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Shirish Gadgeel
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MA25 - Precision Medicine in Advanced NSCLC (ID 352)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:Sebastian Defranchi, Karen Kelly
- Coordinates: 9/10/2019, 14:30 - 16:00, Dublin (1997)
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MA25.01 - Pembrolizumab Plus Chemotherapy for Advanced NSCLC Without Tumor PD-L1 Expression: Pooled Analysis of KN021G, KN189 and KN407 (Now Available) (ID 1399)
14:30 - 16:00 | Author(s): Shirish Gadgeel
- Abstract
- Presentation
Background
Randomized studies have demonstrated that pembrolizumab plus chemotherapy improves OS, PFS, and ORR compared with chemotherapy alone in patients with advanced NSCLC regardless of tumor PD-L1 expression level. We present a post hoc pooled analysis of pembrolizumab plus chemotherapy versus chemotherapy alone in patients with advanced NSCLC and no PD-L1 expression (ie, TPS <1%), representing an area of unmet need.
Method
Patients enrolled in KEYNOTE-021 cohort G (nonsquamous; NCT02039674), KEYNOTE-189 (nonsquamous; NCT02578680), and KEYNOTE-407 (squamous; NCT02775435) were included. Patients with nonsquamous NSCLC were randomized to pemetrexed-platinum with or without pembrolizumab; those with squamous NSCLC were randomized to carboplatin-paclitaxel/nab-paclitaxel with or without pembrolizumab. OS, PFS, and ORR were evaluated for the pooled intent-to-treat population. Response was assessed per RECIST v1.1 by blinded independent central review. Across studies, PD-L1 expression was assessed centrally using PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies, Carpinteria, CA). Analyses were descriptive.
Result
Of 1298 patients enrolled across the 3 trials, 428 (33%) had PD-L1 TPS <1% (pembrolizumab plus chemotherapy, n=243; chemotherapy alone, n=185) and were included in this analysis. 52% had nonsquamous histology, 63% had ECOG PS of 1. Median (range) follow-up at data cutoff was 10.2 (0.1‒34.9) months. OS, PFS, and ORR were improved with pembrolizumab plus chemotherapy versus chemotherapy alone (Table). Grade ≥3 AEs (all-cause) occurred in 68% of patients receiving pembrolizumab plus chemotherapy versus 72% receiving chemotherapy alone. Immune-mediated AEs and infusion reactions occurred in 26% who received pembrolizumab plus chemotherapy versus 12% who received chemotherapy alone.
ConclusionPembrolizumab + Chemotherapy
n=243
Chemotherapy
Alonen=185
Median (95% CI) OS, mo
19.0 (15.2–24.0)
11.0 (9.2–13.5)
Hazard ratio (95% CI)
0.56 (0.43–0.73)
Median (95% CI) PFS, mo
6.5 (6.2–8.5)
5.4 (4.7–6.2)
Hazard ratio (95% CI)
0.67 (0.54–0.84)
ORR, % (95% CI)
46.9% (40.5%–53.4%)
28.6% (22.3%–35.7%)
Difference (95% CI)
18.3% (9.0%–27.1%)
Our results highlight the clinically meaningful efficacy benefit and acceptable safety profile of pembrolizumab plus chemotherapy versus chemotherapy alone in patients with advanced NSCLC and no PD-L1 expression. Benefit was consistent with that observed in the overall study populations, suggesting pembrolizumab plus chemotherapy should be considered standard-of-care first-line therapy for all patients with NSCLC, irrespective of PD-L1 expression.
