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Vassiliki A Papadimitrakopoulou
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MA 01 - SCLC: Research Perspectives (ID 650)
- Event: WCLC 2017
- Type: Mini Oral
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:John V Heymach, Eun Kyung Cho
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 503
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MA 01.03 - The Potential of ctDNA Sequencing in Disease Monitoring and Depicting Genomic Evolution of Small-Cell Lung Cancer Under Therapy (ID 9682)
11:10 - 11:15 | Author(s): Vassiliki A Papadimitrakopoulou
- Abstract
- Presentation
Background:
Although small cell lung cancer (SCLC) is sensitive to initial therapy, almost all patients relapse and survival remains poor. Outgrowth of treatment-resistant subclones could be responsible for recurrence. However, genomic evolution of SCLC after treatment hasn’t been well investigated, partially due to the challenge of obtaining longitudinal samples. CT is the standard modality for response assessment and disease monitoring. But it doesn’t always accurately assess the disease status. SCLC is characterized by early hemagenous spread, which makes circulating tumor DNA (ctDNA) analysis a promising modality for genomic profiling and disease monitoring of SCLC.
Method:
Targeted-capture deep sequencing (mean target coverage 538x-1866x) of 545 cancer genes was performed to 44 ctDNA samples collected before therapy as baseline and at different timepoints during treatment from 23 SCLC patients. Pretreatment tumor biopsies from 8 patients were also sequenced (mean target coverage 348x-1281x) of the same gene panel. DNA from peripheral blood mononuclear cells was served as the germline control.
Result:
Mutations were identified in all 44 ctDNA samples with a median of 16 mutations per sample (average mutation burden of 6.6/Mb). TP53 and RB1 were the most frequently mutated genes, detected in 91% (21/23) and 65% (15/23) patients, respectively. 74 mutations were identified from the 8 tumor biopsies, among which, 69 (93.2%) were detected in matched ctDNA. We inferred subclonal architecture of each ctDNA sample based on cancer cell fraction derived using PyClone. A median of 10 (ranging 2-26) subclones was inferred from each ctDNA sample and only 17% (2% to 60.%) of mutations were clonal mutations suggesting substantial genomic heterogeneity. Single gene mutations were not associated with survival. However, mean variant allele frequency of clonal mutations (clonal-VAF) at baseline was associated with progression-free survival (PFS) and overall survival (OS) independent of stage, age, or platinum sensitivity. The median PFS of patients with higher versus lower than median clonal-VAF was 5.2 months (95% CI, 4.6 to 5.8 months) versus 10.0 months (95% CI, 9.3 to 10.7 months), p=0.002. The median OS was 8.1 months (95% CI, 5.5 to 10.7 months) versus 24.9 months (95% CI, 0.0 to 51.2 months) in patients with higher versus lower than median clonal-VAF, respectively, p=0.004. Analysis of serial ctDNA before and during treatment showed that clonal-VAF closely tracked closely with treatment responses.
Conclusion:
ctDNA sequencing is a promising modality for genomic profiling and disease monitoring for SCLC patients. Clonal VAF may be a better ctDNA metric than single gene mutations.
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MA 05 - Immuno-Oncology: Novel Biomarker Candidates (ID 658)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Yoichi Nakanishi, P. Mitchell
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 303 + 304
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MA 05.02 - STK11/LKB1 Loss of Function Genomic Alterations Predict Primary Resistance to PD-1/PD-L1 Axis Blockade in KRAS-Mutant NSCLC (ID 10367)
15:50 - 15:55 | Author(s): Vassiliki A Papadimitrakopoulou
- Abstract
- Presentation
Background:
The genomic landscape of primary resistance to PD-1 blockade in lung adenocarcinoma (LUAD) is largely unknown. We previously reported that co-mutations in STK11/LKB1 (KL) or TP53 (KP) define subgroups of KRAS-mutant LUAD with distinct therapeutic vulnerabilities and immune profiles. Here, we present updated data on the clinical efficacy of PD-1/PD-L1 inhibitors in co-mutation defined KRAS mutant and wild-type LUAD patients and examine the relationship between genetic alterations in individual genes, tumor cell PD-L1 expression and tumor mutational burden (TMB) using cohorts form the SU2C/ACS Lung Cancer Dream Team and Foundation Medicine (FM).
