Virtual Library
Start Your Search
Karen Kelly
Author of
-
+
ES04 - Strategies to Increase Cure Rates in Stage III NSCLC: Optimising Checkpoint Inhibitors and Beyond (ID 181)
- Event: WCLC 2020
- Type: Educational Session
- Track: Locoregional and Oligometastatic Disease
- Presentations: 1
- Moderators:
- Coordinates: 1/29/2021, 11:45 - 12:45, Scientific Program Auditorium
-
+
ES04.01 - Navigating the Evaluation of Novel Systemic Agents in Stage III Disease (ID 4009)
11:45 - 12:45 | Presenting Author(s): Karen Kelly
- Abstract
- Presentation
Abstract
Navigating the Evaluation of Novel Systemic Agents in Stage III Disease. Karen Kelly, MD University of California, Davis, Sacramento California. Stage III non-small cell lung cancer (NSCLC) is diagnosed in approximately 22% of lung cancer patients. For the majority of patients who are unresectable, the standard treatment is chemoradiotherapy followed by one year of consolidation durvalumab based upon the PACIFIC results that compared consolidation durvalumab to placebo (1). The recent 4-year efficacy data continued to show a significant overall survival and progression free survival benefit with durvalumab 49.6% versus 36.3% (HR=0.71 ;95% CI 0.57 – 0.88) and 35.4% versus 19.5% (HR=0.55; 95% CI 0.44-0.67), respectively (2). Durvalumab consolidation is the first major advancement in the treatment of Stage III disease in decades. However distant metastases remain the barrier to cure. Hence, continued evaluation of systemic agents is needed but how do we incorporate the evaluation of novel agents within this new regimen? There are multiple approaches: 1) the evaluation of dual immunotherapy regimens in the consolidation setting, 2) adding immunotherapy to the chemoradiotherapy backbone followed by consolidation immunotherapy, 3) the addition of neoadjuvant regimens, and 4) substituting immunotherapy for chemotherapy in combination with radiotherapy. Trials evaluating each of these approaches are underway. Similar strategies are being pursued with tyrosine kinase inhibitors (TKI) for patients with oncogenic driven stage III NSCLC. For patients with resectable stage III NSCLC, consistent and impressive antitumor activity has been demonstrated with neoadjuvant immunotherapy plus chemotherapy across several small phase II trials. For example, NADIM a multi-center phase II trial administered 3 cycles of paclitaxel, carboplatin and nivolumab prior to resection in 46 patients with N2 or T4N0/1 NSCLC (3). The study met its primary endpoint of progression free survival at 24 months with 77% of patient’s progression free at this time point. Major pathological response was seen in 82.6% of patients with 63.4% of patients achieving a complete pathological response. Neoadjuvant TKIs are also being evaluated in this setting but face unique challenges.
An important component of drug development includes parallel development of predictive biomarkers. This is critical for achieving our goal of precision therapy for Stage III patients. In the PACIFIC study, an unplanned subset analysis revealed patients whose tumors did not express PD-L1 did not have a progression free or overall survival benefit compared to placebo (1). This information led the EMA to approve consolidation durvalumab in PD-L1 expressors while the FDA approval included all patients regardless of tumor PD-L1 expression level. Both tissue and blood based predictive biomarkers are under consideration.
This presentation will review the multiple trial designs evaluating novel agents, show the current data utilizing these designs, discuss associated biomarkers and close with future directions.
1. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med 377: 1919-1931, 2017.
2. Faivre-Finn C, Vicente D, Kurata T, et al. Durvlaumb after Chemoradiotherapy in Stage III NSCLC: 4-year survival update from the Phase 3 PACIFIC trial. ESMO 2020.
3. Provencio M, Nadal E, Insa A, et al. Neoadjuvant Chemotherapy and Nivolumab in Resectable Non- Small-Cell Lung Cancer (NADIM): An Open-Label, Multicenter, Single-Arm, Phase II Trial. Lancet Oncol 2020; published online Sept. 24.Only 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.
