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Taofeek K Owonikoko
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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)
11:00 - 12:30 | Presenting Author(s): Taofeek K Owonikoko
- 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 09 - EGFR TKI Resistance (ID 663)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Thanyanan Reungwetwattana, Lecia V Sequist
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 301 + 302
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OA 09.01 - Characterizing the Genomic Landscape of EGFR C797S in Lung Cancer Using ctDNA Next-Generation Sequencing (ID 10213)
11:00 - 12:30 | Author(s): Taofeek K Owonikoko
- Abstract
- Presentation
Background:
Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) active in T790M-positive lung cancer. Acquired resistance to osimertinib is driven by EGFR C797S in ~20-30% of cases. Next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) can be used to identify resistance mechanisms. The allelic configuration (cis vs. trans) of C797S with respect to T790M has therapeutic implications, but the relative frequency of each and other co-occurring genomic alterations are not well defined in clinical samples.
Method:
We queried the Guardant Health database for lung adenocarcinoma patients and an EGFR C797S mutation. All patients had comprehensive ctDNA testing using the Guardant360 NGS assay between June 2015 and June 2017. Cis/trans configuration for T790M and C797S was determined using Integrated Genomics Viewer software.
Result:
We identified 50 unique patients with a total of 66 samples which were C797S positive. All had a co-existent EGFR activating mutation (del19 74%, L858R 24%, other 2%). 60/66 (91%) C797S+ samples were also T790M+. In the 6 samples with C797S but without T790M in ctDNA, 4 were from patients who were T790M+ on a prior Guardant360 assay, 1 never had T790M in blood or tissue and developed C797S while on 1[st]-line afatinib, and 1 had no further clinical details available. T790M and C797S were on the same allele (cis configuration) in 44/46 evaluable patients (98%); 1 (2%) was in trans. One sample had two different C797S mutations, one cis and one trans to T790M. 13 C797S+/T790M+ samples (22%) had multiple C797X mutations detected and 12 samples carried other mutations in or adjacent to the EGFR ATP-binding pocket (e.g. L792, F795, G796, etc). The most common non-EGFR mutations co-occurring with C797S were BRAF amplification/mutation (20%), MET amplification (17%), PIK3CA mutation/amplification (15%), CCNE1 amplification 14% and MYC amplification (14%).
Conclusion:
Understanding EGFR TKI resistance mechanisms is critical to developing more effective therapies. ctDNA offers a non-invasive method to characterize the resistance landscape. Our data suggests C797S most commonly occurs with T790M in cis (98%), a state associated with resistance to all currently available EGFR TKIs. The trans configuration, which may respond to combined 1[st]/3[rd]-gen EGFR TKIs, is rare (2%). Moreover, C797S is frequently detected along with other resistance mechanisms in ctDNA, underscoring the heterogeneity of resistant cancers. New treatments targeting C797S/T790M are needed, as is a deeper understanding of therapeutic targeting of heterogeneity in resistant cancers.
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P1.08 - Locally Advanced NSCLC (ID 694)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Locally Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.08-003 - Concomitant Chemotherapy and Radiotherapy with SBRT Boost for Unresectable, Stage III Non-Small Cell Lung Cancer: A Phase I Study (ID 8181)
09:30 - 16:00 | Author(s): Taofeek K Owonikoko
- Abstract
Background:
Stereotactic Body Radiation Therapy (SBRT) is now the standard of care in medically inoperable stage I non-small cell lung cancer, yielding high rates of local control. It is unknown if SBRT can be safely utilized in the locally advanced NSCLC setting. This multi-institution phase I study evaluated the safety of 44 Gy conventionally fractionated thoracic radiation with concurrent chemotherapy plus a dose escalated SBRT boost to both the primary tumor and involved mediastinal lymph nodes. The primary endpoint of this study was to establish the maximum tolerated dose (MTD) of the SBRT boost.
