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Heather A Wakelee
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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 07.02 - Response to Ensartinib in TKI Naïve ALK+ NSCLC Patients (ID 10247)
15:50 - 15:55 | Presenting Author(s): Heather A Wakelee
- Abstract
- Presentation
Background:
Ensartinib is a novel, potent anaplastic lymphoma kinase (ALK) small molecule tyrosine kinase inhibitor (TKI) with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1, and SLK. Ensartinib has demonstrated significant anti-tumor activity in both ALK TKI-naïve and crizotinib-resistant NSCLC patients. We report on data from ALK TKI treatment naïve patients.
Method:
Pts with advanced solid tumors and ECOG PS 0-1 were treated with ensartinib 225 mg qd on a continuous 28-day schedule. In expansion phase, pts were required to have measurable ALK+ NSCLC with tissue confirmed centrally via FISH or IHC. Asymptomatic brain metastases were allowed. Targeted NGS of cfDNA was performed retrospectively at baseline and on study and compared with tissue results.
Result:
As of 01Apr2017, 102 pts enrolled. In the ALK TKI naïve cohort, 15 (8 female, 7 male) ALK+ NSCLC pts treated at doses ≥ 200 mg evaluable for response. 4 pts had received prior chemotherapy. Median age 59 (34-80) yrs, 60% had ECOG PS 1. Partial response (PR) achieved in 13 pts (87%). Six pts had ALK detected via plasma NGS. In two patients who did not respond to ensartinib, tissue was positive via FISH and plasma was negative. Seven patients had insufficient plasma for NGS evaluation. Median PFS in the initial 13 evaluable ALK+ pts was 25.6 mos with the longest being 44+ mos. The PFS for all patients is still maturing. In 3 pts with central nervous system (CNS) target lesions and no prior radiation, 1 had a complete response (CR) and 2 had PR for an ORR of 100%. Most common drug-related AEs (>20% of pts) included rash (54%), nausea (34%), pruritus (26%), vomiting (25%), and fatigue (21%). Most AEs were Grade (G) 1-2. Most common G3 tx-related AE was rash (12 pts).
Conclusion:
Ensartinib was well-tolerated and induced responses in ALK TKI naïve ALK+ NSCLC pts, including pts with CNS lesions. Enrollment is ongoing in the phase 3 study of ensartinib vs. crizotinib in ALK TKI naïve NSCLC patients.
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MA 13 - New Insights of Diagnosis and Update of Treatment (ID 674)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:S. Ishikura, H. Nakayama
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 311 + 312
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MA 13.01 - Clinical and Pathological Variables Influencing Noninvasive Detection of Early Stage Lung Cancer Using Circulating Tumor DNA (ID 8686)
15:45 - 15:50 | Author(s): Heather A Wakelee
- Abstract
Background:
Analysis of circulating tumor DNA (ctDNA) represents a potential strategy for the early detection of lung cancer. Despite significant interest, few studies have evaluated ctDNA levels in early stage lung cancer patients and the feasibility of ctDNA-based screening remains unclear.
Method:
We applied lung cancer-focused Cancer Personalized Profiling by deep Sequencing (CAPP-Seq) to assess ctDNA levels in 55 localized lung cancer patients treated with curative intent (stage I: n=22, stage II: n=7, stage III: n=26) and 50 healthy controls. Histological subtypes included: adenocarcinoma (n=30), squamous cell carcinoma (n=19), NSCLC NOS (n=4), and small cell lung cancer (n=2). Sensitivity and specificity of ctDNA detection were evaluated in all patients and in a subset of NSCLC patients with node negative (N0) stage I-II disease. Additionally, for patients with stage I adenocarcinoma in whom ctDNA was not detectable using the standard population-based CAPP-Seq approach, we designed personalized CAPP-Seq assays covering a median of 320 mutations/patient based on tumor exome sequencing from the respective patients.
