Virtual Library
Start Your Search
J. Heymach
Moderator of
-
+
OA11 - Angiogenesis in Advanced Lung Cancer (ID 387)
- Event: WCLC 2016
- Type: Oral Session
- Track: Advanced NSCLC
- Presentations: 8
- Moderators:L.M. Montuenga, J. Heymach
- Coordinates: 12/06/2016, 11:00 - 12:30, Stolz 2
-
+
OA11.01 - Prolonged OS of Patients Exposed to Weekly Paclitaxel and Bevacizumab: Impact of the Cross-Over in the IFCT-1103 ULTIMATE Study (ID 4988)
11:00 - 11:10 | Author(s): A.B. Cortot, C. Audigier Valette, O. Molinier, S. Le Moulec, F. Barlesi, G. Zalcman, P. Dumont, D. Pouessel, S. Hiret, C. Poulet, P.J. Souquet, A. Dixmier, P. Renault, A. Langlais, M. Lebitasy, F. Morin, D. Moro-Sibilot, B. Besse
- Abstract
- Presentation
Background:
Overall survival (OS) is considered as the gold standard for evaluating efficacy of antineoplastic treatments, including chemotherapy and targeted therapies. In randomized trials, allowing patients to cross-over to the other arm usually prevents demonstration of a survival benefit. However, it may provide important information with clinical relevance.
Methods:
The phase III IFCT-1503 ULTIMATE study compared weekly paclitaxel and bevacizumab (wPB) vs. docetaxel (DOC) as second- or third-line therapy in non-squamous NSCLC. At progression, patients were allowed to cross over to the other arm. Date of progression was collected for patients who crossed over to the other arm and for those who did not cross over but received a post-discontinuation treatment within 60 days following progression. Post-discontinuation progression-free survival (PFS2) and OS2 were calculated from day 1 of post-discontinuation treatment.
Results:
The study met its primary endpoint, PFS, which was significantly improved in the wPB arm (medians 5.4 vs. 3.9 mo, hazard ratio (HR) 0.62, p=0.006). No overall survival was observed (medians 9.9 vs. 11.4 mo, HR 1.18, p=0.4). Out of patients treated with DOC (n=55), those who crossed over to wPB (n=21, 38.2%) had a median PFS2 of 4.9 mo [3.1-6.2] and a median OS2 of 12.5 mo (7.0-NR), whereas those who did not cross over but received a post-discontinuation treatment (n=13, 23.7%) had a median PFS2 of 1.7 mo [1.1-2.2] and a median OS2 of 4.1 mo [2.1-5.9]. Out of patients treated with wPB (n=111), median PFS2 was 1.9 mo [1.2-2.2] for those who crossed over to DOC (n=9, 8.3%) and median PFS2 and OS2 were 1.9 mo [1.7-2.6] and 5.0 m [3.4-9.0] for those who did not cross over but received a post-discontinuation treatment (n=57, 52.3%).
Conclusion:
Allowing patients to cross over to the other arm demonstrated benefit of wPB following progression on docetaxel and explains the absence of OS benefit.
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.
-
+
OA11.02 - Randomized Phase 1b/3 Study of Erlotinib plus Ramucirumab in First-Line EGFR Mut + Stage IV NSCLC: Phase 1b Safety Results (ID 3827)
12:10 - 12:20 | Author(s): K. Nakagawa, E.B. Garon, L. Paz-Arez, S. Ponce, J. Corral, O.J. Vidal, E. Nadal, K. Kiura, J. Liu, S. He, J. Treat, R. Dalal, P. Lee, M. Reck
- Abstract
- Presentation
Background:
Ramucirumab, an antiangiogenic IgG1 VEGFR2-targeted monoclonal antibody, and erlotinib, an EGFR tyrosine kinase inhibitor, are both active in advanced NSCLC. This global phase 1b/3 study (NCT02411448) will assess safety, tolerability and efficacy of the combination of ramucirumab with erlotinib in previously untreated patients with EGFR mutation-positive stage IV NSCLC. Here we report phase 1b safety results.
Methods:
Eligible patients with ECOG PS 0-1, an activating EGFR mutation, and previously untreated stage IV NSCLC received ramucirumab 10 mg/kg intravenously on day 1 of repeating 14-day (± 3 days) cycle and erlotinib 150 mg orally daily. Treatment continued until disease progression or unacceptable toxicity. The primary objective of part A was to assess the safety and tolerability, in terms of dose limiting toxicities (DLT), of adding the recommended dose of ramucirumab for phase 3 (part B) to standard dose erlotinib. Data were analyzed separately for Japan (JP) (cohort 1) and US/EU (cohort 2). The DLT assessment occurred during the first 2 cycles (approximately 28 days).
Results:
As of Dec 16th, 2015, 14 patients were treated in the phase 1b part of this trial and 12 were DLT evaluable (6 JP; 6 US/EU). Overall, 6 grade (Gr) 3 treatment-emergent adverse events (TEAE) were noted, with at least one TEAE in 5 patients; no serious adverse events or Gr 4-5 TEAEs occurred. In the JP cohort the median age was 73 (64-79), 57% had ECOG PS 1 and 29% had a history of smoking. Four patients (57%) experienced a Gr 3 TEAE, of which one was a DLT (elevation of alanine aminotransferase) while the others (hypertension [n=2], dermatitis acneiform, and diarrhea) were not DLTs. In the US/EU cohort the median age was 71 (31-83), 86% had ECOG PS 1, and no patients had a history of smoking. One patient experienced Gr 3 TEAE of rash; no DLTs were observed in this cohort.
Conclusion:
Enrollment on the phase 1b portion of this trial is complete and the safety results were consistent with previous combinations of antiangiogenic/erlotinib in this patient population. No unexpected toxicities were identified. Phase 3 enrollment has been initiated maintaining the dose of ramucirumab at 10 mg/kg Q2W.
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.
-
+
- Abstract
- Presentation
Background:
Targeting the tumor microenvironment, such as tumor angiogenesis, has led to the successful development and approval of a number of targeted therapies thereby changing the standard of care for many types of cancer. However, treatment options are limited in third-line non-small cell lung cancer (NSCLC) patients. Fruquintinib is a potent and highly selective oral kinase inhibitor targeting vascular endothelial growth factor receptors and is currently in late stage development for multiple cancers. This Phase II study was designed to evaluate the efficacy and safety of fruquintinib in third-line NSCLC patients (NCT02590965).
Methods:
A total of 91 patients were randomized to receive best supportive care (BSC) plus fruquintinib or BSC plus placebo in a 2:1 ratio from 12 Chinese clinical centers. Fruquintinib initial dose was 5 mg once daily and treatment was given in every 4-week cycle (3 weeks treatment followed by 1 week off). The primary objective was to compare progression free survival (PFS) between the two treatment groups. Secondary efficacy parameters included objective response rate (ORR), disease control rate (DCR), overall survival (OS). Tumor response was assessed per RECIST 1.1.
Results:
As of August 7, 2015, median PFS was 3.8 months for the fruquintinib group comparing with 1.2 months for the placebo group (hazard ratio=0.27, p<0.001). The ORR was 16.4% for the fruquintinib group comparing with 0% for the placebo group (p=0.02). The DCR of the fruquintinib group was significantly higher than that of the placebo group with a difference of 53.8% (36.3, 71.4; 95% CI, p<0.001). OS was not mature and initial analysis revealed 3- and 6-month OS rates of 90.2% and 68.3% for the fruquintinib group, and 73.3% and 58.2% for the placebo group, respectively. Adverse event was reported in 68.9% and 60.0% patients in fruquintinib and placebo group, respectively. The incidence of serious adverse events was 3.3% in the fruquintinib group and 6.7% in the placebo group.
Conclusion:
Fruquintinib in third-line NSCLC met the primary efficacy endpoint of PFS and demonstrated superiority in the secondary endpoints of ORR and DCR as compared with placebo. OS has yet to mature. Fruquintinib was generally well tolerated and safety profile consistent with previously reported. These results support further development of fruquintinib in third-line NSCLC patients. A randomized, double-blind, multi-center Phase III registration study was initiated in December 2015 (NCT02691299). Clinical trial information: NCT02590965.