-
+
MA08 - Advances in Biomarkers for Immune Checkpoint Blockade and Targeted Therapy in Non Small Cell Lung Carcinoma (ID 166)
- Event: WCLC 2020
- Type: Mini Oral
- Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
- Presentations: 1
- Moderators:
- Coordinates: 1/30/2021, 16:45 - 17:45, Scientific Program Auditorium
-
+
MA08.10 - LUNGMAP Master Protocol (LUNGMAP): Concordance Between Plasma ctDNA and Tissue Molecular Analysis (ID 3146)
16:45 - 17:45 | Author(s): Karen Kelly
- Abstract
Introduction
The national LUNGMAP clinical trial is predicated on molecular screening enabling patient enrollment to biomarker-matched sub-studies for rapid evaluation of new precision medicine concepts in advanced NSCLC. To date, LUNGMAP has used a tissue-based Next-Generation Sequencing (NGS) approach for biomarker assessment. Given the utility of circulating tumor DNA (ctDNA) for biomarker identification, LUNGMAP investigators are evaluating the feasibility of plasma ctDNA as a screening approach.
Methods
Plasma samples for ctDNA testing were required for patients submitting fresh tissue biopsies for LUNGMAP screening. Tissue and plasma ctDNA were analyzed using the FoundationONE CDx and FoundationACT platforms at Foundation Medicine, Inc., respectively. Alterations detectable in both platforms were evaluated. Using tissue-detected driver alterations (referred to as drivers) as the gold standard, sensitivity was calculated as the proportion of patients with drivers also detected in ctDNA in addition to tissue, and specificity was calculated as the proportion of patients without drivers in ctDNA among those without drivers in tissue. Proportions and 95% exact confidence interval (CI) estimates were calculated.
Results
From January 2019 to June 2020, 129 patients had paired data and 54 (42%) had recognized oncogene drivers detected (EGFR [n=7], KRAS [n=37], MET [n=7], RET [n=2], BRAF [n=1], Table 1). Fifty-two patients had drivers detected in tissue; of these 43 were also observed in ctDNA, with 9 found in tissue only, for a ctDNA driver sensitivity of 83% (43/52, 95% CI: 74-93%). Of the 77 patients with no drivers in tissue, 2 drivers were detected in ctDNA (EGFR Ex20ins, MET amp) for a ctDNA specificity of 97% (75/77, 95% CI: 91-100%). For drivers, median variant allele frequency (VAF) in ctDNA was 2.22% (range: 0.13%-46.27%). For all single nucleotide variants (SNVs) and rearrangements detectable on both platforms, 386 variants were detected. Short variants (point mutations and small in/dels) showed the most fidelity, with 54% detected in both platforms (Table 1). Copy number alterations using an earlier platform version were least reproduced, with 8% identified by both.
Conclusion
In the LUNGMAP population, ctDNA (FoundationAct) had an 83% sensitivity and 97% specificity for NSCLC drivers detected in tissue. For non-driver alterations, additional variants were detected exclusively in plasma or tissue, likely reflecting differential sensitivity and/or non-shedding and tissue heterogeneity. These results, consistant with other recent studies, support the planned use of ctDNA for enrollment onto LUNGMAP sub-studies, with a positive finding meriting inclusion in study but a negative finding, considered inconclusive, requiring use of tissue results.
Table 1 N (%)
Total Alterations Detected
Number of Patients
................... In ctDNA ................
...................... In Tissue ................
