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Vincent K Lam
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MA16 - Novel Mechanisms for Molecular Profiling (ID 917)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 13:30 - 15:00, Room 203 BD
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MA16.01 - Frequency and Genomic Context of Emerging Markers for Molecular Testing in Lung Adenocarcinoma in Cell-Free DNA NGS Analysis (ID 13465)
13:30 - 13:35 | Presenting Author(s): Vincent K Lam
- Abstract
- Presentation
Background
The recently updated CAP/IASLC/AMP lung cancer molecular testing guideline (Lindeman et al 2018) recommends several genes be analyzed by next-generation sequencing (NGS) in lung adenocarcinoma (LUAD), including EGFR, ALK, BRAF, KRAS, and others. It also includes a list of 20 emerging markers (EMs) for molecular testing and suggests practitioners remain aware of these and other genes between guideline updates. We investigated the frequency of genomic alterations (GAs) in several of these EMs in a cohort of patients with advanced lung adenocarcinoma who underwent clinical cell-free DNA (cfDNA) NGS analysis and assessed co-occurrence with canonical driver GAs.
a9ded1e5ce5d75814730bb4caaf49419 Method
Genomic data was reviewed from 6530 patients with at least one GA detected on clinical Guardant360 cfDNA NGS testing (Guardant Health, Inc) with an indicated diagnosis of lung adenocarcinoma from 11/25/16-3/1/18. Synonymous alterations were excluded from further analyses.
4c3880bb027f159e801041b1021e88e8 Result
2600 patients (40%) had at least one nonsynonymous alteration in the EM genes assessed; excluding GAs classified as variants of unknown significance (VUS), 1350 patients (21%) had at least one characterized alteration. Table 1 shows number and frequency of GAs observed per patient by gene and alteration type. Of EMs assessed, GAs were observed most commonly in NF1, PIK3CA, PDGFRA, KIT, and FGFR1-2. GAs in multiple EMs, including RIT1, NRAS, FGFR2-3, NTRK1, KIT, and AKT1, were observed co-occurring with established driver alterations, often in a genomic context consistent with resistance to targeted therapy at allelic fractions suggestive of subclonality.
8eea62084ca7e541d918e823422bd82e Conclusion
Effective therapies are continually emerging for a growing number of molecular biomarkers in lung cancer. Comprehensive genomic profiling with cfDNA NGS can identify GAs in both recommended and EM genes to guide therapeutic decision-making and catalyze clinical trial enrollment. Further investigation of mutual exclusivity and co-occurrence of established drivers and EMs may reveal novel resistance mechanisms and facilitate identification of rational combination therapeutic strategies.
6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MA19 - Genomic Markers of IO Response (ID 922)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Immunooncology
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 15:15 - 16:45, Room 201 BD
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MA19.10 - Impact of STK11/LKB1 Genomic Alterations on Clinical Outcomes with Chemo-Immunotherapy in Non-Squamous NSCLC (ID 14295)
16:15 - 16:20 | Author(s): Vincent K Lam
- Abstract
- Presentation
Background
Chemo-immunotherapy with pemetrexed/carboplatin/pembrolizumab represents a standard of care for the first-line treatment of patients with metastatic non-squamous NSCLC, irrespective of tumor cell PD-L1 expression. Genomic determinants of response to chemo-immunotherapy in NSCLC have not been reported thus far. We previously identified STK11/LKB1 alterations as a major genomic driver of de novo resistance to PD-1/PD-L1 inhibitor monotherapy in NSCLC (Skoulidis et al., Cancer Discovery, 2018). Here, we examine the impact of STK11/LKB1 mutations on clinical outcomes with chemo-immunotherapy with pemetrexed/carboplatin/pembrolizumab.
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients with metastatic non-squamous NSCLC that received at least 1 cycle of pemetrexed/carboplatin/pembrolizumab at MD Anderson Cancer Center, were alive for ≥14 days thereafter and had available next generation sequencing- based comprehensive tumor genomic profiling were eligible. Response assessment was based on RECIST1.1. PD-L1 expression on tumor cells was evaluated using the FDA-approved 22C3 pharmDx assay. All patients consented to collection of clinical and molecular data as part of the GEMINI protocol.
4c3880bb027f159e801041b1021e88e8 Result
Among 49 eligible patients (median age 61 years, 51% female, 96% adenocarcinoma histology, 34.7% KRAS-mutant) the objective response rate to pemetrexed/carboplatin/pembrolizumab was 51% (25/49) for the overall population. The disease control rate (PR+SD≥ 6 months) differed significantly between STK11/LKB1-mutant and STK11/LKB1-wild-type tumors (31.3% vs 72.7%, P=0.011, two-tailed Fisher’s exact test). The objective response rate was 31.3% for STK11/LKB1-mutant and 60.6% for STK11/LKB1 wild-type tumors (P=0.07, two-tailed Fisher’s exact test). 37.5% (6/16) of STK11/LKB1-mutant tumors exhibited progressive disease as best overall response to chemo-immunotherapy compared with 6.1% (2/33) STK11/LKB1-wild-type tumors (P=0.01, two-tailed Fisher’s exact test). Patients bearing STK11/LKB1-mutant tumors exhibited shorter progression-free survival with chemo-immunotherapy (median PFS 4.4 months vs 11.0 months, P=0.039, log-rank test). STK11/LKB1-mutant tumors were less likely to be positive for PD-L1 expression (PD-L1 TPS ≥ 1%), although the difference did not reach statistical significance (43.8% vs 72%, P=0.1, two-tailed Fisher’s exact test).
