Osimertinib Established as Preferred EGFR TKI Treatment in EGFR-Mutated NSCLC

Zofia Piotrowska, MD, MHS

Osimertinib (Tagrisso) has been established as a preferred frontline EGFR tyrosine kinase inhibitor (TKI) compared with first-generations TKIs for the treatment of patients withEGFR-mutant non—small lung cancer (NSCLC), according to Zofia Piotrowska, MD, MHS.

The updated findings from FLAURA, which were presented at the 2019 ESMO Congress, showed that the median overall survival (OS) for osimertinib was 38.6 months (95% CI, 34.5-41.8) compared with 31.8 months (95% CI, 26.6-36.0) for erlotinib (Tarceva) or gefitinib (Iressa) in patients with metastaticEGFR-mutant NSCLC (HR, 0.799; 95% CI, 0.647-0.997;P= .0462).¹At 3 years, 54% of patients who received osimertinib were alive versus 44% in the erlotinib/gefitinib arm, despite crossover between arms.

Initial results showed that frontline osimertinib reduced the risk of disease progression or death by 54% compared with erlotinib or gefitinib in this patient population. The median progression-free survival (PFS) was 18.9 months (95% CI, 15.2-21.4) with osimertinib versus 10.2 months (95% CI, 9.6-11.1) with standard therapy (HR, 0.46; 95% CI, 0.37-0.57;P<.0001).²These preliminary data led to the April 2018approval of osimertinibin the frontline setting for patients with NSCLC whose tumors harborEGFRmutations (exon 19 deletions or exon 21 L858R substitution mutations).

&ldquo;There are a lot of exciting things still to come inEGFR-mutant lung cancer, but for now, the main message is that osimertinib is our preferred first-line treatment,&rdquo; said Piotrowska, a medical oncologist at Massachusetts General Hospital and an instructor at Harvard Medical School.

In an interview withTargeted Oncologyduring the14th AnnualNew York Lung Cancers Symposium, Piotrowska discussed the role of the EGFR TKI osimertinib as a treatment for patients withEGFR-mutant NSCLC. She also highlighted how it compares with other therapeutic options available for this patient population.

Targeted Oncology:Could you provide an overview of research updates in EGFR-mutant NSCLC?

Piotrowska:The randomized phase III FLAURA trial, which compared osimertinib with erlotinib and gefitinib, showed that osimertinib improved both PFS and OS compared with the first-generation EGFR drugs. The FLAURA trial really establishes osimertinib as a standard of care for newly diagnosedEGFR-mutant patients.

Some combination treatment strategies may potentially become a standard of care in the future, including the combination of EGFR inhibitors with VEGF-targeted therapies, such as bevacizumab (Avastin) and ramucirumab (Cyramza), as well as the combination of EGFR inhibitors and chemotherapy. Both of those strategies have shown promise when combined with first-generation EGFR inhibitors. In upcoming trials, we will be looking at those combinations together with osimertinib. They have the potential to transform our standard of care.

It's important to identify these [EGFR-mutant] patients early, because even if they have high PD-L1 expression, EGFR inhibitors are the mainstay of treatment; there is a risk to starting immunotherapy prior to the results of theEGFRtest coming back. We know that immunotherapy is not an effective treatment strategy for patients withEGFR-mutant lung cancer and, additionally, we have also seen that the risks of the EGFR inhibitor can be increased if it is started after immunotherapy. It's important to wait for the testing to return and treatEGFR-mutant patients with the appropriate TKI and not with immunotherapy in the first-line setting.

Targeted Oncology: What ongoing studies in theEGFR-mutant lung cancer space would you like to highlight?

Piotrowska:The most exciting data that we saw at the 2019 ESMO Congress was the OS data from the FLAURA trial. Previously, we had seen that FLAURA, which was a randomized phase III study comparing frontline osimertinib with first-generation EGFR inhibitors, was positive for its primary endpoint, which was PFS.

We had eagerly awaited the results of the OS analysis from that study, and at the 2019 ESMO Congress, we saw those results come out. Osimertinib improved OS compared with those older drugs in newly diagnosedEGFR-mutant patients, with a median OS of about 38 months and a hazard ratio of about 0.79. These data really solidify the role of osimertinib as the preferred agent for frontline use inEGFR-mutant lung cancer.