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MS05 - Novel Biological Pathways and Druggable Targets (ID 68)
- Event: WCLC 2019
- Type: Mini Symposium
- Track: Biology
- Presentations: 1
- Now Available
- Moderators:Jin Jen, Marisol Arroyo-Hernandez
- Coordinates: 9/09/2019, 11:00 - 12:30, Vancouver (2003)
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MS05.03 - Notch Signalling (Now Available) (ID 3463)
11:00 - 12:30 | Presenting Author(s): Shirish Gadgeel
- Abstract
- Presentation
Abstract
Notch Signaling
The Notch signaling pathway is a highly conserved pathway that has a vital role in embryonic development and post-embryonic functions such as hematopoiesis, neural cell development and angiogenesis (1). The signaling pathway is activated by the interaction of 4 Notch receptors and their interactions with 5 different ligands. Signaling is characterized by juxtacrine interaction between ligands and receptors on neighboring cells or within the same cell. Alterations in this pathway have been detected in several tumors both as tumor promoter and tumor suppressor.
Notch signaling does appear to have relevance in non-small cell lung cancers (NSCLC) (2). In approximately 30% of NSCLCs loss of Numb, a negative regulator of Notch1, leads to increased Notch activity and about 10% of NSCLCs have gain of function mutations in Notch1. A meta-analysis demonstrated that higher expression of Notch1 was correlated with more advanced tumors (3). In addition, higher expressions of both Notch1 and Notch3 were associated with poor prognosis (4,5). In pre-clinical studies inhibition of Notch3 signaling has reduced growth of lung cancers. In addition, it has been demonstrated that there is cross talk between Notch3 and EGFR pathways and inhibition of both pathways can induce expression of anti-apoptotic protein BIM. Finally, Notch signaling may have a role in induction of the epithelial to mesenchymal phenotype (EMT) in cancers (6). EMT is known to be associated with resistance to both cytotoxic agents and targeted agents and inhibition of Notch signaling can not only reverse EMT but also can enhance the anti-tumor activity of cytotoxic agents such as cisplatin and targeted agents such as erlotinib. The EMT phenotype is frequently observed in a sub-population of cancer cells with self-renewal capacity or cancer stem cells. Notch signaling may be crucial to survival of cancer stem cells and persistence of this population may contribute to resistance to therapeutic agents.
In squamous cell lung cancers Notch signaling may have tumor suppressive properties (7). Loss of function mutations in Notch family of genes, predominantly in Notch receptors, are frequently identified in several squamous cell cancers including squamous cell cancer of the lung. Similarly, loss of function mutations in Notch genes, particularly Notch1 have been identified in small cell lung cancer (SCLC). Expression of Notch receptor in a mouse model of SCLC reduced tumor burden, suggesting its tumor suppressive properties. The expression of DLL3, one of the Notch ligands is induced in SCLC by a key transcription factor ASCL1.DLL3 is shown to downregulate Notch signaling in SCLCs and enhance the carcinogenic phenotype.
All the above data suggest that Notch signaling is highly contextual. In some tumors this pathway may have tumor suppressive properties but in others tumor promoting properties. Defining the role of this pathway in tumor types may guide development of therapeutic strategies targeting the Notch signaling pathway.
References
Bigas A, Espinosa L. The multiple usages of Notch signaling in development, cell differentiation and cancer. Curr Opin Cell Biol 2018;55:1-7.
Westhoff B, Colaluca IN, D’Ario G, et al. Alterations of the Notch pathway in lung cancer. Proc Natl Acad Sci 2009;106:22293-8.
Yuan X, Wu H, Xu H, et al. Meta-analysis reveals the correlation of Notch signaling with non-small cell lung cancer progression and prognosis. Sci Rep 2015;5:10338.
Donnem T, Andersen S, Al-shibili K, et al. Prognostic impact of Notch ligands and receptors in nonsmall cell lung cancer: coexpression of Notch-1 and vascular endothelial growth factor-A predicts poor survival. Cancer 2010:116:5674-85.
Hassan WA, Yoshida R, Kudoh S, et al. Evaluation of role of Notch3 signaling pathway in human lung cancer cells. J Cancer Res Clin Oncol 2016;142:981-93.
Yuan X, Wu H, Han N, et al. Notch signaling and EMT in non-small cell lung cancer: biological significance and therapeutic application. J Hematol Oncol 2014;7:87.
Nowell CS, Radtke F. Notch as a tumor suppressor. Nat Rev Cancer 2017;17:145-159.
