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J. Elvin
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MA04 - HER2, P53, KRAS and Other Targets in Advanced NSCLC (ID 380)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 2
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MA04.01 - Non-Amplification Mutation of ERBB2 in EGFR-Mutated Lung Cancer (ID 6138)
16:00 - 16:06 | Author(s): J. Elvin
- Abstract
- Presentation
Background:
Amplification of ERBB2 in EGFR-mutant lung cancers is a reported mechanism of acquired resistance to tyrosine kinase inhibitor (TKI) therapy. Comprehensive genomic profiling (CGP) of NSCLC tumors shows mutation of ERBB2, most often affecting the encoded HER2 receptor at residue S310, is also prevalent, particularly in the context of EGFR L858R.
Methods:
CGP was performed on hybridization-captured, adaptor ligation-based libraries for up to 315 cancer-related genes plus select introns from 28 genes frequently rearranged in cancer on 14,887 consecutive cases of lung cancer. All classes of genomic alterations (GA) were assessed simultaneously, including base substitutions, indels, rearrangements/fusions, and copy number changes. Short variants (SV) include base substitutions or indels.
Results:
A total of 2,516 (16.9%) samples featured EGFR alterations, including amplification (amp) and SV. Of these, 2.9% (73/2,516) harbored alterations in ERBB2 (amp and/or SV). 18 samples (0.7%) harbored SV alterations in ERBB2, 14 of which were mutations at S310. ERBB2 S310 mutations were most often found with EGFR L858R. The ratio of observed to expected mutation at HER2 S310 in EGFR-mutated lung cancers was 2.12, and the ratio for HER2 S310 in combination with EGFR L858R was 5.03. The co-occurrence of HER2 S310 and EGFR L858R was highly significant (p<0.00005). The combination of EGFR and ERBB2 alterations was more common in women. The ratio of male:female patients with any lung cancer in this dataset was 1:1.1, whereas the ratio of male:female with any EGFR alteration was 1:1.7 and for both EGFR and ERBB2 alterations (amp or SV) was 1:3.4. Patients with a combination of EGFR and ERBB2 alterations have been shown to respond to treatment with the pan-ERBB inhibitor afatinib, or combinations of afatinib with the HER2-targeted therapy trastuzumab.
Conclusion:
Short variant alterations in ERBB2 may be an additional mechanism for tumors to acquire resistance to treatment with EGFR-targeted TKIs. Mutations at residue S310, in the extracellular domain of HER2, are the most common ERBB2 SV observed in EGFR-mutant lung cancer, and are significantly associated with EGFR L858R. The co-occurence of alterations in ERBB2 and EGFR is far more common in women than in men. Treatment with the pan-ERBB inhibitor afatinib, alone or in combination with agents targeting HER2, has been shown to benefit patients with lung cancer harboring mutations in both EGFR and ERBB2.
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MA04.09 - RICTOR Amplification in Non-Small Cell Lung Cancer: An Emerging Therapy Target (ID 6177)
17:00 - 17:06 | Author(s): J. Elvin
- Abstract
- Presentation
Background:
Comprehensive genomic profiling (CGP) can discover novel therapy targets in NSCLC. Amplification of RICTOR, encoding a component of the MTORC2 complex, has recently been identified as a targetable alteration leading to clinical benefit.
Methods:
CGP was performed on hybridization-captured, adaptor ligation-based libraries for up to 315 cancer-related genes plus select introns from 28 genes frequently rearranged in cancer on 14,698 consecutive cases of NSCLC, comprising lung adenocarcinoma, squamous cell carcinoma (SCC) or NSCLC not otherwise specified (NOS). Tumor mutational burden (TMB) was determined on 1.1 Mb of sequenced DNA. All classes of genomic alterations (GA) were assessed simultaneously, including base substitutions, indels, rearrangements/fusions, and copy number changes.
Results:
747 (5.0%) NSCLC featured RICTOR amplification (amp). There were 380 (51%) male and 367 (49%) female patients with a mean age of 64.1 years (range 18-88 years). The primary tumor was analyzed in 333 (45%) cases and a metastasis biopsy in 414 (55%) cases. Genes most frequently co-altered with RICTOR amp included TP53 (79.5%) and FGF10 (64.6%), which is located close to RICTOR on chromosome 5 and is frequently co-amplified. Several known oncogenes in NSCLC were mutated at significantly higher rates in tumors with RICTOR amp, including EGFR (22%), MET (8.4%), ERBB2 (7%), as well as FGFR1 (5%), FGFR3 (1.4%), and FGFR4 (1.6%). 42.2% of tumors with RICTOR amp did not harbor additional alterations in KRAS or genes indicated in the NCCN guidelines. KRAS GA were identified in 19.6% of RICTOR amp tumors, compared with 29.8% of all NSCLC, but this difference was not statistically significant. Mean TMB in RICTOR amp tumors was intermediate (14.9 mut/Mb), and is higher than the overall average for NSCLC (9.2 mut/Mb). The number of RICTOR-amplified tumors with high TMB (>20 mut/Mb) was 23%, higher than the rate for non-RICTOR amp NSCLC (12.9%). Examples of patients with RICTOR amplification within late stage NSCLC responding to MTOR inhibitors will be presented.
Conclusion:
RICTOR amplification, when compared to other non-EGFR known drivers of NSCLC, is a relatively frequent clinically relevant GA that has been shown to respond to MTOR inhibitors. The co-occurrence of RICTOR amplification with mutation of known oncogenic drivers suggests a possible mechanism of acquired resistance to therapy that should be explored further. Tumors with RICTOR amp more often have higher levels of TMB than other NSCLC. Further study of RICTOR amp as a therapy target NSCLC in a clinical trial setting appears warranted.
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