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Karen Kelly
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MA 02 - Emerging Targets (ID 656)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 2
- Moderators:Ravi Salgia, Shun Lu
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 511 + 512
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MA 02.10 - Phase I Study of ABBV-399 (Telisotuzumab Vedotin) as Monotherapy and in Combination with Erlotinib in NSCLC (ID 9466)
12:05 - 12:10 | Author(s): Karen Kelly
- Abstract
- Presentation
Background:
The c-Met receptor is overexpressed in ~50% of patients (pts) with non-small cell lung cancer (NSCLC). ABBV-399 is a first-in-class antibody-drug conjugate composed of ABT-700, an anti–c-Met antibody, conjugated to monomethyl auristatin E (a microtubule inhibitor). Preclinical data demonstrate that ABBV-399 can deliver a potent cytotoxin directly to c-Met+ tumor cells.
Method:
ABBV-399 was administered at doses ranging from 2.4 to 3.0 mg/kg (dose expansion and combination cohorts at 2.7 mg/kg) once every 21 days to 29 pts with advanced c-Met+ (immunohistochemistry [IHC] H-score ≥150) NSCLC both as monotherapy (ABBV-399/monotherapy; 16 pts) and in combination with oral erlotinib 150 mg daily (ABBV-399/ERL; 13 pts) (NCT02099058). c-Met expression was assessed by IHC utilizing the SP44 antibody (Ventana; Tucson, AZ, USA).
Result:
As of April 26, 2017, 16 pts with c-Met+ NSCLC received ≥1 dose of ABBV-399/monotherapy. Monotherapy treatment-related adverse events (TRAEs) occurring in ≥10% of pts (all dose levels and all grades) were fatigue (43.8%), nausea (37.5%), neuropathy (25.0%), vomiting (18.8%), anemia, constipation, and diarrhea (12.5% each). Three of 16 (19%) ABBV-399–treated c-Met+ NSCLC pts had a confirmed partial response (PR) with duration of response (DOR) 3.1, 4.8, and 11.1 months. At week 12, 9 of 16 pts (56.3%) had disease control. TRAEs in ABBV-399/ERL occurring in ≥10% of pts (all grades) were neuropathy (46.2%), nausea (23.1%), fatigue, acneiform rash, dry skin, and diarrhea (15.4% each). Four of 13 (31%) evaluable ABBV-399/ERL–treated c-Met+ pts had a PR (3 confirmed, 1 unconfirmed) with DOR 2.8, 5.3, 4.2+, and 9.1+ months. Three of the 4 pts with PR had EGFR-mutated tumor and recently progressed on TKI. At week 12, 10 of 13 pts (76.9%) had disease control. There were no treatment-related deaths as monotherapy or in combination with erlotinib. Responses were seen in both squamous and non-squamous histology.
Conclusion:
ABBV-399 is well tolerated at 2.7 mg/kg once every 21 days and has demonstrated antitumor activity in pts with c-Met+ NSCLC both as monotherapy and in combination with erlotinib. Early evidence suggests that ABBV-399 represents a novel treatment paradigm effective against multiple c-Met+ NSCLC molecular subtypes and histologies. Updated efficacy/safety data and c-Met IHC status will be presented. Safety and efficacy data from Q2week dosing of ABBV-399 will also be presented.
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MA 02.11 - A Phase I Trial of Erlotinib and Onalespib in EGFR-mutant NSCLC: Focus on EGFR Exon 20 Insertions (ID 9046)
12:10 - 12:15 | Author(s): Karen Kelly
- Abstract
- Presentation
Background:
Onalespib (AT13387) is a non-ansamycin small molecule that inhibits heat shock protein-90 (Hsp90). Hsp90 inhibitors (Hsp90i) preferentially degrade overexpressed and mutated oncoproteins including those that mediate resistance to EGFR-TKIs. Previous Hsp90i studies demonstrated activity in EGFR-mutant NSCLC including EGFR Exon 20 insertions (EGFRex20ins) - uncommon EGFR mutations typically refractory to 1[st] and 2[nd] generation EGFR-TKIs. A phase I study of onalespib plus erlotinib was conducted to determine the MTD, DLT, RP2D, pharmacokinetics (PK) and preliminary antitumor activity for a planned phase 2 trial in EGFR-mutant NSCLC including EGFRex20ins.