Method:
The cohorts included 924 LUAD with NGS (FM cohort) and 188 patients with KRAS non-squamous NSCLC (SU2C cohort) who received at least one cycle of PD-1/PD-L1 inhibitor therapy and had available molecular profiling. Tumor cell PD-L1 expression was tested using E1L3N IHC (SU2C) and the VENTANA PD-L1 (SP142) assay (FM). TMB was defined as previously described and was classified as high (TMB-H), intermediate (TMB-I) or low (TMB-L).
Result:
188 immunotherapy-treated (83.5% nivolumab, 11.7% pembrolizumab, 4.8% anti-PD1/PD-L1 plus anti-CTLA-4) pts with KRAS-mutant NSCLC were included in the efficacy analysis. The ORR differed significantly between the KL (8.8%), KP (35.9%) and K-only sub-groups (27.3%) (P=0.0011, Fisher’s exact test). KL LUAC exhibited significantly shorter PFS (mPFS 1.8m vs 2.7m, HR=0.53, 95% CI 0.34-0.84, P<0.001, log-rank test) and OS (mOS 6.8m vs 15.6m, HR 0.53, 95% CI 0.34 to 0.84, P=0.0072, log rank test) compared to KRAS-mutant NSCLC with wild-type STK11. Loss-of function (LOF) genetic alterations in STK11 were the only significantly enriched event in PD-L1 negative, TMB-I/H compared to PD-L1 high positive (TPS≥50%), TMB-I/H tumors in the overall FMI cohort (Bonferroni adjusted P=2.38x10[-4], Fisher’s exact test) and among KRAS-mutant tumors (adjusted P=0.05, Fisher’s exact test) . Notably, PD-1 blockade demonstrated activity among 10 PD-L1-negative KP tumors, with 3 PRs and 4SDs recorded. In syngeneic isogenic murine models PD-1 blockade significantly inhibited the growth of Kras mutant tumors with wild-type LKB1 (K), but not those with LKB1 loss (KL), providing evidence that LKB1 loss can play a causative role in promoting PD-1 inhibitor resistance.
Conclusion:
Loss of function genomic alterations in STK11 represent a dominant driver of de novo resistance to PD-1/PD-L1 blockade in KRAS-mutant NSCLC. In addition to tumor PD-L1 status and tumor mutational burden precision immunotherapy approaches should take into consideration the STK11 status of individual tumors.
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OA 07 - Biomarker for Lung Cancer (ID 659)
- Event: WCLC 2017
- Type: Oral
- Track: Biology/Pathology
- Presentations: 1
- Moderators:Philip Christopher Mack, Shinichi Toyooka
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 503
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OA 07.02 - Characteristics of Lung Cancer Cell-Free Tumor DNA (CfDNA) Shedding and Correlation with Tumor Burden as Measured by RECIST (ID 9663)
15:55 - 16:05 | Author(s): Vassiliki A Papadimitrakopoulou
- Abstract
- Presentation
Background:
cfDNA is a promising biomarker for early recurrence detection and disease monitoring in the NSCLC curative setting. However, less is known about cfDNA shedding characteristics and correlation with tumor burden in advanced NSCLC.
Method:
We reviewed cfDNA results of NSCLC patients tested at our institution between November 2015 and December 2016 with Guardant 360, a comprehensive cfDNA assay that detects genomic alterations in 70-73 cancer genes. 141 cases with evaluable imaging were selected for this analysis, enriching for EGFR and KRAS mutated cases to facilitate comparisons of major genomic subtypes (Table 1). Tumor burden was approximated using the sum of longest diameters (SLD), per RECIST v1.1.
