Osimertinib Eclipses Current Treatment Options in EGFR-Mutant NSCLC

Sawsan Rashdan, MD

Osimertinib (Tagrisso) continues to be the frontline standard of care of care for patients with metastatic EGFR-mutant non–small cell lung cancer (NSCLC), said Sawsan Rashdan, MD, who added that the third-generation EGFR inhibitor is slated to have the same potential for patients with resectable disease.

Osimertinib is currently approved by the FDA as a first-line treatment for patients with metastatic NSCLC with tumors that have EGFR mutations, which includes exon 19 deletions or exon 21 L858R mutations. The regulatory decision is based on data from the phase 3 FLAURA trial in which frontline osimertinib showcased a 36-month survival rate of 54% in patients with metastatic, EGFR-mutant NSCLC versus 44% in those who received erlotinib (Tarceva) or gefitinib (Iressa).¹

Additionally, in patients with stage IB to IIIA disease, osimertinib demonstrated a 79% reduction in the risk of disease recurrence or death versus placebo, according to findings from the phase 3 ADAURA trial that were presented at the 2020 ASCO Virtual Scientific Program(HR, 0.21; 95% CI, 0.16-0.28; P <.0001).²

On July 30, 2020, the FDA granted a breakthrough therapy designation to osimertinib for the adjuvant treatment of patients with stage IB, II, and IIIA EGFR-mutated NSCLC following complete resection with curative intent, according to data from ADAURA.³

“Single-agent osimertinib is still the golden standard of care for patients with metastatic EGFR-mutant NSCLC,” said Rashdan.” This drug is going to be used very soon in the adjuvant setting as well, so be on the lookout for the FDA approval because that’s going to change our practice.”

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on lung cancer, Rashdan, an assistant professor in the Department of Internal Medicine at UT Southwestern Medical Center, discussed the current treatment paradigm of patients with resectable and metastatic EGFR-mutant NSCLC.

OncLive: How has the FLAURA trial shaped the frontline treatment of patients with metastatic EGFR-mutant NSCLC?

Rashdan: The most important study in the metastatic setting is the FLAURA trial, which looked at first-line treatment with osimertinib versus standard of care in patients with advanced EGFR-mutant NSCLC. The results of the study led to the approval of osimertinib, [which is now] the current standard of care [in this setting]. In the trial, we saw a significant improvement in progression-free survival (PFS) with osimertinib compared with the standard of care. Specifically, 18.9 months compared with 10.2 months. We also saw an improvement in overall survival (OS). Though, that was not as robust as the PFS data because of the crossover between arms. But still, this data was really impressive [and confirmed its use] as the first-line standard of care. Osimertinib is also very well tolerated.

Could you highlight the importance of the ARCHER 1050 trial?

Several other agents have been evaluated as first-line treatment in this setting, including dacomitinib (Vizimpro), which is a second-generation EGFR inhibitor. This study evaluated dacomitinib compared with gefitinib and showed improvement in PFS and OS. However, [we did see increased] adverse effects (AEs) with dacomitinib. Additionally, the quality of life with dacomitinib was worse compared with gefitinib. As such, osimertinib remains the standard of care agent in this setting.

How have combinations impacted the first-line landscape?

Some studies have evaluated combinations of an EGFR inhibitor and an antiangiogenic agent. In the RELAY trial, we evaluated the combination of erlotinib (Tarceva) and ramucirumab (Cyramza) versus erlotinib alone. The study did show an improvement in PFS of 7 months. However, again, there were increased AEs [with the combination]. Specifically, AEs related to antiangiogenics, such as hemorrhagic events, hypertension, and proteinuria. As such, in the first-line metastatic EGFR-mutant NSCLC setting, I do still use osimertinib. The drug is not only effective, but it’s not associated with severe AEs. The AEs with osimertinib are much better tolerated than what we’re used to seeing with erlotinib, gefitinib, and afatinib (Gilotrif).

Are there any plans to evaluate osimertinib in combination with an antiangiogenic agent like ramucirumab?

Some studies are currently ongoing that are looking at combining osimertinib with antiangiogenic inhibitors. A study is currently looking at combining osimertinib with the VEGF inhibitor ramucirumab in the frontline setting.

Could you discuss some of the work that’s being done in the post-osimertinib setting?

The question of what to do after osimertinib failure is an area of research that has several studies ongoing right now.

How do you approach sequencing in practice?

