Osimertinib Preferred in Adjuvant and Frontline Metastatic EGFR+ NSCLC, But More Therapies Are Needed to Overcome Resistance

Sherri Cervantez, MD

With significant level 1 data, osimertinib (Tagrisso) has been established as a preferred treatment option in the adjuvant setting for patients with EGFR-positive non–small cell lung cancer (NSCLC) and in the frontline setting for those with EGFR-positive advanced or metastatic NSCLC, said Sherri Cervantez, MD.

Significant research is needed, she added, to determine the optimal approach for patients who develop resistance to osimertinib.

“[Because of the data from] the ADAURA trial, [we have] a strong [rationale] to use osimertinib in the adjuvant setting,” said Cervantez. “[Osimertinib] is well tolerated and it seems to have a significant effect on disease-free [survival]. We will see the overall survival data down the road, but it is an important step [towards improving outcomes for patients].”

“[Osimertinib] outperformed the other TKIs it was compared with in the first-line setting [for patients with] advanced or metastatic [disease]. We have great data for [using osimertinib in this setting]; it’s safe, and it has good central nervous system [CNS] penetration. [Osimertinib is a good drug that has multiple uses that we should take advantage of,” added Cervantez.

In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on lung cancer, Cervantez, director of Palliative Oncology and a faculty member in the Division of Hematology/Oncology at UT Health San Antonio, discussed the utility of osimertinib in NSCLC, as well as remaining questions regarding the treatment of patients who develop resistance to the third-generation EGFR inhibitor.

OncLive®: How have the data from the phase 3 ADAURA trial changed the treatment landscape of EGFR-positive NSCLC?

Cervantez: The ADAURA trial showed great efficacy [with osimertinib]. Adding [osimertinib] in the adjuvant setting will change the outcomes for a lot of our patients with lung cancer. Typically, lung cancer has a high rate of recurrence, even in the locally advanced setting. Although we try to treat patients for cure, we are not always successful, unfortunately. In those patients who have this particular EGFR mutation, [adjuvant osimertinib] is going to be really efficacious.

The duration of therapy [with adjuvant osimertinib] is quite long at 3 years; however, the drug is also well tolerated. On the whole, this is going to change the face of lung cancer for these patients and, hopefully, get many more patients to cure compared with previously.

Should osimertinib be considered a preferred adjuvant therapy across all subgroups of patients with EGFR-positive NSCLC?

Across different subgroups of patients based on age, ethnicity, and EGFR mutation status, [osimertinib] performed similarly. [Osimertinib] preferentially outperformed standard of care, which is observation. For all subgroups analyzed, [osimertinib] was the preferred line of treatment.

How are adverse effects (AEs) managed in patients receiving osimertinib?

Osimertinib is pretty well tolerated, but there are some AEs that we can see. Sometimes we see rash and fatigue, but on the whole, [AEs] can be managed with medications, such as creams or ointments.

Sometimes we have to dose reduce [osimertinib], but that is pretty atypical because, in general, the AEs [associated with osimertinib] are not very severe.

What efforts are being made to overcome resistance to EGFR TKIs?

Most of the efforts so far have been in the advanced/metastatic setting to try to figure out how we can overcome resistance to first- and second-generation TKIs. That is where osimertinib has really found its role in being able to manage [patients who harbor] an EGFR T790M mutation.

In the adjuvant setting or in the first-line setting for patients with advanced or metastatic disease, we don’t have a lot of data [on overcoming resistance].

Osimertinib is being used in the first-line setting for patients with advanced or metastatic disease [because osimertinib] has been shown to be an effective drug in patients who have [EGFR] mutations at the time [of treatment].

We don’t know what happens once [a patient develops] resistance or [has] disease progression following [osimertinib]. We don’t have great options [for those patients].

How do you currently approach sequencing for patients with EGFR-mutant NSCLC?

Certainly, in the up-front setting, patients with stage I through IIIA disease who have gone through curative[-intent] treatment should still receive surgical resection if appropriate, followed by adjuvant chemotherapy if indicated. Following [adjuvant chemotherapy], patients should get maintenance osimertinib if they have an EGFR mutation.

For patients who do not have [an EGFR mutation], we aren’t sure what to do. Most commonly, [those patients will receive] surveillance. For the patients with more advanced disease, we’re not sure what to do. For instance, patients with stage IIIB disease might go through chemotherapy and radiation, but we are not sure what to do in the adjuvant setting for the EGFR-unmutated [population].

The PACIFIC trial demonstrated the best data for adjuvant or maintenance immunotherapy, but for patients with EGFR mutations, we just don’t know.

As far as [treating] more advanced or metastatic patients with EGFR mutations, my practice is to go right to osimertinib. [Osimertinib] has good data, as well as CNS penetration, which is important. That’s typically what I use in the first-line setting instead of first- or second-generation TKIs.

What questions remain unanswered in EGFR-positive NSCLC? How could the uptake of molecular profiling provide some insight into answering those questions?

It will be important to [answer the question]: What do we do for patients who have had chemotherapy and radiation? What do we do next? If a patient progresses on a TKI, what do we do after? Is it general chemotherapy? Is it immunotherapy in combination with chemotherapy?

One of the interesting things we are seeing as we are able to do more molecular profiling is [co-mutations]. How do we approach that [clinical scenario]? What do we do when a patient has high PD-L1 expression and an EGFR mutation? The current line of thought would be that we follow the EGFR mutation and use [targeted] therapy first. However, it is going to be interesting to see what we should do in that landscape of overlapping mutations, as well as what we should do in the second-line setting.