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J.F. Gainor
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MINI 02 - Immunotherapy (ID 92)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:P. Forde, S.J. Antonia
- Coordinates: 9/07/2015, 10:45 - 12:15, Four Seasons Ballroom F3+F4
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MINI02.02 - Programmed Cell Death Ligand (PD-L1) Expression in Stage II and III Lung Adenocarcinomas and Nodal Metastases (ID 1519)
10:45 - 12:15 | Author(s): J.F. Gainor
- Abstract
Background:
Inhibition of PD-L1 can lead to reactivation of tumor immunity and assist in cancer therapy. PD-L1 expression in tumor cells has been reported to correlate with clinicopathological parameters and prognosis in a variety of cancers including lung adenocarcinomas (ADC). However, it has not been well studied whether PD-L1 expression is altered along with tumor progression. In addition, little is known about the role of PD-L1 expression in predicting response to chemotherapy in ADC. Thus, we sought to compare PD-L1 expression in the main tumor and lymph node metastases of stage II and III ADC, and correlate PD-L1 expression with survival in patients who underwent adjuvant chemotherapy.
Methods:
The study cohort consisted of 109 ADC who underwent curative resection without neoadjuvant therapy and were diagnosed to have stage II or III disease. Of those, 60 cases received platinum-based adjuvant therapy and were followed at our institution. Immunohistochemistry for PD-L1 (E1L3N, 1:200, CST) was performed on sections of the primary tumor and/or metastatic lymph nodes and the primary tumor sections were also stained with CD8 (4B11, RTU, Leica Bond). Membranous staining of any intensity present in 5% or more of the tumor cells was deemed positive for PD-L1 expression. CD8+ tumor infiltrating lymphocytes (TILs) were evaluated using a 4-tier grading system (0-3). The PD-L1 expression in the primary tumor was correlated with that in lymph node metastases as well as clinicopathological parameters, including CD8+ TILs, and recurrence free survival (RFS).
Results:
Of the 109 cases, 53 (48.6 %) exhibited PD-L1 expression in the primary tumor, which was significantly associated with smaller tumor size, lower pT stage, nodal disease, solid-predominant pattern, the presence of tumor islands, necrosis and lymphovascular invasion, and increased CD8+ TILs (grade 2-3). Upon multivariate analysis, only increased CD8+ TILs remained significant (p=0.039). As for the primary – lymph node correlation, PD-L1 expression was seen in 57.6% of 59 N1 nodes, 53.1% of 32 N2 nodes, and 100% of one N3 node available for evaluation. The PD-L1 expression status was the same between the primary tumor and nodal metastases in the majority (76.3 % of N1 nodes, and 75.0% of N2; p<0.001 and p=0.005, respectively), and the upregulation of PD-L1 expression (positive expression was present in nodal metastasis with negative primary) was seen in only small fractions of the cohort (6.8% of N1 nodes and 9.3% of L2 nodes). Interestingly, PD-L1 expression in the primary tumor was associated with longer RFS in patients who underwent platinum-based adjuvant therapy (mean 84 months vs. 41 months in PD-L1 negative patients, p=0.016), but not in those without adjuvant therapy.
Conclusion:
PD-L1 expression in the primary tumor was associated with prominent CD8+ TILs as well as several adverse clinicopathological parameters including nodal disease, but PD-L1 expression in the nodal metastasis was similar to that in the primary tumor in the majority of cases. Although the evaluation was limited due to a small size of the cohort, PD-L1 expression in the primary tumor appears to be predictive of response to platinum-based adjuvant therapy.
