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J. Ross
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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 - 17:30 | Author(s): J. Ross
- 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)
16:00 - 17:30 | Author(s): J. Ross
- 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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OA10 - EGFR Mutations (ID 382)
- Event: WCLC 2016
- Type: Oral Session
- Track: Biology/Pathology
- Presentations: 1
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OA10.01 - Comprehensive Genomic Profiling and PDX Modeling of EGFR Exon 20 Insertions: Evidence for Osimertinib Based Dual EGFR Blockade (ID 4375)
11:00 - 12:30 | Author(s): J. Ross
- Abstract
Background:
EGFR exon 20 insertion mutations (EGFRex20ins) comprise a subset of EGFR activating alterations relatively insensitive to 1[st] and 2[nd] generation EGFR-TKIs. Comprehensive genomic profiling (CGP) integrated with PDX modeling may identify new EGFR-inhibition strategies for EGFRex20ins.
Methods:
EGFRex20ins and co-occurring genomic alterations were identified by hybrid-capture based CGP performed on 14,483 consecutive FFPE lung cancer specimens to a mean coverage depth of >650X for 236 or 315 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer. An EGFRex20ins(N771_P772>SVDNP)/EGFR-amplified tumor (24 copies) from this cohort was implanted subcutaneously into the flank of NOD.Cg-Prkdc[scid]Il2rg[tm1Wjl]/SzJ (NSG) mice for tumor growth inhibition studies (TGI) with vehicle, erlotinib (50 mg/kg PO daily), osimertinib (25 mg/kg PO daily), and osimertinib (25 mg/kg PO daily) plus cetuximab (10 mg/kg IV, 2x/week) administered for 21 days.
Results:
CGP identified 263/14,483 cases (1.8%) with EGFRex20ins, which represent 12% (263/2,251) of EGFR activating mutations in this series. 90% (237/263) were NSCLC-adenocarcinoma, 9% (23/263) were NSCLC-NOS, and 1% (2/263) were sarcomatoid carcinoma. Over 60 unique EGFRex20ins were identified, most commonly D770_N771>ASVDN (21%) and N771_P772>SVDNP (20%); 6% (15/263) harbored EGFR A763_Y764insFQEA, an EGFRex20ins typically sensitive to erlotinib. Among EGFRex20ins cases, EGFR-amplification occurred in 22% (57/263). Putative co-occurring driver alterations including EGFR (ex19del and L858R), Her2, MET and KRAS tended to be mutually exclusive, occurring only in 5% (12/263) of cases. The most common co-occurring alterations affected TP53 (56%), CDKN2A (22%), CDKN2B (16%), NKX2-1 (14%) and RB1 (11%). Average tumor mutation burden was low (mean 4.3 mutations/Mb, range 0-40.3 mutations/Mb). Clinical outcomes to 1st and 2nd generation EGFR-TKIs were obtained for a subset of cases with various EGFRex20ins, and 0/6 patients had responses. However, robust TGI was observed with combination osimertinib and cetuximab in a highly EGFR-amplified PDX model with a conserved EGFRex20ins (N771_P772>SVDNP) not associated with response to earlier generation EGFR-TKI, and was superior to vehicle, erlotinib or osimertinib alone (D21 mean tumor size 70 mm[3] vs. 1000, 800, 225 mm[3] respectively; p-values all <0.001).
Conclusion:
Diverse EGFRex20ins were detected in 12% of EGFR-mut NSCLC. Available clinical outcomes data demonstrated lack of response to 1[st] and 2[nd] generation EGFR-TKIs. Identification of co-occurring EGFR-amplification in 22% of cases led to testing of a dual EGFR blockade strategy with an EGFR monoclonal antibody and osimertinib, which demonstrated exceptional tumor growth inhibition in an EGFRex20ins PDX minimally responsive to erlotinib. These findings can rapidly be translated into an ongoing clinical trial of osimertinib and necitumumab.
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P1.02 - Poster Session with Presenters Present (ID 454)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.02-061 - Kinase Fusions in Non-Small Cell Lung Carcinoma Identified by Hybrid Capture Based ctDNA Assay (ID 7014)
14:30 - 15:45 | Author(s): J. Ross
- Abstract
Background:
For the detection of genomic driver alterations in NSCLC, comprehensive genomic profiling(CGP) or focused molecular testing of biopsied tissue is a well-accepted approach for matching targeted therapies in first line treatment. For NSCLC patients where invasive biopsy represents a serious risk, assessment of circulating tumor DNA(ctDNA) is an emerging alternative.
Methods:
In patients with clinically advanced NSCLC, two 10 mL aliquots of peripheral, whole blood were collected and plasma was isolated. ctDNA was extracted to create adapted sequencing libraries prior to hybrid capture and sample-multiplexed sequencing on an Illumina HSQ2500 to >5000x unique coverage. Results were analyzed with a proprietary pipeline to call substitutions, indels, rearrangements and copy number amplifications.