Sequencing strategies for patients with EGFR-mutant NSCLC is an area of discussion. Right now, there are multiple options. In the past, [we gave a] first- or second-generation EGFR inhibitor, and if the patient developed a T790M mutation, we gave osimertinib, and, if not, we gave chemotherapy. Generally, the standard of care is single-agent osimertinib. If the patient develops progressive disease on osimertinib, really the only option is chemotherapy.

There are no studies to show the efficacy of a first-generation EGFR inhibitor combined with a VEGF inhibitor in the second-line setting after osimertinib. We don’t know the efficacy of the combination of an EGFR inhibitor with chemotherapy after osimertinib. Positive data from osimertinib combined with chemotherapy or a VEGF inhibitor will probably change our practice.

However, if you start the patient off on a combination, for example, an EGFR inhibitor and a VEGF inhibitor, or an EGFR inhibitor and chemotherapy, you can certainly use osimertinib afterward if the patient is T790M positive. If the patient is negative, [you could give] chemotherapy. However, if you do that, you’re losing the opportunity to give osimertinib to everyone because you can only use it for T790M-positive patients in that situation.

Turning to the adjuvant setting, how have the results of the ADAURA trial impacted the use of osimertinib for patients with resectable EGFR-mutant NSCLC?

The ADAURA trial was presented at the 2020 ASCO Virtual Scientific Program. In the trial, patients with stage IB through IIIA EGFR-mutant NSCLC were randomized to receive osimertinib or placebo after adjuvant chemotherapy. The study showed extremely impressive results. We saw a significant improvement in the primary end point of disease-free survival (DFS). The hazard ratio, which is 0.17, is almost unheard of in NSCLC and was highly significant.

The OS data are still not mature. However, in looking at the DFS data, adjuvant osimertinib should be considered for patients with resectable stage IB to IIIA NSCLC who received adjuvant chemotherapy and have an EGFR mutation. [Adjuvant osimertinib] is not yet approved, but we hope it will be in the next few weeks.

Now that osimertinib is expected to receive regulatory approval in the adjuvant setting, do you anticipate that tissue biopsy will remain the standard testing method?

We can use tissue or liquid biopsy. Whatever can give us an accessible result [should be used]. Especially if the patient is already resected, we should have enough tissue to test and enough time until we have to think about giving osimertinib.

My preference would be tissue biopsy, but in certain situations where we don’t have enough tissue, we can certainly use liquid biopsy. However, that has to be done prior to resection. Also, liquid biopsy is less sensitive in terms of catching EGFR mutations if the tumor is small in size. Liquid biopsy is more sensitive in patients who have high volume disease or metastatic disease.

If the patient does develop metastatic disease, is that tissue sample from the adjuvant setting still viable, or is it worth retesting in the in the metastatic setting?

I always retest in patients who develop metastatic disease after resectable disease. First, we need to confirm the diagnosis before committing the patient to an incurable definite treatment. Additionally, even if the patient had an EGFR mutation in the resectable setting, we can’t guarantee that the recurrence is going to be EGFR positive. There are situations of transformation from EGFR-positive NSCLC to small cell lung cancer.

What is the biggest current unmet need that you would like to see addressed moving forward?

The biggest area of unmet need is what to do after osimertinib in the first-line metastatic setting. We have really good first-line agents, whether it’s osimertinib or the combination of erlotinib plus ramucirumab, or gefitinib plus chemotherapy, but we don’t know what to use after osimertinib.

What developments have we seen for patients with EGFR exon 20 insertions?

Two studies were presented at the 2020 ASCO Virtual Scientific Program in this realm. One evaluated a higher dose of osimertinib. Instead of 80 mg a day, patients received 160 mg a day, and that showed some efficacy.

We also saw data on a new compound called amivantamab in patients with EGFR exon 20 mutations, so we’re pretty excited about that compound, and we’re hopeful that it will be in the clinic very soon.

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(suppl 5):v851-v934. doi:10.93/annonc/mdz394
2. Tagrisso granted Breakthrough Therapy Designation in the US for the adjuvant treatment of patients with stage IB-IIIA EGFR-mutated lung cancer. News release. AstraZeneca. July 30, 2020. Accessed September 14, 2020. https://bit.ly/2P8Lgin.
3. Herbst RS, Tsuboi M, John T, et al. Osimertinib as adjuvant therapy in patients with stage IB-IIIA EGFR mutation-positive NSCLC after complete tumor resection: ADAURA. J Clin Oncol. 2020;38(suppl 18):LBA5. doi:10.1200/JCO.2020.38.18_suppl.LBA5