Optimizing Osimertinib Treatment Strategies Relies on Identification of Resistance

Jonathan Riess, MD, MS

Strategies focused on improving the efficacy of the EGFR tyrosine kinase inhibitor (TKI) osimertinib (Tagrisso) in the first line setting are the key to unlocking the next wave of success in treating lung cancer, according to Jonathan W. Riess, MD, MS, associate professor of medicine at the University of California School of Medicine, UC Davis Comprehensive Cancer Center.¹

The largest hurdle facing investigators is identifying and overcoming resistance mechanisms. First-and-fourth-generation (TKIs) in combination with osimertinib may prevent the emergence of known resistance mechanisms, particularly C797S; however, the future of care will lean heavily on the identification of more actionable targets.

Riess provided an overview of the available data for osimertinib, establishing its role in the present and future of care for patients with EGFR-mutant non–small cell lung cancer (NSCLC) as part of the 22nd Annual International Lung Cancer Congress.

“I can’t emphasize enough the need to find these [targets] as early as possible to forestall resistance developing in [patients with] EGFR-mutant lung cancer,” Riess said during a live presentation of the data. “In later lines of therapy, there’s so much clonal heterogeneity, and it becomes really challenging to target [these mechanisms] with only a few [available] targeted therapies.”

Osimertinib made its way into the frontline setting for patients with EGFR-mutant NSCLC in 2018 based on data from the phase 3 FLAURA trial (NCT02296125), which showed the clinical benefit of the agent compared with standard first-generation EGFR TKIs (erlotinib [Tarceva] or gefitinib [Iressa].²

Specifically, a 54% reduction in the risk of progression was observed with a median progression-free survival (PFS) of 18.9 months (95% CI, 15.2-21.4) reported with osimertinib compared with 10.2 months (95% CI, 9.6-11.1) with erlotinib or gefitinib (HR, 0.46; 95% CI, 0.37-0.57; P < .0001). Overall survival (OS) data trended similarly with a reported median OS of 38.6 months (95% CI, 34.5-41.8) and 31.8 months (95% CI, 26.6-36.0), respectively (HR, 0.799; 95% CI, 0.641-0.997; P = .0462).

“You can see here a tremendous improvement in PFS,” Riess said. “And over 3 years, [there is] a 6-month improvement in OS compared with first-generation in EGFR TKIs. But for a 30-year-old patient with children who has EGFR-mutant metastatic lung cancer, it’s a cold comfort to know that there’s a 6-month improvement at 3 years. I’m always reminded that we could always do better, and we need to do better.”

Riess noted that deeper in the FLAURA data, the forest plots demonstrate that there are certain subsets that do not perform quite as well as others indicating that they may provide opportunities for improvement. “[These include] patients with the L85AR mutations, as opposed to those with exon 19 deletions,” he said. “Although [the trial was] underpowered in subset analysis, [osimertinib] did not show any clear benefit vs first-generation [TKIs].”

The identification of patients who perform well with frontline osimertinib begins to stratify the population a bit further, opening avenues to determine new treatment strategies for those who perform worse on first-line EGFR TKIs. Investigators have identified that those patients with EGFR-mutant disease who also harbor TP53 and TP53/RB1 mutations have a shorter time to discontinuation of treatment.1,3 In an analysis of 863 patients, those whose disease only harbored an EGFR mutation discontinued treatment after a median of 36.6 months, those with EGFR/TP53 at 12.3 months, and those with EGFR/TP53/RB1 mutant disease discontinued at a median of 9.5 months.³

This extended to a survival analysis which demonstrated a media OS of 56.4 months, 40.5 months, and 20.1 months across the mutations, respectively.1,3 Additionally, investigators noted that patients with the triple mutation are approximately 25% more likely to experience disease transformation to small cell lung cancer.³

Although identified in only a small subset of patients in a retrospective analysis, MET amplification was also a marker of poor prognosis with frontline EGFR TKIs, Riess said.

Investigators have also determined that the presence of circulating tumor DNA (ctDNA) as a marker of poor prognosis. In a mutational analysis of the FLAURA trial, patients with ctDNA present at baseline had a median PFS was 15.2 months with osimbertinib vs 9.7 months with standard EGFR TKI. Those with no ctDNA present at baseline experienced a greater benefit regardless of treatment with reported median PFS of 23.5 and 15 months, respectively.⁴

“I would highlight those patients with baseline, detectable ctDNA and those with ctDNA that persists at week 3 and week 6 appear to do worse,” Riess said, who cited data from the analysis of the FLAURA trial in which investigators examined early clearance of plasma EGFR mutations after 3 and 6 weeks of EGFR TKI therapy.⁵ The median PFS for all patients with detectable EGFR at 3 weeks was 9.5 months (95% CI, 7.0-10.9) compared with 13.5 months (95% CI, 11.1-15.2) regardless of therapy received (HR, 0.50; 95% CI, 0.3-0.8; P = .001). At 6-week analysis, the median PFS was the same for those with no detectable EGFR in plasma analysis, but worsened to 8.3 months (95% CI, 6.8-10.9) for those who maintained measurable EGFR, for an HR of .70 (95% CI, 0.4-1.2; P = .191).

