov, NCT03066778) evaluates EP plus either pembrolizumab or placebo as first-line therapy for ES-SCLC.
Method:
Section not applicable
Result:
Section not applicable
Conclusion:
In this international, double-blind, phase 3 trial, adults with newly diagnosed ES-SCLC, ECOG PS ≤1, and no previous systemic therapy for SCLC are randomized 1:1 to receive either EP plus a 200-mg fixed dose of pembrolizumab intravenously (IV) once every 3 weeks (Q3W) or EP plus placebo IV Q3W. Randomization is stratified by the chosen platinum therapy (carboplatin vs cisplatin), ECOG PS (0 vs 1), and baseline lactate dehydrogenase concentration (≤ upper limit of normal [ULN] vs > ULN). Study treatment includes a total of 4 cycles of EP and 2 years of pembrolizumab/placebo and continues until documented PD, intolerable toxicity, or withdrawal of consent. Patients with a response after 4 cycles of EP plus placebo or pembrolizumab may receive prophylactic cranial irradiation. Patients who complete 2 years of pembrolizumab treatment or stop pembrolizumab for reasons other than PD/intolerability, but subsequently have documented PD confirmed by blinded independent review, may receive an additional 1 year of pembrolizumab provided that no other systemic therapy has been administered. Patients must meet the eligibility criteria for retreatment; patients in the placebo arm are not eligible for treatment with pembrolizumab at the time of PD. Tumor response is assessed every 6 weeks for 48 weeks, and every 9 weeks thereafter by RECIST version 1.1 by blinded independent central review. AEs occurring during treatment and 30 days thereafter (90 days for serious AEs) are graded per Common Terminology Criteria for Adverse Events, version 4.0. Primary endpoints are PFS and OS. Secondary endpoints are ORR, duration of response, safety, and patient-reported outcomes. Approximately 430 patients will be enrolled.
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P3.15 - SCLC/Neuroendocrine Tumors (ID 731)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.15-008 - [F18]PARPi PET as an In Vivo Pharmacodynamic Biomarker of PARP Inhibitor Therapy in Patient-Derived Xenografts of Small Cell Lung Cancer (ID 10378)
09:30 - 09:30 | Author(s): Charles M Rudin
- Abstract
Background:
Inadequate drug delivered to target tumors contributes to ineffective treatment. However, the delivered drug concentration is difficult to assess in patients in a timely and clinically-relevant manner. To address this barrier to PARP inhibitor(PARPi) therapy, we evaluated a radiolabeled PARP inhibitor([F18]PARPi) as a pharmacodynamic biomarker. We hypothesized that [F18]PARPi PET imaging can measure PARP inhibitor concentration and activity intratumorally, thereby, predicting therapeutic efficacy. Here, we applied this approach to patient-derived xenografts(PDX) of small cell lung cancer(SCLC).
Method:
To study [F18]PARPi PET as a biomarker of talazoparib(TAL), SCRX-Lu149 PDXs were orally gavaged with different doses of TAL. Mice were injected with [F18]PARPi and imaged with PET, with the expectation that TAL would competitively block [F18]PARPi binding to PARP. Organ retrieval and gamma counting was performed for drug and radiotracer biodistribution. Ex vivo PARP enzymatic activity was measured by ELISA of PAR levels. Differences in PET uptake and the tumor volumetric endpoint (time to reach 1000 mm[3]) were analyzed by student t-test and the log-rank test, respectively.
Result:
In PK PET imaging with 0.2 mg/kg TAL, greatest blocking of the radiotracer was noted at 1 hour after gavage with less blocking as time from dosing was extended (avg of 3 mice: 4.5, 2.2, 2.7, 3.1, and 3.4% max injected dose per gram [ID/g] for untreated, 1, 3, 6, and 24 h after drug, respectively). [F18]PARPi PET differentiated between doses of 0.1 and 0.3 mg/kg TAL at 3 h after dosing (3.9 vs 2.1% ID/g or 13% vs 53% relative blocking, respectively; p=0.003). No differences were noted in heart, lung, esophagus, muscle, or bone. PET uptake correlated with ex vivo enzymatic inhibition/PAR levels (p=0.0009). PET measured differences in drug doses corresponded with improved outcomes for PDXs treated with 0.3 mg/kg in combination with radiotherapy(RT; median 84 days, p=0.04) but not 0.1 mg/kg + IR (66 days) compared to RT alone (52 days).
Conclusion:
[F18]PARPi PET can differentiate between multiple doses and timing of orally administered TAL and correlates with drug efficacy. This likely reflects differences in intratumoral drug level and demonstrates the potential of this PET radiotracer to assess differences in drug delivery and efficacy for patients treated with PARP inhibitors.
