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Jeffrey S. Ross
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MA 05 - Immuno-Oncology: Novel Biomarker Candidates (ID 658)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Yoichi Nakanishi, P. Mitchell
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 303 + 304
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MA 05.02 - STK11/LKB1 Loss of Function Genomic Alterations Predict Primary Resistance to PD-1/PD-L1 Axis Blockade in KRAS-Mutant NSCLC (ID 10367)
15:50 - 15:55 | Author(s): Jeffrey S. Ross
- Abstract
- Presentation
Background:
The genomic landscape of primary resistance to PD-1 blockade in lung adenocarcinoma (LUAD) is largely unknown. We previously reported that co-mutations in STK11/LKB1 (KL) or TP53 (KP) define subgroups of KRAS-mutant LUAD with distinct therapeutic vulnerabilities and immune profiles. Here, we present updated data on the clinical efficacy of PD-1/PD-L1 inhibitors in co-mutation defined KRAS mutant and wild-type LUAD patients and examine the relationship between genetic alterations in individual genes, tumor cell PD-L1 expression and tumor mutational burden (TMB) using cohorts form the SU2C/ACS Lung Cancer Dream Team and Foundation Medicine (FM).
Method:
The cohorts included 924 LUAD with NGS (FM cohort) and 188 patients with KRAS non-squamous NSCLC (SU2C cohort) who received at least one cycle of PD-1/PD-L1 inhibitor therapy and had available molecular profiling. Tumor cell PD-L1 expression was tested using E1L3N IHC (SU2C) and the VENTANA PD-L1 (SP142) assay (FM). TMB was defined as previously described and was classified as high (TMB-H), intermediate (TMB-I) or low (TMB-L).
Result:
188 immunotherapy-treated (83.5% nivolumab, 11.7% pembrolizumab, 4.8% anti-PD1/PD-L1 plus anti-CTLA-4) pts with KRAS-mutant NSCLC were included in the efficacy analysis. The ORR differed significantly between the KL (8.8%), KP (35.9%) and K-only sub-groups (27.3%) (P=0.0011, Fisher’s exact test). KL LUAC exhibited significantly shorter PFS (mPFS 1.8m vs 2.7m, HR=0.53, 95% CI 0.34-0.84, P<0.001, log-rank test) and OS (mOS 6.8m vs 15.6m, HR 0.53, 95% CI 0.34 to 0.84, P=0.0072, log rank test) compared to KRAS-mutant NSCLC with wild-type STK11. Loss-of function (LOF) genetic alterations in STK11 were the only significantly enriched event in PD-L1 negative, TMB-I/H compared to PD-L1 high positive (TPS≥50%), TMB-I/H tumors in the overall FMI cohort (Bonferroni adjusted P=2.38x10[-4], Fisher’s exact test) and among KRAS-mutant tumors (adjusted P=0.05, Fisher’s exact test) . Notably, PD-1 blockade demonstrated activity among 10 PD-L1-negative KP tumors, with 3 PRs and 4SDs recorded. In syngeneic isogenic murine models PD-1 blockade significantly inhibited the growth of Kras mutant tumors with wild-type LKB1 (K), but not those with LKB1 loss (KL), providing evidence that LKB1 loss can play a causative role in promoting PD-1 inhibitor resistance.
Conclusion:
Loss of function genomic alterations in STK11 represent a dominant driver of de novo resistance to PD-1/PD-L1 blockade in KRAS-mutant NSCLC. In addition to tumor PD-L1 status and tumor mutational burden precision immunotherapy approaches should take into consideration the STK11 status of individual tumors.
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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)
16:25 - 16:30 | Author(s): Jeffrey S. Ross
- 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)
11:10 - 11:15 | Author(s): Jeffrey S. Ross
- 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)
16:20 - 16:25 | Author(s): Jeffrey S. Ross
- 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)
12:10 - 12:20 | Author(s): Jeffrey S. Ross
- 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)
14:50 - 15:00 | Author(s): Jeffrey S. Ross
- 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: 2
- 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 - 09:30 | Presenting Author(s): Jeffrey S. Ross
- 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.