“How can we better use ctDNA to select those patients who are going to do worse with first-line osimertinib and intervene in the first line setting? I think this is an area we really need to improve on.”

Resistance to osimertinib also depends on the line of therapy, Riess explained. In an analysis of 62 patients with EGFR-mutant NSCLC, the most common off-target genetic resistance obeserved in patients treated with first-line osimertinib were MET amplification (7%), RET fusion (4%), BRAF fusion (4%), and KRAS fusion (4%); on-target acquired mutations were EGFR amplification (4%) and EGFR G724S (4%). In later lines of therapy off-target and on-target genomic alterations increased, the most notable of which is the reported incidence of EGFR C797 which was reported for 27% of patients.⁶

“After the first line, you see a high rate of on-target mutations, including C797 and others, whereas with first-line osimertinib, you still see those, but the on-target mutations appear at a diminished frequency,” Riess said.

“EGFR C797 is the primary target resistance mechanism; it impedes covalent bond formation with irreversible EGFR inhibitors, such as osimertinib,” Riess explained, adding that recent data of osimertinib in combination with gefitinib has demonstrated that this strategy may have the potential to stall the development of C797.

In a phase 1 study (NCT03122717) of 27 treated patients, the combination resulted in rapid plasma clearance of EGFR with an objective response rate of 87.9% (95% CI, 71.9%-96.1%) and a disease control rate of 100% (95% CI, 87.5%-100%). The median depth of response was 58.5% (range, 6.5%-94.2%), and no grade 4 or 5 adverse effects were reported with the therapy.⁷

Combination strategies leveraging fourth-generation EGFR inhibitors also have potential to overcome acquired resistance mechanisms. In particular BLU-945 has demonstrated efficacy in patients whose disease harbors activated L858R or exon 19 deletion mutations, plus acquired T790M and C797S mutations. “In xenograph models, the combination of osimertinib with BLU-945 looked to be the most efficacious in terms of tumor growth inhibition,” Riess said. “I think is definitely a promising avenue to reduce these, these on target resistance mechanisms and improve clinical outcomes.”

Other areas for exploration include the ability to inhibit other mechanisms of resistance, in particular RAS/RAF/MAPK alterations. Riess highlighted the phase 2 study (NCT03392246) in which investigators are evaluating osimertinib in combination with the MEK inhibitor selumetinib (Koselugo) for patients with EGFR inhibitor–naïve advanced EGFR-mutant lung cancer.

The future, Riess explained, will depend on treatment selection based on ctDNA analysis to determine indicators of poor prognosis and then finding a window of opportunity to optimal induction of osimertinib in combination with proven effective therapies.

Strategies outlined by alteration may include osimertinib plus carboplatin/etoposide for those with a TP53 mutation; osimertinib in combination with a MET inhibitor for those with a MET amplification; osimertinib plus a MEK inhibitor for those with RAS/RAF/MAPK alterations; and osimertinib plus a fourth-generation EGFR TKI for those with C797 alterations.

References

1. First line osimertinib: what can we add to enhance activity? Presented at: 22nd Annual International Lung Cancer Congress; July 29-31, 2021; virtual.
2. Ramalingam S, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA. Ann Oncol. 2017;28(suppl 5):V635. doi:10.1093/annonc/mdx440.050
3. Offin M, Chan JM, Tenet M, et al. Concurrent RB1 and TP53 alterations define a subset of EGFR-mutant lung cancers at risk for histologic transformation and inferior clinical outcomes. J Thorac Oncol. 2019;14(10):P1784-P1793. doi:10.1016/j.jtho.2019.06.002
4. Gray JE, Okamoto I, Sriuranpong V, et al. Tissue and plasma EGFR mutation analysis in the FLAURA trial: osimertinib versus comparator EGFR tyrosine kinase inhibitor as first-line treatment in patients with EGFR-mutated advanced non–small cell lung cancer. Clin Cancer Res. 2019;25(22):6644-6652. doi:10.1158/1078-0432.CCR-19-1126
5. Zhou C, Imamura F, Cheng Y, et al. Early clearance of plasma EGFR mutations as a predictor of response to osimertinib and comparator EGFR-TKIs in the FLAURA trial. J Clin Oncol. 2019;37(suppl 15):9020. doi:10.1200/JCO.2019.37.15_suppl.9020
6. Schoenfeld AJ, Chan JM, Kubota D, et al. Tumor analyses reveal squamous transformation and off-target alterations as early resistance mechanisms to first-line osimertinib in EGFR-mutant lung cancer. Clin Cancer Res. 2020;26(11):2654-2663. doi:10.1158/1078-0432.CCR-19-3563
7. Rotow JK, Botelho Costa D, Paweletz CP, et al. Concurrent osimertinib plus gefitinib for first-line treatment of EGFR-mutated non-small cell lung cancer (NSCLC). J Clin Oncol. 2020;38(suppl 15):9507. doi:10.1200/JCO.2020.38.15_suppl.9507