Method:
Inclusion criteria included unresectable stage IIIA or IIIB disease, primary tumor ≤8 cm, and N1 or N2 lymph nodes ≤5 cm. Tumors were staged with PET/CT while four dimensional CT simulation was employed for radiation planning. The treatment schema was 44 Gy thoracic radiation (2 Gy/day) with weekly carboplatin and paclitaxel chemotherapy. A second CT simulation was obtained after 40 Gy was delivered, and a SBRT boost was planned to the remaining gross disease at the primary site and involved lymph nodes. Four SBRT boost dose cohorts were tested: Cohort 1 (9 Gy x 2); cohort 2 (10 Gy x 2); cohort 3 (6 Gy x 5); and cohort 4 (7 Gy x 5). Patients were treated in cohorts of three patients and using Bayesian Escalation with Overdose Control (EWOC) method to determine Maximum tolerated dose of the SBRT boost. Dose limiting toxicities (DLT) were defined as any grade 3 or higher toxicities within 30 days of treatment attributed to treatment, not including hematologic toxicity, or any grade 5 toxicity attributed to treatment.
Result:
The study enrolled 19 patients from 11/2012-12/2016. There were 4 screen failures and 15 patients were treated on study. There were no DLTs in dose cohort 1 (n = 3) and 2 (n = 6). One patient in dose cohort 3 (n = 3) developed a DLT, and 2 patients in dose cohort 4 (n = 3) developed a DLT. The calculated MTD was 6 Gy x 5. The DLT observed at this dose level was a tracheoesophageal fistula; given this substantial toxicity, there was investigator reluctance to enroll further patients in this dose level. Thus the calculated MTD is 6 Gy x5, however 10 Gy x 2 is felt to be a reasonable dose as well given no grade 5 toxicities occurred with this dose.
Conclusion:
The MTD of a SBRT boost combined with 44 Gy thoracic chemoradiation is 6 Gy x 5. A SBRT boost dose of 10 Gy x 2 could be considered very safe with no grade 3 or higher toxicities observed at this dose level.
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P3.13 - Radiology/Staging/Screening (ID 729)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Radiology/Staging/Screening
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.13-027 - Utilization of PET Scan in Advanced Stage Non-Small Cell Lung Cancer in the United States (ID 10031)
09:30 - 16:00 | Author(s): Taofeek K Owonikoko
- Abstract
Background:
PET scans are used during diagnosis and staging of lung cancer. The role of PET scan in guiding therapy for advanced stage non-small cell lung cancer (NSCLC) is not proven, but it continues to be used during the treatment course at many centers. We studied the Surveillance, Epidemiology, and End Results (SEER) Program database and Medicare claims data to evaluate the use of PET scan in advance stage NSCLC patients in the United States and the impact on patient outcome.
Method:
The SEER-Medicare database was queried to capture patients with stage IV non-small cell lung cancer diagnosed between the years 2000-2011. The cohort of patients that received PET scan after diagnosis were analyzed and compared with the cohort that did not receive PET. The univariate (UV) association between covariates and overall survival (OS) were compared by log-rank tests. Time dependent Cox Model was used in multivariable (MV) analysis, with time from diagnosis to first PET scan as time-dependent variable, while the other covariates as time-independent. All analyses were performed using SAS Version 9.4.
Result:
A total of 52,712 eligible patients with stage IV NSCLC were identified between 2000-2011, out of which 13,873 (26.3%) had received PET scan. Characteristics of PET cohort: median age 74 years, 53% male, 87% white and 82% from metro locations. 87% of the patients that received PET were diagnosed between 2006-2011. In the first year after diagnosis, 70% of the patients had 1 PET, 16% had 2 PETs and 14% had 3 or more PETs. About 64% of the patients had received their first PET scan within 2 months of diagnosis and 19% had it between 2 to 6 months. The average Medicare cost associated with patients that received PET was significantly higher than that of patients that did not receive PET scan ($60,417 vs. $34,287; p<0.001). Chemotherapy and radiation were given in a higher proportion of patients that received PET versus those that did not receive it (56% and 45% versus 26% and 36% respectively; p<0.001). Though univariate analysis revealed that a PET scan within a year of diagnosis was associated with better 1-year survival (HR 0.87, P<0.001), this did not translate into overall survival advantage on multivariable analysis (HR 0.99, P=0.56).
Conclusion:
The utilization of PET scan in stage IV NSCLC patients was associated with higher cost, but without a tangible improvement in survival compared to those that did not have a PET scan.
