Osimertinib Continues to Flourish as Frontline Standard in EGFR-Mutant NSCLC

Khaled A. Hassan, MD, MS

Updated data from the phase III FLAURA trial showed a significant improvement in overall survival (OS) with frontline osimertinib (Tagrisso) versus erlotinib (Tarceva) or gefitinib (Iressa) in patients with metastatic EGFR-mutant non—small cell lung cancer (NSCLC), thus solidifying the role of osimertinib as the frontline standard of care in this patient population, said Khaled A. Hassan, MD, MS.

“Osimertinib is still the standard of care based on its really low toxicity profile, its ability to cross the blood-brain barrier and control the central nervous system (CNS), and its significant improvement in progression-free survival (PFS) [and OS],” said Hassan.

In results from the analysis, which were presented at the 2019 ESMO Congress, the median OS was 38.6 months (95% CI, 34.5-41.8) and 31.8 months (95% CI, 26.6-36.0) with osimertinib and erlotinib or gefitinib, respectively (HR, 0.799; 95% CI, 0.647-0.997; P = .0462).¹ At 3 years, 54% of patients who received osimertinib remained alive versus 44% in the erlotinib/gefitinib arm, despite crossover.

The second-generation EGFR TKI dacomitinib (Vizimpro) has also shown promise in the frontline setting. According to updated findings from the phase III ARCHER 1050 trial, patients with EGFR mutations experienced a median OS of 34.1 months with dacomitinib versus 26.8 months with gefitinib.² Although the drug was approved in 2018 for use in this setting, many felt it did not have a role in the frontline space due to its toxicity profile, said Hassan. However, in a subset analysis of the trial, the benefit of dacomitinib became more apparent when it was administered at lower doses; this could prompt investigators to revisit its use in the space, predicted Hassan.

Additionally, combinations of earlier-generation EGFR TKIs and antiangiogenic agents as well as EGFR TKIs and chemotherapy are also under investigation.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Hassan, a medical oncologist at the University of Michigan Rogel Cancer Center, discussed the use of EGFR TKIs in the treatment of patients with advanced EGFR-mutant NSCLC and the emergence of osimertinib as the frontline standard of care.

OncLive: What is the history of the available EGFR-directed agents in EGFR-mutant NSCLC?

Khaled: The phase III IPASS trial was a seminal trial, which showed that patients who have EGFR mutations do better and respond better [to EGFR TKIs] compared with chemotherapy. Since then, we’ve begun to screen patients for EGFR mutations, so that we can give them drugs that target EGFR. We used to [prescribe] gefitinib and erlotinib, which are first-generation EGFR TKIs. Then, we moved to second-generation drugs, such as afatinib (Gilotrif). However, osimertinib showed a significant PFS advantage compared with the first-generation EGFR TKIs. Thus, it became the standard first-line treatment in patients with EGFR mutations.

Could you discuss the initial findings from the FLAURA trial? What did the updated analysis show?

The FLAURA trial changed the management of patients with EGFR-driven cancers. We saw a significant improvement in PFS with osimertinib of 18.9 months compared with [10.2 months] for first-generation EGFR TKIs. This set the standard. In addition to that finding, we saw significant efficacy in patients with brain metastases compared with the first-generation inhibitors, which are not as potent in that regard. Additionally, the toxicity levels were really low with the agent. Osimertinib inhibits EGFR mutations better than first-generation EGFR TKIs; [it doesn't] have as much of an effect on EGFR that's expressed normally in other tissues.

Everyone was awaiting the OS data from this trial. At the 2019 ESMO Congress, we saw a significant improvement in OS with osimertinib of about 38 months compared with 31 months with the first-generation EGFR TKIs. At 3 years, around 28% of patients were still taking osimertinib compared with only 9% of patients in the standard EGFR TKI arm. We saw this benefit even though patients crossed over to the osimertinib arm. These data solidify the role of osimertinib as a first-line treatment for patients with EGFR mutations. In any trial moving forward, osimertinib should be the [control] arm.

Could you elaborate on the CNS activity seen with osimertinib?

As we know, lung cancer metastasizes to the brain, which is one of the major organs of the body, in addition to the adrenal [glands], the liver, and the bones. We usually use radiation [for brain metastases], so having a drug that can cross the blood—brain barrier and has significant efficacy on brain tumors is great. If the [brain metastases] are not symptomatic, we would start with osimertinib and get its effect. With the updated analysis, we know 52% of patients had controlled brain metastases with osimertinib. It's a very important aspect of the drug that the other drugs have not shown.

Could you speak to the data from the phase III ARCHER 1050 trial with dacomitinib?

In the trial, investigators evaluated dacomitinib, which is a second-generation, irreversible EGFR TKI. Results showed an improvement in PFS with dacomitinib versus the first-generation EGFR TKIs. However, significant toxicities [with dacomitinib] were also observed. Investigators looked at subgroups who were given a decreased dose of the agent and assessed PFS and OS. Patients who received a decreased dose had an even better PFS and OS [than patients who received the standard dose] of dacomitinib. These data are going to generate many questions regarding whether we need to reassess dacomitinib at a lower dose than what was initially prescribed. The results of the subgroup analysis are really significant and mimic what we're seeing with the third-generation EGFR TKI osimertinib.

Could you highlight some of the novel combinations that are being explored?

Data from the phase III RELAY trial were presented at the 2019 ASCO Annual Meeting. Investigators compared the combination of the first-generation EGFR TKI erlotinib plus a VEGF2 monoclonal antibody ramucirumab (Cyramza) versus erlotinib alone. Investigators reported an improvement in PFS and OS with the combination. However, toxicities are a concern with combinations. With the use of a VEGF drug, we're concerned about high blood pressure, bleeding, clots, and kidney function. Investigators did see an increase in blood pressure in [those who received the combination]. An increase in proteinuria in the kidneys was also observed. There wasn't a lot of information regarding clots, but a couple cases of bleeding were reported. [However], that combination appeared to be promising and similar to previous clinical trials that used different antiangiogenic agents such as bevacizumab (Avastin).

The other idea is to use combinations of chemotherapy plus EGFR TKIs. At the 2019 ASCO Annual Meeting, there was a study from India in which investigators combined the first-generation TKI gefitinib with chemotherapy; those data were encouraging. An increase in PFS and OS were observed. However, toxicity remains an issue when you're combining 3 different drugs.

Where will future research focus?

The main challenge that we are all facing is what's next. We used to use gefitinib or erlotinib as frontline therapy. If patients developed a T790M mutation, we sequenced with osimertinib. Now that we are using osimertinib first, we don't see the T790M resistance mutation. We are seeing new mutations and other pathways that are being activated for which there is no second-line standard of care available. Now we're focusing on determining what the next best drug is.

References

1. Ramalingam SS, Gray JE, Ohe Y, et al. Osimertinib vs comparator EGFR-TKI as first-line treatment for EGFRm advanced NSCLC (FLAURA): Final overall survival analysis. Ann Oncol. 2019;30(5 suppl; abstr LBA5_PR). doi: 10.1093/annonc/mdz394.076.
2. Mok T, Cheng Y, Zhou X, et al. Improvement in overall survival in a randomized study comparing dacomitinib with gefitinib in patients with advanced non-small cell lung cancer harboring EGFR-activating mutations. J Clin Oncol. 2018;36(22):2244-2250. doi: 10.1200/JCO.2018.78.7994.