Result:
We detected ctDNA in the pre-treatment plasma of 43/55 (78%) patients at a median allele fraction (AF) of 0.48% (range: 0.004%-26.1%). ROC analysis revealed an area under curve of 0.91, with sensitivity and specificity of 78% and 98%, respectively. Among patients with non-adenocarcinoma histologies, 92% (23/25) had detectable ctDNA (median AF: 0.90%), compared to 67% of patients with adenocarcinoma (20/30; median AF: 0.23%; P=0.046). However, tumor volumes were significantly smaller in adenocarcinomas (P=0.01) and in multivariate analysis ctDNA detection was significantly associated with tumor volume (P=0.01) but not histological subtype (P=0.16). In N0 stage I-II NSCLC patients (n=22), ctDNA was detected in 64% of patients (7/14 adeno vs 7/8 non-adeno) with a specificity of 98% and median AF of 0.022% (median AF of 0.018% vs 0.030% in adeno vs non-adeno patients, respectively). Using personalized CAPP-Seq assays, we detected ctDNA in 3/4 patients with stage I adenocarcinoma in whom ctDNA was not detected using our standard lung-cancer focused CAPP-Seq assay. In these 3 patients, tumor volumes ranged from 11.6-14.7 mL and the ctDNA AF ranged from 0.0014%-0.003%. Taken together, we detected ctDNA in 17/22 (77%) N0 stage I-II tumors.
Conclusion:
These data suggest tumor volume is a stronger determinant of ctDNA levels than histology in localized lung cancers. Additionally, our findings suggest that the majority of localized lung cancers shed ctDNA and that ultra-sensitive assays will be required for early detection of lung cancer using ctDNA
Information from this presentation has been removed upon request of the author.
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MA 16 - Mediastinal, Tracheal and Esophageal Tumor: Multimodality Approaches (ID 675)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:K. Shibuya, Francoise Mornex
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 313 + 314
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MA 16.01 - Characterization of Autoantibody Responses in Thymoma with Myasthenia Gravis by Single-Cell Sequencing of B-cells (ID 8351)
15:45 - 15:50 | Author(s): Heather A Wakelee
- Abstract
- Presentation
Background:
Thymomas are frequently associated with paraneoplastic autoimmune syndromes, with the most common being Myasthenia Gravis (MG). MG is characterized by autoantibodies against muscle antigens, most frequently the acetylcholine receptor (AChR). Patients with thymoma also present with autoantibodies against striational muscle proteins (STR-Abs), such as the sarcomeric protein titin and the ryanodine receptor. These autoantibodies have been primarily regarded as diagnostic or prognostic markers, but little is known about their pathological mechanisms. Comprehensive mechanistic studies have been hindered by the lack of patient-derived monoclonal antibodies (mAbs). Such mAbs could help to define immunogenic epitopes in known or novel autoantigens, and would be useful for deciphering pathological mechanisms in vitro or in animal models.
Method:
We studied mAbs derived from a patient with thymoma and MG, with the patient’s written informed consent and under a Stanford IRB approved protocol. The patient had Masaoka-Koga stage II type B2 thymoma, with multiple recurrences over a period of 8 years. The patient’s MG symptoms included fatigable muscle weakness, the presence of anti-AChR antibodies, and high titer STR-Abs. The patient also had myositis with muscle-related symptoms worsening after thymectomy. We sequenced the repertoire of the patient’s plasmablasts, which are antibody-producing cells derived from the activated B-cell clones, using a barcode-based method for sequencing single-cell immunoglobulin genes developed in our lab. We then expressed 26 mAbs from clonally expanded families of antibodies from two different timepoints that are six months apart. The first timepoint was two years post-Rituximab, coinciding with a tumor recurrence and slow progression of muscle weakness. The second timepoint was a month after radiotherapy when the patient was admitted with severe muscle weakness and pain. Treatment included plasmapheresis/IVIG and Rituximab, with limited improvement over the weeks following hospitalization. The patient was on steroids at both timepoints. Anti-Titin serum antibody titers increased by 60% between these two timepoints.
Result:
Two of the mAbs that were expressed reacted with the main immunogenic region of titin in ELISA, and one of the clones was present at both of the timepoints investigated. These clones were detected despite B-cell depletion by treatment with Rituximab.
Conclusion:
Our results suggest that (i) sequencing single-cell immunoglobulins is a powerful technique for isolating and functionally characterizing mAbs against autoantigens in thymoma and that (ii) persisting or recurring autoreactive clones in patients with thymoma, such as anti-titin clones, may be associated with refractory paraneoplastic syndromes despite use of immunosuppressive therapies.
