Osimertinib Continues to Gain Momentum as Frontline Therapy in EGFR+ NSCLC

Arek Z. Dudek, MD, PhD

Findings from the FLAURA study indicate that frontline osimertinib (Tagrisso) is more effective than erlotinib (Tarceva) or gefitinib (Iressa), especially for patients with brain metastases, and does not create more aggressive disease in patients with EGFR-mutated non—small cell lung cancer (NSCLC), explained Arek Z. Dudek, MD, PhD.

The phase III FLAURA study found frontline osimertinib reduced the risk of progression or death by 54% versus erlotinib or gefitinib in patients with EGFR-positive local advanced or metastatic NSCLC. Additionally, the median progression-free survival (PFS) was 10.2 months (95% CI, 9.6-11.1) for standard therapy and 18.9 months (95% CI, 15.2-21.4) with osimertinib (HR, 0.46; 95% CI, 0.37-0.57; P <.0001).¹ The results of the FLAURA study led to the approval of osimertinib in the frontline setting for patients with NSCLC whose tumors harbor EGFR mutations (exon 19 deletions or exon 21 L858R).²

In August 2019, it was announced that frontline osimertinib significantly improved overall survival (OS) versus erlotinib or gefitinib in this patient population in the FLAURA trial. Results will be presented at the 2019 ESMO Congress.

According to Dudek, there is some discussion regarding whether osimertinib should be used in frontline therapy or follow therapy with a first- or second-generation EGFR TKI. Some physicians are concerned using osimertinib in the frontline setting will create a more aggressive disease in the patient and decrease survival; however, Dudek states there is currently no data supporting that hypothesis.

“Osimertinib provides very good control in patients with EGFR-mutated lung cancer, specifically exon 19 deletion and exon 21 L858R mutations. Current data suggest it should be preferred frontline therapy,” said Dudek, an oncologist at Health Partners Institute and a professor at University of Minnesota.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Dudek discussed the research surrounding osimertinib in the treatment of EGFR-positive NSCLC.

OncLive: Could you give an overview of the current use of EGFR TKIs in EGFR-positive NSCLC?

Dudek: We have so many different EGFRs and TKIs available. We have first-, second-, and third-generation EGFR TKIs. The main question was whether to start with the best one upfront and use some other form of therapy later or to start with the first- or second-generation EGFR TKI and follow up with a third-generation EGFR TKI.

Results of the FLAURA study showed the superiority of osimertinib versus gefitinib or erlotinib. In that study, there was a significant improvement in PFS and improvement later analyzed in secondary PFS.

Additionally, osimertinib protected patients from brain metastases or the brain metastases were under control during osimertinib treatment, which is much better than a first-generation EGFR TKI.

Osimertinib in first-line treatment is going to be better than using sequential treatment. In the longer follow-up of the FLAURA study, it was clear that time to determination EGFR TKIs in patients who started on osimertinib [was improved compared to] those who started on erlotinib or gefitinib. There is also a suggestion that has not yet been met because this small percentage of patients died on both arms of the study, but there is a suggestion OS is also affected by starting osimertinib versus gefitinib or erlotinib.

There's also recent interesting data suggesting the combination of EGFR TKI therapy erlotinib with ramucirumab (Cyramza) produce an antibody that bonds to a VEGF receptor. It also created a significant PFS advantage. Perhaps in the future, if this combination is approved in the frontline setting, the question will be whether it is better to start with erlotinib/ramucirumab and then follow up with osimertinib or start osimertinib in the frontline setting? These data do not exist today, but it creates and interesting question.

In addition, all those studies were done with specific EGFR mutations, exon 19 deletion and exon 21 L858R mutations. Yet, there are some other less frequent mutations where the activity of the therapy is unknown. We know, however, that second-generation therapy EGFR inhibitor afatinib (Gilotrif) has specific activities in those rare mutations. Therefore, it is recommended to carefully evaluate your patients on what type of EGFR mutation the patient has and make decisions based on that. In addition, the presence of brain metastases will favor using osimertinib in the frontline setting.

What impact has this research had on the NSCLC field and what are the next steps?

Today, because of this research, we have so many different options. The decisions have become more granular regarding what type of EGFR mutation should be treated with what medication. In addition, a decision has to be made regarding the best EGFR TKI therapy for patients with brain metastases. A group of patients with brain metastases was always very challenging. That was probably the first biggest impact, even before the FLAURA study became available. This intrigued many oncologists and caused them to use osimertinib in the frontline setting for patients with brain metastases.

There is going to be a significant need for the development of new agents that will address methods of resistance to osimertinib. There will also be interest in combining osimertinib with angiogenesis inhibitors. There's clearly intriguing data with erlotinib/ramucirumab. I wonder whether a combination of osimertinib with another VEGF inhibitor can provide additional survival advantage.

The main goal of the future research is to address methods of resistance and specific mutations and activation of additional pathways. We also want to improve the diagnostics to allow the detection of resistance mechanisms that are building up on the frontline treatment. An appropriate second-line therapy should be selected.

What data have demonstrated effective strategies with targeting prior resistance mechanisms following osimertinib?

There is really helpful data in the context of finding out there is a third EGFR mutation that occurs in the setting and, therefore, the development of agents targeted at that specific mutation is critical. One could argue that you have a disease control over a long time, and suddenly after that you have a very aggressive biology that will result in shorter survival for patients. However, in the study, there was no development of more aggressive behavior or more aggressive biology of lung cancer due to the prolonged use of frontline osimertinib therapy. It was not different from using a first-line first- or second-generation EGFR TKI followed by osimertinib.

What is the role of chemotherapy after disease progression on EGFR TKIs?

In the field of lung cancer oncology, we have been fascinated by activity of immunotherapy. It's clear, however, that patients with EGFR-mutated lung cancer tend not to respond to immune checkpoint inhibitors. There is activity when chemotherapy is combined with immune checkpoint inhibitor therapy and antiangiogenic therapy. In [the IMpower150] study that randomized patients to have atezolizumab (Tecentriq) plus bevacizumab (Avastin), carboplatin, and paclitaxel versus bevacizumab, carboplatin, and paclitaxel, there was clear activity [in the atezolizumab arm in] patients who had prior treatment with TKI or EGFR-mutated lung cancer. That study really gives hope that this therapy could serve as solid treatment for patients progressing on osimertinib.

References

1. 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. Annals of Oncology. 2017;28 (Abstract LBA2_PR). doi: 10.1093/annonc/mdx440.050.
2. Tagrisso significantly improves overall survival in the phase III FLAURA trial for 1st-line EGFR-mutated non-small cell lung cancer. AstraZeneca. Posted August 9, 2019. https://bit.ly/2ZGF7gZ. Accessed August 9, 2019.