Method:
Using a 3 + 3, dose escalation design, onalespib was examined at 2 dose levels (DL) from 150 (DL0) to 120 (DL-1) mg/m[2] IV weekly (D1, D8, D15 on a q28 day cycle). Daily erlotinib was given at 150 mg at both DL. Key eligibility: NSCLC with EGFR activating mutation including EGFRex20ins, age ≥ 18, ECOG PS≤2, acceptable organ function, and ≥1 systemic therapy for advanced disease (platinum-based chemotherapy for EGFRex20ins and EGFR-TKI for other EGFR-mutations). Plasma for PK and ctDNA for next-generation sequencing of ~70 cancer related genes was collected at relevant timepoints.
Result:
9 pts have been treated on 2 DL (3 DL0, 6 DL-1). Pt characteristics: median age 65, M/F (2/7), ECOG PS 0-1 (4/5), EGFRex20ins (8), EGFR E19del (1). 7 pts completed ≥1 cycle. Two DLTs (grade (Gr) 3 maculopapular rash and Gr 3 hypophosphatemia) occurred in DL0. Common drug-related adverse events (AE) of any Gr were diarrhea (100%) and rash (44%), fatigue (55%), increased bilirubin (22%), nausea (44%) and vomiting (33%). Drug-related Gr 3 AEs were diarrhea (55%), maculopapular rash (11%) and hypophosphatemia (11%). At the planned 2-month evaluation, 5 pts had SD, 3 PD, and 1 had withdrawn for toxicity. Of the 5 pts continuing, 2 had SD and 1 PD at the 4-month evaluation. Kaplan-Meier estimate on therapy without progression at the second evaluation is 30% (95% CI: 10 to 87%).
Conclusion:
In patients with EGFR-mutant NSCLC, onalespib plus erlotinib is feasible, tolerable and demonstrates disease control in EGFRex20ins, thereby addressing a key unmet need in NSCLC. The RP2D is erlotinib 150 mg PO daily and onalespib 120 mg/m[2] weekly (D1, D8, D15 q28days). Diarrhea was the most common AE, and generally manageable with supportive care and dose reduction to DL-1. Updated results including PK as well as ctDNA for EGFR-mutation and relevant bypass tracts mediating EGFR-TKI resistance will be presented.
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MA 18 - Global Tobacco Control and Epidemiology II (ID 676)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Epidemiology/Primary Prevention/Tobacco Control and Cessation
- Presentations: 1
- Moderators:H. Kawai, Christian Klaus Manegold
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 511 + 512
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MA 18.06 - Clinical Prognostic Model for Older Patients with Advanced Non-Small Cell Lung Cancer (ID 8113)
16:20 - 16:25 | Author(s): Karen Kelly
- Abstract
- Presentation
Background:
The median age at diagnosis of lung cancer is 70 years. Older patients are often not prescribed standard therapy. Due to multiple competing causes of death, older patients often do not demonstrate a benefit in overall survival (OS). It is important to know which older patients would actually be candidates for aggressive therapy based on their prognosis, and to develop a simple prognostic model that can help clinicians determine individual prognosis.
Method:
Data on patients enrolled on 38 NCI-sponsored cooperative group clinical trials of advanced non-small cell lung cancer (NSCLC) from 1991 to 2011 were analyzed. Multivariable Cox PH model was built with a stepwise procedure with all potential predictors: age, sex, race, ethnicity (Hispanic or non-Hispanic), performance status, initial stage, BMI, and weight loss in the past 3/6 months. We derived a prognostic score using the estimated Cox PH regression coefficient in the training set. To assess the performance of our prognostic model, we calculated the area under receiver operating characteristic (ROC) curve of 1- and 2-year survival in the testing set.
