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Stanley Gutiontov
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P14 - Immuno-biology and Novel Immunotherapeutics (Phase I and Translational) - Immuno-Biology (ID 153)
- Event: WCLC 2020
- Type: Posters
- Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P14.27 - Pathogenic Genomic Alterations of CDKN2A Predict Immunotherapy Resistance in NSCLC (ID 2353)
00:00 - 00:00 | Presenting Author(s): Stanley Gutiontov
- Abstract
Introduction
Immune checkpoint blockade (ICB) has improved outcomes for patients with non-small cell lung cancer (NSCLC). However, most patients experience disease progression. There are limited data regarding molecular predictors of progression, particularly in those patients predicted to respond most favorably. We used a next-generation sequencing (NGS) platform to identify genomic aberrations associated with clinical outcomes following ICB in NSCLC.
Methods
We retrospectively reviewed NSCLC patients who received ICB at our institution and underwent NGS with “OncoPlus”, a proprietary 1212-gene hybrid capture genomic sequencing assay. We characterized tumor mutations and copy number variations and investigated their associations with clinical outcome.
Results
139 patients with advanced treatment-naïve or recurrent NSCLC received ICB from 2016-2020 and underwent “OncoPlus” testing. Median age was 66, 87% had adenocarcinoma, and 88% had a smoking history. AJCC 8th edition initial staging: IA/IIB (n=6), IIIA/B/C (n=38), IVA (n=25), and IVB (n=70). 53% of patients (n=73) received ICB in the treatment-naïve, metastatic setting. 82% had PD-L1 staining: unavailable in 25 patients (18%), 0% in 31 (22%), 1-49% in 36 (26%), and ≥50% in 47 (34%).
64% of patients received ICB monotherapy (n=89), 28% of patients received concurrent chemo-ICB (n=39), and the remaining 7% of patients received some combination of molecularly targeted therapies + ICB +/- cytotoxic chemotherapy. ICB included pembrolizumab (n=85, 58%), nivolumab +/- ipilimumab (n=19 monotherapy, n=18 dual blockade, 27%), atezolizumab (n=17, 12%), and durvalumab (n=11, 8%). The majority received radiotherapy to at least 1 lesion (n=104, 75%). Median follow-up after ICB initiation was 11 months (range 0-44); 2-yr PFS and OS for the overall cohort were 21% and 41%, respectively.
The most frequent pathogenic genomic alterations affected TP53 (67%, n=93), KRAS (38%, n=51), STK11 (27%, n=38), and CDKN2A (22%, n=31). We found that tumors with alterations in CDKN2A (mutation/deletion 48%/52%) were associated with inferior median progression-free survival (PFS; 3.4 vs. 7.4 mo., p=0.043) and more markedly median overall survival (OS; 11.6 vs. 22.1 mo., p=0.020) compared to wild-type tumors. On multivariate Cox proportional hazards analysis including age, gender, BMI, ECOG, TMB, PD-L1 status, and ICB indication, CDKN2A loss/mutation was independently associated with a 2.1-fold risk of progression (p=0.015) and a 3.0-fold risk of death (p=0.001). In high TMB NSCLCs (≥ 10 mutations/megabase, n=66), CDKN2A alteration was associated with a trend to worsened OS (median OS 9.4 vs. 16.6 mo., p=0.055). In high PD-L1 NSCLCs (≥50%; n=47), CDKN2A alteration remained negatively associated with OS (median OS 10.4 vs. 22.2 mo., p=0.020). Using RECIST 1.1 criteria, CDKN2A loss-of-function tumors were twice as likely to exhibit progressive disease as their best response to ICB when compared to CDKN2A wild-type tumors (48% vs. 22%, p=0.02).
Conclusion
In a large cohort of NSCLC patients treated with ICB, NGS identified CDKN2A mutation/deletion as a predictor of poor clinical outcomes. In the context of recent evidence for sensitivity to CDK4/6 inhibition of CDKN2A-deficient tumors, our findings raise the possibility of utilizing currently available targeted agents in the treatment of CDKN2A-deficient NSCLCs receiving ICB.
