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Kathleen Danenberg
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MA19 - Genomic Markers of IO Response (ID 922)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Immunooncology
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 15:15 - 16:45, Room 201 BD
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MA19.06 - Blood Based Biomarkers: RNA, KRAS and PD-L1 Strongly Matching with Tissue and Showing Correlation with Clinical Responses In NSCLC Patient’s (ID 12358)
15:45 - 15:50 | Author(s): Kathleen Danenberg
- Abstract
- Presentation
Background
Circulating cell-free tumor RNA (cfRNA) can be now safety isolated as cfDNA and used to measure changes in the tumor burden in the blood and changes in gene expression in non-small cell lung cancer (NSCLC) patients (pts). We are correlating these changes in cfRNA and PD-L1 with clinical response to therapy (chemotherapy, immunotherapy (IMMUNO) or targeted therapy) in stage IV NSCLC pts. Our group has been the first one to use cfRNA to detect PD-L1.
a9ded1e5ce5d75814730bb4caaf49419 Method
Blood was drawn from 31 pts under various treatments (tx) every 6-8 weeks, at the same time that CT scans were done. CfRNA was extracted from the resulting plasma and reverse transcribed with random hexamers to cDNA. Levels of cfRNA were quantitated by RT-qPCR and correlated with pts clinical response (CR/PR/SD/PD), as determined by CT scans.
4c3880bb027f159e801041b1021e88e8 Result
A total of 31 lung cancer pts were enrolled in a 2-year clinical study. 25 of 31 pts completed already the first two cycles of tx and had CT scans done. Of these, 6/8 pts with progressive disease (PD) showed increased (INC) levels of cfRNA, 9/13 pts with stable disease (SD) showed either no change (NC) or decreased (DEC) cfRNA, and 4/4 pts with partial response (PR) had NC or DEC cfRNA, corresponding to 76% concordance between cfRNA and clinical responses. PD-L1 expression measured in plasma cfRNA matched the tissue expression in 7/10 pts. In the one pt where PD-L1 was (-) in blood and (+) in tissue there was PD on IMMUNO. Among 8 pts treated with IMMUNO: 3/3 pts with PD showed INC PD-L1 cfRNA expression, 3/3 pts with SD had NC in negative PD-L1 status, and 2 pts with PR showed DEC PD-L1 cfRNA, corresponding to 100% correlation between PD-L1 expression levels and pt response. Of the 31 pts, 32% (10/31) harbored KRAS mutations in cfDNA. Of those with KRAS+ status by tissue-based testing, 83% matched with cfDNA results. Among KRAS+ pts, 80% (8/10) showed PD-L1 cfRNA expression in same blood draws with KRAS+ cfDNA, suggesting correlation between these cfDNA and cfRNA analyses.
8eea62084ca7e541d918e823422bd82e Conclusion
Significant association was observed between clinical response and changes in plasma cfRNA levels in NSCLC pts (76%). There was concordance between tissue- and blood-based testing in both DNA (KRAS mutations, 83%) and RNA (PD-L1 expression, 70%). While on IMMUNO levels of PD-L1 expression could be used to monitor response to immunotherapy.
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P1.04 - Immunooncology (Not CME Accredited Session) (ID 936)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.04-09 - Immunomodulatory Effects of Afatinib and Pembrolizumab in EGFR-Mutant NSCLC with Progression on Prior EGFR-TKI (ID 12185)
16:45 - 18:00 | Author(s): Kathleen Danenberg
- Abstract
Background
EGFR-mutant NSCLC is less responsive to single agent PD-1 blockade than smoking associated NSCLC. Preclinical models suggest EGFR-TKI can render a more immunocompetent tumor microenvironment. This study examined the immunomodulatory effects of combination second generation EGFR-TKI and PD-1 antibody.
a9ded1e5ce5d75814730bb4caaf49419 Method
In this phase 1 dose de-escalation study, patients were treated with afatinib 40 mg oral daily and pembrolizumab 200 mg IV q21day. Key Eligibility: advanced EGFR-mutant NSCLC with progression (PD) on prior EGFR-TKI, age≥18, ECOG PS≤1, acceptable organ function, no significant autoimmune diseases, measurable disease and controlled brain metastases. Tissue biopsy performed baseline and week 5-6 on treatment for PD-L1 IHC (22C3) and quantitative immunofluorescence for immune cell subsets and next-generation sequencing. Blood at baseline and at serial on-treatment timepoints were collected for ctRNA of PD-L1, EGFR, HER2 and MET; changes in circulating immune cell subsets, T-Cell repertoire and cytokine levels were evaluated by flow cytometry and Luminex.
4c3880bb027f159e801041b1021e88e8 Result
No DLTs were observed in the first 6 patients and the 10 patient expansion cohort proceeded at afatinib 40 mg daily and pembrolizumab 200 mg IV q21day. Eleven patients enrolled to date. Key molecular and pathologic characteristics: adenocarcinoma 9, neuroendocrine 1, squamous 1. EGFR-TKI resistance mechanism: EGFR-T790M 4, EGFR-T790M/C797S 1, HER2 amp 1, MET 2, Her2 amp+neuroendocrine differentiation 1, unknown 2. Five patients had prior second line osimertinib. Three (27%) patients had immune related AEs (G2 adrenal insufficiency, G2 nephritis, G3 colitis). Nine patients were evaluable for response: (1 PR, 7 SD ((6/7) with tumor reduction <30%)). The responding patient had squamous histology tumor, prior PD on erlotinib, and PFS of 11 months with PD-L1 (22C3) TPS 40% and PD-L1 and PD-L2 amplification. Treatment with afatinib and pembrolizumab induced systemic immune changes including trend for increased soluble IDO, MIG, TIM3, IP-10, LAG3, PD-L1 and PD-L2 and decreased IFN-gamma. ctRNA for EGFR and PD-L1 were detected in 7/7 and 6/7 patients, respectively, with dynamic changes in allele frequency of EGFR and PD-L1 observed. Baseline PD-L1 (22C3) TPS ranged from 0% to 75% expression. Four patients had repeat biopsy and in paired samples analyzed PD-L1 (22C3) expression decreased in the stroma.
8eea62084ca7e541d918e823422bd82e Conclusion
Immunomodulatory effects of afatinib with pembrolizumab were noted in the tumor microenvironment and peripheral blood. Only modest clinical activity has been observed thus far in patients with PD on prior EGFR-TKI. Genomic and immune-profiling is feasible in EGFR-mutant NSCLC and may identify EGFR-mutant NSCLC patients who may respond or lack benefit to PD-1 blockade.
6f8b794f3246b0c1e1780bb4d4d5dc53