Result:
There was a statistically significant correlation of moderate strength between cfDNA maximum variant allele frequency (VAF) detected and SLD (Spearman’s rho = 0.35, p < 0.001). This correlation was strongest in KRAS mutant cases (rho = 0.52, p = 0.001) and weakest in EGFR mutated tumors (rho = 0.21, p < 0.24). Multi-variate regression that included stage, histology, and mutation status confirmed the predictive value of cfDNA VAF for SLD (p = 0.03). TP53 mutants had higher cfDNA VAF (Wilcox p < 0.001), even after accounting for SLD. Increased cfDNA VAF was also seen with EGFR mutants and patients with visceral metastasis, though possibly confounded by concomitant EGFR amplification and increased tumor burden, respectively. CNS metastasis was not associated with differential cfDNA shedding. Figure 1
Conclusion:
In this primarily metastatic cohort, cfDNA VAF correlated with radiographic assessment of tumor burden by RECIST. This correlation was partially mediated by the presence of key driver mutations. TP53 and EGFR mutant tumors and the presence of visceral metastasis are associated with higher cfDNA VAF. These findings have potential implications for the use of cfDNA in advanced-stage NSCLC disease monitoring, where RECIST is more clinically applicable than formal volumetrics.
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OA 13 - Immuno-Biology (ID 677)
- Event: WCLC 2017
- Type: Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Hiroyuki Suzuki, Scott N. Gettinger
- Coordinates: 10/18/2017, 11:00 - 12:30, Room 301 + 302
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OA 13.01 - CD38-Mediated Immunometabolic Suppression as a Mechanism of Resistance to PD-1/PD-L1 Axis Blockade (ID 10157)
11:00 - 11:10 | Author(s): Vassiliki A Papadimitrakopoulou
- Abstract
- Presentation
Background:
Although immune checkpoint inhibitors of the PD-1/PD-L1 axis provide significant clinical benefit for patients with lung cancer, effective use of these agents is encumbered by a high rate of primary or acquired resistance. Strategies for optimal therapeutic application of immunotherapy require a thorough understanding of resistance mechanisms. To date, there have been only a few studies reporting potential mechanisms of resistance to PD-1/PD-L1 blockade.
Method:
In multiple immunocompetent syngeneic and spontaneous animal models of K-ras/p53 mutant lung cancer, we explored the resistance mechanisms to PD-1/PD-L1 blockade using both pharmacologic and genetic approaches (therapeutic antibody treatment and CRISPR/Cas9-mediated editing). The molecular and immune profiles of the tumor microenvironment were evaluated. Additionally, to determine the applicability to patients with lung cancer, we analyzed 259 tumor specimens with IHC staining and mRNA expression, and further confirmed the analyses in publically-available TCGA datasets.
Result:
In multiple models of antibody blockade and genetic knockout of PD-L1, we identified the up-regulation of CD38 on tumor cells as a marker of treatment resistance. Furthermore, by manipulating CD38 on a panel of lung cancer cell lines we demonstrated in vitro and in vivo that CD38 expression inhibits CD8[+] T cell proliferation, anti-tumor cytokine secretion, and tumor cell killing capability. The T cell suppressive effect is dependent upon the ectoenzyme activity of CD38 that regulates the extracellular levels of adenosine. To test whether CD38 blockade might be therapeutically efficacious to prevent anti-PD-L1/PD-1 resistance, we applied combination therapy with anti-CD38 and anti-PD-L1 and demonstrated dramatic therapeutic benefit on primary tumor growth and metastasis. Additionally, in a set of 259 resected lung cancer specimens, ~15% exhibited positive staining for CD38 on tumor cells, and the expression correlated with cytolytic T cell score and an immune/inflammatory signature across multiple large datasets.
Conclusion:
CD38 was found to be a novel mechanism for tumor escape from immune checkpoint PD-1/PD-L1 inhibitor therapy. Targeting this resistance pathway may broaden the benefit of PD-L1/PD-1 axis blockade for lung cancer treatment.
