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Lyudmila Bazhenova
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FP07 - Pathology (ID 109)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP07.12 - Underdiagnosis of EGFR Exon 20 Insertion Mutation Variants: Estimates from NGS-based Real-World Datasets (ID 3399)
00:00 - 00:00 | Author(s): Lyudmila Bazhenova
- Abstract
- Presentation
Introduction
Exon 20 insertion mutations (Exon20ins) account for up to 10% of all mutations in epidermal growth factor receptor (EGFR) mutant non-small cell lung cancers (NSCLCs). Exon20ins specific drugs are in development. Because Exon20ins are molecularly heterogenous, the ability to identify the range of variants is dependent on the test methods used. Real-time polymerase chain reaction (PCR) and next-generation sequencing (NGS) are two molecular tests widely used to identify mutations in the EGFR. We analyzed real-world genomic data to determine the frequency of Exon20ins variants and to assess the ability of PCR and NGS to comprehensively identify them.
Methods
Two US-based genomic databases were utilized for this analysis. NGS data from US institutions were extracted from the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database, version 8.5 (The AACR Project GENIE Consortium. Cancer Discov. 2017;7(8):818-831). The FoundationInsights™ database (Foundation Medicine, Cambridge, MA) was used to obtain EGFR Exon20ins variants in real-world NSCLC samples. Coverage of Exon20ins from commercially available PCR tests (therascreen® and cobas®) was obtained from their instructions for use.
Results
The GENIE database included 12,497 patients with NSCLC. A total of 2,316 patients with EGFR mutant lung adenocarcinoma were identified and of these patients, 175 (7.6%) harbored Exon20ins. A total of 40 unique Exon20ins variants were identified. Of the 9 most common Exon20ins variants (≥5 patients), only 4 would have been identified at the protein level using commercially available PCR tests. PCR tests would have identified only 89 (50.9%) of the 175 patients with Exon20ins identified by NGS (Figure). The FoundationInsights™ database included 627 patients with lung adenocarcinomas who harbored Exon20ins and identified 102 unique Exon20ins variants. Of the 17 most common variants (≥5 patients), only 4 would have been identified at the protein level with commercially available PCR tests. PCR tests would have identified just 305 (48.6%) of the 627 patients with Exon20ins identified by NGS (Figure).
Conclusion
PCR methods are projected to miss 50% or more of Exon20ins. Reliance on commercially available PCR kit methods may provide insufficient information to support appropriate decision-making for emergent Exon20ins-directed therapies. The large number of insertion variants suggests that NGS platforms, academic or commercially available, would also improve their detection rate by capturing the full breadth of variants that have been identified.
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MA04 - Health Policy and the Real World (ID 217)
- Event: WCLC 2020
- Type: Mini Oral
- Track: Health Services Research/Health Economics
- Presentations: 1
- Moderators:
- Coordinates: 1/29/2021, 16:45 - 17:45, Scientific Program Auditorium
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MA04.07 - Comparative Clinical Outcomes for Patients with NSCLC Harboring EGFR Exon 20 Insertion Mutations and Common EGFR Mutations (ID 3390)
16:45 - 17:45 | Author(s): Lyudmila Bazhenova
- Abstract
- Presentation
Introduction
Approximately 85–90% of the mutations seen in EGFR-mutant non-small cell lung cancers (NSCLCs) are common mutations (cEGFR), Exon 19 deletions and Exon 21 L858R. Up to 10% of EGFR-mutant NSCLC harbors Exon 20 insertion mutations (Exon20ins). We conducted a retrospective cohort study using real-world data to compare clinical outcomes between patients harboring Exon20ins and cEGFR.
Methods
This retrospective cohort study included patients from the Flatiron Health database (1 January 2011 through 31 May 2020) who had advanced NSCLC. The objectives of the study were to assess the prognostic value of Exon20ins compared with cEGFR (start date of first-line therapy as the index date) and the effect of tyrosine kinase inhibitor (TKI) treatment between the groups (start date of first TKI line as the index date). Analysis was stratified by line of TKI use. Endpoints included real-world overall survival (rwOS), progression-free survival (rwPFS), and time to next therapy (rwTTNT) and were analyzed using multivariable Cox proportional hazards model and summarized by Kaplan-Meier method.
