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Siraj M Ali
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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 07.07 - Clinical Outcomes and ALK Resistance Mutations in ALK+ Non-Small Cell Lung Cancer According to EML4-ALK Variant (ID 8255)
15:45 - 17:30 | Author(s): Siraj M Ali
- Abstract
- Presentation
Background:
Advanced ALK+ non-small cell lung cancers (NSCLCs) are effectively treated with ALK tyrosine kinase inhibitors (TKIs). However, clinical outcomes among patients treated with ALK TKIs vary, and the clinical benefit of TKI therapy is limited due to acquired resistance. To date, emerging data suggest that the specific EML4-ALK variant may impact clinical outcome, but whether variant is associated with mechanisms of TKI resistance is unknown.
Method:
We identified 108 advanced ALK+ NSCLC cases with known ALK fusion variants. Progression-free survival (PFS) on ALK TKIs and resistance mechanisms were retrospectively evaluated according to ALK variant.
Result:
The 108 ALK+ cases consisted of: 42 (39%) EML4-ALK v1 (E13;A20), 8 (7.4%) v2 (E20;A20), 45 (41.7%) v3 (E6;A20), 3 (2.8%) v5 (E2;A20), 4 (3.7%) v5’ (E18;A20), 1 (0.9%) v7 (E14;A20), and 5 (4.6%) non-EML4-ALK variants. Given the small numbers of non-v1/v3 cases, v1 and v3 cases were selected for further analysis. Among the 21 v1 and 25 v3 cases treated with first-line crizotinib, there was no significant difference in PFS (HR = 0.81 [95% CI, 0.42-1.57], p = 0.526). Similarly, there was no difference in PFS on second-generation ALK TKIs among 35 v1 and 35 v3 patients who received ceritinib, alectinib, or brigatinib following first- or later-line crizotinib (HR = 1.32 [95% CI, 0.77-2.26], p = 0.308). Interestingly, among 12 v1 and 17 v3 patients who received the third-generation TKI lorlatinib after failure of a second-generation TKI, v3 was associated with significantly longer PFS than v1 (HR = 0.250 [95% CI, 0.09-0.72], p = 0.006). From our cohort, we identified 11 v3 and 14 v1 post-crizotinib biopsies. No difference was noted in the presence of ALK resistance mutations (27% and 21%, respectively; p = 1.000). In contrast, among 30 v3 and 18 v1 post-second generation TKI biopsies, ALK resistance mutations were more common among v3 vs v1 cases (66% vs 44%, respectively; p = 0.147). Furthermore, the ALK G1202R solvent front mutation occurred more frequently in v3 vs v1 (47% vs 0%, respectively; p = 0.001).
Conclusion:
Our findings suggest that EML4-ALK variants 1 and 3 may not be associated with significantly different PFS outcomes on crizotinib or second-generation ALK TKIs. However, ALK resistance mutations, particularly G1202R, occur more frequently in v3 vs v1 post–second generation TKI. Patients with this variant may therefore derive particular benefit from third-generation, pan-inhibitory ALK TKIs. Larger, prospective studies will be needed to confirm these findings.
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MA 12 - Circumventing EGFR Resistance (ID 665)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Wan Ling Tan, Nobuyuki Yamamoto
- Coordinates: 10/17/2017, 11:00 - 12:30, F205 + F206 (Annex Hall)
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MA 12.03 - Kinase Fusions as Recurrent Mechanisms of Acquired Resistance in EGFR-Mutated Non-Small Cell Lung Cancer (NSCLC) (ID 10309)
11:00 - 12:30 | Author(s): Siraj M Ali
- Abstract
- Presentation
Background:
Resistance invariably develops in EGFR-mutated NSCLC treated with EGFR tyrosine kinase inhibitors (TKI). In approximately 50% of cases, resistance is mediated by the EGFR T790M mutation; however, multiple other mechanisms of resistance have also been described, including case reports of acquired kinase fusions (PMIDs: 26187428, 28089157).
Method:
Hybrid-capture based genomic profiling (FoundationOne® or FoundationACT™) was performed prospectively on DNA isolated from tissue-based FFPE samples or blood-based circulating tumor (ctDNA) samples from NSCLC patients.