8eea62084ca7e541d918e823422bd82e Conclusion
STK11/LKB1 genomic alterations are associated with inferior clinical outcomes with chemo-immunotherapy in non-squamous NSCLC, with response rates comparable to those previously reported for platinum doublet chemotherapy alone. Assessment of STK11/LKB1 status may help refine treatment approaches in non-squamous NSCLC.
6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MA23 - Early Stage Lung Cancer: Present and Future (ID 926)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Treatment of Early Stage/Localized Disease
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 10:30 - 12:00, Room 105
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MA23.02 - Circulating Tumor DNA Analysis with a Novel Variant Classifier for Recurrence Detection in Resected, Early-Stage Lung Cancer (ID 13498)
10:35 - 10:40 | Presenting Author(s): Vincent K Lam
- Abstract
- Presentation
Background
ctDNA is a blood-based biomarker with promising potential in lung cancer for minimal residual disease (MRD) assessment and early detection of recurrence. However, data regarding feasibility are limited, especially for stage I-II disease.
a9ded1e5ce5d75814730bb4caaf49419 Method
We performed longitudinal plasma ctDNA profiling of early-stage lung cancer patients (pts) that underwent resection at MD Anderson Cancer Center from Apr 2016 to Jan 2017. Plasma ctDNA was analyzed from pre-operative and multiple post-operative time points until disease recurrence. ctDNA profiling was performed using a 30kb Digital Sequencing panel (Guardant Health) covering SNVs in 21 genes and indels in 9 genes that are commonly present in lung cancer. ctDNA profiles from ~30,000 lung cancer pts were used to train a classifier to exclude non-tumor related mutations.
4c3880bb027f159e801041b1021e88e8 Result
A total of 40 pts were included in this analysis, comprised of the first 17 pts with recurrence in the longitudinal study and 23 consecutive pts without recurrence. This cohort was primarily stage I and II (15 [38%], 16 [40%]). Histology included adenocarcinoma (29 [73%]), SCC (6 [15%]), and SCLC (2 [5%]). 58% had adjuvant therapy. Median follow-up was 17.7 (3.4 – 24.5) months and median time to recurrence was 7.1 (3.4 – 16.5) months in this selected cohort. At least one ctDNA alteration was detected in 55% (21/38) of pts with evaluable pre-op samples and in 22% (8/37) of pts at 4 weeks post-op. Presence of ctDNA at 4 weeks post-op heralded eventual recurrence with 43% sensitivity and 91% specificity (75% PPV, 73% NPV) and was significantly associated with worse recurrence free survival (p=0.022, HR 6.52; 95% CI 1.3 – 32.6), while also accounting for stage. In the absence of the variant classifier, an additional 7/37 pts had non-tumor alterations detected at 4 weeks post-op with a recurrence sensitivity and specificity of 57.1% and 69.6%. ctDNA was identified in 76% (13/17) of pts prior to or at the time of recurrence. The median interval between ctDNA detection and radiographic recurrence was 91 days.
8eea62084ca7e541d918e823422bd82e Conclusion
Detection of post-op ctDNA, as early as 4 weeks after resection of early-stage lung cancer, is associated with significantly increased risk of recurrence. Accurate detection of ctDNA in this MRD setting is enabled by a highly sensitive sequencing platform that incorporates a novel variant classifier to enhance clinical specificity.
6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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OA02 - Novel Therapies in ROS1, HER2 and EGFR (ID 893)
- Event: WCLC 2018
- Type: Oral Abstract Session
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 10:30 - 12:00, Room 105
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OA02.06 - A Phase II Trial of Poziotinib in EGFR and HER2 exon 20 Mutant Non-Small Cell Lung Cancer (NSCLC) (ID 14277)
11:25 - 11:35 | Author(s): Vincent K Lam
- Abstract
- Presentation
Background
Insertions/mutations in exon 20 of EGFR or HER2 occur in ~3% of all lung adenocarcinomas. These alterations are characterized by primary resistance to tyrosine kinase inhibitors (TKIs) with response rates of <12%. We previously showed that exon 20 insertions restrict the size of drug-binding pocket, limiting binding of most available TKIs. However, poziotinib can potentially circumvent these steric changes due to its smaller, flexible structure and is a potent inhibitor of EGFR and HER2 exon 20 mutants (Robichaux et al. Nat Med, 2018). Herein, we report the results of an investigator-initiated study of poziotinib in EGFR and HER2 exon 20 mutant NSCLC (NCT03066206).