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P2.02-052 - A Clinically-Validated Universal Companion Diagnostic Platform for Cancer Patient Care (ID 8212)
09:30 - 09:30 | Author(s): Jeffrey S. Ross
- Abstract
Background:
The increase in targeted therapies and associated companion diagnostics (CDx) has led to the need for efficient determination of therapeutic eligibility from a single assay. Comprehensive genomic profiling (CGP) provides a solution, but due to the complexity and number of assays available today, standardization of validation has become critically important. We present here the first NGS-based universal CDx platform developed and performed in compliance with FDA 21 CFR part 820. The assay interrogates 324 genes, and is anticipated initially to have eight CDx indications (Table 1). The versatile assay design will facilitate streamlined development of future CDx indications.
Method:
DNA extracted from FFPE tumor tissue underwent whole-genome shotgun library construction and hybridization-based capture, followed by sequencing using Illumina HiSeq 4000. Sequence data were processed using a proprietary analysis pipeline designed to detect base substitutions, indels, copy number alterations, genomic rearrangements, microsatellite instability (MSI), and tumor mutational burden (TMB).
Result:
Concordance with FDA-approved CDx are shown in Table 1. Clinical validity was established such that the concordance between CGP and approved CDx were statistically non-inferior to that of two runs of approved CDx. For analytical validity, limit of detection (LoD) was at allele frequency 4% for known substitutions and indels. LoD was 16% tumor content for copy number amplifications, 30% for homozygous deletions, 11% for genomic rearrangements, 12% for MSI, and estimated 20% for TMB. Positive percent agreement (PPA) with an orthogonal NGS platform was 95.8% in substitutions and indels. PPA with FoundationOne was 98.3% across all variant types. Within-assay reproducibility was measured with PPA 99.4%.Companion diagnostic Indicated use PPA Comparator CDx assay EGFR exon 19 deletions and L858R erlotinib, afatinib or gefitinib in NSCLC 98.1% (106/108) cobas® EGFR Mutation Test v2 EGFR T790M osimertinib in NSCLC 98.9% (87/88) cobas® EGFR Mutation Test v2 ALK rearrangements crizotinib in NSCLC 92.9% (78/84) Ventana ALK (D5F3) CDx Assay Vysis ALK Break-Apart FISH KRAS cetuximab or panitumumab in CRC 100% (173/173) therascreen® KRAS PCR ERBB2 (HER2) Amplifications trastuzumab, pertuzumab and ado-trastuzumab-emtansine in breast and gastric cancer 89.4% (101/113) Dako HER2 FISH PharmDx® BRAF V600E/K vemurafenib, dabrafenib, trametinib in melanoma 99.4% (166/167) cobas® BRAF V600 PCR BRCA1/2 rucaparib in ovarian cancer N/A N/A: Novel CDx that was previously validated in PMA P160018
Conclusion:
Rapid expansion of targeted therapies and CDx has necessitated a new approach and urgency to defining performance standards. We developed a universal CDx assay and established a robust approach for demonstrating clinical and analytical validity to support and accelerate the use of CGP for routine clinical care.
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P3.02 - Biology/Pathology (ID 620)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 2
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.02-061 - An ALK Follow-On Companion Diagnostic Using CGP for Clinical Care of Patients with NSCLC (ID 10396)
09:30 - 09:30 | Author(s): Jeffrey S. Ross
- Abstract
Background:
Advanced NSCLC patients may benefit from treatment with ALK inhibitors if they harbor ALK rearrangements such as an EML4-ALK fusion. While the FDA has approved companion diagnostics (CDx) using IHC and FISH-based assays for ALK, molecular diagnostic testing in NSCLC is rapidly evolving towards comprehensive genomic profiling (CGP) to test for a growing number of established predictive biomarkers. Clinical validity of ALK testing using CGP however, has not yet been demonstrated in an FDA approved manner. We present here the first follow-on CDx ALK test using CGP as a part of our universal CDx platform.