Results
Among 62,464 patients with advanced NSCLC, 181 with Exon20ins and 2833 with cEGFR met eligibility criteria. Population demographics between the groups were comparable with minor exceptions. With median 34-month follow-up, Exon20ins was associated with a 75% increased risk of death (adjusted hazard ratio [adjHR] of 1.75 [95%CI, 1.45–2.13]; p˂0.0001); median rwOS was 16.23 (95%CI, 11.04–19.38) for Exon20ins and 25.49 months (95%CI, 24.48–27.04) for cEGFR (Table). The estimated 5-year survival rate for Exon20ins is 8% compared with 19% for cEGFR.
The predictive value of TKI treatment, stratified by line, was assessed in 76 Exon20ins and 2749 cEGFR patients who were treated with TKIs. With median 20.6-month follow-up, there was a 170% increase in risk of progression or death associated with Exon20ins (adjHR of 2.7 [95% CI, 2.06–3.55]; p˂0.0001); median rwPFS was 2.86 months (95%CI, 2.14–3.91) compared with 10.45 months (95%CI: 10.05–10.94) for cEGFR. Furthermore, there was a 170% increased risk of death (adjHR of 2.70 [95% CI, 2.04–3.57]; p˂0.0001) associated with Exon20ins; median rwOS was 7.46 months (95%CI, 5.45–13.34) for Exon20ins and 25.49 months (95%CI, 24.28–26.81) for cEGFR (Table).
Conclusion
Patients with Exon20ins have a worse prognosis compared with patients with cEGFR. Furthermore, EGFR TKI treatment was substantially less effective for patients with Exon20ins, as the risk of disease progression and mortality was higher compared with patients with cEGFR. These findings highlight the need for new treatment options for Exon20ins.
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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
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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): Lyudmila Bazhenova
- 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.
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OA04 - New Data from Rare EGFR Alterations (ID 223)
- Event: WCLC 2020
- Type: Oral
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/29/2021, 11:45 - 12:45, Scientific Program Auditorium
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OA04.05 - Trastuzumab Deruxtecan in HER2-Overexpressing Metastatic Non-Small Cell Lung Cancer: Interim Results of DESTINY-Lung01 (ID 1419)
11:45 - 12:45 | Author(s): Lyudmila Bazhenova
- Abstract
- Presentation
Introduction
Trastuzumab deruxtecan (T-DXd) is a novel antibody-drug conjugate composed of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and topoisomerase I inhibitor payload. DESTINY-Lung01 (NCT03505710) is an ongoing, multicenter, phase 2 study evaluating T-DXd in 2 separate cohorts of patients with unresectable and/or metastatic nonsquamous non-small cell lung cancer (NSCLC): overexpressing HER2 (centrally confirmed, IHC 2+ or 3+) or containing a HER2-activating mutation. We have previously shown promising activity of T-DXd in patients with HER2-mutated NSCLC (confirmed objective response rate [cORR] by independent central review [ICR], 61.9%; Smit ASCO 2020). Here we report data from an interim analysis of the HER2-overexpressing cohort.
Methods
Patients with HER2-overexpressing metastatic NSCLC were treated with T-DXd 6.4 mg/kg every 3 weeks. The primary endpoint was ORR (CR + PR) by ICR. Additional endpoints were disease control rate (DCR; CR + PR + stable disease), duration of response (DOR), progression-free survival (PFS), and safety.
Results
At data cutoff (May 31, 2020), 49 patients had received T-DXd. Median age was 63 years (range, 37-85 years); 61.2% were male; 34.7% had CNS metastases at enrollment; 32.7% were never-smokers. 79.6% of patients (n=39) had HER2 IHC 2+ and 20.4% (n = 10) had HER2 IHC 3+. 91.8% of patients had received prior platinum-based chemotherapy and 73.5% had received anti−PD-1/PD-L1 treatment; median number of prior regimens was 3 (range, 1-8). Median treatment duration was 18.0 weeks (range, 3.0-57.1 weeks); 22.4% of patients remained on treatment.