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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): Vassiliki A Papadimitrakopoulou
- 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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OA 17 - Immunotherapy II (ID 683)
- Event: WCLC 2017
- Type: Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Yuichiro Ohe, Anne Tsao
- Coordinates: 10/18/2017, 14:30 - 16:15, Room 301 + 302
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OA 17.01 - Pemetrexed-Carboplatin Plus Pembrolizumab as First-Line Therapy for Advanced Nonsquamous NSCLC: KEYNOTE-021 Cohort G Update (ID 9059)
14:30 - 14:40 | Author(s): Vassiliki A Papadimitrakopoulou
- Abstract
- Presentation
Background:
Cohort G of the multicenter, open-label, phase 1/2 KEYNOTE-021 study (ClinicalTrials.gov, NCT02039674) evaluated efficacy and safety of pembrolizumab + pemetrexed and carboplatin (PC) compared with PC alone as first-line therapy for patients with advanced nonsquamous NSCLC. At the primary analysis of cohort G (minimum follow up, 6 months; median, 10.6 months), pembrolizumab significantly improved ORR (estimated treatment difference, 26%; P=0.0016) and PFS (hazard ratio [HR], 0.53; P=0.010). The HR for OS was 0.90 (95% CI, 0.42‒1.91). In a subsequent analysis (median follow-up, 14.5 months), the HR for OS was 0.69 (95% CI, 0.36‒1.31). We present results from the May 31, 2017 data cutoff.
Method:
Patients with stage IIIB/IV nonsquamous NSCLC, no prior systemic therapy, and no EGFR mutation or ALK translocation were randomized 1:1 (stratified by PD-L1 TPS ≥1% versus <1%) to receive 4 cycles of carboplatin AUC 5 + pemetrexed 500 mg/m[2] Q3W with or without pembrolizumab 200 mg Q3W. Pembrolizumab treatment continued for up to 2 years; maintenance pemetrexed was permitted in both arms. Eligible patients in the PC arm with radiologic progression could cross over to pembrolizumab monotherapy. Response was assessed by blinded, independent central review per RECIST v1.1. All P values are nominal (one-sided P<0.025).
Result:
123 patients were randomized. Median follow-up was 18.7 months (range, 0.8‒29.0 months). 40 of 53 (75%) patients in the PC arm who discontinued received subsequent anti-PD-1/anti-PD-L1 therapy (including 25 who received pembrolizumab in the on-study cross over). ORR was 57% with pembrolizumab + PC versus 32% with PC (estimated difference, 25%; 95% CI, 7%‒41%; P=0.0029). PFS was significantly improved with pembrolizumab + PC versus PC (HR, 0.54; 95% CI, 0.33‒0.88; P=0.0067) with median (95% CI) PFS of 19.0 (8.5‒NR) months versus 8.9 (6.2‒11.8) months. The HR for OS was 0.59 (95% CI, 0.34‒1.05; P=0.0344). Median (95% CI) OS was not reached (22.8‒NR) months for pembrolizumab + PC and 20.9 (14.9‒NR) months for PC alone; 18-month OS rates were 70% and 56%, respectively. Grade 3–5 treatment-related AEs occurred in 41% of patients in the pembrolizumab + PC arm versus 29% in the PC arm.
Conclusion:
Over the course of the 3 analyses, the HR for OS continues to improve for pembrolizumab + PC versus PC (HR: 0.90 to 0.69 to 0.59). The significant improvements in PFS and ORR with pembrolizumab + PC versus PC first observed in the primary analysis have been maintained with longer follow-up (median, 18.7 months).
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P2.01 - Advanced NSCLC (ID 618)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:00 - 16:00, Exhibit Hall (Hall B + C)
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P2.01-040 - Pemetrexed plus Platinum Chemotherapy with or Without Immunotherapy in Non-Squamous NSCLC: Descriptive Safety Analysis (ID 9882)
09:00 - 09:00 | Presenting Author(s): Vassiliki A Papadimitrakopoulou
- Abstract
Background:
Pemetrexed/platinum doublet chemotherapy is under investigation in combination with various immunotherapeutic agents (atezolizumab, nivolumab, pembrolizumab) for treatment of advanced non-squamous (NS) NSCLC, with reported durable efficacy and tolerability in early-phase clinical trials. Recently, the combination of pembrolizumab plus pemetrexed/carboplatin received US FDA accelerated approval as front-line treatment for patients with this disease based on the data from a randomized phase II trial, KEYNOTE-021 Cohort G. We present our descriptive analysis of the safety outcomes of pemetrexed (combination) from 3 randomized trials (PRONOUNCE, PARAMOUNT, and KEYNOTE-021 Cohort G).