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P2.03 - Chemotherapy/Targeted Therapy (ID 704)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 2
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.03-043 - A Phase 1b Study of Erlotinib and Momelotinib for TKI-Naïve EGFR-Mutated Metastatic Non-Small Cell Lung Cancer (ID 9551)
09:30 - 09:30 | Author(s): Heather A Wakelee
- Abstract
Background:
In this study (NCT02206763), momelotinib, an inhibitor of Janus kinases 1 and 2, was administered in combination with erlotinib, a tyrosine kinase inhibitor (TKI) in patients with TKI-naïve epidermal growth factor receptor (EGFR)-mutated metastatic non-small cell lung cancer (NSCLC), to determine the maximum tolerated dose and safety of momelotinib in combination with erlotinib. As previously reported, dose limiting toxicities (DLTs) of grade 3 diarrhea (n=1) and grade 4 neutropenia (n=1) without fever were seen at dose level (DL) 2B and trial enrollment was halted. Here, we report the final results.
Method:
Patients received oral erlotinib 150 mg QD (including 11-31 day run-in). Momelotinib was administered orally in a standard 3+3 dose-escalation design: DL1, momelotinib 100 mg QD; DL2A, 200 mg QD; and DL2B, 100 mg BID. DLTs were evaluated in the first 28 days. Plasma samples were collected for PK/PD analyses.
Result:
Eleven patients enrolled: 3 in DL1, 3 in DL2A, and 5 in DL2B. The median duration of exposure to momelotinib was 40 weeks (range 2.4-63.1) and median number of cycles was 10 (range 0.6-15.8). Treatment was discontinued for progressive disease (n=7), adverse event (n=3), and patient decision (n=1). The objective response rate was 54.5% (90% CI: 27.1%–80.0%) and all responses (n=6) were partial responses; 4 patients had stable disease and 1 patient had progressive disease. The median duration of response was 7.1 (90% CI: 4.4–9.6) months. The median progression-free survival was 9.2 (90% CI: 6.2–12.4) months. The estimated median overall survival was not reached. The most common treatment-emergent adverse events (TEAEs) were decreased appetite, dry skin, and fatigue (7 patients each) and diarrhea (6 patients). In addition to the patient with grade 4 neutropenia (DLT), decreased neutrophil count was recorded in 4 additional patients (grade 1-2 [n=3], grade 3 [n=1]); median time to first neutrophil abnormality was 0.5 (range 0.5–3.7) months. Momelotinib-related TEAEs of interest (one patient each) included grade 1 sensory peripheral neuropathy, grade 1 paresthesia, and reactivation of hepatitis B. There was one momelotinib-related serious adverse event, grade 3 pneumonitis. There was no PK interaction between momelotinib and erlotinib.
Conclusion:
The combination of momelotinib and erlotinib had more toxicity than expected at DL2B. Neutropenia was common. Although the small number of patients in this phase 1 study limits our ability to make a definitive conclusion regarding efficacy, the response rate and progression-free survival was similar to previous reports with erlotinib alone.
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P2.03-058 - Tiger-3: A Phase 3 Randomized Study of Rociletinib Vs Chemotherapy in EGFR-mutated Non-small Cell Lung Cancer (NSCLC) (ID 8395)
09:30 - 09:30 | Author(s): Heather A Wakelee
- Abstract
Background:
Rociletinib, an oral, irreversible tyrosine kinase inhibitor (TKI), selectively targets activating mutations in EGFR and the acquired resistance mutation T790M and demonstrated antitumor activity in the phase 1/2 TIGER-X study (NCT01526928). Initial results are reported from the TIGER-3 study (NCT02322281) of rociletinib vs chemotherapy in EGFR TKI-resistant patients with EGFR-mutated NSCLC.
Method:
Eligibility criteria included: metastatic or unresectable, locally advanced, EGFR-mutated NSCLC; radiological progression on most recent TKI therapy; ≥1 line of platinum doublet chemotherapy. Patients were not selected based on T790M status. Patients (N=900) were to be randomized (1:1:1) to rociletinib 500 or 625 mg BID or investigator’s choice of chemotherapy (pemetrexed, gemcitabine, docetaxel, or paclitaxel). The primary endpoint was investigator-assessed progression-free survival (PFS) (RECIST v1.1); objective response rate (ORR) was a secondary endpoint. The rociletinib dosing groups were combined and compared with chemotherapy in a step-down procedure (patients with a centrally confirmed T790M mutation, followed by all randomized patients).