Method:
Clinical validity was established against the FDA-approved IHC and FISH CDx, using 291 samples from the ALEX clinical trial (NCT02075840), including ALK-negative screen-failed patients. Clinical validity was established such that the CGP concordance versus an FDA-approved test was statistically non-inferior to the performance comparison between IHC and FISH. Concordance reported in Table 1 was calculated on samples that were in agreement between IHC and FISH.
Result:
Concordance in patients in consensus between IHC and FISH is shown in Table 1. Positive percent agreement of 92.9% and negative percent agreement of 100% was achieved. Statistical non-inferiority demonstrates a non-inferiority margin of 5.4%. Limit of detection studies demonstrated the ability to detect ALK rearrangements down to 1.8% tumor content. Table 1.Companion diagnostic ALK rearrangements Indicated use ALK inhibitors in NSCLC Approved CDx comparator Ventana ALK (D5F3) CDx Assay Vysis ALK Break-Apart FISH Probe Kit Positive percent agreement 92.9% (78/84) Negative percent agreement 100% (75/75) Median unique sequence coverage 807X Precision 100% Limit of Detection 1.8% tumor content
Conclusion:
We developed and validated a follow-on CDx for ALK as part of a universal CDx platform. The platform provides a single assay with well-defined performance characteristics, identifies patients with cancer who may be eligible to receive FDA-approved targeted therapeutics, conserves tissue by avoiding serial testing and can serve as clinical trial assay for studies requiring a molecular biomarker for eligibility. The data demonstrating clinical and analytical validity of ALK may accelerate the use of CGP for routine clinical care.
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P3.02-062 - An EGFR Follow-On Companion Diagnostic for Clinical Care of Patients with NSCLC (ID 10414)
09:30 - 09:30 | Author(s): Jeffrey S. Ross
- Abstract
Background:
Late-stage NSCLC patients may benefit from treatment with EGFR tyrosine kinase inhibitors if they harbor certain activating mutations in EGFR. While the FDA has approved companion diagnostics (CDx) using PCR to detect EGFR mutations, molecular diagnostic testing is evolving towards comprehensive genomic profiling (CGP). However, clinical validity of EGFR testing using CGP has not yet been demonstrated in an FDA-approved manner. We present here the first follow-on CDx EGFR test using CGP as part of our universal CDx platform.
Method:
Clinical validity was established against FDA-approved PCR-based cobas® EGFR Mutation Test v2, using 406 procured samples containing EGFR L858R mutations and exon 19 deletions, and 354 samples from the AURA clinical trials for T790M mutations. For each sample, two tests of cobas were run, and clinical validity was established such the concordance between CGP and cobas were statistically non-inferior to the performance between two runs of cobas. Concordance (PPA and NPA) reported on Table 1 was calculated on samples that were in agreement between the two cobas runs.
Result:
Concordance is shown in Table 1. For L858R and exon 19 deletions, statistical non-inferiority demonstrated a non-inferiority margin of 1.9%. For T790M, our assay has higher sensitivity: of the 61 samples that were below 10% mutant allele fraction (MAF) as detected by NGS, 30 were missed by cobas. Table 1.Companion diagnostic EGFR exon 19 deletions and L858R EGFR T790M Indicated use erlotinib, afatinib, or gefitinib in NSCLC osimertinib in NSCLC Approved CDx comparator cobas® EGFR Mutation Test v2 cobas® EGFR Mutation Test v2 Positive Percent Agreement (PPA) 98.1% (106/108) 98.9% (87/88) Negative Percent Agreement (NPA) 99.4% (153/154) 86.1% (93/108) Median unique sequence coverage L858R: 1165X Exon 19: 1028X 1126X Precision 100% 100% Limit of Detection L858R: 1.9% MAF Exon 19 deletions: 3.4% MAF 1.8% MAF
Conclusion:
We present a follow-on CDx for EGFR as part of the universal CDx platform. The platform provides a single assay with well-defined performance characteristics, identifies patients with cancer who may be eligible to receive FDA-approved targeted therapeutics, conserves tissue by avoiding serial testing and can serve as clinical trial assay for studies requiring a molecular biomarker for eligibility. The data demonstrating clinical and analytical validity of EGFR may accelerate the use of CGP for routine clinical care.