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.
-
+
OA11.04 - Discussant for OA11.01, OA11.02, OA11.03 (ID 7018)
11:20 - 11:35 | Author(s): M. Pérol
- Abstract
- Presentation
Abstract not provided
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.
-
+
OA11.05 - A Phase 2 Study of Cabozantinib for Patients with Advanced RET-Rearranged Lung Cancers (ID 5731)
11:35 - 11:45 | Author(s): A. Drilon, R. Somwar, R.S. Smith, L. Delasos, M. Albano, M. Van Voorthuyson, L. Wang, N. Rekhtman, A. Ni, A. Plodkowski, M. Ginsberg, G.J. Riely, C. Rudin, M. Ladanyi, M.G. Kris
- Abstract
- Presentation
Background:
RET rearrangements are actionable drivers found in 1-2% of non-small cell lung cancers. We previously reported the efficacy and safety of the multikinase RET inhibitor cabozantinib in 16 patients with RET-rearranged lung cancers in the first stage of our Simon two-stage phase 2 clinical trial (overall response rate 38%; Drilon, ASCO 2015). This study has since completed accrual of both stages, now with 26 patients treated with cabozantinib.
Methods:
This was an open-label, single center, phase 2 trial (NCT01639508). Eligibility criteria: stage IV pathologically-confirmed lung cancers, presence of a RET rearrangement, KPS >70%, and measurable disease. RET rearrangements were detected by FISH or next-generation sequencing. Cabozantinib was administered in tablet form at 60 mg daily until progression of disease or unacceptable toxicity. The primary objective was to determine the overall response rate (ORR, RECIST v1.1). Secondary objectives included determining progression-free survival (PFS), overall survival (OS), and toxicity. 5 responses in 25 response-evaluable patients were required to meet the primary endpoint (Simon two-stage minimax design: H~0~ 10% vs H~A~ 30% ORR). All patients who received at least one dose of cabozantinib were evaluable for toxicity.
Results:
26 patients with RET-rearranged lung adenocarcinomas were treated with cabozantinib. KIF5B-RET was the predominant fusion type identified in 16 (62%) patients. The median number of prior chemotherapy lines was 1 (0-5). One patient who discontinued therapy in cycle 1 and did not undergo a response assessment was not response-evaluable as per protocol. The study met its primary endpoint with confirmed partial responses observed in 7 (ORR 28% [95% CI 12-49%]) of 25 response-evaluable patients. The median PFS was 5.5 months (95% CI 3.8-8.4). The median OS was 9.9 months (95% CI 8.1-not reached). Response by RET fusion partner: Unknown (FISH+) 2/6 (33%), KIF5B 3/15 (20%), CLIP1 1/1, TRIM33 1/1, CCDC6 0/1, ERC1 0/1. In 26 patients evaluable for toxicity, the most common all-grade treatment-related adverse events were increased alanine aminotransferase in 25 (96%) patients, increased aspartate aminotransferase in 19 (73%) patients, hypothyroidism in 18 (69%) patients, diarrhea in 16 (62%) patients, and palmar plantar erythrodysesthesia in 15 (58%) patients. Nineteen (73%) patients required dose reduction.
Conclusion:
This study met its primary endpoint. Cabozantinib is an active agent in patients with RET-rearranged lung cancers. An improved understanding of tumor biology and novel therapeutic approaches will be required to improve outcomes with RET-directed therapy.
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.
-
+
OA11.06 - Role of Fibroblasts in the Subtype-Specific Therapeutic Effects of Nintedanib in Non-Small Cell Lung Cancer (NSCLC) (ID 5029)
12:20 - 12:30 | Author(s): M. Gabasa, R. Ikemori, F. Solca, F. Hilberg, N. Reguart, J. Alcaraz
- Abstract
- Presentation
Background:
There is growing evidence that tumor-associated fibroblasts (TAFs) play a major role in critical steps of tumor progression in solid tumors including NSCLC. However the role of TAFs in regulating the response to targeted therapies is poorly understood. One of such targeted therapies is nintedanib (NTD), a multi-kinase inhibitor of VEGF, FGF and PDGF receptors that has been recently approved to treat advanced lung adenocarcinoma (ADC) patients. Although the therapeutic effects of NTD in lung cancer have been associated with its anti-angiogenic functions, NTD has also been shown to exhibit anti-fibrotic effects in patients with idiopathic pulmonary fibrosis. Since lung fibrosis is largely driven by activated fibroblasts/myofibroblasts, and TAFs are positive for myofibroblasts markers, it is conceivable that NTD anti-tumor effects may be additionally driven through its direct action on lung TAFs. The main goal of this study was to analyze the latter hypothesis.
Methods:
Patient derived lung TAFs from ADC and SCC patients as well as paired control fibroblasts from non-malignant pulmonary tissue were exposed to increasing concentrations of NTD and analyzed for growth and activation upon stimulation with growth factors and TGF- β1, respectively. Activation markers included alpha-smooth muscle actin and collagen-I.
Results:
We found that NTD exhibited a dual inhibitory role in TAFs in terms of growth and TGF-β1-induced activation in a subtype-specific fashion. Specifically, NTD-mediated growth inhibition was larger in SCC-TAFs than in ADC-TAFs, which correlated with the larger Erk signaling previously reported by our group in SCC-TAFs in the absence of mitogenic stimuli. Conversely, inhibition by NTD of TGF-β1-mediated activation was larger in ADC-TAFs than SCC-TAFs. Likewise, NTD inhibited the growth and invasive advantages of ADC cancer cells in vitro elicited by the conditioned medium of ADC-TAFs treated with TGF-β1 compared to those advantages elicited in the absence of NTD. These results reveal for the first time that the pro-tumorigenic effects of ADC-TAFs in vitro are markedly reduced in the presence of NTD.
Conclusion:
TAFs in vivo are largely activated and quiescent, and TGF-β1 is a potent fibroblast activator that is frequently upregulated in lung cancer and associated with poor prognosis. Based on these previous observations, we argue that our new findings strongly suggest that the selective therapeutic advantage observed for NTD in ADC patients may be in part related to its selective inhibition of TGF-β1-dependent activation of ADC-TAFs. These findings provide novel mechanistic insights on the subtype-specific therapeutic effects of NTD in NSCLC.
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.
-
+
- Abstract
- Presentation
Background:
Increasing studies have shown that anti-angiogenic therapy targeting VEGF/VEGFR2 axis are furnishing demonstrable therapeutic effect on lung cancer，but the treatment benefit is transitory in clinic, generally followed by restoration of tumor growth and disease progression. Blockade of VEGF/VEGFR2 pathway can not only induce anti-vascular effect, but also remodel the immunosuppressive tumor microenvironment probably due to promoting suppressive cells infiltration and enhancing PD-L1 expression, resulting in impairing antitumor immunity. Therefore, the current study aimed to investigate whether combining anti-angiogenic and anti-PD-L1 treatments can induce synergistic antitumor effect by enhancing antitumor immune response in murine lung cancer.
Methods:
We evaluated the antitumor effects of anti-VEGFR2 agent (apatinib) as monotherapy or in combination with anti-PD-L1 monoclonal antibody in a murine lung cancer model using Lewis lung cancer cells (LLCs). The changes of immune components in tumor and spleen were dynamically tested in different treatment groups and time points by flow cytometry and immunohistochemistry.
Results:
The results showed that VEGF/VEGFR2 blockade could retard tumor growth and inhibit tumor neovascularization via eradicating Foxp3[+ ]regulatory T cells (Tregs) and myeloid derived suppressive cells (MDSCs) and reducing the density of microvessels in the first two weeks of treatment. On the third week of apatinib monotherapy, the number of Foxp3[+ ]Tregs and MDSCs had increased again. Although VEGF/VEGFR2 blockade induced more tumor infiltrating lymphocytes (TILs), especially CD8[+] T cells, infiltrating into the tumor mass than control group (P < 0.01), the expression of PD-1 and PD-L1was also significantly upregulated than that control group (P < 0.01). Compared to apatinib monotherapy, combining treatment demonstrated that anti-VEGFR2 plus anti-PD-L1 therapy could significantly inhibit tumor growth (P < 0.01) by persistently eliminating Foxp3[+ ]Tregs and MDSCs. Furthermore, combining anti-VEGFR2 and anti-PD-L1 therapy could not only dramatically increase TILs infiltration, especially CD8[+] T cells, but also significantly reduce the expression of PD-1 and PD-L1.