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OA02 - A New Vision of Targets and Strategies (ID 120)
- Event: WCLC 2019
- Type: Oral Session
- Track: Targeted Therapy
- Presentations: 1
- Now Available
- Moderators:Frank Griesinger, Luis Paz-Ares
- Coordinates: 9/08/2019, 10:30 - 12:00, Seoul (2007)
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OA02.05 - First-In-Human Phase 1/2 Trial of Anti-AXL Antibody–Drug Conjugate (ADC) Enapotamab Vedotin (EnaV) in Advanced NSCLC (Now Available) (ID 343)
10:30 - 12:00 | Author(s): Shirish Gadgeel
- Abstract
- Presentation
Background
AXL, a transmembrane receptor tyrosine kinase, is aberrantly expressed in various cancers, and associated with poor prognosis and treatment resistance. AXL overexpression is associated with resistance to PD-1 immune checkpoint inhibitors (Hugo et al. 2016). EnaV, a novel ADC of anti-AXL human IgG1 and monomethyl auristatin E, demonstrated potent anti-tumor activity in preclinical models, including NSCLC (Boshuizen et al. 2018). In a phase 1, dose escalation, multi-cohort trial (NCT02988817) in heavily pretreated patients with relapsed or refractory solid tumors, EnaV 2.2 mg/kg once every 3 weeks (1Q3W; recommended phase 2 dose) showed preliminary anti-tumor activity. Here we present initial results from patients with NSCLC in the phase 2a, expansion phase of this trial.
Method
We analyzed data from EnaV 2.2 mg/kg 1Q3W, in the cohort of pretreated patients with stage III/IV NSCLC without sensitizing EGFR mutations (EGFR WT) or ALK rearrangements (ALK-) who had failed ≤4 prior lines of therapy, including platinum-based chemotherapy and PD-1/PD-L1 inhibitor (either in combination or sequentially). Endpoints include safety, objective response rate (ORR; RECIST 1.1), and AXL expression in fresh tumor biopsies (immunohistochemistry).
Result
In the EGFR WT/ALK- cohort, 26 patients (median age 65.5 years, range 38–74; 57.7% male) with ECOG PS of 0 (11.5%) or 1 (88.5%) have been enrolled. Most patients (23/26) were treated with a checkpoint inhibitor. At a median follow-up of 18 weeks (range: 2–54), the most common (≥20%; any grade) treatment-emergent adverse events (TEAEs) were fatigue, constipation, nausea, decreased appetite, decreased weight, diarrhea, and vomiting. Two patients had a TEAE leading to dose reduction. Grade ≥3 TEAEs occurred in 12 patients, with the most common being gastrointestinal disorders in eight patients (constipation [n=1]; colitis, diarrhea, nausea, vomiting [n=2 each]; abdominal distension [n=1]. The confirmed ORR is 19% (95% CI: 8.5%, 37.9%). The disease control rate (CR+PR+SD) is 50% (13/26). Nine of 12 (75%) evaluable fresh biopsies were positive for AXL tumor cell staining.
Conclusion
In this high unmet need patient population, with advanced EGFR WT and ALK- NSCLC who are pretreated with PD-1/PD-L1 inhibitors and platimum-based therapies, EnaV monotherapy demonstrated a manageable safety profile and encouraging preliminary clinical activity. This cohort has expanded to allow up to 60 patients to gain further knowledge of AXL as a potential biomarker for responsiveness to EnaV and to gather additional data on safety and efficacy. Funding: Genmab A/S
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OA04 - Immuno Combinations and the Role of TMB (ID 126)
- Event: WCLC 2019
- Type: Oral Session
- Track: Immuno-oncology
- Presentations: 2
- Now Available
- Moderators:Solange Peters, Martin Reck
- Coordinates: 9/08/2019, 15:15 - 16:45, Copenhagen (1980)
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OA04.05 - KEYNOTE-021: TMB and Outcomes for Carboplatin and Pemetrexed With or Without Pembrolizumab for Nonsquamous NSCLC (Now Available) (ID 2630)
15:15 - 16:45 | Author(s): Shirish Gadgeel
- Abstract
- Presentation
Background
KEYNOTE-021 cohort C was the first study to show antitumor activity for pembrolizumab plus platinum-based chemotherapy in previously untreated advanced nonsquamous NSCLC; the combination significantly improved efficacy vs platinum-based chemotherapy alone in cohort G. We explored the relationship between TMB and outcomes in KEYNOTE-021 cohorts C and G.