Result:
TIGER-3 enrollment was halted upon discontinuation of rociletinib development in NSCLC in 2016; therefore, target enrollment was not achieved. TIGER-3 enrolled 75 patients in the rociletinib groups [500 mg BID, n=53; 625 mg BID, n=22] and 74 in the chemotherapy group. Median age was 62 years, 69.1% had ECOG Performance Status of 1, 39.6% were Asian, 58.4% were female, and median number of prior therapies was 3. PFS and ORR data are presented in the Table. The most common adverse events (all grade; grade ≥3) in the rociletinib group were diarrhea (62.7%; 2.7%), hyperglycemia (58.7%; 24.0%), nausea (37.3%; 4.0%), fatigue (37.3%; 8.0%), and decreased appetite (37.3%; 0%) and in the chemotherapy group were nausea (27.4%; 5.5%), anemia (24.7%; 2.7%), and fatigue (24.7%; 9.6%).Outcome Centrally Confirmed T790MPositive Centrally Confirmed T790MNegative Intent-to-Treat Population* Rociletinib[†] (n=25) Chemotherapy (n=20) Rociletinib[†] (n=36) Chemotherapy (n=41) Rociletinib[†] (n=75) Chemotherapy (n=73) Median PFS, mo (95% CI) 6.8 (3.7–12.2) 2.7 (1.3–7.0) 4.1 (2.5–4.6) 1.4 (1.3–2.7) 4.1 (2.8–5.5) 2.5 (1.4–2.9) HR (95% CI) 0.570 (0.285–1.140); P=0.105 0.532 (0.322–0.878); P=0.011 0.609 (0.423–0.875); P=0.006 Confirmed ORR, n (%) [95% CI] 9 (36.0) [18.0%–57.5%] 3 (15.0) [3.2%–37.9%] 3 (8.3) [1.8%–22.5%] 2 (4.9) [0.6%–16.5%] 13 (17.3) [9.6%–27.8%] 6 (8.2) [3.1%–17.0%] *Includes patients with undetermined T790M mutation status. [†]Rociletinib 500 mg BID and 625 mg BID dose groups were pooled for the analysis. CI, confidence interval; HR, hazard ratio.
Conclusion:
Incomplete enrollment precluded hypothesis testing. However, the data show a trend toward longer PFS and higher ORR with rociletinib.
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P2.04 - Clinical Design, Statistics and Clinical Trials (ID 705)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 2
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.04-004 - IMpower010: A Phase III Study of Atezolizumab vs Best Supportive Care Following Adjuvant Chemotherapy in Completely Resected NSCLC (ID 8896)
09:30 - 09:30 | Author(s): Heather A Wakelee
- Abstract
Background:
Atezolizumab is an anti–PD-L1 mAb that blocks PD-L1 from interacting with its receptors PD-1 and B7.1 and restores anti-cancer immunity. In patients with 2L/3L advanced NSCLC, the OAK trial showed improved mOS in the atezolizumab arm (13.8 mo) vs the docetaxel arm (9.6 mo), with survival benefit observed across all PD-L1 expression levels on tumor cells (TC) or tumor-infiltrating immune cells (IC). In patients with fully resected NSCLC (stages IB [tumors ≥ 4 cm]-IIIA), adjuvant chemotherapy remains the standard of care, but survival benefit is limited. Therefore, more effective therapies are still needed for patients with early-stage NSCLC. IMpower010 (NCT02486718) is a global Phase III, randomized, open-label trial conducted to evaluate the efficacy and safety of atezolizumab vs best supportive care (BSC) following adjuvant cisplatin–based chemotherapy in patients with resected stage IB (tumors ≥ 4 cm)-IIIA NSCLC.