Conclusion:
Simultaneous blockade of VEGF/VEGFR2 and PD-1/PD-L1 pathways induced a synergistic anti-tumor effect in-vivo, possibly through eliminating immunosuppressive components including Tregs and MDSCs and enhance antitumor immune response.
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.
-
+
OA11.08 - Discussant for OA11.05, OA11.06, OA11.07 (ID 7015)
11:55 - 12:10 | Author(s): R. Wiewrodt
- Abstract
- Presentation
Abstract not provided
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.
Author of
-
+
MA04 - HER2, P53, KRAS and Other Targets in Advanced NSCLC (ID 380)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
-
+
MA04.07 - Impact of Major Co-Mutations on the Immune Contexture and Response of KRAS-Mutant Lung Adenocarcinoma to Immunotherapy (ID 6343)
16:42 - 16:48 | Author(s): J. Heymach
- Abstract
- Presentation
Background:
Activating mutations in the KRAS proto-oncogene define a prevalent and clinically heterogeneous molecular subset of lung adenocarcinoma (LUAC). We previously identified three major subgroups of KRAS-mutant LUAC on the basis of co-occurring genetic events in TP53 (KP), STK11/LKB1 (KL) and CDKN2A/B (KC) and reported that LKB1-deficient tumors exhibit a “cold” tumor immune microenvironment, with reduced expression of several immune checkpoint effector/mediator molecules, including PD-L1 (CD274). Here, we extend these findings and examine the clinical outcome of co-mutation defined KRAS subgroups to therapy with immune checkpoint inhibitors.
Methods:
We conducted a single-institution analysis of clinical and molecular data (PCR-based next generation sequencing of panels of 50, 134 or 409 genes) prospectively collected from patients enrolled into the MD Anderson Lung Cancer Moon Shot GEMINI database. KRAS-mutant LUAC were separated into KP, KL and K (wild-type for TP53 and STK11) groups. The log- rank test and Fisher’s exact test were used for comparison of progression-free survival (PFS) and objective response rate (ORR) respectively between the groups. In addition, automated IF-based enumeration of lymphocyte subsets was performed in 40 surgically resected LUAC (PROSPECT cohort) with available whole exome sequencing data.
Results:
Among 229 patients with KRAS-mutant LUAC who consented to the protocol we identified 35 patients with metastatic disease (17 KP, 6 KL, 12 K) that received immunotherapy with nivolumab (N=29), pembrolizumab (N=3), nivolumab/urelumab (N=1) and durvalumab/tremelimumab (N=2) and had robust clinical outcome data. There was no impact of different KRAS alleles (G12C/G12V/G12D) on PFS (P=0.6149, log-rank test) or ORR to immune checkpoint inhibitors (P=0.88, Fisher’s exact test, 2x3 contingency table). In contrast, co-mutation defined KRAS subgroups exhibited significantly different median PFS to immunotherapy (KP: 18 weeks, KL: 6 weeks, K: 16 weeks, P=0.0014, log-rank test). Objective responses were observed in 9/17 (52.9%) KP and 3/12 (25%) K tumors compared to 0/6 (0%) KL tumors (P=0.049, Fisher’s exact test, 2x3 contingency table). In the PROSPECT cohort of surgically resected LUACs with available whole exome sequencing data, somatic mutation in STK11 was associated with reduced intra-tumoral densities of CD3+ (P=0.0016), CD8+ (P=0.0125) and CD4+ (P=0.0036) lymphocytes.
Conclusion:
Mutations in STK11/LKB1 are associated with an inert tumor immune microenvironment and poor clinical response of KRAS-mutant LUAC to immune checkpoint blockade. The mechanism that underlies this phenotype and strategies to overcome it are under investigation. The impact of additional co-mutations on the immune profile and response of KRAS-mutant LUAC to immunotherapy is also being explored.
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.
-
+
MA11 - Novel Approaches in SCLC and Neuroendocrine Tumors (ID 391)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:P. Lara, A. Mohn-Staudner
- Coordinates: 12/06/2016, 14:20 - 15:50, Strauss 3
-
+
MA11.07 - Improved Small Cell Lung Cancer (SCLC) Response Rates with Veliparib and Temozolomide: Results from a Phase II Trial (ID 5517)
15:02 - 15:08 | Author(s): J. Heymach
- Abstract
- Presentation
Background:
PARP1 is overexpressed in small cell lung cancer (SCLC) and represents a novel therapeutic target for this disease. Preclinical data indicates that combining veliparib (an oral PARP-1/2 inhibitor) and temozolomide (TMZ) results in synergistic tumor growth delay or regression. In this study, we investigated whether adding veliparib to TMZ would improve outcomes in patients with relapsed sensitive and refractory SCLCs. Candidate predictive biomarkers, including SLFN11, were then explored.
Methods:
SCLC patients previously treated with 1 or 2 prior regimens were enrolled in the trial and randomized 1:1 to receive oral TMZ 150-200mg/m[2]/day (D1-5) with either veliparib or placebo 40mg twice daily, orally (D1-7) (NCT01638546). Primary endpoint was 4-month progression free survival (PFS). Data were analyzed in patients with platinum sensitive (progression >60 days after 1st line therapy) or refractory disease (progression ≤60 days after 1st line therapy, or in need of 3rd line treatment). Archived tissue was available for 53 patients for biomarker analysis.
Results:
104 patients were enrolled and 100 patients were treated. Baseline characteristics were balanced between treatment arms: 52% female; median age 62.5 (range, 31-84); 59% refractory disease; 33% needing 3rd-line therapy. Progression free survival at 4-months was similar between the two arms, 36% vs. 27% (p=0.39). However, in 93 evaluable pts, response rate was significantly higher in pts treated with veliparib/TMZ compared to TMZ alone (39% vs 14%, p =0.016). Median overall survival: 8.2 mos (95% CI: 6.4-12.2) in veliparib arm and 7 mos (95% CI: 5.3-9.5) in placebo arm, p = 0.50. Grade 3/4 thrombocytopenia and neutropenia more commonly occurred in the veliparib/TMZ arm: 50% vs 9% and 31% vs 7%, respectively. Levels of SLFN11, a marker of SCLC response to PARP inhibition in preclinical models, were assessed by immunohistochemistry. High SLFN11 in patient tumors (obtained at original diagnosis) was associated with a trend towards better overall survival in the veliparib/TMZ arm, but no difference in outcome in the TMZ alone arm. Additional correlative studies are ongoing, including assessment of MGMT promoter methylation, and will be available at the time of presentation.
Conclusion:
The combination of veliparib/TMZ increased response rates significantly, compared to TMZ alone. Hematologic toxicities of the combination may have impacted PFS (which was not significantly different between the arms) by limiting dosing. Biomarkers such as SLFN11, ATM, or MGMT promoter methylation could potentially help guide patient selection in the SCLC population.
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.
-
+
MA14 - Immunotherapy in Advanced NSCLC: Biomarkers and Costs (ID 394)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:M. Reck, D.R. Spigel
- Coordinates: 12/06/2016, 16:00 - 17:30, Strauss 2
-
+
MA14.03 - The Impact of Genomic Landscape of EGFR Mutant NSCLC on Response to Targeted and Immune Therapy (ID 6242)
16:12 - 16:18 | Author(s): J. Heymach
- Abstract
- Presentation
Background:
EGFR mutations define a distinct subset of NSCLC characterized by clinical benefit from tyrosine kinase inhibitors. The impact of genomic alterations that coexist with EGFR mutations is not fully understood. In addition, the responsiveness of EGFR mutant NSCLC to immune checkpoint blockade is not well defined.