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MINI 08 - Prognostic/Predictive Biomarkers (ID 106)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:T.E. Stinchcombe, N. Pavlakis
- Coordinates: 9/07/2015, 16:45 - 18:15, Mile High Ballroom 4a-4f
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MINI08.14 - Discussant for MINI08.08, MINI08.09, MINI08.10, MINI08.11, MINI08.12, MINI08.13 (ID 3328)
16:45 - 18:15 | Author(s): J.F. Gainor
- Abstract
- Presentation
Abstract not provided
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MINI 30 - New Kinase Targets (ID 157)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:K. Park, M. Villalona
- Coordinates: 9/09/2015, 18:30 - 20:00, Four Seasons Ballroom F3+F4
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MINI30.06 - Activity of AUY922 in NSCLC Patients With EGFR Exon 20 Insertions (ID 1744)
18:30 - 20:00 | Author(s): J.F. Gainor
- Abstract
- Presentation
Background:
EGFR exon 20 insertions (ins20) represent a rare subtype (4%) of EGFR mutations and are refractory to EGFR-specific tyrosine kinase inhibitors (TKIs). No effective targeted therapies exist for patients (pts) with ins20; median PFS on the irreversible EGFR TKI Afatinib is 2.8 months (mos). Based on a durable RECIST partial response (PR) to AUY922, a Heat Shock Protein 90 (Hsp90) inhibitor, observed in an EGFR ins20 patient in a previous study (NCT01124864), we designed a phase II investigator-initiated trial to assess the activity of AUY922 in NSCLC pts with EGFR ins20. Since pts with these mutations are rare, we identified other international investigators who have treated ins20 patients with AUY922. Here, we present the results of a pooled international experience of 21 patients with EGFR ins20 treated with AUY922 in the United States, Taiwan and the Netherlands.
Methods:
A total of 21 patients with EGFR in20 are included in this analysis. 14 were treated on a single-arm, multi-center, open-label study of AUY922 in advanced NSCLC pts with EGFR ins20 mutations in the US (NCT01854034). Five were treated on a multicenter Taiwanese trial of AUY922 across a variety of molecular NSCLC subtypes (NCT01922583) and two were treated on a compassionate-use basis in the Netherlands. The starting dose of AUY922 was 70mg/m2 IV weekly for all patients.
Results:
21 pts, including 14 females and 7 males, average age 55 (range, 27-75) were included in this analysis. The median number of prior therapies was 2 (range, 1-6.) 6 pts received a prior EGFR TKI; none responded to TKI monotherapy. The most common AUY922-related toxicities were grade 1-2 visual changes (18/21; 86%) diarrhea (18/21; 86%) and fatigue (15/21; 71%). The only treatment-related grade 3 toxicities was hypertension (2/21; 1%) and AST elevation (1/21; 0.5%). There was one death on study, related to pre-existing comorbidity/unrelated to AUY922. Among the 21 patients treated, 5 achieved a partial response by RECIST 1.1 (ORR 24%) (Figure 1.) The median PFS estimate is 3.9 mos (95% CI, 2.9 to 10.7.) 6 patients remain on treatment at the time of abstract submission. Updated results and correlation with specific ins20 mutations will be presented. Figure 1
Conclusion:
This international experience suggests that AUY922 may be an active therapy for advanced NSCLC pts with EGFR ins20 mutations with an ORR 24% and median PFS 3.9 mo. AUY922 is generally well-tolerated, though reversible low-grade ocular toxicity is common. Further study of AUY922 in this population is warranted.
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ORAL 02 - PD1 Axis Immunotherapy 2 (ID 87)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:E.B. Garon, H.J. Ross
- Coordinates: 9/07/2015, 10:45 - 12:15, Four Seasons Ballroom F1+F2
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ORAL02.01 - Phase 3, Randomized Trial (CheckMate 017) of Nivolumab (NIVO) vs Docetaxel in Advanced Squamous (SQ) Cell Non-Small Cell Lung Cancer (NSCLC) (ID 736)
10:45 - 12:15 | Author(s): J.F. Gainor
- Abstract
- Presentation
Background:
Treatment options for patients with advanced SQ NSCLC who fail platinum-based doublet chemotherapy (PT-DC) are limited. NIVO, a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor, demonstrates activity across NSCLC histologies and is approved in the US for treatment of metastatic SQ NSCLC with progression on or after platinum-based chemotherapy. We report results from a randomized, open-label, global phase 3 study (CheckMate 017; NCT01642004) comparing NIVO vs docetaxel in patients with previously treated SQ NSCLC and disease progression during/after one prior PT-DC regimen.
Methods:
Patients (N=272) were randomized 1:1 to receive either NIVO 3 mg/kg every 2 weeks (Q2W; n=135) or docetaxel 75 mg/m[2] Q3W (n=137) until disease progression or discontinuation due to toxicity or other reasons. For NIVO patients, treatment after initial progression was permitted at the investigator’s discretion, per protocol criteria. The primary objective was overall survival (OS). Secondary objectives included investigator-assessed objective response rate (ORR; per RECIST v1.1), progression-free survival (PFS), efficacy by PD-L1 expression (PD-L1 testing not required for enrollment), patient-reported outcomes (PRO), and safety. PRO analyses are presented in a separate abstract.
