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Gregory J Riely
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GR 01 - What to Do at the Time of Progression on Targeted Therapy (ID 520)
- Event: WCLC 2017
- Type: Grand Rounds
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:D. Kim, Lecia V Sequist
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 303 + 304
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GR 01.04 - EGFR-Positive NSCLC Cases Who Failed Previous EGFR-TKI (ID 7629)
11:00 - 12:30 | Presenting Author(s): Gregory J Riely
- Abstract
- Presentation
Abstract not provided
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OA 03 - Mediastinal and Esophageal Tumor: Insight and New Treatment (ID 654)
- Event: WCLC 2017
- Type: Oral
- Track: Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:M. Chida, Jhingook Kim
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 311 + 312
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OA 03.03 - Phase II Trial of Cetuximab and Chemotherapy Followed by Surgical Resection for Locally Advanced Thymoma (ID 10288)
11:00 - 12:30 | Author(s): Gregory J Riely
- Abstract
- Presentation
Background:
The mainstay of treatment for thymoma is surgery with neoadjuvant chemotherapy recommended to patients with locally advanced disease. EGFR is overexpressed in thymoma. Clinical responses to single-agent cetuximab have been reported in patients with advanced cetuximab. We conducted this two-site prospective phase II trial of cetuximab combined with a standard induction chemotherapy regimen of cisplatin, doxorubicin and cyclophosphamide (PAC) in patients with locally advanced thymoma prior to surgical resection.
Method:
Patients with clinical Masaoka stage III-IVA thymoma were treated with cetuximab (250mg/m[2] weekly x 4 weeks) followed by cetuximab (250 mg/m[2] weekly) combined with cisplatin (50mg/m[2]), doxorubicin (50 mg/m[2]) and cyclophosphamide (500mg/m[2]) 3 weeks x 4 cycles). Radiographic response was assessed by CT using RECIST 1.1 and FDG-PET using PERCIST. All patients went on to surgery after completion of induction therapy. The primary endpoint was major pathologic response (MPR, >90% treatment effect). Planned enrollment was 18 patients in first stage of a two stage design. If 1 MPR was observed, then enrollment would expand to 28 patients.
Result:
Eighteen patients were enrolled: 8 women, median age 53 (range 32-73). WHO Histologic subtype A: 2, AB: 3, B1: 3, B2: 7, B3: 3. Final Masaoka stage I: 2, II: 2, III: 5, IVA: 9. There were no responses to cetuximab alone by RECIST criteria, although 1 patient had a 25% reduction in indicator lesions. Response rate (CR+PR), in evaluable patients after complete treatment course was 50% (8/16, 95% CI 28-72%). Partial responses by PERCIST criteria were seen on PET in 11/18 (61%) evaluable patients. There were no MPRs. R0 resection was obtained in 7 patients; 5 had R1 and 6 had R2 resections.
Conclusion:
The addition of cetuximab to PAC chemotherapy did not lead to pathologic complete responses in the neoadjuvant setting. Cetuximab alone appears to have little effect during 4 weeks of treatment. There was no apparent increase in radiographic response rate with the addition of cetuximab to PAC chemotherapy compared to historical series.
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OA 10 - Liquid Biopsy for Genomic Alterations (ID 678)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- 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)
11:00 - 12:30 | Author(s): Gregory J Riely
- 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 12 - Emerging Genomic Targets (ID 679)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:H. Akita, Maurice Pérol
- Coordinates: 10/18/2017, 11:00 - 12:30, F203 + F204 (Annex Hall)
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OA 12.06 - Plasma Genomic Profiling and Outcomes of Patients with MET Exon 14-Altered NSCLCs Treated with Crizotinib on PROFILE 1001 (ID 9385)
11:00 - 12:30 | Author(s): Gregory J Riely
- Abstract
- Presentation
Background:
MET exon 14 alterations occur in ~4% of non-squamous non-small cell lung cancers (NSCLCs). Treatment with the MET inhibitor, crizotinib, achieves confirmed and durable responses in patients with MET exon 14-altered NSCLCs, underscoring the need to test for these drivers (as of August 1, 2016, objective response rate was 39% and median duration of response was 9.1 months). Comprehensive molecular tumor profiling is required to detect MET exon 14 alterations that are highly heterogeneous. The utility of plasma profiling to detect these drivers has not previously been explored in a prospective trial.
Method:
Patients with advanced NSCLCs harboring MET exon 14 alterations by local tumor profiling performed in a CLIA-certified or equivalent environment were treated with crizotinib at 250 mg twice daily on an expansion cohort of the ongoing phase I PROFILE 1001 study (NCT00585195). Objective response was assessed by RECIST v1.0. Prospective plasma profiling of circulating tumor DNA (ctDNA) for MET exon 14 alterations was performed using the PlasmaSELECT64 targeted gene panel (sequencing and analysis output by Personal Genome Diagnostics, Boston MA).