Methods:
We queried our prospectively collected MD Anderson Lung Cancer Moon Shot GEMINI Database to identify EGFR mutant NSCLC patients. We analyzed the genomic landscape of these tumors derived from next generation sequencing, performed as part of routine clinical care, to comprehensively describe the concurrent genomic aberrations in EGFR mutant NSCLC and their impact on clinical outcomes. We used log rank and Fisher’s exact tests to identify associations between co-concurrent mutations and clinical outcomes.
Results:
1958 non-squamous NSCLC patients were identified in the GEMINI database. The frequency of EGFR mutations was 14.1% (n=276). Among EGFR mutant patients, 188 underwent targeted next generation sequencing of a minimum of 46 cancer related genes. The majority of EGFR mutant patients (77.6%, n=146) had at least one coexisting mutation. The most frequent co-mutations identified were TP53 (47%, n=88), CTNNB1 (7.5%, n= 14) and PIK3CA (6.5%, n=12). ALK and ROS1 translocations were found to coexist with EGFR mutations in one patient each. Of patients treated with a first or second generation TKI, concurrent TP53 mutations were associated with a shorter progression free survival (HR= 1.81, P= 0.039). Eight patients with EGFR/CTNNB1 co-mutations developed acquired TKI resistance with T790M secondary mutation being the resistance mechanism in six (75%) of them suggesting that coexisting mutation can dictate emerging resistance mechanisms. Twenty patients were treated with anti PD1/PD-L1 agents (nivolumab n= 18, pembrolizumab n=2). Only two (10%) patients achieved confirmed radiological response, one lasting for 6 months and the second ongoing at 6 months. Both patients were never smokers, one with EGFR exon 20 insertion and no concurrent mutations, and the other with EGFR exon 19 deletion and TP53 mutation. Sixteen patients developed confirmed progressive disease. Finally, one patient with 17 pack-year smoking history, EGFR G719/S768I double mutation and concurrent PIK3CA mutation achieved stable disease lasting for four months. The median progression free survival for the cohort treated with immunotherapy was 2 months (range: 1-not reached).
Conclusion:
Concurrent genomic aberrations may predict response duration to TKIs and may be associated with particular emerging resistance mechanisms to TKIs in EGFR mutant NSCLC. Immunotherapy results in durable clinical benefit in a subset of EGFR mutant NSCLC patients.
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.
-
+
MA16 - Novel Strategies in Targeted Therapy (ID 407)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:G. Purkalne, J. Von Pawel
- Coordinates: 12/07/2016, 14:20 - 15:50, Strauss 2
-
+
MA16.07 - Drug Repurposing to Overcome De Novo Resistance of Non-Traditional EGFR Mutations (ID 6203)
14:56 - 15:02 | Author(s): J. Heymach
- Abstract
- Presentation
Background:
Approximately 10% of EGFR mutant NSCLCs have an in-frame insertion in exon 20 of EGFR resulting in innate resistance to 1[st] generation TKIs. The reported response rate of patients with EGFR exon 20 insertions to gefitinib and erlotinib is 5% with a median progression free survival of 1.5 months. It has been shown that exon 20 insertions stabilize the active conformation of EGFR and increase affinity to ATP over TKIs. We hypothesize that exon 20 insertions induce conformational changes to the drug binding pocket resulting in EGFR TKI resistance which can be overcome by covalently binding TKIs.
Methods:
Ba/F3 cells expressing 7 different clinically observed EGFR exon 20 insertion mutations spanning the helix (residues 763-766) and loop (residues 767-773) regions were generated and screened against 1[st], 2[nd], and 3[rd] generation EGFR inhibitors including erlotinib, gefitinib, afatinib, dacomitinib, neratinib, poziotinib, ibrutinib rocilentinib, EGF816, and osimertinib. Computational modeling was conducted to analyze the conformational changes and drug binding affinity.
Results:
In Ba/F3 cells with EGFR exon 20 insertions, most 1[st] and 3[rd] generation TKIs failed to inhibit growth of EGFR exon 20 insertions after residue 767 with IC~50 ~values above 100nM. However, poziotinib significantly inhibited cell growth of all EGFR exon 20 insertions tested across the helix and loop regions with an average IC~50~ value of 2.9nM, as compared to osimertinib and rocilentinib (IC~50~ values =103nM and 850nM, respectively). Further characterization using three-dimensional modeling revealed that exon 20 insertions induce conformational changes which cause a decreased affinity for 1[st] generation TKIs and steric hindrance of C797 reducing the ability of 3[rd] generation TKIs to covalently bind. A significant shift of the c-helix and p-loop result in a sterically hindered binding pocket. Therefore, the smaller, more flexible 1,2-dichloro-3-fluorobenzene terminal group of poziotinib can overcome the structural changes induced by the exon 20 insertions, whereas the ridged 1-methylindole terminal group of osimertinib cannot.
Conclusion:
EGFR exon 20 insertions induce a shift of the p-loop and c-helix resulting in steric hindrance of the binding pocket thereby preventing binding of 1[st] generation and 3[rd] generation EGFR inhibitors including rocilentinib and osimertinib. A smaller, more flexible inhibitor such as poziotinib can overcome the steric hindrance of the drug binding pocket. Currently, in vivo studies of the EGFR D770insNPG GEMM, and EGFR H773insNPH PDX model with poziotinib are underway, and a clinical trial testing poziotinib in EGFR exon 20 mutant NSCLC patients will begin enrollment this year.
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.
-
+
OA19 - Translational Research in Early Stage NSCLC (ID 402)
- Event: WCLC 2016
- Type: Oral Session
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:G. Heller, G. Goss
- Coordinates: 12/07/2016, 11:00 - 12:30, Schubert 3
-
+
OA19.02 - Sex Differences Are Detected in the Profile of Tumor Associated Inflammatory Cells (TAICs) Are Lung Adenocarcinoma (ID 5451)
11:10 - 11:20 | Author(s): J. Heymach
- Abstract
- Presentation
Background:
A number of studies have characterized TAICs in lung cancer and associated their levels of infiltration with patients’ outcome. There is limited information about the correlation of TAICs infiltration with clinical and pathological features of lung cancer. We investigated the association between patterns of tumor infiltrating lymphocytes and macrophages with detailed clinical and pathological features in lung adenocarcinoma.
Methods:
We studied archival tumor tissue from 93 surgically resected lung adenocarcinomas, stages I to III. Density of TAICs expressing CD3, CD4, CD8, and CD68 was evaluated using immunohistochemistry (IHC) and image analysis. TAICs density was correlated with tumor’s histological characteristics and patients’ characteristics.
Results:
We found significant differences in the TAICs infiltrate density of lung adenocarcinomas based on patients’ characteristics. Overall: a) females showed higher levels of CD8+ (P=0.01) and CD3+ (P=0.03) cell density than males; b) smaller tumors (<3cms) showed more CD4+ (P=0.01) and CD3+ (P=0.03) cells than larger tumors; and, c) tumors with solid histology pattern showed higher levels of CD8+ (P=0.03) cells than non-solid pattern. No overall significant differences on TAICs infiltrates were detected by age, tobacco exposure by pack-years and TTF-1 IHC expression score. However when TAICs density of tumors was examined by sex we found the following: a) in larger tumor (>3cms), females demonstrated higher levels of CD8+ cells (P=0.0007) than males; b) tumors from females older than the median age (63 years) showed more CD4+ (P=0.04), CD8+ (P=0.009) and CD3+ (P=0.042) cells than males; c) tumors from females with <40 pack-years of tobacco history showed significantly higher levels of CD3+ (P=0.004) and CD68+ (P=0.004) cells than males; d) tumors from females with high levels of TTF1 expression (score >150) showed higher levels of CD8+ cells(P=0.03) than males; e) females with tumors having non-solid histology pattern showed higher CD8+ (P=0.02) and CD3+ (P=0.02) cells than males. Finally, tumors expressing low levels of TTF-1 and lower CD4+ cells correlated significantly with worse overall recurrence free survival and overall survival in both males (P<0.0001) and females (P=0.0072).
Conclusion:
In lung adenocarcinoma, TAICs infiltration correlates with clinical characteristics of patients and pathological features of tumors, particularly, sex, age, size and TTF-1 expression. Compared with men, lung adenocarcinomas from females showed higher levels of TAICs, particularly at older age, larger tumor size, less exposure to tobacco, and more differentiated histological patterns. (UT Lung SPORE and MD Anderson Moon Shot Program).