Result:
The final analysis included 1454 NSCLC patients ≥70 years of age. These patients were randomly divided into a training set (n=962) and a testing set (n=492). The prognostic risk score was calculated as: 3 (if male) + 3 (if PS=1) + 8 (if PS=2) + 11 (if initial stage=IV) + 4 (if weight loss). Patients were classified into three prognostic groups by tertiles: good (0-6), intermediate (7-14) and poor (≥15). The median OS in the three groups in the testing set were: 14.6 months (95% CI, 12.2-18.5); 12.2 months (95% CI, 10.7-14.4) and 7.0 months (95% CI, 5.6-8.9), respectively. Despite its simplicity, the present model had area under the 1-year and 2-year ROCs (0.63 and 0.68, respectively) that were higher than existing models.
Conclusion:
Male gender, poor performance status, distant metastases and weight loss immediately prior to diagnosis predict for poor OS in older patients with advanced NSCLC. This study proposes a simple prognostic model for older adults with advanced NSCLC based on basic clinical characteristics that are part of the routine evaluation process for every patient with NSCLC.
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MS 17 - Lessons Learned from Negative Trials (ID 539)
- Event: WCLC 2017
- Type: Mini Symposium
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:V. Sriuranpong, Johan F. Vansteenkiste
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 303 + 304
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MS 17.04 - MET-Lung: A Phase III Trial of Onartuzumab (METMab) Plus Erlotinib vs Erlotinib in Previously Treated Stage IIIB or IV NSCLC (ID 7724)
16:30 - 16:40 | Presenting Author(s): Karen Kelly
- Abstract
- Presentation
Abstract:
A well-known mechanism of resistance to EGFR-TKIs is MET upregulation. MET inhibitors were developed to overcome and prevent this resistance mechanism. Onartuzumab is a monoclonal antibody that binds the extracellular domain of MET. By blocking the interaction with its HGF ligand, activation of the MET signaling pathway does not occur and tumor growth is halted. The clinical evaluation of onartuzumab followed the traditional phase I, II and III registration pathway. In the randomized Phase II trial of erlotinib and placebo versus erlotinib and onartuzumab the trial failed to meet the co-primary endpoint of PFS in the intent to treat population but was positive for the co-primary endpoint of PFS in 66 patients with MET positive tumors defined as IHC > 2+ expression (HR, .53; P .04) (1). Overall survival was also significant (HR, .37; P .002). Objective response rate (ORR) was reported as 8.6% and 3.2% for onartuzumab versus placebo, respectively. Based on these results a randomized placebo controlled phase III trial was launched in patients with MET expressing tumors (2). Surprisingly this trial did not meet its OS primary endpoint and numerically favored the placebo arm. A total of 499 patients were enrolled. The median OS was 6.8 months for onartuzumab versus 9.1 months for placebo (HR, 1.27; 95% CI, 0.98 to 1.65; P = .067). Median progression-free survival was 2.7 months versus 2.6 months (HR, 0.99; 95% CI, 0.81 to 1.20; P = .92) and the ORR was 8.4% compared with 9.6% respectively. When a trial is negative scrutinizing all aspects of the trial and its predecessor trial to determine if there were instructive signals is needed. In this case, reported patient characteristics were similar between the two trials but other patient variables such as the frequency of patients with brain metastases, sites of metastases, and time from previous therapy were not provided. However a large magnitude of difference would be required to significantly alter the results which is unlikely. Adverse events profiles were unrevealing. There were differences related to the MET biomarker that may have influenced the phase III results. In the phase II trial MET IHC expression was retrospectively determined compared to its prospective determination in the phase III trial and its use as a stratification factor. Although the frequency of MET 2+ versus 3+ IHC expression was similar in the two trials, the retrospective nature of the analysis in the phase II trial with its inherent imbalance in patient characteristics may have been misleading especially in the context of the small sample size. Had this been a randomized biomarker selected Phase II trial with a larger sample size we might have seen a different outcome. The assay itself was not a factor. Rigorous validation of the MET IHC assay was conducted. The assay