Result:
Plasma samples were obtained for MET exon 14 alteration analysis after study amendment approval in 20 of 52 crizotinib-treated patients, of which 18 samples were deemed sufficient for analysis. MET exon 14 alterations were detected in ctDNA in 11 of 18 patients (61% agreement of plasma ctDNA testing with tumor testing) mapping to the same exon 14 splice site region in 10 of the 11 cases. Of the 11 patients with ctDNA-positive tumors, all were evaluable for response. Of these evaluable patients, a confirmed partial response and stable disease were observed in 2 and 4 patients, respectively.
Conclusion:
MET exon 14 alterations can be detected in plasma ctDNA in a subset of patients with advanced NSCLCs that harbor MET exon 14 alterations by tumor testing. Responses to crizotinib were observed in patients with ctDNA-positive testing for a MET exon 14 alteration. Plasma profiling should be considered as an adjunct to tumor profiling in screening patients for MET exon 14 alterations, pending further confirmation.
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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)
11:00 - 12:30 | Author(s): Gregory J Riely
- 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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P1.01 - Advanced NSCLC (ID 757)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.01-012 - Ceritinib in Anaplastic Lymphoma Kinase (ALK)+ NSCLC Patients Pretreated With Only Crizotinib: ASCEND-1 Subgroup Analysis (ID 8972)
09:30 - 16:00 | Author(s): Gregory J Riely
- Abstract
Background:
In phase 1 ASCEND-1 study (NCT01283516), ceritinib 750 mg/day (fasted) demonstrated durable whole-body and intracranial responses in both anaplastic lymphoma kinase inhibitor (ALKi)-naïve and ALKi-pretreated patients with ALK-rearranged non-small cell lung cancer (NSCLC). Here, we report the efficacy and safety of ceritinib in patients who were pretreated with crizotinib only from the ASCEND-1 study.
Method:
Patients with ALK+ NSCLC who were enrolled globally received ceritinib 750 mg/day (fasted). Efficacy and safety were evaluated in a subset of patients who had received prior crizotinib only (no other prior antineoplastic therapy). Data cut-off was May 03, 2016.
Result:
Overall, 246 patients with ALK+ NSCLC (83 ALKi-naïve and 163 ALKi-pretreated) received ≥1 dose of ceritinib, of whom, 26 had received prior crizotinib only. Among the 26 crizotinib-pretreated patients, 11 (42.3%) had baseline brain metastases, of which, 7 received prior radiotherapy, 6 (23.1%) had an ECOG performance status of 0, and 24 (92.3%) patients had stage IV disease. The median time from initial diagnosis to ceritinib initiation was 10.5 months (range, 2.4-33.0). At data cut-off, the median duration of exposure (range) was 41.0 weeks (2.9-180.4). In the 26 crizotinib-pretreated patients, per investigator assessment, the overall response rate was 65.4% (95% confidence interval [CI]: 44.3, 82.8), and the disease control rate was 80.8% (95% CI: 60.6, 93.4) (Table). The most frequently reported grade 3/4 adverse events (AEs), regardless of study drug relationship, were ALT increased (30.8%), AST increased (15.4%), diarrhea (11.5%), nausea (7.7%), fatigue (7.7%), and blood alkaline phosphatase increased (7.7%). All 26 patients discontinued treatment due to disease progression (n=12), consent withdrawal (n=6), AEs (n=2), administrative problems (n=4), or death (n=2).
*Median value derived from summary statistics; **Median value estimated by Kaplan-Meier method.Investigator Assessment N=26 Blinded Independent Review Committee Assessment N=26 Best overall response Complete response (CR), n (%) 1 (3.8%) 1 (3.8%) Partial response (PR), n (%) 16 (61.5%) 15 (57.7%) Stable disease (SD), n (%) 4 (15.4%) 5 (19.2%) Progressive disease (PD), n (%) 2 (7.7%) 1 (3.8%) Unknown, n (%) 3 (11.5%) 4 (15.4%) Overall response rate (ORR), % [95% CI] 65.4% [44.3-82.8] 61.5% [40.6-79.8] Disease control rate (DCR), % [95% CI] 80.8% [60.6-93.4] 80.8% [60.6-93.4] Median time to response*, weeks [95% CI] 6.1 [5.1-23.6] 6.4 [5.1-14.0] Median DOR**, months [95% CI] 8.3 [4.2-11.2] 8.5 [3.0-13.6] Median PFS**, months [95% CI] 8.5 [5.3-9.9] 8.2 [4.4-15.2]
Conclusion:
Ceritinib demonstrated durable efficacy in crizotinib-pretreated patients with ALK-rearranged NSCLC. Safety was consistent with the overall ASCEND-1 study population.
