Brahmer Highlights Next Steps for Osimertinib in EGFR-Mutant NSCLC

Julie R. Brahmer, MD

Results from the phase III FLAURA trial solidified osimertinib (Tagrisso) as the standard frontline option for patients with EGFR-mutated non—small cell lung cancer (NSCLC), and now research efforts are focused on examining combinations with the agent and developing strategies to overcome resistance, according to Julie R. Brahmer, MD.

“The FLAURA trial took patients who had EGFR-positive disease with standard EGFR abnormalities in exon 19 and exon 21 and found that osimertinib increased survival,” said Brahmer. “This was truly a [significant] advancement made in the field.”

The FLAURA trial examined osimertinib, a third-generation EGFR TKI, compared with the first-generation TKIs erlotinib (Tarceva) and gefitinib (Iressa) in patients with EGFR-mutant NSCLC. Osimertinib showed a median overall survival (OS) of 38.6 months (95% CI, 34.5-41.8) versus 31.8 months (95% CI, 26.6-36.0) with erlotinib or gefitinib (HR, 0.80; 95% CI, 0.64-1.00; P = .046).¹ The 12-, 24-, and 36-month OS rates were 89%, 74%, and 54% in the osimertinib arm (n = 279), and 83%, 59%, and 44% in the erlotinib or gefitinib arm (n = 277), respectively.²

Furthermore, at 3 years, 28% of patients in the osimertinib arm continued on treatment versus 9% in the comparator arm, and the median exposure was 20.7 months versus 11.5 months, respectively.

“For targeted therapies, we want to use the best drug upfront. At the time of resistance, we will try to determine the mechanism of resistance or refer [patients] for clinical trials,” said Brahmer. “Typically, we turn to chemotherapy if a patient's disease progresses on targeted therapies and we don't have any further [options available]. Chemotherapy is a great backup.”

In an interview with OncLive during the 2020 Winter Lung Conference, Brahmer, co-director of the Upper Aerodigestive Department, Bloomberg Kimmel Institute for Cancer Immunotherapy, and professor of oncology at John Hopkins Medicine, discussed the impact of osimertinib in EGFR-mutant NSCLC, ongoing research with the agent, and the importance of molecular testing.

OncLive: What are some of the key developments that have been made with targeted therapies in lung cancer?

Brahmer: We've seen a great advancement of multiple new options for patients with driver mutations, from osimertinib being offered in the first-line treatment setting for those with the standard EGFR mutations in exon 19 and exon 21 to alectinib (Alcensa) for those with ALK-positive disease. Other driver mutations include BRAF, RET, ROS1, and NTRK alterations. There is a huge opportunity for us to look even further to see what driver mutations we can design therapies [to target]. Emerging therapies are now targeting KRAS G12C. We are very excited to see these inhibitors come into the clinic via clinical trials.

Osimertinib has moved to the frontline setting for patients with EGFR mutations due to the pivotal FLAURA study. Could you provide an overview of the study and its findings?

Patients with EGFR abnormalities in exon 19 and exon 21 were randomized to receive osimertinib or either erlotinib or gefitinib. Patients remained on these therapies until progression. We were able to see an improvement in progression-free survival as well as OS [with osimertinib], which was quite dramatic. [Much better] central nervous system control was observed in patients treated with osimertinib [compared with those] who were treated with either erlotinib or gefitinib.

Are there any circumstances in which you would not give osimertinib over erlotinib or gefitinib?

For most patients with the standard EGFR abnormalities noted on next-generation sequencing, we are choosing osimertinib over erlotinib or gefitinib. Sometimes we can run into particular adverse events where we have to try to drop the dose [of osimertinib] from the standard dose. If that continues to be a problem, we can try to [switch] over [to the first-generation EGFR TKIs], like erlotinib or gefitinib, to see if those patients can tolerate it. However, that does not happen very often because osimertinib tends to be very well tolerated.

What are you doing for patients who develop resistance to osimertinib?

Right now, the standard practice is to put these patients on chemotherapy or the IMpower150 regimen of chemotherapy plus bevacizumab (Avastin) plus atezolizumab (Tecentriq). When talking with patients, the standard treatment would be some type of chemotherapy or chemotherapy plus a VEGF antibody plus a PD-L1 antibody. We like to try to continue with that precision medicine [approach to] care. We do biopsy those patients to see whether or not another resistance mechanism [has occurred; in that case,] we could go back to some of the first-generation EGFR TKIs or add other drugs to osimertinib. We would try to do this on a clinical trial.

Could you expand on some of the research examining osimertinib combinations?

We're particularly interested in combining osimertinib with a VEGF antibody; some clinical trials are already doing that. Osimertinib [is also being combined] with chemotherapy, in the hopes that we can combat resistance early and [maybe even] prevent it. However, we have to take into account that adding drugs to osimertinib will increase AEs. We're trying to make these patients live longer and better, but we have to consider the additive cost from a [toxicity] standpoint. Trials are looking at following [the presence or absence of] blood mutations and using that information to guide whether patients need to go on this type of therapy. It's exciting to have all this technology available on clinical trials.

How and when should patients receive molecular testing?

I believe, and the guidelines actually back this up, that all patients with non—small cell lung cancer should undergo molecular testing at the time of their diagnosis, mainly those with advanced disease. A controversial question is whether patients with early-stage disease, where we're not routinely using these driver mutations and standard therapy is adjuvant chemotherapy, [should receive molecular testing at diagnosis]. We have many clinical trial options available. We’re able to check the molecular testing and then, depending if patients have EGFR mutations or ALK fusions in their tumors, those patients [could] be placed on the ALCHEMIST study or other studies in the adjuvant setting. For advanced disease, all patients should receive molecular testing to determine the presence or absence of driver mutations or fusions, as that [testing could] change their prognosis [by directing us to] the right targeted therapy.

How do you manage patients as you wait for molecular testing results?

If patients are doing well at the time of their diagnosis, and you're waiting for molecular testing, starting platinum-based chemotherapy would be appropriate if you're concerned about progression and symptoms that are rapidly worsening. I would hold immunotherapy for the first cycle [of treatment] until I get those [molecular] tests back because immunotherapy may cause potential interactions with targeted therapy [later on in the treatment journey]. We certainly don't want to delay therapy, but again, [giving] immunotherapy could cause problems down the road.

What is the future of targeted therapies in this space?

Like Benjamin P. Levy, MD, of Johns Hopkins Medicine, said today, “Leave no gene behind.” Trying to figure out the genetic profile of a tumor, at least at the start, is very helpful—even if a patient doesn't have a gene [mutation] that we can target today. Depending on how that patient is doing, we may have a therapy available for them in the next 1 to 5 years.

References

1. Ramalingam SS, Vansteenkiste J, Planchard D, et al; FLAURA Investigators. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382(1):41-50. doi: 10.1056/NEJMoa1913662.
2. Ramalingham 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; abstr LBA_PR). doi: 10.1093/annonc

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