was performed at Genentech for the phase II study and these investigators carefully trained the central laboratories personnel performing the assay for the phase III trial. A robust quality check and audit program was followed. A frequently asked question is whether IHC accurately characterize drivers of MET dysregulation that would result in EGFR tyrosine kinase inhibitor (TKI) resistance and onartuzumab responsiveness. In an exploratory biomarker analysis from the Phase II study MET IHC remained the most robust predictor of efficacy for the combination (3). In the phase III trial a detailed EGFR and MET pathway analysis that included MET and EGFR FISH, EGFR amplification and EGFR, KRAS BRAF, PIK3CA mutational analysis failed to find a biological explanation for onartuzumab inactivity (3). An analysis of MET Exon 14 splicing mutations was not conducted because these mutations had not been discovered at the time of study conduct. Although it would be intriguing to know the frequency of these mutations and their association to onartuzumab activity this is unlikely to be performed. The subgroup results supported further investigation of onartuzumab in a MET positive population but the results were modest. The statistically significant 1.4 month improvement in median PFS is not clinically significant and objective response rates were similar between the arms. Driving the phase III design was the impressive 8.8 month improvement in median OS for the combination but without strong efficacy signals in ORR and PFS to account for this survival outcome suggests other factors were at play such as subsequent therapies and warrants caution. The dilemma with encouraging preliminary data is what is the optimal next study design especially in this instance where the findings were modest? Too many times we have seen positive phase II trials lead to negative phase III results. While a phase III trial is the quickest route to a definitive answer it is done at the price of hundreds of patients. This is particularly highlighted by this study where the combination was approaching an inferior overall survival. Alternative design strategies such as a randomized Phase II/III design that can better balance benefit and risk for our patients and still achieve the goal should be considered. Criteria should be established to help investigators select the appropriate design. References 1. Spigel DR, Ervin TJ, Ramlau RA, Daniel DB, Goldschmidt JH Jr, Blumenschein GR Jr, Krzakowski MJ, Robinet G, Godbert B, Barlesi F, Govindan R, Patel T, Orlov SV, Wertheim MS, Yu W, Zha J, Yauch RL, Patel PH, Phan SC, Peterson AC. Randomized phase II trial of Onartuzumab in combination with erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2013, 31:4105-14. 2. Spigel DR, Edelman MJ, O'Byrne K, Paz-Ares L, Mocci S, Phan S, Shames DS, Smith D, Yu W, Paton VE, Mok T. Results From the Phase III Randomized Trial of Onartuzumab Plus Erlotinib Versus Erlotinib in Previously Treated Stage IIIB or IV Non-Small-Cell Lung Cancer: METLung. J Clin Oncol. 2017, 35:412-20. 3. Koeppen H, Yu W, Zha J, Pandita A, Penuel E, Rangell L, Raja R, Mohan S, Patel R, Desai R, Fu L, Do A, Parab V, Xia X, Januario T, Louie SG, Filvaroff E, Shames DS, Wistuba I, Lipkind M, Huang J, Lazarov M, Ramakrishnan V, Amler L, Phan SC, Patel P, Peterson A, Yauch RL. Biomarker analyses from a placebo-controlled phase II study evaluating erlotinib±onartuzumab in advanced non-small cell lung cancer: MET expression levels are predictive of patient benefit. Clin Cancer Res. 2014, 20:4488-98.
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OA 14 - New Paradigms in Clinical Trials (ID 681)
- Event: WCLC 2017
- Type: Oral
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:Alex Adjei, Eun Kyung Cho
- Coordinates: 10/18/2017, 11:00 - 12:30, Room 311 + 312
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OA 14.07 - Progress in Lung Squamous Cell Carcinoma from the Lung-MAP Master Protocol (S1400) Sub-Studies S1400A, S1400B, S1400C and S1400D (ID 9593)
12:05 - 12:15 | Author(s): Karen Kelly
- Abstract
- Presentation
Background:
Lung-MAP (S1400) is a master umbrella protocol designed to establish genomic screening for previously treated squamous cell lung cancer patients (SqCCA), and independently evaluate targeted therapies with matching biomarkers and alternative therapies (designated non-match therapy) in patients without putative markers. The protocol opened June 16, 2014 with four biomarker-driven sub-studies and one non-match sub-study.