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients ≥18yrs with metastatic NSCLC bearing mutations/insertions in EGFR or HER2 exon 20 (except EGFR T790M) were eligible. Unlimited prior systemic and targeted therapies were permitted. Poziotinib 16mg PO daily was administered until progression, death, or withdrawal. The primary endpoint was objective response rate (ORR) based on RECIST v1.1. Response was evaluated every eight weeks. A Bayesian design was used with a plan to enroll patients in cohorts of 10 and to terminate the study if ORR was ≤20%. Secondary endpoints included DCR, PFS, OS and safety
4c3880bb027f159e801041b1021e88e8 Result
As of May 3, 2018, the planned EGFR cohort of 50 patients was fully enrolled, and 40 patients were evaluated for response. 65.1% of patients had received at least two prior lines of therapy for metastatic disease. 60% of patients had ≥grade 3 adverse events; most common were skin-rash (27.5%) and diarrhea (12.5%). 45.0% of patients required dose reduction to 12mg, while 17.5% required dose reduction to 8mg. One patient stopped treatment due to grade 3 skin rash. ORR at eight weeks was 58% (95%-CI 40.9-73.0) and the DCR was 90% (95%-CI 76.3-97.2). Among 23 patients who achieved partial response, 15 responses were confirmed with subsequent scans, five responses were unconfirmed, and three patients are pending confirmation. Responses were observed in 8/13 (62%) patients that were previously treated with TKI. Median PFS was 5.6mo (95%-CI 5.06-NA). Furthermore, 13 patients were enrolled in HER2 cohort. Toxicities were similar to EGFR cohort except one case of grade 5 pneumonitis, assessed to be possibly drug related. Twelve patients were evaluated for response with ORR of 50% (95% CI 21.1-78.9) at eight weeks and DCR of 83%.
8eea62084ca7e541d918e823422bd82e Conclusion
In heavily pre-treated population with EGFR and HER2 exon 20 mutant NSCLC, poziotinib demonstrated encouraging antitumor activity in both TKI-naive and -refractory patients, and manageable toxicity profile.
6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.13-37 - Clinical Evaluation of Plasma-Based (cfDNA) Genomic Profiling in Over 1,000 Patients with Advanced Non-Small Cell Lung Cancer (ID 14332)
16:45 - 18:00 | Author(s): Vincent K Lam
- Abstract
Background
Tumor genomic information from a simple blood collection revealing actionable mutation can improve clinical outcome without the need for an invasive tissue biopsy. We report on the clinical utility of a cell-free DNA (cfDNA) next generation sequencing (NGS) blood test in our patients with non-small cell lung cancers (NSCLC) and the outcome of treatments with targeted therapies based on the reported mutations.
a9ded1e5ce5d75814730bb4caaf49419 Method
From May 2015 to February 2017, 1078 blood samples from 1011 consecutive patients with a diagnosis of NSCLC were collected and analyzed using next-generation sequencing of cfDNA with a panel of up to 70 cancer-related genes at a CLIA-certified lab (Guardant360, Guardant Health, Redwood City, CA) with reported sensitivity of 0.02% mutant allele fraction with high specificity (> 99.9999%) (CCR 2018 (17):3831). Patients in this retrospective study received targeted therapy as indicated by cfDNA molecular profiling. Tumor response was evaluated by RECIST V1.1 and standard clinical evaluation.
4c3880bb027f159e801041b1021e88e8 Result
From 1011 patients, 1078 cfDNA tests sent (additional follow-up tests: 1 in 64 patients and 2 in 3 patients). In 223/1011 (22%) patients had cfDNA report with at least 1 targetable mutations; with 48/223 (22%) patients meeting criteria for this retrospective review. Study population were 31 female:17 male, median age of 63 years (ranged:31-94). The rationale for the blood test included: insufficient tissue or not available (32%), addition to tissue molecular analysis (17%), alternative to tissue biopsy(10%), on-going treatment evaluation/resistance (41%). Mutations included:EGFR T790M (15), EGFR exon 19del (12), EGFR L858R (9), EGFR exon 20 insertion (4), EGFR others (1), ALK gene fusions (5) and MET exon 14 skipping (2). The median line of therapy was 2(ranged:1-7) with 28 patients receiving TKI as 1st line of therapy based on cfDNA mutations. With targeted treatments based on ctDNA results, the responses (RECIST V1.1) were: CR(3), PR(26), SD(14) and PD(4); median PFS was 8.5 months (ranged:1-26mos) for the overall population with 4 patients still receiving targeted therapy. Median PFS was 9.5 months (ranged:1-20 months) for those receiving TKI as 1st line.
8eea62084ca7e541d918e823422bd82e Conclusion
This is the largest analysis of response rates with cfDNA directed therapy in advanced NSCLC and demonstrates positive clinical outcomes in patients treated with targeted therapy based on plasma identified biomarkers.
6f8b794f3246b0c1e1780bb4d4d5dc53