Result:
From a dataset of 3,014 unique EGFR-mutated (exon 19 deletion, L858R, G719X, L861Q, or S768I) TKI naïve or relapsed NSCLCs we identified 28 (0.9%) cases with co-occurring likely activating kinase rearrangements (BRAF [12], FGFR3 [5], RET [5], ALK [4], NTRK1 [1], EGFR [1]), including 24 confirmed fusions. Treatment histories were available for 21/28 cases, and prior evidence of EGFR mutation and treatment with an EGFR TKI was evident in 21/21 (100%) cases. In 25/28 cases no other known mechanisms of acquired resistance co-occurred with the primary EGFR mutation and the kinase fusion. The 3 cases with co-occurring known resistance mechanisms (T790M or MET amplification) were those with BRAF rearrangements for which no fusion partner was identified. Additionally, our dataset included 10 paired pre- and post-EGFR TKI treatment samples where the latter sample showed an acquired kinase fusion (4 FGFR3-TACC3, 2 EML4-ALK, 2 CCDC6-RET, 1 AGK-BRAF, 1 TPM3-NTRK1) in addition to the primary EGFR alteration. Notably, in 3/10 paired cases (2 FGFR3 and 1 BRAF) the fusion was acquired in the setting of dropout of an existing T790M mutation.
Conclusion:
Acquired kinase fusions are rare yet recurrent mechanisms of acquired resistance in EGFR-driven NSCLCs, and may be enriched in the setting of resistance to T790M-specific inhibitors. Genomic profiling capable of detecting all classes of genomic alterations, including base substitutions, indels, copy number alterations, and fusions, is warranted at the time of progression on EGFR TKIs, and often provides rationale for treatment in such cases.
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MA 15 - Lung Cancer Biology II (ID 670)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Biology/Pathology
- Presentations: 1
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MA 15.06 - ERBB Receptor Feedback Inhibitor-1 Alterations in Non-Small Cell Lung Cancer (ID 10454)
15:45 - 17:30 | Author(s): Siraj M Ali
- Abstract
- Presentation
Background:
ERBB Receptor Feedback Inhibitor-1 (ERRFI-1) encodes MIG6, which is a negative regulator of EGFR and ERBB2 signaling. Loss of function alterations at ERRFI-1 would be expected to promote oncogenesis, but the role of ERRFI-1 alterations in conferring sensitivity to targeted therapies remains to be fully investigated.
Method:
We reviewed 19,347 cases of NSCLC in the Foundation Medicine data base for ERRFI-1 alterations that had been previously assayed by hybrid-capture based genomic DNA profiling of FFPE tissue specimens. Two patients, so identified, had been treated with EGFR pathway antagonist therapies and their outcomes are reported herein.
Result:
ERRFI-1 truncating mutations were identified in 0.62 % (120/ 19,347) of all screened NSCLC specimens. ERRFI-1 alterations were seen in all NSCLC histologic subtypes examined at similar frequencies: adenocarcinoma (0.7%), squamous carcinoma (0.3%), large cell carcinomas (0.8%), adenosquamous (0.6%), sarcomatoid (0.6%), and not otherwise specified (0.6%). Co-existing alterations included: P53 (59%), KRAS (19%), EGFR exon 19 del (9.2%), EGFR L858R (3.3%), EGFR T790M (3.3%), EGFR amp (6.7%), ERBB2 mut (7.5%), and ERBB2 amp (3.3%). Two female patients with ERRFI-1 mutations who were wildtype for known NSCLC driver mutations and targeted therapy naive, achieved RECIST criteria partial responses after treatment with single agent EGFR TKI therapies. Following subsequent disease progression, one of these patients also achieved a secondary response to single agent EGFR directed monoclonal antibody therapy. To our knowledge, these are the first two reported patient outcomes for targeted therapies in ERRFI-1 altered NSCLC.
Conclusion:
The index cases presented here suggest that NSCLC patients with genetic lesions in ERRFI-1 may respond to both anti-EGFR TKIs and monoclonal antibodies. However, co-occurrence between ERFFI-1 mutations and alterations in known NSCLC drivers such as EGFR exon 19 del and L858R may also indicate that in some contexts, ERRFI-1 alterations may provide a mechanism for acquired resistance to targeted therapies as well. Further investigation including assessment of ERRFI-1 loss of heterozygosity, ERRFI-1 VUSs , and clinical evaluation of additional cases including response and resistance to targeted therapy will be performed to more fully delineate the role of ERRFI-1 in NSCLC.
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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 12.08 - Genomic Analysis of Non-Small Cell Lung Cancer (NSCLC) Cases with Focal and Non-Focal MET Amplification (ID 9520)
11:00 - 12:30 | Author(s): Siraj M Ali
- Abstract
- Presentation
Background:
MET amplification (METamp) is a known driver and a mechanism of resistance in EGFR-mutated lung cancers treated with targeted therapy. However, development of therapies targeting METamp has been hampered in part due to poor genomic stratification of patients. We investigated the natural distribution of the size of the MET amplicon and associated genomic characteristics.
Method:
Hybrid-capture based comprehensive genomic profiling (CGP) was performed prospectively on DNA isolated from FFPE samples from NSCLC. Tumor mutational burden (TMB) was calculated from 1.1 Mbp of sequenced DNA and reported as mutations/Mb, as previously described (PMID: 28420421).
