Continued Emergence of Targeted Therapies for EGFR+ NSCLC Underscores Importance of Molecular Testing

With osimertinib (Tagrisso) available as a treatment option in both the metastatic and adjuvant settings for patients with EGFR-mutated non–small cell lung cancer (NSCLC) and ongoing trials evaluating combination therapies for this patient population, molecular testing to identify these aberrations in patients with NSCLC remains critical, according to Pasi A. Jänne, MD, PhD.

“No patient should be left behind for EGFR mutation testing, either in the metastatic setting or in the adjuvant setting, because there are effective therapies for patients [in both settings]. If these therapies fail, understanding resistance is important. New therapeutic combinations are likely on the horizon, hopefully leading to further improvements in outcomes for this patient population with common EGFR-mutant NSCLC,” Jänne said in an interview with OncLive^® during the 24th Annual International Lung Cancer Congress^®.

In the interview, Jänne detailed his presentation on common EGFR mutations in NSCLC, touching on the importance of testing for EGFR mutations in all patients, the clinical implications of overall survival (OS) data for adjuvant osimertinib from the phase 3 ADAURA trial (NCT02511106), and ongoing trials examining combination therapies to potentially improve upon the use of single-agent osimertinib.

Jänne is a senior physician, director of the Lowe Center for Thoracic Oncology, director of the Belfer Center for Applied Cancer Science, and director of the Chen-Huang Center for EGFR Mutant Lung Cancers at Dana-Farber Cancer Institute, and a senior physician and professor of medicine at Harvard Medical School in Boston, Massachusetts.

OncLive: What was the primary focus of your presentation on common EGFR mutations in patients with NSCLC?

Jänne: Common EGFR mutations include exon 19 deletions and exon 21 L858R mutations, which account for about 85% of all EGFR mutations found in NSCLC. [In patients with these mutations], the standard of care is osimertinib in both the first-line metastatic setting and in the adjuvant setting.

I also highlighted some of the trials where we will have upcoming data over the next year, including the [phase 3] FLAURA2 [NCT04035486] and the MARIPOSA [NCT04487080] trials that aim to build on the single-agent use of a third-generation EGFR TKI to [evaluate] if [combination] therapies are better.

How should testing be conducted for EGFR mutations? Are they typically on reflex panels?

This varies a little bit from institution to institution. In general, they should be tested on reflex panels, and the standard of care is to test everyone's cancer for an EGFR mutation. That includes surgical specimens as well because of the approval [of osimertinib] in the adjuvant setting.

If you can't test from the tumor or the tumor biopsy is insufficient, then we test from a liquid biopsy. That would be the other way of doing this.

Looking at the data for osimertinib in the adjuvant setting from the ADAURA trial, we saw the OS data presented at the 2023 ASCO Annual Meeting. What was the significance of that readout and the implication on practice patterns?

It is significant. It's the first molecular-targeted therapy that has shown improvement in OS in the adjuvant setting in any subset of lung cancer. That is an important consideration. We recognize that despite effective surgery or even adjuvant chemotherapy, there are patients who still recur, and by administering adjuvant osimertinib to those with EGFR mutations, we know it leads to a decrease in recurrence and an increase in OS.

In the United States, the practice patterns had already changed a fair bit due to the decrease in the likelihood of recurrence and improvement in disease-free survival. There were other parts of the world where these OS data were still awaited. Now that we finally have that [OS data], hopefully that will mean that more patients who should be treated with [osimertinib] following successful surgical resection will actually be treated around the world.

Looking at the phase 3 FLAURA trial (NCT02296125), what do mature data indicate about osimertinib’s use in the metastatic setting?

[These data] also demonstrate an improvement in OS over a prior generation of EGFR inhibitors. The other aspect of osimertinib that we as practicing clinicians are all happy about is the ability to penetrate the blood-brain barrier and treat central nervous system metastases. Therefore, having a pharmacological alternative to radiation is certainly welcome and has been for a while in this field. We look forward to the data on FLAURA2, which will come later on in 2023.

Could you expand on the design and objectives of the FLAURA2 and MARIPOSA trials, which could potentially put osimertinib's role as standard frontline therapy into question?

FLAURA2 [evaluated] the combination of chemotherapy and osimertinib vs osimertinib [alone]. Chemotherapy [consisted of] carboplatin plus pemetrexed or cisplatin plus pemetrexed, so this was standard platinum-based chemotherapy added to osimertinib. The primary end point was progression-free survival, and a recent press release [stated] that the trial met its primary end point, and the data will be available later in 2023.

The MARIPOSA trial is [evaluating] the EGFR inhibitor lazertinib [formerly YH25448], which is a drug similar to osimertinib, [in combination with] an EGFR/MET bispecific antibody called amivantamab-vmjw [Rybrevant]. The second arm is lazertinib alone, and the third arm is osimertinib alone. [The concept here is] hitting the target harder or alternative approaches, because you have both a small molecule EGFR inhibitor and an EGFR-directed antibody. We don't know anything about those data, and we’ll see if [the combination] proves to be effective compared with the single agents.

[There is] a critical question from both of these trials: which patients need a more intensified therapy than just a single-agent, third-generation EGFR inhibitor? We all have patients who receive osimertinib or other third-generation inhibitors in the frontline, metastatic setting who do fine for many years in some cases, whereas some patients progress rather quickly. Perhaps those are individuals who would benefit from a more intensified treatment. However, what we need to figure out is how to identify these patients from the beginning. [We need to] identify the high-risk features that would steer that patient to receive a combination therapy vs a single-agent inhibitor.

Are there any data or current theories as to what some of those high-risk features may be?

Some of them may be concurrent genetic alterations, such as a p53 mutation. If a patient has a detectable EGFR mutation in their cell-free DNA in the blood that doesn't go away after treatment in 3 or 6 weeks, that [may be] a patient with high-risk disease who has a poorer prognosis and a shorter time to recurrence.

There may be clinical features, too. There may be more than 1 feature, both molecular and clinical, but we as a community need to work towards identifying these individuals, because they may be better served by a combination of therapy as opposed to single-agent osimertinib.

Looking at progression and resistance, what do we know about resistance mutations? What opportunities for treatment are available both in the clinic and the research realm?

Resistance is heterogeneous, and there are multiple ways in which resistance can happen. It's important to understand how the cancer developed resistance [with another biopsy] and resequencing the cancer to identify of there are targetable alterations, such as MET amplifications or EGFR C797S mutations, where new therapies could be available to be used. In addition, it's important to determine if small cell lung cancer transformation happened. This can happen in a subset of EGFR-mutant NSCLC treated with osimertinib, which would lead to a different therapy.

Then there is a whole series of other treatments being examined. For example, antibody-drug conjugates [ADCs], such as a HER3 ADC [patritumab deruxtecan (formerly U3-1402)] or Trop-2 ADC [datopotamab deruxtecan (Dato-DXd; DS-1062a)], both of which have clinical data in patients who have progressed on EGFR inhibitors, independent of the specific resistance mechanisms. These are broader approaches to treating resistance that do not rely on the actual resistance mechanism, because HER3 and Trop-2 are broadly expressed in EGFR-mutant cancers.

Reference

Tagrisso plus chemotherapy demonstrated strong improvement in progression-free survival for patients with EGFR-mutated advanced lung cancer in FLAURA2 Phase III trial. News release. AstraZeneca. May 17, 2023. Accessed July 27, 2023. https://www.astrazeneca.com/media-centre/press-releases/2023/tagrisso-plus-chemo-improved-pfs-in-lung-cancer.html