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J. Wang
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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)
16:42 - 16:48 | Author(s): J. Wang
- 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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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
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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. Wang
- 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.
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