Method
All patients in cohort C received pembrolizumab plus carboplatin and pemetrexed. Patients in cohort G were randomized 1:1 to pembrolizumab plus carboplatin and pemetrexed or carboplatin and pemetrexed alone. TMB was determined by whole-exome sequencing of tumor and matched normal DNA. Association of TMB (continuous, log10 transformed) with outcomes for pembrolizumab plus chemotherapy and chemotherapy alone were assessed using logistic regression for ORR and Cox proportional hazards models for PFS and OS adjusted for ECOG PS; statistical significance was determined at the 0.05 level without multiplicity adjustment. The correlation of TMB (continuous, log10 transformed) with PD-L1 TPS (square root scale) was assessed in the combined population. The clinical utility of TMB for ORR using a prespecified TMB cutpoint of 175 Mut/exome (~13 Mut/Mb by FoundationOne CDx) was assessed for pembrolizumab + chemotherapy.
Result
TMB data were evaluable for 70 patients: 12/24 (50.0%) in cohort C, 32/60 (53.3%) in the cohort G pembrolizumab plus chemotherapy arm, and 26/63 (41.3%) in the cohort G chemotherapy only arm; median age was 65 years (IQR, 57-70) and 61% were female. Baseline characteristics were generally similar in the TMB-evaluable and total populations. TMB as a continuous variable was not significantly associated with ORR, PFS, or OS for pembrolizumab plus chemotherapy (one-sided P = 0.180, 0.187 and 0.081, respectively) or chemotherapy alone (one-sided P = 0.861, 0.795 and 0.763, respectively). There was no significant correlation between TMB and TPS (r=0.12, P=0.34). ORR (95% CI) in patients treated with pembrolizumab plus chemotherapy was 60.8% (38.5-80.3) in the 23 patients with TMB <175 and 71.4% (47.8-88.7) in the 21 patients with TMB ≥175.
Conclusion
In this exploratory analysis, TMB was not significantly associated with efficacy of pembrolizumab plus carboplatin and pemetrexed or carboplatin and pemetrexed alone as first-line therapy for metastatic nonsquamous NSCLC. TMB was not significantly correlated with PD-L1 expression. Among pembrolizumab plus chemotherapy-treated patients, ORR was high in both the TMB low and high subgroups. Sample size is a limitation of this study; exploration in larger datasets is required to understand any differential efficacy of pembrolizumab plus chemotherapy vs chemotherapy alone based on TMB status.
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OA04.06 - Evaluation of TMB in KEYNOTE-189: Pembrolizumab Plus Chemotherapy vs Placebo Plus Chemotherapy for Nonsquamous NSCLC (Now Available) (ID 1936)
15:15 - 16:45 | Author(s): Shirish Gadgeel
- Abstract
- Presentation
Background
First-line pembrolizumab plus chemotherapy with pemetrexed and platinum significantly improved OS (HR 0.49, P < .001), PFS (HR 0.52, P < .001) and ORR (47.6% vs 18.9%, P < .001) vs placebo plus chemotherapy with pemetrexed and platinum for metastatic nonsquamous NSCLC in the double-blind phase 3 KEYNOTE-189 study (NCT02578680); benefit was observed in all analyzed subgroups, including PD-L1 TPS <1%, 1-49%, and ≥50%. We explored the association of TMB with efficacy in KEYNOTE-189.
