Efficacy of Osimertinib in Patients with Lung Cancer Positive for Uncommon EGFR Exon 19 Deletion Mutations

Author:

Grant Michael J.1ORCID,Aredo Jacqueline V.23ORCID,Starrett Jacqueline H.4ORCID,Stockhammer Paul1ORCID,van Alderwerelt van Rosenburgh Iris K.456ORCID,Wurtz Anna4ORCID,Piper-Valillo Andrew J.7ORCID,Piotrowska Zofia7ORCID,Falcon Christina8ORCID,Yu Helena A.8ORCID,Aggarwal Charu9ORCID,Scholes Dylan9ORCID,Patil Tejas10ORCID,Nguyen Christina10ORCID,Phadke Manali11ORCID,Li Fang-Yong11ORCID,Neal Joel2ORCID,Lemmon Mark A.56ORCID,Walther Zenta4ORCID,Politi Katerina14ORCID,Goldberg Sarah B.1ORCID

Affiliation:

1. 1Department of Medicine (Section of Medical Oncology), Yale School of Medicine, New Haven, Connecticut.

2. 2Department of Medicine (Oncology), Stanford University, Stanford, California.

3. 3Department of Medicine, University of California San Francisco School of Medicine, San Francisco, California.

4. 4Department of Pathology, Yale School of Medicine, New Haven, Connecticut.

5. 5Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut.

6. 6Yale Cancer Biology Institute, West Haven, Connecticut.

7. 7Department of Medicine (Hematology/Oncology), Massachusetts General Hospital, Boston, Massachusetts.

8. 8Department of Medicine (Thoracic Oncology), Memorial Sloan Kettering Cancer Center, New York, New York.

9. 9Department of Medicine (Division of Hematology/Oncology), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.

10. 10Department of Medicine (Division of Medical Oncology), University of Colorado School of Medicine, Aurora, Colorado.

11. 11Yale Center for Analytical Sciences, Yale School of Public Health, New Haven, Connecticut.

Abstract

Abstract Purpose: The uncommon EGFR exon 19 deletion (ex19del), L747_A750>P, demonstrates reduced sensitivity to osimertinib compared with the common ex19del, E746_A750del in preclinical models. The clinical efficacy of osimertinib in patients with non–small cell lung cancer harboring L747_A750>P and other uncommon ex19dels is not known. Experimental Design: The AACR GENIE database was interrogated to characterize the frequency of individual ex19dels relative to other variants, and a multicenter retrospective cohort was used to compare clinical outcomes for patients with tumors harboring E746_A750del, L747_A750>P, and other uncommon ex19dels who received osimertinib in the first line (1L) or in second or later lines of therapy and were T790M+ (≥2L). Results: ex19dels comprised 45% of EGFR mutations, with 72 distinct variants ranging in frequency from 28.1% (E746_A750del) to 0.03%, with L747_A750>P representing 1.8% of the EGFR mutant cohort. In our multi-institutional cohort (N = 200), E746_A750del was associated with significantly prolonged progression-free survival (PFS) with 1L osimertinib versus L747_A750>P [median 21.3 months (95% confidence interval, 17.0–31.7) vs. 11.7 months (10.8–29.4); adjusted HR 0.52 (0.28–0.98); P = 0.043]. Osimertinib efficacy in patients with other uncommon ex19dels varied on the basis of the specific mutation present. Conclusions: The ex19del L747_A750>P is associated with inferior PFS compared with the common E746_A750del mutation in patients treated with 1L osimertinib. Understanding differences in osimertinib efficacy among EGFR ex19del subtypes could alter management of these patients in the future.

Funder

Yale SPORE in Lung Cancer

National Institutes of Health

Yale Cancer Center

American Society of Clinical Oncology

Conquer Cancer Foundation

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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