Method:
Criteria for selection of studies included randomized trials, first-line treatment for NS NSCLC patients with pemetrexed-based combination treatment, with or without immunotherapy, followed by continuation maintenance (at least one arm or cohort). Parameters such as baseline characteristics, dose exposure, and safety outcomes (AE, SAE, death, dose delay or discontinuation, AE management, and hospitalization) are compared.
Result:
Using data from PRONOUNCE (n=182), PARAMOUNT (n=359), and KEYNOTE-021 (Cohort G, n=123) we describe the safety outcomes of pemetrexed/platinum-based combination therapy. Median age of patients from 3 studies was 61- 66 years. The majority of patients in PRONOUNCE and PARAMOUNT were male, whereas female in KEYNOTE-021G; with ECOG PS 1, and adenocarcinoma. The number of patients who completed 4 cycles of induction were 70.8%, 67.8%, 88.1%, and 71.0% in PRONOUNCE, PARAMOUNT, and KEYNOTE 021G Combo arm and Pem+Cb only arm, with median number of treatment cycles of 6, 8, 11, 8, respectively. All pemetrexed combinations with/without immunotherapy had a reasonable and manageable safety profile in our analysis (Table 1). Figure 1
Conclusion:
This analysis provides a comprehensive safety overview of pemetrexed/platinum with or without immunotherapy in NS NSCLC. Ongoing phase 3 randomized studies of the combination could further inform the safety/efficacy of pemetrexed/platinum plus immunotherapy.
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P2.07 - Immunology and Immunotherapy (ID 708)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.07-062 - PIVOT-02: Phase 1/2 Study of NKTR‐214 and Nivolumab in Patients with Locally Advanced or Metastatic Solid Tumor Malignancies (ID 9130)
09:30 - 09:30 | Presenting Author(s): Vassiliki A Papadimitrakopoulou
- Abstract
Background:
Abundance and functional quality of tumor infiltrating lymphocytes are positively linked with tumor response and improved survival with checkpoint inhibitors. NKTR-214 is a CD122-biased agonist that targets the IL2 pathway and is designed to provide sustained signaling through the heterodimeric IL2 receptor pathway (IL2Rβɣ) to preferentially activate and expand NK and effector CD8+ T cells over CD4+ T regulatory cells within the tumor microenvironment. NKTR‐214 is administered on an outpatient basis as a 15-minute IV infusion and has been administered to 28 patients with advanced solid tumors. Single-agent NKTR-214 demonstrates a substantial increase in both CD8+ T and NK cells within the tumor microenvironment in those patients with prior immune checkpoint therapy (Bernatchez et al, SITC poster 2016). Given the favorable safety profile and strong biomarker data, a trial combining NKTR‐214 and nivolumab was initiated.
Method:
PIVOT‐02 is a phase 1/2 open‐label trial in patients with locally advanced or metastatic melanoma (MM), non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), urothelial carcinoma, or triple‐negative breast cancer (TNBC). Approximately 250 patients will be enrolled across 5 tumor types and 8 indications, with 26-38 patients per indication. Patients who are immunotherapy naïve will be studied for all 5 tumor types. MM, RCC, or NSCLC patients who are relapse/refractory on one prior anti-PD-1/PD-L1 containing regimen will be studied separately. The primary objectives are to evaluate safety and tolerability, determine the recommended phase 2 dose (RP2D), and assess tumor response by RECIST 1.1. The dose-escalation portion of the trial has enrolled 23 patients (MM= 8, RCC= 11, NSCLC=4), in 5 different cohorts including NKTR-214 at 0.003 (q2w), 0.006 (q2w or q3w), or 0.009 (q3w) mg/kg in combination with a flat dose of nivolumab at 240 (q2w) or 360 (q3w) mg. Extensive blood and tumor tissue samples are being collected in both escalation and expansion phase to measure immune activation using immunophenotyping including flow cytometry, immunohistochemistry (IHC), T-cell clonality and gene expression analyses. Based on safety/tolerability, PK/PD and early biomarker data, the recommended phase 2 dose of NKTR-214 is 0.006 mg/kg q3w with nivolumab 360 mg q3w. The expansion phase of the study is now open for accrual.
Result:
Section not applicable
Conclusion:
Section not applicable
