Osimertinib Continues to Pick Up Indications
Meanwhile, the indications for osimertinib have expanded within the subgroup of EGFR exon 19 or exon 21 L859R-mutated cancers. On December 18, 2020, the agent received approval for use in the adjuvant setting after tumor resection for patients with NSCLC that harbors an EGFR exon 19 deletion or exon 21 L858R mutation.15 This was a result of the ADAURA study (NCT02511106), in which investigators randomly assigned 682 patients with resected EGFR mutation-positive NSCLC to receive either osimertinib or placebo for 3 years. Among patients in the stage II to IIIA group, 89% of osimertinib recipients were found to be disease-free after 2 years compared with 52% of placebo recipients.16
The study marks a paradigm shift in lung cancer therapy, according to Dr Santos. Typically, 30% of patients with stage IB disease will have died at the 5-year mark, Santos explained. The ADAURA results suggest that by “treating patients with EGFR mutant [targeted therapy] after surgery, we can significantly change the natural history of lung cancer for these patients,” he said.
For patients in the II to IIIA stage group, Dr Mok has “little doubt” that he should discuss the use of osimertinib with a patient, he said. It remains debatable, however, “whether the patient should have chemotherapy [first] and then osimertinib for 3 years, or whether [they should] just go [directly onto] osimertinib.” Though the trial investigated both regimens, data demonstrated no significant difference in the hazard ratios. At present, it is not clear what the best strategy is, Mok added.
Another question concerns the optimal duration of osimertinib therapy in this setting. “Should we stop after 3 years?” Dr Ramalingam asked.
Though osimertinib is a good option for patients now, OS data are not yet available. “If we can show that using adjuvant osimertinib improves overall survival, that will clearly change the standard of care for this particular patient population,” he said.
Researchers are in the early days of understanding mechanisms of resistance to osimertinib—both in the early-stage and metastatic setting—and how to manage it. Patients whose disease becomes resistant to first-line osimertinib have often acquired
EGFR C797X, or MET or HER2 amplification, Dr Mok said. Several trials such as the phase 1 CHRYSALIS (NCT02609776) study and another phase 1 evaluation (NCT02143466) are currently investigating a number of different therapies that target such mutations. These investigational agents could become so-called “fourth-generation drugs,” he added.
Although successive approvals of TKIs for EGFR exon 19 deletions or exon 21 L858R mutations have been transformative for the patients who have them, they’ve also paved the way for developing precision therapies for other molecular subsets of lung cancer, Dr Ramalingam said. “As a result, now we’re able to personalize therapies for almost 25% to 30% of patients with non-small cell lung cancer, which is a huge step up over what we had a few years ago.”
Dr Santos disclosed speaker bureau fees from Genentech, Pfizer, Merck, Takeda, Boehringer-Ingelheim, AstraZeneca, Amgen, Sanofi-Genzyme, Eli Lilly, and Novartis.
Dr Mok disclosed
- Grants or research support from: AstraZeneca, BMS, G1 Therapeutics, MSD, Merck Serono, Novartis, Pfizer, Roche, SFJ, Takeda, and XCovery.
- Speaker’s fees from: ACEA Pharma, Alpha Biopharma Co., Ltd., Amgen, Amoy Diagnostics Co., LTD., AstraZeneca (before January 1, 2019), BeiGene, BI, BMS, Daiichi Sankyo, Fishawack Facilitate Ltd., InMed Medical Communication, Lilly, MD Health Brazil, Medscape LLC, Merck Sharp & Dohme, Novartis, OrigiMed Co. Ltd., P. Permanyer SL, PeerVoice, Physicians’ Education Resource, Pfizer, PrIME Oncology, Research to Practice, Roche Pharmaceuticals/Diagnostics/Foundation One, Sanofi-Aventis, Taiho, Takeda Oncology, and touchIME.
- Honoraria for consultation services from: Abbvie Inc., ACEA Pharma, Alpha Biopharma Co., Ltd., Amgen, Amoy Diagnostics Co., LTD., AstraZeneca (before January 1, 2019), BeiGene, Berry Oncology, BI, Blueprint Medicines Corporation, BMS, CStone Pharmaceuticals, Curio Science, Daiichi Sankyo, Eisai, Fishawack Facilitate Ltd., Gritstone Oncology, Inc., Guardant Health, Hengrui Therapeutics Inc., Ignyta, Inc., Incyte Corporation, Inivata, IQVIA, Janssen, Lilly, Loxo-Oncology, Lunit, Inc., Merck Serono, MSD, Mirati Therapeutics Inc., MoreHealth, Novartis, OrigiMed, Pfizer, Puma Biotechnology Inc., Qiming Development (HK) Ltd., Roche Pharmaceuticals, Sanofi-Aventis, SFJ Pharmaceutical Ltd., Takeda Pharmaceuticals HK Ltd., Vertex Pharmaceuticals, and Yuhan Corporation.