Confirmed ORR by ICR was 24.5% (95% CI, 13.3%-38.9%), including 1 CR and 11 PRs; IHC 2+, 25.6% (95% CI, 13.0%-42.1%); IHC 3+, 20.0% (95% CI, 2.5%-55.6%). Median DOR was 6.0 months (95% CI, 3.2-NE months); DCR was 69.4% (95% CI, 54.6%-81.8%); estimated median PFS was 5.4 months (95% CI, 2.8-7.0 months).
All patients had ≥ 1 treatment-emergent adverse event (TEAE); the most common any-grade TEAEs were nausea (59.2%), decreased appetite (38.8%), and fatigue (32.7%). Grade ≥ 3 TEAEs were reported in 73.5% of patients (55.1% drug-related); the most common were decreased neutrophil count (20.4%) and fatigue (10.2%). There were 8 cases (16.3%) of drug-related interstitial lung disease (ILD) as adjudicated by an independent committee (grade 1, n = 2; grade 2, n = 3; grade 5, n = 3). TEAEs were associated with dose interruption in 26 patients (53.1%), dose reduction in 17 patients (34.7%), and treatment discontinuation in 11 patients (22.4%).
Conclusion
In this interim analysis, T-DXd demonstrated preliminary evidence of antitumor activity in heavily pretreated patients with HER2-overexpressing NSCLC. The safety profile of T-DXd was generally manageable, but ILD remains a known serious risk that requires proactive monitoring and care. An additional cohort to evaluate T-DXd 5.4 mg/kg in patients with HER2-overexpressing NSCLC has opened and started enrollment to further understand and characterize the safety and efficacy profile of T-DXd in this population.
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P01 - Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics (ID 227)
- Event: WCLC 2020
- Type: Posters
- Track: Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P01.23 - Veliparib (V) in Combination with Carboplatin/Paclitaxel (C/P)-Based Chemoradiotherapy (CRT) in Patients With Stage III NSCLC (ID 786)
00:00 - 00:00 | Author(s): Lyudmila Bazhenova
- Abstract
Introduction
CRT is a standard treatment for patients with stage III NSCLC. V is a potent, orally bioavailable PARP1/2 inhibitor that inhibits DNA repair following chemotherapy- or radiation-induced damage. Here, we report final results of a Phase 1 study (NCT02412371) of V + C/P-based CRT in stage III NSCLC.
Methods
Dose-escalation followed a 3+3 design to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). Patients with newly diagnosed unresectable stage III NSCLC received V (escalated sequentially) + C (area under the curve [AUC] 2 mg/mL/min) + P (45 mg/m2 weekly) + 60–63 Gy (total dose over 6–9 weeks), followed by V + consolidation therapy (C AUC 6 mg/mL/min + P 200 mg/m2) for up to two cycles. V was escalated from 60 mg twice daily (BID) to a maximum planned dose of 240 mg BID during CRT and was tested at 120 mg BID (Cohorts 1–5) or 240 mg BID (Cohort 6) during consolidation therapy. Safety was assessed according to NCI CTCAE v4.0. Radiographic assessments were evaluated according to RECIST v1.1.
Results
Forty-eight patients (median age 65 years, 40% male) were enrolled into Cohorts 1–6 between May 2015 – February 2018. Three patients experienced dose-limiting toxicities; one in Cohort 4 (V 200/120 mg BID in CRT/consolidation phase) and two in Cohort 6 (V 240/240 mg BID in CRT/consolidation phase). V 240 mg BID + C/P-based CRT/V 120 mg BID + C/P consolidation (Cohort 5; n=12) was determined to be the MTD/RP2D. In Cohort 5, the most common AEs were nausea (83%), neutropenia, thrombocytopenia, and esophagitis (all 75%), leukopenia and fatigue (both 58%). In Cohort 5, 25% of patients experienced serious AEs (Table). Overall, median PFS was 19.6 months (95% CI 9.7, 32.6), median OS was 32.6 months (95% CI 15.0, not evaluable) and median follow-up was 32.6 months. ORR was 63% (95% CI 46.7, 77.0) for the total evaluable population (≥1 post-baseline tumor assessment; N=43) and 73% (95% CI 39.0, 94.0) for Cohort 5 (N=11).