Results:
Treatment with NIVO led to 41% reduction in risk of death (hazard ratio [HR]=0.59; 95% CI: 0.44, 0.79; P=0.00025) and improved ORR (20% vs 9%; P=0.0083) and PFS (HR=0.62; 95% CI: 0.47, 0.81; P=0.0004) vs docetaxel (Table). Twenty-eight patients were treated with NIVO beyond initial progression, nine of whom demonstrated a non-conventional pattern of benefit (ie, reduction in target lesions with simultaneous appearance of new lesions, initial progression followed by tumor reduction, or no further progression for ≥2 tumor assessments). Across pre-specified cut-points (1%, 5%, and 10%), PD-L1 expression was neither prognostic nor predictive of benefit. OS HRs favored NIVO across most predefined patient subgroups. Grade 3–4 drug-related adverse events (AEs) were reported in 7% (9/131) of NIVO and 55% (71/129) of docetaxel patients. Grade 3–4 drug-related select AEs are shown below (Table). No deaths were related to NIVO vs 3 docetaxel-related deaths. Figure 1
Conclusion:
CheckMate 017 achieved its primary objective, demonstrating clinically superior and statistically significant OS with NIVO vs docetaxel in patients with advanced, previously treated SQ NSCLC. Benefit was seen regardless of PD-L1 status. The safety profile of NIVO 3 mg/kg Q2W is favorable vs docetaxel and consistent with prior studies. AEs were manageable with established guidelines. NIVO represents a new standard of care in this patient population. Updated OS and safety data will be presented.
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ORAL 13 - Immunotherapy Biomarkers (ID 104)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:D. Kim, D. Grunenwald
- Coordinates: 9/07/2015, 16:45 - 18:15, Four Seasons Ballroom F3+F4
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ORAL13.01 - PD-L1 Expression in Lung Adenocarcinomas Correlates with KRAS Mutations and Th1/Cytotoxic T Lymphocyte Microenvironment (ID 2496)
16:45 - 18:15 | Author(s): J.F. Gainor
- Abstract
- Presentation
Background:
The interaction of PD-1, with its ligand, PD-L1 induces apoptosis of T cells and inhibits cytokine production, allowing tumor cells to bypass immune surveillance. PD-L1 expression on tumor cells can be upregulated via interferon gamma that is secreted by CD8+ cytotoxic T lymphocytes (CTLs) and/or Th1 pathway activation, counterbalancing the Th1/CTL microenvironment. Blockade of the PD-1/PD-L1 immune checkpoint in solid tumors has resulted in durable responses in early phase clinical trials. Moreover, protein expression of PD-L1 by immunohistochemistry (IHC) reportedly predicts patient response to anti-PD-1/PD-L1 therapies. Multiple studies have reported associations of PD-L1 expression with clinicopathological variables in lung adenocarcinomas (ADC), but such studies have produced conflicting results, possibly due to use of different antibody clones and cutoffs and possibly different ethnicities of the cohort. Thus, we correlated PD-L1 expression with clinicopathological and molecular profiles including subtypes of tumor infiltrating lymphocytes (TILs) in a large lung ADC cohort using a cut-off commonly used in clinical trials.
Methods:
PD-L1 (E1L3N, 1:200, CST), CD8 (4B11, RTU, Leica Bond), T-bet (Th1 transcription factor, D6N8B, 1:100, CST), and GATA3 (Th2 transcription factor, L50-823, 1:250, Biocare) IHC were performed on tissue microarrays constructed of 242 resected lung ADC. All cases underwent detailed histological analysis and a subset (n=128) of cases underwent clinical molecular testing. Membranous expression (regardless of intensity) in 5% or more tumor cells was deemed positive for PD-L1 expression. CD8+, T-bet+ and GATA3+ tumor infiltrating lymphocytes (TILs) were evaluated using a 4-tier grading system (0-3).