Overall
In Tissue
Not in Tissue
Overall
In ctDNA
Not in ctDNA
Driver Alterations
54
54
45
43 (96%)
2 (4%)
52
43 (83%)
9 (17%)
Non-driver Alterations
439
75
294
169 (57%)
125 (43%)
314
169 (54%)
145 (46%)
Short Variants
316
273
158 (58%)
115 (42%)
201
158 (79%)
43 (21%)
Copy Number Alts
104
10
8 (80%)
2 (20%)
102
8 (8%)
94 (92%)
Rearrangements
19
11
3 (27%)
8 (73%)
11
3 (27%)
8 (73%)
Overall
493
129
339
212 (63%)
127 (37%)
366
212 (58%)
154 (42%)
Short Variants
365
314
198 (63%)
116 (37%)
249
198 (80%)
51 (20%)
Copy Number Alts
107
12
9 (75%)
3 (25%)
104
9 (9%)
95 (91%)
Rearrangements
21
13
5 (38%)
8 (62%)
13
5 (38%)
8 (62%)
TP53
150
128
77 (60%)
51 (40%)
99
77 (78%)
22 (22%)
-
+
MA11 - Expanding Targetable Genetic Alterations in NSCLC (ID 251)
- Event: WCLC 2020
- Type: Mini Oral
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/31/2021, 14:15 - 15:15, Scientific Program Auditorium
-
+
MA11.10 - Lung Master Protocol (Lung-MAP) Next Generation Sequencing Analysis of Advanced Squamous Cell Cancers (SWOG S1400) (ID 3055)
14:15 - 15:15 | Author(s): Karen Kelly
- Abstract
Introduction
SWOG S1400, the original screening protocol of Lung-MAP, enrolled patients with Stage IV or recurrent squamous cell lung cancer previously treated with at least one line of systemic therapy. Tumors were profiled by NGS using Foundation Medicine’s FoundationOne T5 research platform, which sequenced the exons and/or introns of 313 cancer-related genes. Here, we report the results of a comprehensive analysis of the S1400 NGS data compared to The Cancer Genome Atlas (TCGA) data, including identification of novel sets of mutually exclusive and co-occurring genetic alterations.
Methods
Analyses included all patients with successful NGS testing enrolled on S1400. Mutually Exclusive Gene Set Analysis (MEGSA) was used to identify sets across genetic alterations with mutated prevalence > 6%. Selected Events Linked by Evolutionary Conditions across human Tumors (SELECT) was used to identify pairwise gene interactions. Comparisons were performed using mutation profiles of 495 squamous cell lung cancers downloaded from the TCGA data portal. Cox proportional hazards models adjusted for clinical covariates including age, sex, smoking history and AJCC TNM categories were used to examine the association between each genetic variant and survival. The Benjamini-Hochberg method was used to adjust significance values for multiple comparisons.
Results
Between June 16, 2014 and January 29, 2019, 1864 patients were enrolled to be screened, of whom NGS was available for 1672. 73% of the sequenced tumor samples were archival and 27% were fresh biopsies; there were no significant differences in prevalence of genetic alterations between these. MEGSA identified two non-overlapping sets of mutually exclusive gene alterations with a false discovery rate (FDR) < 15%: NFE2L2, KEAP1 and PARP4 (FDR = 4.1%) and CDKN2A and RB1 (FDR = 13.1%). Mutual exclusivity of NFE2L2 and KEAP1 alterations has been previously observed, e.g., in TCGA, however mutual exclusivity of PARP4 and NFE2L2 or KEAP1 alterations is a novel finding. SELECT identified 41 pairs of mutually exclusive and 95 pairs of co-occurring gene alterations. Top significant co-occurring pairs that appeared in this dataset but not TCGA include CDKN2A and TP53, KRAS and STK11, HGF and MLL2, PDGFRB and SMARCA4, NFE2L2 and TP53, ATRX and RUNX1T1, GRIN2A and NCOR1, and MCL1 and MYCN. Male sex and smoking history were associated with poorer survival. When these and other clinical covariates were incorporated in Cox proportional hazards models, there were no individual genetic variants that were associated with survival; however, NFE2L2 and KEAP1 alterations when taken together were associated with poorer survival.
