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S. Ignatius Ou
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MA 07 - ALK, ROS and HER2 (ID 673)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Robert C. Doebele, J.C. Ho
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 316
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MA 07.01 - Patients with ALK IHC-Positive/FISH-Negative NSCLC Benefit from ALK TKI Treatment: Response Data from the Global ALEX Trial (ID 9008)
15:45 - 17:30 | Author(s): S. Ignatius Ou
- Abstract
- Presentation
Background:
Patients with ALK-positive NSCLC have seen significant advances and increased options in ALK targeted therapies recently, and therefore rely on high quality, robust ALK status testing. Fluorescence in-situ hybridization (FISH) and immunohistochemistry (IHC) are the most common methods to determine ALK status for ALK tyrosine kinase inhibitor (TKI) treatment. However, availability of clinical outcome data from randomized trials linked directly to specific methods is limited. The ALEX trial (BO28984, NCT02075840) provides a unique dataset to assess ALK IHC- and FISH-based assays regarding clinical outcome for alectinib and crizotinib, particularly for the subset of patients with IHC-positive/FISH-negative NSCLC.
Method:
The VENTANA ALK (D5F3) CDx Assay (ALK IHC) performed in central laboratories was used as an enrollment assay for the selection of patients with ALK-positive NSCLC for inclusion in the ALEX trial. Additional samples from these patients were retrospectively tested in central laboratories with the Vysis ALK Break Apart FISH Probe Kit (ALK FISH).
Result:
Overall, 303 patients all with ALK IHC-positive NSCLC were randomized in the ALEX trial, of those 242 patients also had a valid ALK FISH result, with 203 patients having ALK FISH-positive disease and 39 patients having ALK FISH-negative disease (alectinib, n=21; crizotinib, n=18). For 61 of 303 (20.1%) patients with an ALK IHC-positive result, a valid ALK FISH result could not be obtained due to the test leading to an uninformative FISH result (10.9%), or not having adequate/no tissue available (9.2%). Ventana IHC staining success rates were higher than for Vysis FISH testing for the ALEX samples. Exploratory analysis of investigator-assessed progression-free survival (PFS) in patients with a FISH-positive result (HR 0.40, 95% CI 0.27–0.61; p<0.0001; median not reached [alectinib] versus 12.7 months [crizotinib]) was consistent with the primary endpoint analysis in the Ventana ALK IHC-positive population. Patient outcome data show that 28% of central ALK IHC-positive/ALK FISH-negative samples were from patients who responded to ALK TKI treatment (complete response or partial response) and 33% had stable disease according to investigator assessment.
Conclusion:
This analysis shows that ALK IHC is a robust testing approach, which may identify more patients with a valid ALK testing result who benefit from ALK TKI treatment than ALK FISH testing. While PFS of patients with ALK FISH-positive NSCLC was similar to that of patients with ALK IHC-positive NSCLC, the analysis also revealed that the majority of patients with ALK IHC-positive/ALK FISH-negative NSCLC may derive clinical benefit from ALK TKI treatment.
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OA 18 - Lung Cancer Pathology and Genetics (ID 687)
- Event: WCLC 2017
- Type: Oral
- Track: Biology/Pathology
- Presentations: 1
- Moderators:George R. Simon, Yoon-La Choi
- Coordinates: 10/18/2017, 14:30 - 16:15, Room 316
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OA 18.03 - Genomic Profiling Reveals Hedgehog Pathway Alterations in Vismodegib Sensitive Lung Squamous Cell Carcinoma (ID 10599)
14:30 - 16:15 | Author(s): S. Ignatius Ou
- Abstract
- Presentation
Background:
The objective response rate of squamous cell carcinoma of the lung (SCCL) to checkpoint inhibitors, as well as the frequency of known NSCLC oncogenic drivers, is low. We performed comprehensive genomic profiling (CGP) on a large set of SCCL cases to identify new opportunities for potential benefit from targeted or immunotherapies.
Method:
Hybrid-capture based CGP of up to 315 genes was performed prospectively on DNA isolated from tissue-based FFPE samples of SCCL, and tumor mutational burden (TMB) was assessed as described previously (PMID: 28420421).