Method:
Eligibility stipulated advanced SqCCA, progressing after at least one prior platinum-based chemotherapy, PS 0–2, and EGFR/ALK wild-type. Tumor samples were required and analyzed for gene alterations by FoundationOne NGS assay (Foundation Medicine). The original biomarker and non-match studies were: S1400B evaluating taselisib for PI3K mutations, S1400C evaluating palbociclib for cell cycle gene alterations (CCGA), S1400D evaluating AZD4547 for FGFR mutations, S1400E evaluating rilotumumab and erlotinib for c-MET positive tumors, and S1400A evaluating durvalumab in patients with no matching biomarkers. The original design included randomization to a control arm, but was amended to a single-arm phase 2 design. The primary endpoint for each modified sub-study was response.
Result:
As of June 16, 2017 all original sub-studies have been closed to accrual; 1298 patients registered to the screening component of the trial and 486 patients have registered to a sub-study. Two new sub-studies have been launched and are currently accruing. Details of the completed sub-studies are included in the table.Sub-study Final Accrual Biomarker prevalence/% of sub-study registrations Closure Date Response to investigational therapy N (%) Status S1400A (non-match) Total: 116 Durvalumab: 78 Docetaxel: 38 NA/59% 12/18/15 Docetaxel arm closed: 4/22/15 11 (16%) Administratively closed to enable activation of new non-match study. S1400B PI3K Total: 39 taselisib: 31 Docetaxel: 8 8%/9% 12/12/16 Docetaxel arm closed: 12/18/15 1 (4%) Closed at interim futility analysis. S1400C (CCGA+) Total: 54 Palbociclib: 37 Docetaxel: 17 19%/15% 09/01/16 Docetaxel arm closed: 12/18/15 2 (6%) Closed at interim futility analysis. S1400D (FGFR+) Total: 45 AZD4547: 35 Docetaxel: 10 16%/12% 10/31/16 Docetaxel arm closed: 12/18/15 2 (7%) Closed at interim futility analysis. S1400E (MET+) Total: 9 R+E: 4 E: 5 N/A (closed too early) 11/26/2014 N/A Closed d/t discontinuation of development of rilotumumab
Conclusion:
Lung-MAP as a master genomic screening protocol has demonstrated feasibility with respect to accrual and evaluation of targeted therapies in lower prevalence patient populations. This dynamic, centralized, single-IRB platform is well positioned to efficiently assess multiple novel therapeutics for advanced SqCCA patients.
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P1.03 - Chemotherapy/Targeted Therapy (ID 689)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.03-026 - Interim Results of a Phase I Study of Nivolumab plus Nab-Paclitaxel/Carboplatin in Patients with NSCLC (ID 8478)
09:30 - 09:30 | Author(s): Karen Kelly
- Abstract
Background:
Chemotherapy, including taxanes, may augment the effects of immune checkpoint inhibitors through tumor cell lysis and subsequent antigen release. This phase I trial is evaluating safety and efficacy of nivolumab plus nab-paclitaxel in NSCLC (+ carboplatin), pancreatic cancer (± gemcitabine), and metastatic breast cancer. Interim results for Arm C, in which patients with NSCLC were treated with nivolumab starting in cycle 1, are presented.
Method:
Potential dose-limiting toxicities (DLTs) were evaluated in Part 1 before Part 2 expansion. Chemotherapy-naive patients with histologically/cytologically confirmed stage IIIB/IV NSCLC received 4 cycles of nab-paclitaxel 100 mg/m[2] days 1, 8, 15 plus carboplatin AUC 6 day 1 plus nivolumab 5 mg/kg day 15 of each 21-day cycle. In cycles ≥ 5, single-agent nivolumab was continued as maintenance therapy. Primary endpoints are number of patients with DLTs (Part 1) and percentage of patients with grade 3/4 treatment-emergent adverse events (TEAEs) or treatment discontinuation due to TEAEs (Parts 1/2). DLT-evaluable patients were those who received ≥ 2 complete nivolumab cycles and remained on study for 14 days after the last nivolumab dose in cycle 2, received ≥ 1 nivolumab dose and discontinued due to DLT before completing 2 nivolumab cycles, or experienced an equivocal DLT after ≥ 1 nivolumab dose. Secondary endpoints included PFS, DCR, ORR, DOR (all by RECIST v1.1), OS, and safety.