Method
616 patients were randomized 2:1 to pembrolizumab plus chemotherapy or placebo plus chemotherapy. TMB was determined by whole-exome sequencing of tumor and matched normal DNA. Association of TMB (continuous log10 transformed) with outcomes in each arm was assessed using Cox proportional hazards models (OS, PFS) and logistic regression (ORR); statistical significance was determined at the 0.05 level without multiplicity adjustment. The clinical utility of TMB on outcomes was assessed using prespecified TMB cutpoints of 175 and 150 Mut/exome (~13 and ~10 Mut/Mb by FoundationOne CDx). Data cutoff was 21 Sep 2018.
Result
293 (48.3%) treated patients had evaluable TMB data: 207 for pembrolizumab plus chemotherapy, 86 for placebo plus chemotherapy. Baseline characteristics and outcomes were generally similar in the TMB-evaluable and total populations. TMB as a continuous variable was not significantly associated with OS, PFS, or ORR for pembrolizumab plus chemotherapy (one-sided P = .174, .075 and .072, respectively) or placebo plus chemotherapy (two-sided P = .856, .055 and .434, respectively). Pembrolizumab plus chemotherapy improved OS, PFS, and ORR for TMB ≥175 and <175 (Table). Results were similar for TMB ≥150 and <150.
Conclusion
TMB was not significantly associated with efficacy of pembrolizumab plus chemotherapy or placebo plus chemotherapy as first-line therapy for metastatic nonsquamous NSCLC. Pembrolizumab plus chemotherapy had a similar OS benefit in the TMB-high and low subgroups.
TMB ≥175 TMB <175 Pembrolizumab plus Chemotherapy
n = 100Placebo plus Chemotherapy
n = 34Pembrolizumab plus Chemotherapy
n = 107Placebo plus Chemotherapy
n = 52Median OS (95% CI), mo 23.5
(20.2-NE)13.5
(7.0-NE)20.2
(15.8-NE)9.9
(7.4-19.1)HR (95% CI) 0.64 (0.38-1.07) 0.64 (0.42-0.97) Median PFS (95% CI), mo 9.2
(7.6-14.0)4.7
(4.0-5.5)9.0
(6.7-11.1)4.8
(4.5-6.6)HR (95% CI) 0.32 (0.21-0.51) 0.51 (0.35-0.74) ORR, % (95% CI) 50.0
(39.8-60.2)11.8
(3.3-27.5)40.2
(30.8-50.1)19.2
(9.6-32.5)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.
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 2
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-127 - Antitumor Activity of the Oral EGFR/HER2 Inhibitor TAK-788 in NSCLC with EGFR Exon 20 Insertions (ID 1302)
09:45 - 18:00 | Author(s): Shirish Gadgeel
- Abstract
Background
We report results of a phase 1/2 open-label, multicenter study of TAK-788 (NCT02716116), an oral investigational EGFR/HER2 inhibitor.
Method
Patients with advanced, previously treated NSCLC received daily TAK-788 in dose escalation and expansion cohorts based on tumor genotype. Antitumor activity was determined for patients with EGFR exon 20 insertions who received TAK-788 160 mg QD. Safety is reported for all patients across all doses and at 160 mg. To improve gastrointestinal tolerability, food intake instructions in this ongoing study were amended to allow for administration with or without a low-fat meal based on emerging clinical pharmacokinetic data in a healthy volunteer study (data on file).
Result
As of 14 Sep 2018, 101 patients (median age, 61 y; female, 70%; ≥2 prior anticancer therapies, 76%; brain metastases, 53%) were treated with TAK-788 at 5–180 mg QD. RP2D was determined to be 160 mg QD. 28 patients with EGFR exon 20 insertions were treated with 160 mg QD during dose escalation or in expansion cohort 1 (3.6 months on treatment; 3.8 treatment cycles [medians]); 24 patients remain on treatment. At data cutoff, best response (RECIST v1.1) among 26 patients with ≥1 disease assessment was PR, n=14; SD, n=9; and PD, n=1 (objective response rate, 54%; 95% CI: 33.4%–73.4%); 2 patients were unevaluable. 7/14 objective responses (all PR) were confirmed (6 awaiting confirmation; 1 unconfirmed PR at 160 mg QD); median time to response in these 14 patients was 56 days. 23/26 patients (89%; 95% CI: 69.9%–97.6%) achieved disease control. 23/24 evaluable patients with EGFR exon 20 insertions treated at 160 mg QD had decreased target lesion measurements (median best percent change, -32.6% [-79.1%–3.8%]). Most common TEAEs (≥20%) in patients treated with 160 mg QD: diarrhea (85%), rash (43%), nausea (41%), vomiting (30%), decreased appetite (28%), stomatitis (22%); grade ≥3 TEAEs (≥5%): diarrhea (26%); hypokalemia, nausea, stomatitis (7% each). Among patients treated with 160 mg QD, median dose intensity was 93%, rate of dose reduction due to AEs was 21.7%, and rate of treatment discontinuation due to AEs was 10.9%. There was no clear trend that response to TAK-788 was enriched in any single EGFR exon 20 insertion variant.