Result:
From a dataset of 958 unique SCCL cases, we identify 2.6% of cases harboring alterations in PTCH1, 0.3% in SMO1, and 01.2% in SUFU, which were primarily mutually exclusive Genes known to be oncogenic drivers in NSCLC were altered at the following frequencies in SCCL 8.0% KRAS, 6.8% EGFR, 3.4% MET, 1.9% BRAF, and less than 1% each for ALK, ROS, and RET. In PTCH1-mutated cases 96% did not harbor alterations in these driver genes (1/23 positive for co-occurrence).. The overall SCCL population has a median TMB of 9.0, with 11.3%) cases higher than 20 mutations/Mb (m/Mb). Two index cases with PTCH1 mutations and no alterations in established NSCLC driver genes were identified. A year 77-year-old male with a 40 pack-year smoking history was diagnosed with metastatic SCCL, basaloid variant, harboring PTCH1 s799fs*29 with TMB of 3.7 m/Mb, and he had a year-long complete response to vismodegib. A 69-year-old male with poorly differentiated SCCL harboring PTCH1 W197* and W460* had a 7 month response to vismodegib. On progression, biopsy of recurrent disease after vismodegib failure demonstrated the same PTCH1 alterations as well as acquisition of the 11q13 (CCND1/FGF3/FGF4/FGF19) amplicon. Both biopsies had TMB > 45 m/mb. Nine additional cases not in this series identified as the basaloid variant of SCCL by expert thoracic pathology review were assayed by CGP and 11% (1/9) harbored PTCH1 mutation, but no other alterations of the hedgehog pathway were identified.
Conclusion:
The index cases presented here suggest a subset of PTCH1-mutated SCCL may see clinical benefit from hedgehog inhibitors, regardless of TMB. In a small series of expert diagnosed basaloid histology in SCCL cases, this histology may enrich for hedgehog pathway alterations. Further investigation of underlying PTCH1 LOH and TMB will be undertaken to assess which SCCL cases can respond to respond to hedgehog pathway inhibitors.
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-073 - TPX-0005 with an EGFR Tyrosine Kinase Inhibitor (TKI) Overcomes Innate Resistance in EGFR Mutant NSCLC (ID 8956)
09:30 - 16:00 | Author(s): S. Ignatius Ou
- Abstract
Background:
Overexpression of several receptor tyrosine kinases (RTKs) substitutes EGFR signaling in EGFR-mutant NSCLC. The MET ligand hepatocyte growth factor (HGF) provides an alternative signaling mechanism for EGFR by inducing inter-receptor cross talk with EphA2, CUB domain-containing protein-1 (CDCP1) or AXL. SHP2, a non-receptor protein tyrosine phosphatase is central in signal transduction downstream of RTK signaling and in Src activation. We previously demonstrated that STAT3 and Src-YAP1 signaling limits EGFR TKI efficacy in EGFR-mutant NSCLC. We are now exploring the possibility of multiple RTK activation through a Src-YAP1-mediated transcriptional program. We are evaluating whether combined EGFR inhibition with TPX-0005, a novel orally available multikinase inhibitor and potent Src/FAK and JAK2 inhibitor, can be more efficient than EGFR inhibition alone in EGFR-mutant NSCLC cells.
Method:
We studied the mRNA expression levels of stromal HGF and tumor RTKs, AXL, CDCP1, MET, and EphA2, as well as SHP2, and clinical outcome in baseline samples of 64 EGFR-mutant NSCLC patients treated with first-line EGFR TKI. We combined in vitro approaches to explore whether gefitinib or osimertinib combined with TPX-0005 can abolish STAT3 and Src-YAP1 and downregulate the expression of RTKs.
Result:
High levels of AXL, CDCP1 and SHP2 mRNA expression were associated with worse outcome to EGFR TKI in 64 EGFR-mutant NSCLC patients. Median progression-free survival (PFS) was 14.5 and 23.4 months for patients with high and low AXL mRNA, respectively (p=0.0359). Median PFS was 9.1 and 20.2 months for patients with high and low CDCP1 mRNA, respectively (p=0.0179). Tumoral EPHA2 and MET or stromal HGF levels did not affect PFS. Median PFS was 11.4 and 24.1 months for patients with high and low SHP2 mRNA, respectively (p=0.0094). The combination of gefitinib/osimertinib with TPX-0005 resulted in highly synergistic suppression of cell viability and reduced colony formation in two EGFR-mutant cell lines. The combination abolished the EGFR inhibition-induced STAT3 and YAP1 phosphorylation, as confirmed by western blotting and immunofluorescence. The results of TaqMan quantitative-PCR assay revealed that gefitinib/osimertinib plus TPX-0005 reduced the mRNA levels of AXL, CDCP1 and MET, an effect that could not be obtained with EGFR inhibition alone. In vivo experiments are ongoing.
Conclusion:
AXL and CDCP1 are adverse predictive markers of PFS in EGFR-mutant NSCLC patients. STAT3 and Src-YAP1 signaling limits the efficacy EGFR TKI. Combined EGFR inhibition with TPX-0005 (currently in phase I clinical testing) is a particularly attractive strategy