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.
-
+
OA20 - Immunotherapy and Markers (ID 401)
- Event: WCLC 2016
- Type: Oral Session
- Track: Biology/Pathology
- Presentations: 2
- Moderators:M. Früh, C.S. Baldotto
- Coordinates: 12/07/2016, 11:00 - 12:30, Stolz 2
-
+
OA20.05 - The Influence of Neoadjuvant Chemotherapy, on Immune Response Profile in Non-Small Cell Lung Carcinomas (ID 5738)
11:35 - 11:45 | Author(s): J. Heymach
- Abstract
- Presentation
Background:
The clinical efficacy observed with PD-1/PD-L1 inhibitors in non-small cell lung carcinoma (NSCLC) has prompted to characterize the immune response in lung tumors treated with chemotherapy. Our goal was to determine the characteristics of immune microenvironment of localized, surgically resected, NSCLCs from patients who received and did not receive neo-adjuvant chemotherapy. Using multiplex immunofluorescence (mIF) and image analysis, we investigated PD-1/PD-L1 expression, and quantified tumor infiltrating lymphocytes (TILs) and tumor associated macrophages (TAMs).
Methods:
We studied formalin-fixed and paraffin embedded (FFPE) tumor tissues from 111 stage II and III resected NSCLC, including 61 chemonaïve (adenocarcinoma, ADC=33; squamous cell carcinoma, SCC=28) and 50 chemotherapy-treated (ADC=30; SCC=20) tumors. mIF was performed using the Opal 7-color fIHC Kit™ and analyzed using the Vectra™ multispectral microscope and inForm™ Cell Analysis software (Perkin Elmer, Waltham, MA). The markers studied were grouped in two 6-antibody panels: Panel 1, AE1/AE3 pancytokeratins, PD-L1 (clone E1L3N), CD3, CD4, CD8 and CD68; and Panel 2, AE1/AE3, PD1, Granzyme B, FOXP3, CD45RO and CD57.
Results:
Positive PD-L1 expression (>5%) in malignant cells (MCs) was detected in 48% (n=53/111) of NSCLCs. Overall, chemotherapy-treated tumors showed significantly higher percentages of MCs expressing PD-L1 (median, 18.2%) than chemo-naïve cases (median, 1.8%; P=0.033). Higher densities of inflammatory cells expressing granzyme B (P=0.036), CD57 (P=0.001) and PD-1 (P=0.016) were detected in chemotherapy-treated NSCLCs compared with chemo-naïve tumors. In contrast, lower densities of FOXP3-positive regulatory T cells were detected in chemotherapy-treated tumors when compared with chemo-naïve cases (P=0.032). Following chemotherapy ADCs exhibited significantly higher levels of CD57-positive cells (P<0.0001) and lower density of FOXP3-positive cells (P=0.002) than chemo-naïve tumors. Chemotherapy-treated SCCs demonstrated higher density of PD-1-positive cells than chemo-naïve tumors (P=0.004). In chemotherapy-treated cancers, lower levels of CD4 helper T positive cells and tumor associated macrophages (TAMs) CD68-positive cells were associated with worse overall survival (OS; P=0.04 and P=0.005, respectively) in univariate analysis. In chemotherapy-treated ADC patients, lower levels of CD68-positive (P=0.010) and higher levels of FOXP3-positive cells correlated with worse OS (P=0.044).
Conclusion:
We developed a robust mIF panel of 10 markers to study inflammatory cells infiltrates in FFPE NSCLC tumor tissues. Chemotherapy-treated NSCLCs exhibited higher levels of PD-L1 expression and T cell subsets compared to chemo-naïve tumors, suggesting that chemotherapy activates specific immune response mechanisms in lung cancer. (Supported by CPRIT MIRA and UT Lung SPORE grants, and MD Anderson Moon Shot Program).
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.
-
+
OA20.06 - Prospective ImmunogenomiC PrOfiling of Non-Small Cell Lung Cancer - The ICON Project (ID 5560)
11:45 - 11:55 | Author(s): J. Heymach
- Abstract
- Presentation
Background:
Previous attempts to define tumor and stromal immunologic environment in non-small cell lung cancer (NSCLC) utilized archival tissue. We established prospective comprehensive immonogenomic profiling protocol in NSCLC (ICON Project). The goal is to integrate immunomic, genomic, transcriptomic, proteomic, demographic, clinical, pathologic, and outcome data from 100 surgically resected early stage NSCLC.
Methods:
Tumor and normal lung tissue are collected at the time of surgery, blood samples before and after surgery. Tumor samples are processed for tumor infiltrating lymphocyte (TILs) isolation and expansion; development of patient derived xenografts (PDX), immunohistochemical immune markers, and immunopeptidome profiling. Blood samples are analyzed with flow cytometry.
Results:
57 patients with median age of 65 years (27 males) have been enrolled within 5 months, of which 33 (66%) contributed samples to the study. Four were never smokers, with others being former or current smokers. Majority (N=27) had adenocarcinoma, 4 squamous cell carcinoma, and 2 pleomorphic carcinoma. 15 patients had stage I, 11 stage II, and 7 stage III disease; 5 patients received induction chemotherapy. Median tumor size was 3.5 cm and 29 underwent R0 and 4 R1 resection. Pre-REP TIL expansion was successful in the majority of samples (68.2%, n=22). Twelve PDX models with a take rate of 40% have been generated. Interim analysis of tumor samples by IHC demonstrated higher median distribution of all cell types: CD3+ T cells, cytotoxic T cells CD8+, PD1+ cells, tumor associated macrophages (TAM) CD68+, TAM CD68+PD-L1+, CD20+B cells, memory T cells CD45R0, natural killer cells CD57+, regulatory FOXP3+ T cells, and cytotoxic granzyme B cells (cells/mm[2]) in the stroma as compared to the tumor compartment. Intra-tumoral regulatory FOXP3+T cells were more abundant in squamous cell carcinomas compared to adenocarcinomas (median 312 vs 51 cells/mm[2], p = 0.05). Higher concentration of intra-tumoral CD68+PD-L1+ expressing cells was observed following neoadjuvant chemotherapy (median 97 vs 60 cells/mm[2] no chemo; p= 0.077), as was the concentration of memory T cells CD45R0 (median 129 vs 30 cells/mm[2], no chemo; p = 0.077). Mass spectrometry-based immunopeptidome analysis identified several thousand peptides, of which 4 promising antigens have been chosen for further development as immunotherapeutic T-cell targets.
Conclusion:
The ICON is an ongoing, ambitious prospective project that aims to define the baseline immunologic characteristics of surgically resectable NSCLC. The rapid enrollment illustrates the enthusiasm for tumor immunoprofiling amongst patients and physicians alike. Data from this patient cohort will serve as a baseline comparison for upcoming neoadjuvant immunotherapy trials.
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.
-
+
P1.05 - Poster Session with Presenters Present (ID 457)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
-
+
P1.05-028 - Phenotypic and Functional Profiling of Tumor-Infiltrating Lymphocytes (TIL) in Early Stage Non-Small Cell Lung Cancer (NSCLC) (ID 6044)
14:30 - 14:30 | Author(s): J. Heymach
- Abstract
Background:
The ICON study aims to perform a comprehensive immunogenomic characterization of early stage localized non-small cell lung cancer (NSCLC) and lay the foundation for the identification of barriers to tumor immunity that may be targeted in future trials. Earlier work has demonstrated the prognostic significance of TIL in localized NSCLC. This work evaluates the functional status of T cells infiltrating the NSCLC tumors and their capacity to expand ex-vivo and perform effector function in the first 22 patients enrolled.
Methods:
Patients enrolled on the ICON study underwent surgery. Fresh tumor samples were mechanically disaggregated and immediately stained for flow cytometry. Panels consisted of markers of T cell subsets, differentiation status, T cell function, activation and exhaustion. PD-L1 expression was assessed on malignant cells as well as CD68+ tumor-associated macrophages (TAMs) by IHC. Fragments from the tumor tissue were also placed in culture in media containing IL-2 for ex-vivo TIL expansion. TIL cultures were maintained for 3-5 weeks and subsequently underwent phenotypical and functional characterization.