Conclusion
This analysis of the Lung-MAP S1400 NGS data features a substantially larger sample size than any previously published dataset of squamous cell lung cancers, although it is limited to genes sequenced on the FoundationOne T5 platform. Compared to TCGA, this dataset features a homogeneous set of subjects all with previously treated advanced disease and enrolled on a clinical trial. Novel findings, including mutual exclusivity of PARP4 and NFE2L2 or KEAP1 alterations, suggest that PARP4 may have a hitherto undiscovered role in a key pathway known to impact responses to oxidative stress and treatment resistance.
-
+
OA01 - Established Drugs in Special Populations and New Drugs in Established Populations (ID 226)
- Event: WCLC 2020
- Type: Oral
- Track: Immunotherapy (Phase II/III Trials)
- Presentations: 1
- Moderators:
- Coordinates: 1/29/2021, 09:15 - 10:15, Scientific Program Auditorium
-
+
OA01.04 - Tumor Mutation Burden (TMB) by Next Generation Sequencing (NGS) Associates with Survival (OS) in Lung-MAP Immunotherapy Trials S1400I and S1400A (ID 3229)
09:15 - 10:15 | Author(s): Karen Kelly
- Abstract
- Presentation
Introduction
TMB is an emerging biomarker for efficacy of immune checkpoint inhibitors (ICI). Lung-MAP is a master protocol for biomarker-driven trials in advanced NSCLC. Two sub-studies in previously treated ICI naïve advanced squamous cell lung cancer (sqNSCLC), S1400I, a phase III trial randomizing patients to nivolumab plus ipilimumab (N/I) versus nivolumab (N), and S1400A, a phase II trial evaluating durvalumab (D), provided the opportunity to evaluate TMB and related biomarkers by NGS and to determine associations with clinical outcomes.
Methods
NGS was performed on DNA from formalin-fixed paraffin-embedded tumor specimens using the FoundationOne T5 platform. TMB was defined as the total number of nonsynonymous mutations per megabase (Mb) of coding sequence. In S1400I, PD-L1 expression was assessed by the 22C3 antibody. A Cox model was used to evaluate associations between TMB (continuous and dichotomized at 10 Mb/mt), PD-L1 (continuous and dichotomized at 0% versus > 0%), overall survival (OS) and progression-free survival (PFS), summarized by hazard ratios (HRs) and 95% confidence intervals (CI). Associations between TMB and genetic alterations were evaluated by Wald test, with false discovery rate (FDR) ≤ 5% scored as positive. Unsupervised hierarchical clustering was performed using combined data from S1400I+S1400A.
Results
Conclusion
252 patients on N/I or N and 68 patients on D were included in the analysis. Higher TMB (per 10-unit difference in TMB value) was significantly associated with better OS and PFS (OS HR(CI): 0.80 (0.67–0.94), P = 0.008 and PFS HR(CI): 0.80 (0.69–0.93), P = 0.004). In S1400I, PD-L1 expression levels were not significantly associated with OS or PFS (N=161, P > 0.05), alone or in combination with TMB. In S1400I+S1400A, no genetic variants were significantly associated with OS or PFS. Genes whose alterations were significantly associated with TMB are shown in the volcano plot. Unsupervised hierarchical clustering suggested a variant-defined subgroup conferred better PFS (HR (CI): 0.41 (0.19–0.88), P = 0.022) but not OS; notably, this subgroup showed 3.8-fold higher TMB and more frequent alterations of genes shown in the plot, compared to other subgroups.
Several different methodologies have been employed to measure TMB. TMB by FoundationOne NGS is an analytically and clinically validated assay correlating well with WES and predicted neoantigen load. Here we report that high TMB, but not PD-L1, is associated with improved OS and PFS in patients treated with ICI on S1400I/S1400A. How genetic alterations associated with high TMB may biologically contribute to clinical outcomes from ICI warrants further consideration.
