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Jacqulyne Ponville Robichaux
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OA02 - Novel Therapies in ROS1, HER2 and EGFR (ID 893)
- Event: WCLC 2018
- Type: Oral Abstract Session
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 10:30 - 12:00, Room 105
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OA02.06 - A Phase II Trial of Poziotinib in EGFR and HER2 exon 20 Mutant Non-Small Cell Lung Cancer (NSCLC) (ID 14277)
11:25 - 11:35 | Author(s): Jacqulyne Ponville Robichaux
- Abstract
- Presentation
Background
Insertions/mutations in exon 20 of EGFR or HER2 occur in ~3% of all lung adenocarcinomas. These alterations are characterized by primary resistance to tyrosine kinase inhibitors (TKIs) with response rates of <12%. We previously showed that exon 20 insertions restrict the size of drug-binding pocket, limiting binding of most available TKIs. However, poziotinib can potentially circumvent these steric changes due to its smaller, flexible structure and is a potent inhibitor of EGFR and HER2 exon 20 mutants (Robichaux et al. Nat Med, 2018). Herein, we report the results of an investigator-initiated study of poziotinib in EGFR and HER2 exon 20 mutant NSCLC (NCT03066206).
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients ≥18yrs with metastatic NSCLC bearing mutations/insertions in EGFR or HER2 exon 20 (except EGFR T790M) were eligible. Unlimited prior systemic and targeted therapies were permitted. Poziotinib 16mg PO daily was administered until progression, death, or withdrawal. The primary endpoint was objective response rate (ORR) based on RECIST v1.1. Response was evaluated every eight weeks. A Bayesian design was used with a plan to enroll patients in cohorts of 10 and to terminate the study if ORR was ≤20%. Secondary endpoints included DCR, PFS, OS and safety
4c3880bb027f159e801041b1021e88e8 Result
As of May 3, 2018, the planned EGFR cohort of 50 patients was fully enrolled, and 40 patients were evaluated for response. 65.1% of patients had received at least two prior lines of therapy for metastatic disease. 60% of patients had ≥grade 3 adverse events; most common were skin-rash (27.5%) and diarrhea (12.5%). 45.0% of patients required dose reduction to 12mg, while 17.5% required dose reduction to 8mg. One patient stopped treatment due to grade 3 skin rash. ORR at eight weeks was 58% (95%-CI 40.9-73.0) and the DCR was 90% (95%-CI 76.3-97.2). Among 23 patients who achieved partial response, 15 responses were confirmed with subsequent scans, five responses were unconfirmed, and three patients are pending confirmation. Responses were observed in 8/13 (62%) patients that were previously treated with TKI. Median PFS was 5.6mo (95%-CI 5.06-NA). Furthermore, 13 patients were enrolled in HER2 cohort. Toxicities were similar to EGFR cohort except one case of grade 5 pneumonitis, assessed to be possibly drug related. Twelve patients were evaluated for response with ORR of 50% (95% CI 21.1-78.9) at eight weeks and DCR of 83%.
8eea62084ca7e541d918e823422bd82e Conclusion
In heavily pre-treated population with EGFR and HER2 exon 20 mutant NSCLC, poziotinib demonstrated encouraging antitumor activity in both TKI-naive and -refractory patients, and manageable toxicity profile.
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P2.04 - Immunooncology (Not CME Accredited Session) (ID 953)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.04-09 - Driver Mutations are Associated with Distinct Patterns of Response to Immune Checkpoint Blockade in Non-Small Cell Lung Cancer (ID 13362)
16:45 - 18:00 | Author(s): Jacqulyne Ponville Robichaux
- Abstract
Background
Immune checkpoint blockade (IO) has demonstrated durable clinical benefit in metastatic non-small cell lung cancer (NSCLC). Tumors with driver mutations such as EGFR exon 19 and 21 mutations and ALK translocation tend to have low response rates to IO. However, IO response in NSCLC patients with rare driver mutations, such as EGFR exon 20 (~2%), HER-2 (~2%) and BRAF (~3%), representing approximately 7% of lung adenocarcinomas, has been poorly addressed.
a9ded1e5ce5d75814730bb4caaf49419 Method
We queried GEMINI (MD Anderson Lung Cancer Moon Shot funded database for prospective collection of clinical information on NSCLC) for patients with mutations in EGFR exon 19, 20, 21, HER-2 and BRAF treated with PD-1/PD-L1 checkpoint inhibitors. We assessed progression-free survival (PFS), overall response rate (ORR) and overall survival (OS) in each molecular group.
4c3880bb027f159e801041b1021e88e8 Result
Between 2014-2018, 108 patients with classic EGFR mutations (exon 19 del + exon 21 L858R, n=37), EGFR exon 20 mutations (n=36; no T790M included), HER-2 mutations (n=22) and BRAF mutations (n=13; V600E: 3pts; non-V600E: 10pts) had been treated with PD-1/PD-L1 inhibitors. EGFR exon 20 mutants and BRAF mutants demonstrated significantly higher PFS (EGFR exon 20: HR 0.4, p<0.001; BRAF: HR 0.2, p<0.001), higher disease control rate at 6 and 12 months as well as higher ORR when compared to classic EGFR mutants (Table). These differences remained significant in multivariate analysis after adjusting for age, smoking, PD-L1 status, radiation prior to treatment initiation, treatment with concurrent agents and prior treatment with TKIs. HER-2 mutants had similar PFS compared to EGFR classic mutants (HR 0.8, p=0.35) (Table).
8eea62084ca7e541d918e823422bd82e Conclusion
EGFR exon 20 and BRAF mutations are associated with superior outcome from PD-1/PD-L1 checkpoint inhibitors compared to classic EGFR and HER-2 mutations. Further studies on co-mutational status and tumor mutation burden in these molecularly-defined groups are ongoing to address potential underlying mechanisms associated with these findings.
6f8b794f3246b0c1e1780bb4d4d5dc53