Conclusion
In NSCLC patients with EGFR exon 20 insertions, TAK-788 demonstrated antitumor activity and a safety profile consistent with other EGFR TKIs.
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P1.01-71 - Bone Metastases and Skeletal-Related Events in Patients with Metastatic NSCLC Treated with ICIs: A Multi-Institutional Study (Now Available) (ID 2421)
09:45 - 18:00 | Author(s): Shirish Gadgeel
- Abstract
Background
Skeletal-related events (SRE) occur frequently in patients (pts) with metastatic NSCLC (mNSCLC) and confer a poor prognosis. Data on SRE and the effects of bone modifying agents (BMA) in NSCLC pts treated with immune checkpoint inhibitors (ICI) are limited as is the effect of bone modifying agents (BMA) on development of SRE and overall survival (OS). Here we report the incidence, impact on survival, and risk factors for SRE in pts with mNSCLC treated with ICI in a multi-institutional cohort.
Method
We conducted a retrospective study of pts with mNSCLC treated with ICI at our institutions from 2014 to 2017. Overall survival (OS) was calculated from the date of ICI initiation to death from any cause or last follow-up. Cox regression model was used to study the association between OS and baseline bone metastases (BM). The associations between SRE and categorical outcomes were studied using chi-square/Fisher’s exact test. The study was approved by each institution’s ethics review board.
Result
Table 1. Multivariate survival analysis. Parameter Level Hazard Ratio 95% HR Confidence Limits P-value BM at baseline Absent Ref <0.0001 Present 1.847 1.414-2.413 ECOG 0 Ref 0.0006 1 1.494 1.017-2.196 2 1.506 0.969-2.341 3 3.788 1.442-9.949 Histology Adenocarcinoma Ref 0.969 Squamous 1.057 0.786-1.420 Lines of Therapy 1 Ref 0.0007 2 1.580 1.123-2.223 >=3 2.064 1.417-3.005 We identified a cohort of 330 pts: 259 (72%) treated in second line or beyond; 211 (64%) received nivolumab; median age 63.4; median OS 10.4 mo (95% CI: 8.6, 12.5). In our cohort, 124 (38%) pts had BM at time of ICI, and 43 (13%) developed SRE after ICI (median 2.8 months; 19 pathologic fractures, 1 cord compression, 26 palliative radiation, 8 surgery). Patients with BM at ICI had shorter OS after controlling for ECOG, histology, and line of therapy (Table 1; Hazard Ratio 1.847; 95% CI 1.414 - 2.413; p <0.0001) compared to pts without baseline BM. Development of SRE was associated with presence of BM at baseline but not age, histology, or mutation status (EGFR, KRAS, and TP53). The use of BMA was not associated with OS or decreased risk of SRE. The development of new or progression of existing BM (22% of pts) during ICI was associated with a worse prognosis (mOS 7.1 vs 11.6 mo, p=0.017).
Conclusion
Bone metastases and SRE are a significant cause of morbidity in pts with mNSCLC treated with ICI. The presence of BM at baseline was associated with a worse prognosis after controlling for multiple clinical characteristics. In our cohort, the use of BMA was not associated with decreased risk of developing SRE, osseous progression, or survival.