Results:
Analysis of freshly disaggregated tumor tissue (n=22) from NSCLC tumor or adjacent normal tissue by flow cytometry demonstrated that effector CD8[+] T cells found in the tumor were less functional than T cells infiltrating normal tissue, revealed by a decrease in the co-expression of the cytotoxic effector molecules perforin and granzyme B (p=0.0004) together with an enhanced expression of the inhibitory receptor PD-1 (p<0.0001). Immunohistochemistry analysis showed PD-L1 expression on malignant cells and/or CD68+ TAMs on all tumor samples except one, strongly suggesting that the PD-1/PD-L1 inhibitory axis was engaged contributing to decreased T cell functionality. TIL could be expanded from the majority of samples (68.2%, n=22). The degree of infiltration predicted the ability to grow TIL ex-vivo (median CD3+ infiltrate of 15.25% of live cells in disaggregated tumor tissue for samples from which TIL could be grown versus 2.9% when TIL could not grow p = 0.015). Immunophenotyping following expansion showed an enrichment in CD8+ aβTCR+ T-cells expressing both perforin and granzyme B indicating that TILs propagated with IL-2 regained functionality (p=0.016). Lastly, NSCLC TIL were rapidly expanded using anti-CD3 antibody, feeder cells and IL-2 over two weeks (n=6) and reached clinically relevant numbers for TIL ACT (range 381-1282 fold expansion).
Conclusion:
Overall, while TILs present in NSCLC are functionally inhibited, they can be expanded ex-vivo from most tumor samples and regain a functional phenotype for potential use in adoptive T-cell therapy.
-
+
P1.07 - Poster Session with Presenters Present (ID 459)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
-
+
P1.07-024 - EGFR Mutations in Small Cell Lung Cancer (SCLC): Genetic Heterogeneity and Prognostic Impact (ID 4154)
14:30 - 14:30 | Author(s): J. Heymach
- Abstract
Background:
EGFR mutations in SCLC were first reported in cases of lung adenocarcinoma which transformed to SCLC after TKI treatment and such mutation was speculated to be a TKI resistance mechanism. Recently case reports and high throughput sequencing in a small number of samples suggested that EGFR mutations do exist in de novo SCLC. But the genetic and clinical characteristics have not been studied in large number of samples. This study aims to conduct a large scale survey of the EGFR mutations among Chinese SCLC patients, and to analyze the genetic and clinical characteristics of such mutations.
Methods:
Mutation status in exon 18-21 of EGFR was assessed by dideoxy-sequencing in 565 SCLC tumors treated in Zhejiang Cancer Hospital, Hangzhou, China from 2009 to 2014 and correlated with clinical parameters. Chi-square test were used to show the correlation of clinic variables with EGFR mutation. Survival analysis was performed using the Kaplan-Meier method.
Results:
40 instances of EGFR mutation are detected in 565 clinical samples. The mutation rate is 7.1%. Besides classic mutations E19 deletion（n=3）and E21 L858R(n=3), the rest of the mutations detected are atypical including E18 (G719D/S, G696R, S695N/D, N700D, I715F, L688F, P694L), E19(K757N, A755V, V742I, E736K, N756Y, E749K, P753L, A755T), E20 (T790M, H773R, S768R/N, R776H/C, G796D, D807N, R803W/Q, Y813C, G810S, A763T, G779D, Q791R, C781Y, N771S), E21(L858V, G874R, K867E). Among the EGFR mutation positive patients, 27.5% (11/40) are non-smokers, higher than the EGFR negative group (16.4%, 86/525). But it is not statistically significant (p=0.129). And EGFR mutation is not correlated with sex (female vs male), age (≥65y vs <65y) or clinical stages (limited stage vs extensive stage). After matching the treatment history of the EGFR mutation positive and negative patients (excluding patients who were not treated ,only treated by traditional Chinese medicine or one cycle chemotherapy or biological therapy , treatment unkown ), univariate analysis shows that the EGFR mutation positive patients have better overall survival than the EGFR negative group, with medium OS of 24.433m±4.864m vs 14.00m±0.838m respectively (p=0.018). COX regression analysis suggests that limited stage (HR=2.610), <65 years (HR=1.476) and EGFR mutation (HR=0.587, p=0. 0.039) were independently predictive of better OS.
Conclusion:
Among the de novo SCLC patients diagnosed, there exists a group harboring EGFR mutations, most of which are non-classic mutations. After matching the treatment history of patients, analysis reveals that EGFR mutations are predictive of better OS.
-
+
P2.01 - Poster Session with Presenters Present (ID 461)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 2
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
-
+
P2.01-054 - Lung Cancer PD-L1 mRNA Expression Profile and Clinical Outcomes - An Analysis From The Cancer Genome Atlas and Cancer Cell Line Encyclopedia (ID 5048)
14:30 - 14:30 | Author(s): J. Heymach
- Abstract
Background:
Programmed death ligand 1 (PD-L1) has become one of the most studied biomarkers in early, and advanced non-small cell lung cancers (NSCLC). Conflicting results have been reported in the literature on the value of PD-L1 in predicting survival in surgically resected lung cancers. Our aim was to evaluate mRNA PD-L1 expression and survival based on the data available from the Cancer Genome Atlas (TCGA), and Cancer Cell Line Encyclopedia (CCLE).
Methods:
To determine the expression profile and clinical correlations of PD-L1 in lung cancers we used publicly available lung adenocarcinoma and squamous cell carcinoma (SCC) data from TCGA, and small cell and NSCLC line data from the CCLE. We performed Kaplan-Meier and correlation analyses to show how PD-L1 expression correlates with overall survival and other clinical variables. Lung cancer and normal tissue expression comparisons were also performed using normal tissue expressions from the Genotype-Tissue Expression (GTEx) project.
Results:
Results: PD-L1 mRNA expression from RNA sequencing was available for 517 lung adenocarcinoma and 501 lung SCC samples in the TCGA. The CCLE database contained PD-L1 expression for 12 small cell and 75 NSCLC cell lines. Lung cancers demonstrated a higher PD-L1 expression than most other cancers and normal tissues, and we found that PD-L1 expression was significantly higher in SCC than in adenocarcinoma (p<0.001). Furthermore, PD-L1 showed a significantly higher expression level in pathologic stage II SCC compared to stages I, III, and IV (p<0.05, p<0.05, p<0.001, respectively). Interestingly, stage IV was associated with a lower PD-L1 expression compared to stages I, II, and III (p<0.001). We did not identify similar expression associations with pathologic stage in adenocarcinoma. However, we found that current and also reformed smokers for less than 15 years had a higher PD-L1 expression in adenocarcinoma (p<0.05), but not in SCC. PD-L1 expression was not significantly associated with a survival difference in any stage or histology subgroups. Using the CCLE data we found that NSCLC cell lines show various expression of PD-L1 that is significantly higher compared to lung small cell carcinoma (p<0.001).
Conclusion:
The value of PD-L1 expression based on mRNA sequencing in predicting survival in anti PD-1 naïve patients appears to be limited. However, the levels of PD-L1 expression in various disease stages and subgroups of lung cancer patients provide rational for neoadjuvant or window-of-opportunity immunotherapy trials, which would enable us to sort out the mechanisms and to identify patients best suited for immunotherapy.
-
+
P2.01-061 - Image Analysis-Based Expression of Nine Immune Checkpoints Identifies Distinct Immunoprofiling Patterns in Non-Small Cell Lung Carcinomas (ID 5548)
14:30 - 14:30 | Author(s): J. Heymach
- Abstract
Background:
The understanding of the co-expression of immune checkpoints in non-small cell lung carcinoma (NSCLC) is important to potentially design combinatorial immunotherapy approaches in this disease. We examined the expression of a panel of immune checkpoints markers by immunohistochemistry (IHC) and quantitative image analysis in a large cohort of surgically resected NSCLCs, and correlated those findings with patients’ clinicopathological features and tumors’ inflammatory cells infiltrate and molecular characteristics.
