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E. Roarty
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MA04 - HER2, P53, KRAS and Other Targets in Advanced NSCLC (ID 380)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
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MA04.07 - Impact of Major Co-Mutations on the Immune Contexture and Response of KRAS-Mutant Lung Adenocarcinoma to Immunotherapy (ID 6343)
16:00 - 17:30 | Author(s): E. Roarty
- 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.
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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
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MA14.03 - The Impact of Genomic Landscape of EGFR Mutant NSCLC on Response to Targeted and Immune Therapy (ID 6242)
16:00 - 17:30 | Author(s): E. Roarty
- 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.
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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)
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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 - 15:45 | Author(s): E. Roarty
- 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).