Conclusion
The RP2D of V 240 mg BID + C/P-based CRT/V 120 mg BID + C/P consolidation therapy is tolerable in patients with stage III NSCLC. The V dose in the CRT phase is double that reported in the S1206 study (Argiris et al, J Clin Oncol 2019; abstract 8523) and may enhance C/P activity. The regimen demonstrated anti-tumor activity with median PFS 19.6 months.
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P19 - Locoregional and Oligometastatic Disease - Oligometastatic Disease (ID 129)
- Event: WCLC 2020
- Type: Posters
- Track: Locoregional and Oligometastatic Disease
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P19.10 - Evaluation of Local Therapy for Oligoprogressive Disease in Metastatic NSCLC Patients on Immunotherapy (ID 3324)
00:00 - 00:00 | Author(s): Lyudmila Bazhenova
- Abstract
Introduction
The use of local ablative therapy to treat NSCLC with oligometastatic disease (metastatic disease present in a limited number of sites) and oligoprogressive disease (disease progression in a limited number of sites) has been explored in multiple small prospective and retrospective series. Both Gomez et al 2016 and Iyengar et al 2017 have shown the benefit of radiation therapy as consolidative therapy for oligometastatic disease treated with chemotherapy or targeted therapy. For oligoprogressive disease, numerous retrospective studies indicate a benefit with the use of local ablative therapies in patients receiving targeted therapy. More recently, Friedes et al 2020 investigated the use of radiation for oligoprogressive disease for patients largely receiving chemotherapy, showing a PFS from local therapy to progression of 7.9 months. These data suggest the utility of local ablative therapy both in the oligometastatic and oligoprogressive disease settings, however have limited focus on these strategies for patients receiving immunotherapy.
Given the demonstrated benefit of incorporating immunotherapy in first line treatment of metastatic NSCLC patients without driver mutations, an investigation of the use of local therapy (radiation or resection) for patients on immunotherapy with progression was undertaken. The treatment of oligoprogressive disease in this setting may promote more durable responses both by eliminating selected colonies of tumor cells that develop resistance through immune surveillance escape and possibly by the release of neoantigens with resultant off target abscopal effects.
Methods
This is a retrospective analysis of 40 patients with pathologically diagnosed metastatic NSCLC without driver mutations who were placed on chemoimmunotherapy or immunotherapy with 1st repeat imaging showing at least stable disease (SD) who then progressed. We compared mPFS in patients who received local therapy (for ≤3 sites of disease) versus a control group who switched therapy for progression of disease and evaluated post local therapy PFS, which was defined as time from endling local therapy for oligoprogressive disease until radiographic progression while maintaining on the same immunotherapy.
Results
Of 40 patients, 52.5% were male, 47.5% were female, median aged 69 years old (ranged 43-83), 80% White, 12.5% Black, 5% Asian, and 2.5% Latino. The mPFS was 40.7 months (n = 7, 95% CI 0-107.94) in the oligoprogressive group vs 7.6 months (n = 33, CI 4.65-10.55) in the control immunotherapy group (p = 0.046). Based on Cox regression for age (<70 vs ≥70, p = 0.452), ECOG (0/1 vs 2, p = 0.142), smoking history (no vs yes, p = 0.197), histology (nonsquamous vs squamous, p = 0.693), and line of therapy (1st vs 2+, p = 0.788), there were no significant interactions. The median post local therapy PFS was 6.1 months (n = 11 events, 95% CI 2.65-9.55).
Conclusion
Retrospectively, in selected patients on immunotherapy, the use of local therapy to treat oligoprogressive disease showed a mPFS benefit and a median post local therapy PFS of 6.1 months. While these data are limited by small numbers and the inherent bias of patients who progress with limited disease possibly having more indolent disease, these results do warrant further investigation.