Method:
Eligibility criteria include complete tumor resection 4-12 weeks prior to enrollment for pathological stage IB (tumors ≥ 4 cm)-IIIA NSCLC, adequate recovery from surgery, ability to receive cisplatin-based adjuvant chemotherapy and ECOG PS 0-1. Patients with other malignancies, autoimmune disease, hormonal cancer or radiation therapy within 5 years and prior chemotherapy or immunotherapy will be excluded. Approximately 1127 patients will be enrolled regardless of PD-L1 status. Patients will receive up to four 21-day cycles of cisplatin-based chemotherapy (cisplatin [75 mg/m[2] IV, day 1] + vinorelbine [30 mg/m[2] IV, days 1, 8], docetaxel [75 mg/m[2] IV, day 1] or gemcitabine [1250 mg/m[2] IV, days 1, 8], or pemetrexed [500 mg/m[2] IV, day 1; only non-squamous NSCLC]). Adjuvant radiation therapy is not permitted. Eligible patients will be randomized 1:1 to receive 16 cycles of atezolizumab 1200 mg q3w or BSC post-adjuvant chemotherapy. Stratification factors include sex, histology (squamous vs non-squamous), disease stage (IB vs II vs IIA) and PD-L1 status by IHC (TC2/3 [≥ 5% expressing PD-L1] and any IC vs TC0/1 [< 5%], and IC2/3 vs TC0/1 and IC0/1 [< 5%]). The primary endpoint is disease-free survival, and secondary endpoints include OS and safety. Exploratory biomarkers will be evaluated, including PD-L1 expression and immune- and tumor-related biomarkers before, during and after treatment with atezolizumab and at radiographic disease recurrence or confirmation of new primary NSCLC.
Result:
Section not applicable
Conclusion:
Section not applicable
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P2.04-012 - First-Line Ensartinib (X396) versus Crizotinib in Advanced ALK-Rearranged NSCLC (eXalt3): A Randomized, Open-Label, Phase 3 Study (ID 8841)
09:30 - 09:30 | Author(s): Heather A Wakelee
- Abstract
Background:
Ensartinib (X-396) is a novel, potent ALK TKI with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1 and SLK. Its phase 1/2 study (NCT01625234) demonstrated that ensartinib is well-tolerated and induces favorable responses in both crizotinib-naïve (ORR 80%) and crizotinib-resistant ALK+ NSCLC patients (ORR 71%), as well as those with CNS metastases.
Method:
In this global, phase 3, open-label, randomized study (eXalt3), approximately 270 patients with ALK+ NSCLC who have received no prior ALK TKI and up to one prior chemotherapy regimen will be randomized with stratification by prior chemotherapy (0/1), performance status (0-1/2), brain metastases at screening (absence/presence), and geographic region (Asia Pacific/other), to receive oral ensartinib (225 mg, once daily) or crizotinib (250mg, twice daily) until disease progression or intolerable toxicity. Eligibility also includes patients ≥ 18 years of age, stage IIIB or IV ALK+ NSCLC. Patients are required to have measurable disease per RECIST 1.1, adequate organ function, and an ECOG PS of ≤2. Adequate tumor tissue (archival or fresh biopsy) must be available for central testing. The primary endpoint was progression-free survival assessed by independent radiology review based on RECIST v. 1.1 criteria. Secondary efficacy endpoints include overall survival, response rates (overall and central nervous system [CNS]), PFS by investigator assessment, time to response, duration of response, and time to CNS progression. The study has > 80% power to detect a superior effect of ensartinib over crizotinib in PFS at a 2-sided alpha level of 0.05.
Result:
Progress report Phase 3 recruitment began in June, 2016 and currently has 66 active sites in 21 countries. The duration of recruitment will be approximately 24 months. This study is registered with ClinicalTrials.Gov as NCT02767804.