- Shareholdings in: Aurora Tele-Oncology Ltd. and Hutchison Chi-Med Sanomics Ltd.
- Advisory board involvement for: AbbVie Inc., ACEA Pharma, Amgen, AstraZeneca, Berry Oncology, Blueprint Medicines Corporation, Boehringer Ingelheim Pharmaceuticals Inc., Bristol-Myers Squibb Company, CStone Pharmaceuticals, Curio Science, Daiichi Sankyo Inc., Eisai, Fishawack Facilitate Ltd., G1 Therapeutics, Inc., Gritstone Oncology, Inc., Guardant Health, geneDecode Co., Ltd. (uncompensated), Hengrui Therapeutics Inc., Hutchison Chi-Med, Ignyta, Inc., Incyte Corporation, Inivata, IQVIA, Janssen, Lily, Loxo-Oncology Inc., Lunit, Inc., Merck Serono, Merck Sharp & Dohme, Mirati Therapeutics, Inc., Novartis, OrigiMed, Pfizer, Puma Biotechnology Inc., Roche/Genentech, SanofiAventis R&D, SFJ Pharmaceutical, Takeda, Vertex Pharmaceuticals, Virtus Medical Group, and Yuhan Corporation.
- Tarceva [package insert]. Farmingdale, NY: OSI Pharmaceuticals Inc.; 2016.
- Iressa [package insert]. Cambridge, UK: AstraZeneca; 2018.
- Kanzandjian D, Blumenthal GM, Yuan W, He K, Keegan P, Pazdur R. FDA approval of gefitinib for the treatment of patients with metastatic EGFR mutation-positive non-small cell lung cancer. Clin Cancer Res. 2016;22(6):1307-1312. doi:10.1158/1078-0432.CCR-15-2266
- Erlotinib (Tarceva). FDA. Published October 18, 2016. Accessed February 17, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/erlotinib-tarceva
- Gilotrif [package insert]. Ingelheim am Rhein, DE: Boehringer Ingelheim; 2019.
- FDA approves dacomitinib for metastatic non-small cell lung cancer. FDA. Published November 26, 2018. Accessed February 17, 2021. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-dacomitinib-metastatic-non-small-cell-lung-cancer
- Wu Y-L, Cheng Y, Zhou X, et al. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomized, open-label, phase 3 trial. Lancet Oncol. 2017;18(11):1454-1466. doi:10.1016/S1470-2045(17)30608-3
- Park K, Tan E-H, O’Byrne K, et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR-mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2b, open-label, randomized controlled trial. Lancet Oncol. 2016;17(5):577-589. doi:2016/S1470-2045(16)30033-X
- Osimertinib (Tagrisso). FDA. Published July 28, 2017. Accessed February 17, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/osimertinib-tagrisso#:~:text=On%20March%2030%2C%202017%2C%20the,detected%20by%20an%20FDA%2Dapproved
- Soria J-C, Ohe Y, Vansteenkiste J, et al; FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. New Eng J Med. 2018;378(2):113-125. doi:10.1056/NEJMoa1713137
- FDA approves osimertinib for first-line treatment of metastatic NSCLC with most common EGFR mutations. FDA. Published April 19, 2018. Accessed February 17, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-osimertinib-first-line-treatment-metastatic-nsclc-most-common-egfr-mutations
- Ramalingam SS, Vansteenkiste J, Planchard D, et al; FLAURA Investigators. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. New Eng J Med. 2020;382(1):41-50. doi:10.1056/NEJMoa1913662
- FDA approves ramucirumab plus erlotinib for first-line metastatic NSCLC. FDA. Published June 01, 2020. Accessed February 17, 2021. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-ramucirumab-plus-erlotinib-first-line-metastatic-nsclc
- Nakagawa K, Garon EB, Seto T, et al; RELAY Study Investigators. Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated advanced non-small-cell lung cancer (RELAY): a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(12):1655-1669. doi:10.1016/S1470-2045(19)30634-5
- FDA approves osimertinib as adjuvant therapy for non-small cell lung cancer with EGFR mutations. FDA. Published December 18 2020. Accessed February 17, 2021. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-osimertinib-adjuvant-therapy-non-small-cell-lung-cancer-egfr-mutations
- Wu Y-L, Tsuboi M, He J, et al. Osimertinib in resected EGFR-mutated non-small-cell lung cancer. New Eng J Med. 2020;383(18):1711-1723. doi:10.1056/NEJMoa2027071