Results:
In 288 NSCLC patients evaluated, 20 (6.9%) harbored kinase fusions. 17/20 (85%) were adenocarcinomas, all stage IV. Median patient age was 61 years (range 41-81), and 59% were female. 13 (4.5%) cases harbored ALK fusions with partners as follows: nine EML4 (one each of novel partners PPFIBP1 and CACNB4), and two with unidentified partners. All but one case had breakpoints in ALK intron 19, the remaining harboring a novel intron 17 breakpoint. Three cases (1%) harbored KIF5B-RET (canonical breakpoint intron 12), three (1%) had CD74-ROS1 (breakpoints: ROS1 intron 33(2) and intron 32(1)), and one had FGFR3-TACC3. ALK, RET, and ROS1 fusions were observed by tissue testing of NSCLC in the FoundationCore database with similar frequencies. Five patients had a biopsy with insufficient tissue for CGP; three had both sufficient tissue and ctDNA available. The remainder had no tissue available. For one patient, EML4-ALK fusion was detected in both ctDNA and tissue, collected six days apart. For another, CGP identified EGFR L858R + EGFR L709K and the patient had a durable response to afatinib/cetuximab. After progression, ctDNA assay identified FGFR-TACC3 as well as EGFR L858R. For a pre-menopausal, therapy naïve never smoker, female of east Asian heritage, both assays detected a CD74-ROS1 fusion, whereas ROS1 rearrangement was not identified by the prior use of another commercially available ctDNA test. The patient had a major radiographic response by the second cycle of crizotinib treatment.
Conclusion:
Hybrid capture based ctDNA assay can identify kinase fusions in NSCLC when CGP of biopsied tissue cannot be performed and can direct rational use of first line TKIs. This series identified a novel mechanism of acquired resistance to EGFR inhibitors, novel fusion partners and intronic breakpoints for ALK, and a case of false negative testing by another ctDNA assay.
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P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02c-024 - Detection of Novel Activating FGFR Rearrangements, Truncations, and Splice Site Alterations in NSCLC by Comprehensive Genomic Profiling (ID 4905)
14:30 - 15:45 | Author(s): J. Ross
- Abstract
Background:
Activation of the fibroblast growth factor receptor (FGFR) family through mutation, amplification , C-terminal truncation, and 3’ fusion has been described in multiple cancer types, and FGFR inhibitors are currently being evaluated in the clinic. Though FGFR1 amplification has been defined in several datasets, other FGFR alterations in NSCLC are not well defined.
Methods:
Hybrid-capture based comprehensive genomic profiling (CGP) was performed on 13,898 consecutive FFPE lung cancer specimens (adeno 71%; squamous 12%) to a mean coverage depth of >650X for 236 or 315 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer.
Results:
CGP of 13,898 NSCLCs led to the identification of 53 cases (0.4%) with FGFR1-4 rearrangements, truncations or splice site mutations resulting in an intact kinase domain (KD). The median age was 63 years old (range 36-83 years). Patients with these alterations were 60% (26/53) male, and 72% (31/43) with available data were stage IV. 26 patients (49%) had adenocarcinomas and 18 patients (34%) had squamous histology. FGFR alterations identified included 19 FGFR3-TACC3 fusions, one FGFR2-KIAA1598 fusion, and 7 novel fusions involving FGFR2, FGFR3 or FGFR4. We also identified 16 cases with C-terminal truncations resulting in loss of exon 18, but retention of the KD, 9 cases with mutations predicted to result in alternative splicing in the FGFR extracellular domain (exons 3 or 4), and one case with deletion of exons 3-6. Genomic analysis revealed concurrent FGFR amplification in 13% (7/53) of cases. Co-occurring alterations were observed in known drivers including EGFR, ERBB2, MET, and BRAF in 15% of (8/53) cases, and KRAS mutation in an additional 15% (8/53) of cases. The average tumor mutation burden in cases with these FGFR alterations was relatively high (mean 16.9 mutations/Mb, median 10.1 mutations/Mb, range 0.9-86.5 mutations/Mb) as compared to a mean of 9.2 mutations/Mb in NSCLCs. One patient with a novel FGFR2-LZTFL1 fusion had a partial response to the pan-FGFR inhibitor JNJ-42756493 and remained progression free for 11 months.
Conclusion:
Diverse FGFR alterations were detected using CGP in 0.4% of NSCLCs. Of the 53 cases identified, 37 (70%) were negative for other known driver alterations. In cases with co-occurring drivers, including two with EGFR exon 19 deletion, the possibility of an FGFR fusion arising in the setting of acquired resistance will be evaluated. One patient with a novel FGFR2 fusion had clinical benefit from an investigational FGFR inhibitor, suggesting that these alterations may predict response to targeted therapies.
