OS Benefit Confirms Osimertinib as Frontline Standard in EGFR+ NSCLC

Clarke A. Low, MD

Overall survival (OS) from the phase III FLAURA trial have confirmed osimertinib (Tagrisso) as the new standard frontline treatment for patients with EGFR-mutated non—small cell lung cancer (NSCLC), said Clarke A. Low, MD, adding that the drug’s tolerability plus its central nervous system (CNS) activity sets it apart from other available TKIs.

“It's standard for me to offer osimertinib for all patients as first-line treatment, whether they have brain metastases or not,” said Low. “I have very few patients who need dose reductions just because the tolerability is quite good with osimertinib. The drug also has the most robust data regarding improvements in OS, which is ultimately what's most important in the treatment of these patients.”

Updated data from the FLAURA trial presented at the 2019 ESMO Congress showed that frontline treatment with the third-generation TKI improved median OS by 6.8 months when compared with the second-generation TKIs erlotinib (Tarceva) or gefitinib (Iressa) in patients with EGFR-mutated metastatic NSCLC, despite crossover between arms.¹

Specifically, the median OS with osimertinib was 38.6 months (95% CI, 34.5-41.8) versus 31.8 months (95% CI, 26.6-36.0) in the comparator arm, which translated to a 20% reduction in the risk of death (HR, 0.799; 95% CI, 0.647-0.997; P = .0462).

With the new standard established, emerging research efforts are examining mechanisms of resistance to osimertinib. For example, interim findings from 2 expansion cohorts of the phase Ib TATTON trial showed that the combination of osimertinib and savolitinib led to early responses with no significant toxicities in patients with EGFR-mutated disease who developed MET-driven resistance.^2,3

During an interview at the 2019 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Low, director of thoracic oncology at Intermountain Healthcare, discussed the role of osimertinib in EGFR-mutated NSCLC and emerging research efforts in the paradigm.

OncLive: Could you discuss the pivotal phase III FLAURA trial with osimertinib? What is the role of this agent in this space now?

Low: The FLAURA trial has convincingly set the standard of care for first-line treatment of EGFR-mutated disease, namely that osimertinib should be used as opposed to earlier first- or second-generation EGFR TKIs. This is based on a combination of factors.

For one, the agent’s demonstrated improvement in OS has not previously been seen in other TKI studies. Also, the drug has shown efficacy in treating CNS disease and [has impressive] tolerability. Its toxicity is on par with first-generation TKIs, but osimertinib is significantly better tolerated than second-generation TKIs. It’s the confluence of these factors that lead me to interpret the FLAURA trial as really setting the standard of care for first-line EGFR-mutated disease.

What were the key takeaways from the ARCHER 1050 trial with dacomitinib (Vizimpro)? How does this agent compare with osimertinib?

ARCHER1050 looked at the second-generation TKI dacomitinib and compared it with the standard first-generation TKIs erlotinib or gefitinib. Patients with brain metastases were excluded, which is a really important thing to consider when interpreting this trial. Also notable is that it is the first phase III randomized trial in EGFR-mutated patients that demonstrated a statistically significant improvement in OS.

The other thing to mention is that [dacomitinib] required a lot of dose reductions. I don't believe that we should see this as prohibitive to using dacomitinib as an agent, but it argues that [we should have the] expectation that dose reductions are going to be required [when using this agent].

Certainly, this is where the art of oncology comes in. You need an oncologist who is pretty experienced in dealing with toxicity associated with TKIs and doing dose reductions. If you look at the actual rate of discontinuation of dacomitinib versus a first-generation TKI, it was not any different. It just requires dose reductions given the high degrees of toxicity that was more consistent with afatinib (Gilotrif), which is another second-generation TKI.

Regardless, it’s still an exciting, important study. Dacomitinib is a very reasonable option. However, the exclusion of patients with CNS metastases [in the trial], to me, is quite significant that compels me to use osimertinib versus dacomitinib for the first-line treatment of the majority of patients with EGFR-mutated disease.

I offer osimertinib to all patients as first-line treatment. Even in patients without brain metastases, I worry about these patients developing isolated progression in the brain, so patients are best served by receiving osimertinib.

What strategies are being examined for those who progress on osimertinib?

I'm excited about [the work examining] what happens subsequently with patients who are on osimertinib as first-line treatment and looking at the mechanisms of resistance to it. We are beginning to get some data suggesting that many different mechanisms of resistance exist, but one of them that is seen quite commonly is MET amplification. There’s an opportunity where we can allow patients to continue osimertinib, add a MET TKI, and then get additional benefit [from that combination] before seeing chemotherapy. [Data with that approach were] reported in the TATTON trial, where [the investigational] MET inhibitor savolitinib was added to osimertinib and [the combination] seemed to be very promising, although it’s still very early.

What is the role of chemotherapy in this space?

Chemotherapy remains the backbone of treatment for subsequent lines of therapy. What is interesting is that we're starting to look again at the role of chemotherapy in the first-line setting in combination with a TKI, which is a little bit “back to the future” because the very first trials with TKIs were examined in combination with chemotherapy.

There were some exciting data presented at the 2018 and 2019 ASCO Annual Meetings. The RELAY trial presented some really interesting progression-free survival (PFS) data; PFS was on the magnitude of 18 months, and was pretty comparable with that was seen in the FLAURA trial. Notably, this trial included patients with brain metastases, although we don't yet have data on the CNS efficacy of that combination. The trial also included some data on mechanisms of resistance, which seemed to be fairly consistent with resistance patterns seen when first-generation TKIs when used alone. Fifty percent to 60% of patients had T790 mutations, which would lend itself to getting subsequent therapy with osimertinib.

These are also exciting data with chemotherapy in a first-line setting. Granted, there is definitely more toxicity with [this approach] and certainly for older, frailer patients, I still believe that TKI monotherapy is the ideal approach. Even still, for younger patients, giving a TKI alone is the ideal approach. However, what I'm excited about are ongoing phase III clinical trials that are starting to look at osimertinib in combination with chemotherapy.

What is your take-home message to your colleagues?

We have to test patients. We must do the appropriate biomarker testing, ideally with a broad-based next-generation sequencing [panel]. However, if that's not available, it's still important to do sequencing by polymerase chain reaction to identify patients. If we don't identify them, they're not going to receive the best first-line treatment.

We know that, even in clinical trials, a significant number of patients don't go on to receive subsequent therapies, and so I believe it's important to get it right when we do first-line treatment. This requires us to do testing upfront and then to be able to interpret both the testing and the available data to select the best treatment.

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(5 suppl, abstr LBA5_PR). doi: 10.1093/annonc/mdz394.076.
2. Yu H, Ahn M-J, Kim S-W, et al. TATTON phase Ib expansion cohort: osimertinib plus savolitinib for patients (pts) with EGFR-mutant, MET-amplified NSCLC after progression on prior first/second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). Cancer Research. 2019;79(13). doi: 10.1158/1538-7445.AM2019-CT032.
3. Sequist LV, Lee JS, Jan, J-Y, et al. TATTON phase Ib expansion cohort: osimertinib plus savolitinib for patients (pts) with EGFR-mutant, MET-amplified NSCLC after progression on prior third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). Cancer Research. 2019;79(13). doi: 10.1158/1538-7445.AM2019-CT033.