Only 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.
-
+
P15 - Immuno-biology and Novel Immunotherapeutics (Phase I and Translational) - Novel Immunotherapeutics (Phase I) (ID 154)
- Event: WCLC 2020
- Type: Posters
- Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
-
+
P15.04 - A Phase I/IB Trial of Pembrolizumab and Trametinib Focused on Advanced KRAS Mutant Non-Small Cell Lung Cancer (ID 1431)
00:00 - 00:00 | Author(s): Karen Kelly
- Abstract
Introduction
KRAS mutant NSCLC is heterogeneous with differential responses to MEK inhibition and immune checkpoint blockade that may be dependent on: KRAS amino acid substitution, associated co-mutations, smoking status, and tumor mutational burden. Preclinical models suggest sequencing of MEK inhibitor before or after PD-1 blockade differentially modulate the immune microenvironment, impacting anti-tumor activity of PD-1 blockade. This phase 1 study examined intercalated sequencing schemes of the MEK inhibitor trametinib and the PD-1 antibody pembrolizumab with planned dose expansion in KRAS mutant NSCLC.
Methods
In this phase 1 dose escalation study, patients were treated with concurrent trametinib 1.5 to 2 mg PO daily D1-D10 and pembrolizumab 200 mg IV on a q21day cycle with either lead in trametinib alone for the first cycle (Cohort A) or lead in pembrolizumab alone for the first cycle (Cohort B). Key Eligibility: advanced non-squamous NSCLC with progression (PD) on prior platinum-based chemotherapy, age≥18, ECOG PS≤1, acceptable organ function, no significant autoimmune diseases, measurable disease and controlled brain metastases. Tissue biopsy performed at baseline and optional week 1-2 on treatment for PD-L1 IHC (22C3) and quantitative immunofluorescence for immune cell subsets and next-generation sequencing. Blood at baseline and at serial on-treatment timepoints were collected for ctRNA of PD-L1 and KRAS-mut, and changes in circulating immune cell subsets. T-Cell repertoire and cytokine levels were evaluated by flow cytometry and Luminex. Response was assessed by RECIST 1.1 and toxicity graded by CTCAE v5.
Results
Twelve patients enrolled thus far. Key clinical and molecular characteristics: 10 (83%) patients with KRAS mutation (5 p53 and 1 STK11 co-mutation), 1 pt with BRAF non-V600E/K mutation, 10 patients (83%) with smoking history, and 8 (66%) patients had prior immune checkpoint blockade. Baseline PD-L1 (22C3) TPS ranged from 0% to 100%. Five (42%) patients had ≥G3 AEs possibly, probably or definitely related to treatment (1 G5 pneumonitis, 1 G3 retinal detachment, 1 G3 diarrhea, 1 G3 anemia, 1 G3 mucositis). Six patients received trametinib 1.5 mg D1-10 (3 cohort A and 3 cohort B) and 6 patients at 2 mg D1-10 (3 Cohorts A and 3 Cohort B). There was 1 DLT in Cohort A at the 2 mg lead in trametinib dose (G3 mucositis). Eleven patients evaluable for response: (2 PR, 3 SD and 6 PD). One responding patient had progressed on prior nivolumab. 3/6 (50%) patients with lead in trametinib had PFS ≥6 months and 2 of these patients had prior PD-1 blockade. No patients with lead in pembrolizumab had PFS ≥6 months. The study continues to accrue patients at dose level 2 (trametinib 2 mg PO daily with both lead in schemes) with planned expansion cohort in KRAS mutant NSCLC. Results of tissue and blood correlative studies will be presented.
Conclusion
Preliminary clinical activity has been observed thus far with trametinib and pembrolizumab, including in a patient with prior treatment on immune checkpoint blockade. The study is currently accruing patients at the highest planned dose levels and a dedicated expansion cohort at the MTD is planned in KRAS mutant NSCLC.