Result:
All patients (N = 22) received nab-paclitaxel/carboplatin; results for those who received nab-paclitaxel/carboplatin plus nivolumab (n = 20) are presented. The median age was 65.5 years (55% ≥ 65 years), 70% had ECOG PS 1, 75% were female, and 80% were white. More patients had adenocarcinoma (50%) than squamous cell carcinoma (35%; adenosquamous carcinoma, atypical, and data pending, 5% each). No DLTs were reported among 6 DLT-evaluable patients (Part 1). The most common grade 3/4 TEAEs were neutropenia (45%) and anemia (40%). No grade 3/4 colitis or pneumonitis was reported. Best ORR was 50% (1 CR [5%] and 9 PRs [45%]; 10 patients [50%] had SD); ORR was 43% (3 PRs among 7 patients) and 54% (1 CR and 6 PRs among 13 patients) in those with squamous and nonsquamous histologies, respectively. Median PFS was 10.5 months (95% CI, 4.9-18.1 months); 10.5 and 10.2 months for those with squamous and nonsquamous histologies, respectively.
Conclusion:
These results suggest that nab-paclitaxel/carboplatin plus nivolumab is tolerable for patients with NSCLC. Preliminary efficacy findings indicate promising antitumor activity across histologies. (NCT02309177)
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-046 - Longitudinal Analysis of Plasma CtDNA in EGFR-Mutant NSCLC: SWOG S1403 Trial of Afatinib with or Without Cetuximab (ID 9535)
09:30 - 09:30 | Author(s): Karen Kelly
- Abstract
Background:
Detection of actionable mutations using circulating tumor DNA (ctDNA) isolated from patient plasma is now accepted as clinical practice in NSCLC. Nevertheless, the full extent to which longitudinal plasma analysis can be utilized to guide clinical decision-making has yet to be realized. We prospectively incorporated serial next-generation sequencing (NGS) of ctDNA into the ongoing SWOG S1403 clinical trial (NCT02438722) of afatinib+cetuximab vs afatinib in treatment-naïve NSCLC patients with EGFR-mutant tumors.
Method:
Time points for specimen collection were pre-treatment, after two months of therapy on Cycle 3 Day1 (C3D1) and at progression. Objectives were to: 1) determine the prognostic and predictive significance the EGFR mutant allele frequency (MAF) at each time point; 2) correlate changes in MAF over time with regard to patient outcome, and 3) identify putative emergent resistance mechanisms and companion mutations. Specimen analysis was conducted using the Guardant360 73-gene digital NGS panel.
Result:
To date, 53 patients with advanced EGFR-mutant NSCLC have contributed baseline samples. Of these, 46 had ctDNA detectable at baseline (87%). 39 of these 46 (85%) had detectable, tissue-identical EGFR mutations, for an overall EGFR detection rate of 74% (39/53). A positive finding for EGFR amplification (Amp) in plasma correlated with high ctDNA MAF: median for Amp 16.9 vs nonAmp 0.9 (range/n: 11.6-43.7/10 vs 0.11-7.7/17; p<0.0001). Of patients with detectable EGFR mutation at baseline, 27 had analyzable ctDNA collected at C3D1. Of these, 26/27 showed decreasing MAFs on-treatment (mean for baseline: 9.8 vs C3D1: 0.14; p<0.0001), with 20 cases having no detectable EGFR mutation at C3D1 (mean of 7 positives at C3D1: 0.55). At progression, samples were collected from 14 patients and 10 had EGFR mutations detectable, with T790M present in 3. Another patient had an FGFR3 fusion at PD, but no previous draws were available to determine if it was emergent.
Conclusion:
Longitudinal analysis of plasma ctDNA in S1403 patients demonstrated significant treatment-induced changes in mutation burden and identified resistance mechanisms at progression. EGFR gene amplification, as assessed in plasma, was significantly associated with increased ctDNA MAFs. Patients showed a significant, one-to-two orders of magnitude decline in EGFR MAF after two months of therapy, with 74% dropping below detectable levels. At progression, EGFR mutation detection rates increased, often concomitantly with a putative emergent resistance factor. Accrual to S1403 is ongoing and patient treatment and outcomes remain blinded. The prognostic and predictive utility of baseline and therapy-induced changes in ctDNA MAF kinetics will be determined at study unblinding.
