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Jin Young Hwang
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P33 - Pathology - Immunotherapy Biomarker (ID 101)
- Event: WCLC 2020
- Type: Posters
- Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P33.06 - Utilizing Serum Proteome to Understand Response and Resistance to Immune Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer (ID 3434)
00:00 - 00:00 | Author(s): Jin Young Hwang
- Abstract
Introduction
Responses and resistance to immune checkpoint inhibition (ICI) are poorly understood and predictive biomarkers are needed. We used a validated serum-based proteomic test, Primary Immune Response (PIR), to predict response and Protein Set Enrichment Analysis (PSEA) scores to elucidate mechanisms of early resistance to ICI in patients with advanced non-small cell lung cancer (NSCLC). (Muller et al., 2020)
Methods
Serum of 43 consented NSCLC patients was collected prospectively at 2 timepoints: baseline (prior to ICI initiation) and 3 weeks after ICI initiation (median 22 days). Blinded samples were classified by the PIR test. Clinical response was evaluated using RECIST. Outcomes, including progression-free survival (PFS) and overall survival (OS), were analyzed by PIR classifications as intermediate/sensitive (not resistant) vs. resistant at baseline and 3 weeks. Multivariable regression was performed. PSEA scores indicating activity of 10 processes of interest (e.g., Type 1 immunity (Th1), complement, interferon-gamma (IFNγ)) were compared between PIR groups.
Results
Of the 43 patients, 28 received chemotherapy with ICI (chemo+ICI) and 15 received ICI alone. 31 of 43 patients (72%) were treatment naïve at baseline blood draw. PIR-resistant patients had worse survival compared to patients classified as not resistant (HR, 10.4; 95%CI, 1.3-81 ; P = 0.025). OS was also significantly lower for patients with PIR resistant result at 3 weeks (HR, 9.1; 95%CI, 1.2-72 ; P = 0.036) . The difference in survival between PIR classification groups was consistently observed in the treatment naïve patients treated with chemo+ICI (log rank P = 0.02). No significant differences were observed in PFS. Clinical and pathologic characteristics, including PD-L1 expression, were not significantly associated with PIR result. In multivariable analysis including performance status, line of therapy, and PD-L1 status, PIR resistant remained a significant negative prognostic factor (HR, 8.2; 95%CI, 1.01-67; P = 0.049). PSEA scores at baseline and 3 weeks after ICI initiation showed significantly higher levels of complement, IFNγ, Th1, immune tolerance, and a lower level of wound healing (all P<0.0001) in PIR-resistant vs. PIR-intermediate/sensitive.
Conclusion
These data further validate the utility of the PIR test in predicting patient survival on ICI. Processes associated with PIR resistant result included activation of complement, IFNγ, Th1, and immune tolerance, elucidating early mechanisms of resistance to ICI in a clinical cohort.
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P86 - Targeted Therapy - Clinically Focused - New Target (ID 263)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P86.07 - CDK12 Mutated Extensive Stage Small Cell Lung Cancer Showed an Exceptional Response to Olaparib and Paclitaxel (ID 3439)
00:00 - 00:00 | Presenting Author(s): Jin Young Hwang
- Abstract
Introduction
The poly ADP ribose polymerase (PARP) expression is significantly higher in SCLC than normal lung epithelial cells and other histologic subtypes of lung cancer. In preclinical models, the loss of function mutation of Cyclin-dependent kinase 12 (CDK12) was related to PARP inhibitor sensitivity (Bajrami et al., 2014). This mutation is found in 1.7% of SCLC (Julie et al., 2015). However, little is known about the clinical implications of CDK12 mutated small cell lung cancer.
Methods
We present a 71-year old male with extensive stage small cell lung cancer harboring CDK12 splice site single nucleotide variation (SNV) mutation. PET scan and CT scan showed metastases to bone, liver, and brain. His disease progressed with no response to carboplatin/etoposide/atezolizumab combination therapy, irinotecan, and ipilimumab/nivolumab combination therapy. Circulating tumor DNA Next Generation Sequencing (NGS) assay (Guardant360) revealed CDK12, PIK3CA, BRAF, TP53 M246V and CCNE1 mutation. Tissue DNA NGS assay (TEMPUS) confirmed TP53, RB1, MYCL, and ATP7B mutation. He was given olaparib, PARP inhibitor, combined with paclitaxel based on his CDK12 mutation, which is known to sensitize cancer cells to PARP inhibitors. Olaparib was given 300mg twice a day, and paclitaxel was given 150mg/m2 every three weeks schedule.
Results
A 6-week follow-up abdomen CT scan revealed a marked shrinkage of metastatic lesions in liver as seen in Fig. 1 (1a: pre-treatment, 1b: 6-week follow-up abdomen CT scans). 40% decrease in the sum of length diameters of lesions was seen which is consistent with partial response per RECIST 1.1 criteria. We observed a deep and durable ongoing partial response for more than five months in this patient receiving olaparib/paclitaxel combination therapy. The dose of paclitaxel was reduced to 80mg/m2 due to worsening neuropathy of bilateral lower extremities.
Fig.1
Conclusion
This case illustrates the need for further exploration of taxanes and PARP inhibitor combination therapy in the treatment of small cell lung cancer especially with CDK12 mutation. It remains unclear how CDK12 mutation is associated with sensitization to PARP inhibitor in small cell lung cancer. Further clinical trials of this combination therapy are required in SCLC or other solid tumors with CDK12 mutation.