Methods:
We studied 225 formalin fixed and paraffin embedded (FFPE) tumor tissues from stage I-III NSCLCs, including 123 adenocarcinomas (ADC) and 83 squamous cell carcinomas (SCC), placed in tissue microarrays (TMAs). Nine immune checkpoints markers, 4 (PD-L1, B7-H3, B7-H4, IDO1) expressed predominantly in malignant cells (MCs), and 5 (ICOS, VISTA, TIM3, LAG3 and OX40) expressed mostly in stromal tumor associated inflammatory cells (TAICs). All IHC markers were examined using quantitative image analysis system (Aperio).
Results:
Using > median value of the immune checkpoint expressions as positive expression we observed that MCs H-score expressing PD-L1, B7-H3, B7-H4 and IDO1was higher in SCC than ADC, with 3 out of 4 markers showing statistically significant (P<0.05) differences. In contrast, density of TAICs expressing ICOS, VISTA, OX40, LAG3 and TIM3 was higher in ADC than SCC, with 3 out of 5 markers demonstrating significant (P<0.05) differences. Furthermore, we identified frequent co-expression of markers: a) 11% ADC (13/123) and 10% SCC (8/83) co-expressed 8 to 9 markers; b) 45% ADC (55/123) and 32% SCC (27/83) co-expressed 6 to 7 markers, c) 28% ADC (35/123) and 40% SCC (33/83) co-expressed 4 to 5 markers, and d) 16% ADC (20/123) and 18% SCC (15/83) co-expressed 2 to 3 markers. In ADC, higher number of TAICs expressing OX40 and lower levels of MCs expressing B7-H4 were detected in tumors with EGFR (median, 7.49 vs. 1.16, P=0.021) and KRAS (median, 6.88 vs. 0.67, P=0.033) mutation compared with wild-type tumors, respectively. Univariate analysis demonstrated that high B7-H4 and low OX40 expression in MCs and in TAICs respectively correlated with worse overall survival (OS; P=0.016 and P=0.037, respectively) in ADC patients.
Conclusion:
We detected different patterns of immune checkpoints expression in NSCLC with higher level of markers found in malignant cells of SCC and in stromal inflammatory cells of ADC. Immune checkpoints expression correlated with the outcome of NSCLC patients. Importantly, co-expression of several immune checkpoints is a frequent event in NSCLC (Supported by CPRIT MIRA and UT Lung SPORE grants).
-
+
P2.02 - Poster Session with Presenters Present (ID 462)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Locally Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
-
+
P2.02-014 - Perioperative Outcomes and Downstaging Following Neoadjuvant Therapy For Lung Cancer – Analysis of the National Cancer Database (ID 4929)
14:30 - 14:30 | Author(s): J. Heymach
- Abstract
Background:
Administration of chemotherapy prior to surgical resection is one of the strategies for the treatment of locally advanced non-small cell lung cancer (NSCLC). Potential benefits of this approach include improved treatment tolerance, tumor downstaging, and the evaluation of tumor response. Utilizing the National Cancer Database (NCDB), we sought to compare short-term perioperative outcomes and treatment response of neoadjuvant chemotherapy followed by surgery with surgery alone.
Methods:
We queried the NCDB Participant User File (PUF) for patients with clinical stage IB-IIIA NSCLC who underwent definitive surgical resection for NSCLC between 2006-2013. We identified 83,274 patients with complete datasets who met the inclusion criteria. Patients were grouped by stage and perioperative outcomes were assessed, comparing those who underwent neoadjuvant therapy to surgery alone. Neoadjuvant therapy response was assessed by downstaging on final pathology in both unmatched and matched cohorts.
Results:
Neoadjuvant chemotherapy was administered to 11.9% (9,961/83,274) of potentially eligible patients. The incidence of neoadjuvant therapy increased with clinical stage; rates of 2.7% (995/37,453) for IB, 5.4% (724/13,435) for IIA, 15% (2,048/13,619) for IIB, and 33% (6,194/18,767) for IIIA. All cause 30-, and 90-day mortality was 3.1% and 6.3% vs. 3.1% and 6.0% for neoadjuvant vs. surgery alone across all stages, (p=0.159, p<0.001). The unplanned 30-day re-admission rates were 3.8% vs. 4.3% for neoadjuvant vs. surgery alone (p<0.001). Median length of hospital stay was similar between the groups, 7.6 vs. 7.2 days for neoadjuvant vs. surgery alone (p=0.015); stage specific analysis revealed similar results. Overall downstaging was seen in 29.5% in the neoadjuvant group compared to 17% in the surgery group (p<0.001). Primary tumor downstaging occurred in 31.5% vs 9.5% (p<0.001) and nodal downstaging in 23% vs 14.4% (p<0.001) for neoadjuvant and surgery groups respectively. Additionally, significantly improved R0 resection rate was achieved for stages IIIA and IIB in the neoadjuvant group 88.1% and 86.1% vs. 82.0% and 84.5% in the surgery alone group respectively (p<0.001 for IIIA and IIB).
Conclusion:
In this largest review of perioperative outcomes and downstaging effect of neoadjuvant chemotherapy prior to definitive surgical resection for NSCLC, we demonstrate that the treatment strategy of neoadjuvant chemotherapy followed by surgery is safe and effective. Tumor downstaging and increased R0 resection rate in locally advanced lung cancer stages support the utilization of this treatment paradigm.
-
+
P2.03a - Poster Session with Presenters Present (ID 464)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
-
+
P2.03a-048 - The CDK4/6 Inhibitor G1T28 Protects Immune Cells from Cisplatin-Induced Toxicity in vivo and Inhibits SCLC Tumor Growth (ID 6225)
14:30 - 14:30 | Author(s): J. Heymach
- Abstract
Background:
Small cell lung cancer (SCLC) is an aggressive form of lung cancer characterized by loss of the tumor suppressor Rb. Chemotherapy remains the standard of care for SCLC patients but produces severe myelosuppression that compromises patient outcomes. G1T28 is a potent and selective CDK4/6 inhibitor in development to reduce chemotherapy-induced myelosuppression and preserve immune system function in SCLC patients. Cyclin dependent kinases 4 and 6 (CDK4/6) phosphorylate Rb protein promoting proliferation of specific cell types such hematopoietic stem progenitor cells (HSPCs) by allowing cells to progress through G1 to S phase. HSPCs are exquisitely dependent upon CDK4/6 for proliferation and become arrested in the G1 phase of the cell cycle upon exposure to G1T28. We hypothesize that G1T28-mediated CDK4/6 inhibition may selectively protect immune cells (Rb intact) from chemotherapy without antagonizing the antitumor efficacy in Rb deficient tumors, such as SCLC. G1T28 preservation of adaptive immunity from cisplatin-induced cytotoxicity may enhance the efficacy of chemotherapy in SCLC tumors by allowing a more robust host-immune response.
Methods:
Syngeneic mouse models were established by flank injection of KP1 and TKOTmG murine cells derived from TP53 and RB1 or TP53, RB1 and P130 mutant mice respectively. When tumors reached 150mm[3], mice were randomized and treated with G1T28, cisplatin and combination of both. Tumor volumes were measured and immune populations from tumor, spleen and peripheral blood were analyzed by flow cytometry.
Results:
CDK4/6 inhibition by G1T28 protects peripheral white blood cells (lymphocytes, monocytes and eosinophils) from cisplatin-induced cytotoxicity in the syngeneic SCLC KP1 mouse model. Additionally, treatment with G1T28 prior to cisplatin inhibited tumor growth to a greater extent than cisplatin alone (46% versus 12%, respectively) in the syngeneic SCLC TKOTmG mouse model.
Conclusion:
G1T28-mediated CDK4/6 inhibition protects immune cells from chemotherapy and potentiates the reduction of tumor volume when combined with cisplatin in a syngeneic Rb deficient SCLC mouse model. Studies are ongoing to determine if the immune protection by G1T28 is enhancing the anti-tumor activity of cisplatin in this model, as well as to evaluate other potential mechanisms. Additionally, clinical trials testing the combination of G1T28 with chemotherapy in patients with extensive stage SCLC are currently in progress (1[st] line, carboplatin-etoposide, NCT02499770; 2[nd] line, topotecan, NCT02514447).