Conclusion:
Section not applicable
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PC 03 - 3-2 Which Do you Prefer: Liquid Biopsy or Tissues Biopsy for Molecular Diagnosis? (ID 596)
- Event: WCLC 2017
- Type: Pros & Cons
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:Rafal Dziadziuszko, Y.O. Tan
- Coordinates: 10/18/2017, 11:40 - 12:30, Room 303 + 304
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PC 03.03 - Liquid Biopsy (ID 8114)
11:40 - 12:00 | Presenting Author(s): Heather A Wakelee
- Abstract
- Presentation
Abstract:
Tissue biopsy has been the gold standard in cancer diagnosis and molecular diagnosis of NSCLC for years. However, “liquid biopsy” is gaining in popularity as the sensitivity and availability of the assays increase. Plasma testing is now a standard approach for EGFR mutation testing with US FDA approved tests (Cobas), and much broader applications are available. Liquid biopsies are preferred, especially from the patient perspective. Would you prefer a simple blood draw or an invasive biopsy with high complication risk? The answer is obvious. As tumor cells die they shed DNA into peripheral blood. This circulating tumor DNA (ctDNA) is transient in nature, but can be detected in the plasma samples of patients. Plasma assays require simple phlebotomy compared to the risks of tissue biopsy. This technology can be applied to many malignancies, but is of particular interest in NSCLC given the number of known actionable driver mutations. Rapid detection of these mutations, and monitoring for development of resistance is already part of standard practice. Tissue biopsy strategies are significantly hampered by difficult to access tumors such as those in the brain or bone, and risks such as hemorrhage or pneumothorax. The issue of tumor heterogeneity is also of significance, as a biopsy in one lesion may not reflect the resistance biology of another location.[1] The application of ctDNA is best illustrated in the setting of EGFRmutant (EGFRmut) NSCLC. Though most patients have an EGFR activating mutation identified in the initial tumor biopsy, on June 1, 2016 the US FDA approved the cobas Mutation Test v2, a real-time PCR based assay for EGFR mutations, for use with plasma for detection of EGFR exon19del and L858R (and others in exons 18-21). ctDNA testing for the T790M EGFR resistance mutation is of greater practical utility as biopsy can be avoided in this setting with a positive liquid biopsy. AURA3 established the third generation EGFR TKI osimertinib as superior to chemotherapy for patients with T790M mutations, making T790M testing of high clinical significance.[2] In addition to tissue testing AURA3 was designed with an imbedded plasma assay. Based on the trial results the cobas EGFR Mutation Test v2 approval was expanded to include detection of T790M mutation in plasma samples. The Cobas assay established liquid biopsies as a standard approach for EGFRmut NSCLC, but has limited sensitivity and more sensitive liquid biopsy approaches exist including droplet digital PCR (ddPCR) and BEAMing (beads, emulsion, amplification, and magnetics), in addition to broader next generation sequencing (NGS) assays. Osimertinib activity has been demonstrated in T790M+ NSCLC patients regardless of how T790M is detected.[3] In a large analysis of hundreds of matched tissue, plasma and urine samples from EGFRmut NSCLC patients, both plasma and urine T790M detection sensitivity were 81% versus tissue testing. In the 181 patients with matched tissue, plasma and urine specimens there were 23 patients with T790M detected in plasma but not tissue, and 24 patients with T790M found in tissue but not plasma. The study utilized BEAMing technology, and a sensitive urine assay with quantitative NGS focused on EGFRdel 19, L585R and T790M.[4 ] One challenge for liquid biopsy is in the setting where there is limited ctDNA shedding, such as in lung only disease (M1a) in which case EGFRmut detection rates can be <50%,[5] but increasingly sensitive assays will ameliorate this issue. In a comparison across various platforms of Cobas (non-digital PCR), ARMS (therascreen EGFR amplification refractory mutation system (ARMS), digital detection droplet PCR (ddPCR) and BEAMing dPCR, the sensitivity ranged from 78-100% for the sensitizing mutations and 29-81% for T790M with specificity of 93-100% for the activating mutation and 58-100% for the T790M assays.[6] As outlined above, there is variability in the assays available for plasma analyses, however these assays correlate well with the tissue testing. In a meta-analysis of 26 studies comparing EGFR mutation detection in plasma versus tissue the specificity was 0.97 (95% CI 0.93-0.99) and sensitivity was 0.65 (95% CI 0.54-0.74).