Results:
Our study cohort consisted of 242 patients with a pathologic stage of 0 in 1 case, I in 188, II in 37, III in 9, and IV in 7. Among those, 38 (15.7%) exhibited PD-L1 expression which was significantly associated with smoking history (p=0.008), large tumor size (p=0.007), solid predominant pattern (p<0.001), high nuclear grade (grade 3, p<0.001), vascular invasion (p=0.012), increased T-bet+ TILs (grade 2, p<0.001) and CD8+ TILs (grade 2, p<0.001), and KRAS mutations (p=0.001). High nuclear grade (p=0.011), KRAS mutations (p=0.004), and increased CD8+ TILs (p=0.005) remained significant predictors of PD-L1 expression in multivariate analysis, while advanced stage (II or higher vs. I, p=0.056) showed a trend towards PD-L1 expression. There was no difference in the 5-year progression free survival (PFS) between the PD-L1 positive and negative patients. In contrast, increased CD8+ TILs showed a borderline significance with favorable outcome (p=0.082), with the 5-year PFS being 87% for the CD8 positive group and 68% for the CD8 negative group, but neither PD-L1 nor CD8+ TILs was a significant predictor of survival by the cox proportional-hazards regression model.
Conclusion:
PD-L1 expression in ADC significantly correlates with KRAS mutations and several clinicopathological signatures of KRAS-mutants, including significant smoking history. The latter may have resulted in development of multiple passenger mutations that serve as neoantigens promoting the Th1/CTL microenvironment. These results suggest that blockade of the PD-1/PD-L1 axis may be a promising treatment strategy to reinstitute the Th1/CTL microenvironment for patients with KRAS-mutated ADC, in which there are currently no available treatment options.
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P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-023 - A Phase II Trial of AUY922, a Heat Shock Protein 90 (HSP90) Inhibitor, in ALK-Positive Lung Cancer Patients Previously Treated with ALK Inhibitors (ID 1739)
09:30 - 17:00 | Author(s): J.F. Gainor
- Abstract
Background:
Anaplastic lymphoma kinase (ALK) fusions are key oncogenic drivers in non-small cell lung cancer (NSCLC) that confer sensitivity to treatment with ALK tyrosine kinase inhibitors (TKIs), such as crizotinib. Despite this activity, ALK-positive patients ultimately develop resistance to ALK TKIs. In preclinical models, ALK fusion proteins are HSP90 clients and remain sensitive to HSP90 inhibition despite acquired resistance to ALK TKIs. We therefore designed a phase II trial of the HSP90 inhibitor AUY922 in patients with previously treated, ALK-positive NSCLC.
Methods:
In this single-arm, multicenter, open-label study, we enrolled patients with advanced, ALK-positive NSCLC who had failed at least one prior ALK inhibitor. Key eligibility criteria included ECOG PS 0-2, measurable disease based upon RECIST version 1.1, and presence of an ALK rearrangement by FISH. Participants were treated with AUY922 at a dose of 70 mg/m[2 ]IV once weekly until disease progression, unacceptable toxicity, or death. The primary endpoint was objective response rate (ORR) according to RECIST version 1.1. Key secondary endpoints included safety, progression-free survival (PFS), and disease control rate (DCR). The planned sample size was 20 patients.
Results:
Between December 2012 and December 2014, 6 patients were enrolled. Median age was 52.5 years (range 42-54 years). A majority of patients (83%) were female. The median number of prior lines of therapy was 3 (range 2-4). All patients had previously received at least 1 ALK TKI (crizotinib n=5, alectinib n=1), and 2 patients had received a second ALK inhibitor (ceritinib n=2). Most patients (n=4) had received an ALK inhibitor as the last line of therapy prior to enrollment. Among the 6 patients enrolled, no objective responses were observed (ORR 0%). Three patients (50%) had a best response of stable disease (SD), but none remained on therapy beyond 3 months from the time of enrollment (Table). The median PFS was 1.43 months (95% CI 1.3-2.8 months). Common adverse events (AEs) included grade 1-2 diarrhea (83%), vision disorders (50%), fatigue (50%), and constipation (33%). The only treatment-related grade 3 AE was alkaline phosphatase elevation in 1 patient. The study was closed due to poor accrual in December 2012. Table 1Patient Best Response RECIST v1.1. Progression-Free Survival (months) 1 -4.9% 2.80 2 36.5 0.73 3 5.1 1.03* 4 121.9 1.43 5 11 2.60 6 69.5 1.30 * Censored (Discontinued due to toxicity)
Conclusion:
Although limited by a small sample size and premature closure, this study suggests that AUY922 is associated with minimal anti-tumor activity in ALK-positive patients previously treated with ALK inhibitors. Combinations of ALK TKIs and HSP90 inhibitors may represent an alternative strategy, and several such studies are now ongoing.