Result:
We identified 545 NSCLC cases with focal, defined as <20 Mbp (n = 457, 84%), or non-focal (n = 88, 16%) amplification of the MET gene using CGP. Within this set, the size of the MET amplicon ranged from 0.095 – 158 Mbp; 25[th], 50[th] and 75[th] quartiles were 1.63 Mbp, 3.46 Mbp, and 11.66 Mbp, respectively. In cases with focal METamp the median MET copy number was 11, compared to a median of 7 copies for cases with non-focal METamp (P <0.001). Median TMB in cases with focal vs. non-focal METamp was 10.8 and 9.0, respectively (P=0.47). MET exon 14 splice site alterations co-occurred with METamp in 45 cases (8%), of which 80% had focal METamp (median amplicon size of 2.02 Mbp). EGFR mutations co-occurred with METamp in 93 cases (17%) in this dataset, of which 78% had focal METamp (median amplicon size: 3.77 Mbp). In contrast, cases with other co-occurring alterations described in the NSCLC NCCN guidelines (ALK, ROS1 or RET rearrangements, BRAF V600E, or ERBB2 mutations) METamp was more commonly non-focal (3 focal and 6 non-focal cases), with a median amplicon size of 25.5 Mbp. Clinical outcomes will be presented, including a subset of cases in the setting of resistance to EGFR inhibitors.
Conclusion:
The size of the MET amplicon in MET-amplified NSCLCs is largely variable. Focal amplification is associated with a higher estimate of MET copy number. Neither TMB or co-occurring MET or EGFR mutations significantly correlated with size of the MET amplicon; however, other co-occurring known drivers were associated with non-focal METamp. Additional investigation is warranted to determine the clinical significance of the size of the MET amplicon in NSCLC.
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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): Siraj M Ali
- 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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P2.02 - Biology/Pathology (ID 616)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.02-016 - Pulmonary Sarcomas: A Comprehensive Genomic Profiling Study (ID 10169)
09:30 - 16:00 | Author(s): Siraj M Ali
- Abstract
Background:
Pulmonary sarcomas (PSRC) are uncommon primary thoracic malignancies that are often clinically aggressive. Comprehensive genomic profiling (CGP) can identify biomarkers for both targeted and immunotherapy. We used CGP to analyze novel treatment options for patients with advanced PSRC.
Method:
CGP using hybridization-captured, adaptor ligation-based libraries for up to 406 genes plus select introns from 31 genes frequently rearranged in cancer was performed on 19 PSRC; 15 cases also underwent RNA sequencing for enhanced fusion detection in 265 of these genes. All classes of genomic alteration (GA) were assessed simultaneously: base substitutions, indels, rearrangements, and copy number changes. Clinically relevant GA (CRGA) are GA associated with drugs on the market or under evaluation in clinical trials. Tumor mutational burden (TMB) was determined on 1.1 Mb of sequenced DNA.
Result:
In this cohort were 10 sarcoma NOS, 5 pulmonary artery intimal sarcomas, 2 pleomorphic/MFH sarcomas, 1 primary IMT, and 1 primary SFT, including 1 stage I, 1 stage II, 9 stage III and 8 stage IV tumors. Patient median age was 52 years (range 33–81 years), with 7 female and 12 male patients. The mean GA per sarcoma was 5.7. Notable alterations not presently considered actionable affected TP53 (53%), CDKN2A (32%), CDKN2B (27%), and RB1 (21%). CRGA alterations were detected in PDGFRA, RICTOR, CDK4 and KIT (11% each), and EGFR, TSC2, ALK and BRAF (5% each); 9 (47%) PSRC featured ≥1 CRGA. An ALK fusion was detected in an IMT localized only to the lung and diagnosed as a primary lesion. Inactivation of SMARCA4 through mutation and loss of heterozygosity was found in 1 case. Mean TMB was 8.65 mutations/Mb (16% had TMB >10 mut/Mb, 11% had TMB >20 mut/Mb); cases with TMB >20 mut/Mb lacked characteristically targetable CRGA. All samples tested for MSI (n=7) were microsatellite stable. Assessment of therapeutic intervention and responses is ongoing.
Conclusion:
PSRC is an extremely rare primary lung malignancy characterized by a relatively high frequency of GA. CGP identified various potentially targetable alterations in this small series, particularly driver mutations or fusions in tyrosine kinases and cell cycle regulatory genes. Furthermore, characteristic genomic profiles can provide diagnostic insight, as for SMARCA loss or ALK fusions. This study also identified a significant number of PSRC with intermediate or high TMB, indicating potential immunotherapy options for these patients. Further study of CGP to help manage patient care and minimize suffering from this rare pulmonary malignancy appears warranted.