[7] Sensitivity is increased with more modern techniques such as BEAMing and droplet digital PCR. As this and other comparisons highlight, specificity is exceedingly high in all available assays, but sensitivity varies amongst the tests and thus a positive ctDNA test should be believed and can spare the patient a biopsy, but a negative test should be followed by further evaluation, bearing in mind that tissue testing can also result in false negatives. Another advantage of “liquid biopsy” is the speed of obtaining results. In a comparison of plasma ddPCR versus biopsy the median turnaround time was significantly faster for the plasma testing (3 days versus 12 days, not including time to arrange the biopsy).[8 ] Thus, for EGFRmut NSCLC it is clear that compared to tissue biopsy, liquid biopsy is highly sensitive and specific, faster, and much more convenient and safe for patients. There should be no debate on the utility of liquid biopsy at initial diagnosis and around development of resistance to 1[st]/2[nd] generation EGFR TKIs. We already have an FDA approved assay in these settings with many improved technologies available as well. EGFR testing lays the foundation for ctDNA testing in NSCLC, but the utility of ctDNA has already expanded to testing for BRAF and other actionable mutations, and tumor rearrangements such as ALK. As an example, a commercially available ctDNA NGS assay performed on 362 NSCLC patients with paired tissue samples identified 51 additional actionable driver mutations via ctDNA analysis compared to the tissue assay, demonstrating real world practicality of this approach and theoretically improved patient outcomes.[9] Other highly sensitive NSCLC platforms looking at panels of dozens to hundreds of genes are available and rapidly changing our ability to detect mutations in larger groups of actionable mutations.[10] Utilization of these technologies at the time of diagnosis and for identification of resistance mechanisms is no longer theoretical but practical. Use of these technologies to monitor treatment response may one day replace or at least supplement imaging, and of particular utility, ctDNA analysis is already showing promise as a measure of minimal residual disease after curative therapy in early stage disease and will likely help guide us in decisions regarding adjuvant therapy in the near future. Liquid biopsy is an established, approved standard for EGFR testing, widely available and practical for tumor genotyping for other actionable mutations, and poised to radically change our surveillance strategies and our management of earlier stages of disease and likely even screening, which is far beyond the scope of what can be done with tissue. The preference for liquid biopsy over tissue biopsy should be clear. REFERENCES: 1) Hata A, Katakami N, Yoshioka H, et al. Spatiotemporal T790M Heterogeneity in Individual Patients with EGFR-Mutant Non-Small-Cell Lung Cancer after Acquired Resistance to EGFR-TKI. J Thorac Oncol 10 (2015) 2) Mok TS, Wu YL, Ahn MJ, et al. AURA3 Investigators, Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med (2016) 3) Oxnard GR, Thress KS, Alden RS, et al. Association Between Plasma Genotyping and Outcomes of Treatment With Osimertinib (AZD9291) in Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 34 (2016) 4) Wakelee HA, Gadgeel SM, Goldman JW, et al.. Epidermal growth factor receptor (EGFR) genotyping of matched urine, plasma and tumor tissue from non-small cell lung cancer (NSCLC) patients (pts) treated with rociletinib. J Clin Oncol 34, (abstr 9001) (2016) 5) Karlovich C, Goldman JW, Sun JM, et al. Assessment of EGFR mutation status in matched plasma and tumor tissue of NSCLC patients from a phase I study of rociletinib (CO-1686). Clin Cancer Res 22(10)(2016) 6) Thress KC, Brant R, Carr TH, et al. EGFR mutation detection in ctDNA from NSCLC patient plasma: A cross-platform comparison of leading technologies to support the clinical development of AZD9291. Lung Cancer (2015). 7) Wu Y, Liu H, Shi X, Song Y. Can EGFR mutations in plasma or serum be predictive markers of non-small-cell lung cancer? A meta-analysis, Lung Cancer Amst. Neth. 88 (2015) 8) Sacher AG, Paweletz C, Dahlberg SE, et al. Prospective validation of rapid plasma genotyping for detection of EGFR and KRAS mutations in advanced NSCLC. Jama Oncology (2016) 9) Zill O, Banks K, Mortimer S, et al. Somatic genomic landscape of over 15,000 advanced stage cancer patients from clinical NGS analysis of ctDNA. J Clin Oncol 34, (LBA11501) (2016) 10) Newman AM, Lovejoy AF, Klass DM, et al. Integrated digital error suppression for improved detection of circulating tumor DNA. Nat Biotechnol 34(5) (2016)
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YI 01 - Young Investigator and First Time Attendee Session (ID 588)
- Event: WCLC 2017
- Type: Young Investigator
- Track: Education/Publication/Career Development
- Presentations: 1
- Moderators:Peter Goldstraw, Giorgio Vittorio Scagliotti
- Coordinates: 10/15/2017, 08:00 - 11:30, F201 + F202 (Annex Hall)
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YI 01.10 - How to Write a Grant Application for Young Investigators (ID 7853)
10:25 - 10:40 | Presenting Author(s): Heather A Wakelee
- Abstract
- Presentation
Abstract:
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