-
+
P2.03b - Poster Session with Presenters Present (ID 465)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
-
+
P2.03b-023 - Circulating Tumor DNA (ctDNA)-Based Genomic Profiling of Known Cancer Genes in Lung Squamous Cell Carcinoma (LUSC) (ID 5393)
14:30 - 14:30 | Author(s): J. Heymach
- Abstract
Background:
Next-generation sequencing (NGS) of ctDNA is increasingly used for non-invasive genomic profiling of human cancers. However, studies to date have not detailed the ctDNA genomic landscape in LUSC.
Methods:
From June 2014 to June 2016, ctDNA from 467 patients with stage 3 or 4 (AJCC 7[th] edition) LUSC (60% male, 40% female; median age of 69 [range 27-96]) were tested with Guardant 360[TM], a ctDNA NGS assay that detects single nucleotide variants (SNVs) of 54-70 cancer genes and certain copy number amplifications (CNAs), indels, and fusions. The median time between diagnosis and ctDNA testing was 238 days. Somatic alterations were compared with those in the 2016 LUSC TCGA dataset.
Results:
426 patients (92.2%) had at least one somatic alteration detected. The most commonly observed SNVs (> 5% frequency) were TP53 (64.8%), PIK3CA (7.8%), CDKN2A (6.1%), and KRAS (5.9%). Frequencies of SNVs known to be significant in LUSC correlated well between our cohort and the TCGA (Spearman r = 0.93) but were generally lower in our cohort (Table 1). Several of our most frequently observed CNAs are strongly associated with LUSC (EGFR, CDK6, MYC, ERBB2, PDGFRA, KIT, CCND1). In addition, MET exon 14 skipping (1.3%), EGFR exon 19 deletion (1.9%), EGFR exon 20 insertion (0.5%), ERBB2 exon 20 insertion (0.3%) and EML4-ALK fusion (0.7%) were detected. These alterations have rarely been reported in LUSC.
Conclusion:
Patterns of SNVs and CNAs in LUSC obtained by ctDNA profiling are largely consistent with those from TCGA tissue profiling, although the frequency of key SNVs is lower. The presence of actionable alterations atypical for LUSC in 4.7% of this clinical cohort may represent underappreciated treatment options. Further investigation is warranted to evaluate whether these findings reflect a distinct mutational landscape in heavily treated advanced disease (which is under-represented in the TCGA) and/or challenges in histopathological classification. Figure 1
-
+
P2.03b-030 - Retrospective Review Clinical Use of a cfDNA Blood Test for Identification of Targetable Molecular Alterations in Patients with Lung Cancer (ID 5969)
14:30 - 14:30 | Author(s): J. Heymach
- Abstract
Background:
The availability of tumor genomic information from simple, minimally invasive blood collection may lead to significant impact in patient(pt) care. We report a retrospective review the clinical utility of a CLIA-certified cell-free DNA (cfDNA) next generation sequencing (NGS) blood test in our pts with lung cancers.
Methods:
From April 2015 to May 2016, blood samples from 250 consecutive pts were collected and sent for molecular profiling at a CLIA-certified lab (Guardant360, Guardant Health, Redwood City, CA) using cfDNA NGS with a panel of 70 cancer-related genes with reported high sensitivity (able to detect mutations of < 0.1% mutant allele fraction) with high specificity (> 99.9999%) (PLoS One, 10(10), 2015).
Results:
254 Guardant360 tests were completed in 250 pts (144/F:106/M); histology: adenocarcinoma(200), squamous(7), sarcomatoid(5), small cell(4) and others(34). Rationale for blood tests: addition to tissue analysis(39%), alternative to tissue biopsy(25%), treatment evaluation/resistant(18%), insufficient tissue(11%), no documentation(7%). Based on Guardant360 results, 77 pt samples (30.3%) demonstrated targetable alterations with FDA-approved agents; concordance with at least 1 genomic alteration (targetable with FDA-approved agent) from paired tissue analysis in 21pts; and in another 29 pts, new genomic alterations provided evaluation for potential change in therapies pts: EGFR T790M(n=21), EML4-ALK fusion(n=4), MET Exon 14 Skipping (3), EGFR ex19del(n=2), EGFR L858R(n=2), other targets(n=6). Significantly, detection of EGFR T790M in cfDNA lead to change in therapy with osimertinib 19 cases and eligibility to clinical studies in 2 cases with alterations in KIF5B-RET and NOTCH1,respectively. Additional clinical outcomes are pending and will be updated.
Conclusion:
Molecular testing of cfDNA is a simple, minimally invasive test. It has utility to obviate a repeat invasive tissue biopsy when the initial tissue sample is not available or inadequate for molecular analysis. It is particularly useful in the long-term management of patients at progression for detection of emergent resistance-associated molecular alterations; such as EGFR T790M.
-
+
P2.05 - Poster Session with Presenters Present (ID 463)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Radiotherapy
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
-
+
P2.05-015 - Long-Term Outcomes of Prospective Phase П Clinical Trial for Stereotactic Ablation Radiotherapy in Recurrent NSCLC (ID 5386)
14:30 - 14:30 | Author(s): J. Heymach
- Abstract
Background:
To evaluate the long-term efficacy, pattern of failure, and toxicity of stereotactic ablative radiotherapy (SABR) for recurrent or multiple primary non-small-cell lung cancer (NSCLC).
Methods:
Patients with histologically confirmed, [18]F-fluorodeoxyglucose ([18]F-FDG)-PET staged, recurrent or multiple primary NSCLC, suitable for SABR (<5 cm, not abutting critical structures, met with SABR dose volume constraints),were prospectively enrolled and treated with volumetric image-guided SABR to 50 Gy in 4 fractions (prescribed to planning target volume). Lobar recurrent disease was defined as recurrence in the same lobe with the same histology after definitive therapy from prior NSCLC (n=9); recurrent or oligo-metastatic disease (<3 lesions) was defined as recurrence with same histology within four years in different lobe (n=35). Multiple primary NSCLC was defined as secondary NSCLC with either different histology, or same histology but located in the different lobe with more than 4 years after initial definitive treatment of prior NSCLC (n=16); synchronous tumors was defined as with two early stage NSCLC in the different side (n=3). Four-dimensional computed tomography (4DCT) was used for simulation and planning. Patients were followed with CT or PET/CT every three months for two years, then every 6 months for three years and then annually.
Results:
From February 2006 to April 2013, 63 patients were enrolled and eligible for evaluation. The median age was 70 years (range 45-86) and median follow-up was 4.2 years (the interquartile range 3.0-7.3 years). A total of 5 (7.9%) patients developed cumulative actual local recurrence within PTV and 18 patients (28.6%) developed any cumulative actual recurrence (local, regional and distant) after SABR. Estimated total local failure rates in the same lobe at 3-, 5-year were both 11.2% (95% CI 6.8-15.6). Estimated 3-, 5-year PFS rates were 60.2% (95% CI 53.7-66.7) and 52.6% (95% CI 43.5-61.7), respectively; corresponding overall survival rates were 64.1% (95% CI 58.0-70.2) and 52.9% (95% CI 45.5-60.3). Three (4.8%) patients developed grade 3 treatment-related adverse events (one [1.6%] dermatitis, one [1.6%] chest wall pain, and one [1.6%] radiation pneumonitis). No patient had grade 4 or 5 event.
Conclusion:
This exploratory prospective study showed excellent 5 years local control, minimal toxicity and outstanding 5 years OS and PFS for recurrent or multiple primary NSCLC treated with SABR, indicating a potential cure for some patients. Close follow up and surveillance after initial definitive treatment should be considered to detect early recurrence in NSCLC.
-
+
SC26 - Angiogenesis Inhibition: Advances & Perspectives (ID 350)
- Event: WCLC 2016
- Type: Science Session
- Track: Biology/Pathology
- Presentations: 1
-
+
SC26.01 - Biology of Angiogenesis (ID 6709)
11:00 - 11:20 | Author(s): J. Heymach
- Abstract
- Presentation
Abstract not provided
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.