Targeted Oncology: What are the central nervous system (CNS) effects of osimertinib?

Piotrowska:Osimertinib has very good CNS penetration and very good activity against both parenchymal brain metastases and even leptomeningeal disease, as we saw in the BLOOM trial. The CNS activity of osimertinib is really part of what contributed to the positive results of the FLAURA study. We often see patients who have been on osimertinib with very good CNS control. Even when their systemic disease may progress, they still maintain good CNS penetration.

One challenge in the clinic is deciding what we do in those scenarios. In those patients, continuing osimertinib can help provide continued CNS control, even when switching to another systemic therapy, such as chemotherapy.

Targeted Oncology: Could you discuss the phase III RELAY trial, which looked at the combination of erlotinib and ramucirumab?

Piotrowska:At the 2019 ASCO Annual Meeting, we saw the results of the RELAY trial, which was a large phase III study that randomized newly diagnosed patients withEGFR-mutant lung cancer to erlotinib plus or minus the VEGF-directed antibody ramucirumab.

RELAY was a positive study; the combination of erlotinib plus ramucirumab led to an improvement in PFS over erlotinib alone. It remains to be seen how we should incorporate this treatment strategy into our current landscape in 2019, because the comparator arm is no longer erlotinib alone, but rather osimertinib.

This newer drug that hasn't yet been combined together with VEGF-directed therapy, such as a ramucirumab or bevacizumab. Right now, there are upcoming clinical trials that will combine osimertinib with bevacizumab. This will be performed through ECOG-ACRIN and I'm excited to see the results of that study.

Targeted Oncology: The ARCHER 1050 trial compared dacomitinib (Vizimpro) with first-generation EGFR inhibitors in the frontline setting. What is important to note from those data?

Piotrowska:ARCHER 1050 was a large randomized phase III study, which compared the second-generation EGFR inhibitor dacomitinib with the first-generation TKIs. ARCHER 1050 showed an improvement in PFS and OS when dacomitinib was compared with the first-generation drugs. Dacomitinib has not been widely adopted as a frontline treatment strategy, because the ARCHER 1050 data came out around the same time as the FLAURA trial, which also showed an improvement in PFS and now OS with osimertinib.

One of the challenges with dacomitinib is some of the adverse events that we have seen, including high rates of skin and gastrointestinal toxicities. All of those are relatively common with dacomitinib, and the safety and toxicity profiles of that drug have led many of us [oncologists] to not use it as much in the frontline setting as we do osimertinib—which is a newer drug that is more wild-type sparing and generally has lower rates of toxicities.

Targeted Oncology: What challenges are being faced for later lines of therapy following osimertinib?

Piotrowska:This is an increasingly frequent challenge in our clinics with frontline osimertinib use. The median PFS of that drug is about 19 months, so more and more we are seeing patients progressing on osimertinib. One treatment strategy is the role of continuing osimertinib beyond progression and, if patients have oligoprogression, [we] incorporate the use of locally ablative therapy, radiation, or sometimes even surgery if there's just one sight of progression seen.

However, for patients who have more widespread or symptomatic progression, a switch in systemic therapy will be indicated. For those patients, [it is important to] obtain a biopsy. Tissue biopsies, rather than liquid biopsies, will allow us to look for histologic transformations, which can come up after osimertinib. Using a tissue biopsy will be important in selecting next lines of therapy.

What we have seen so far is that osimertinib resistance can arise through several different mechanisms, the most common of which seems to be second-siteEGFRmutations and resistance mutations, such as the C797S mutation. This occurs at the site of osimertinib binding to EGFR and blocks osimertinib binding, and it seems to happen in about 10% to 20% of patients who receive osimertinib, not as frontline therapy but as later-line therapy.

[The osimertinib resistance occurrence rates] may be a little bit lower after first-line osimertinib use, although the numbers are still small. About 15% of patients or so seem to have resistance throughMETamplification, a bypass pathway that can mediate osimertinib resistance, and those patients may be sensitive to the combination of an EGFR/MET inhibitor.

Some patients can have histologic transformation; we have known that small cell transformation can occur. From some recent data presented out of Memorial Sloan Kettering Cancer Center, we have seen that that squamous cell transformations can occur in patients progressing on osimertinib.

All of these are important to identify. In some cases, they can lead to changes in treatment and certainly should lead us to enroll patients in clinical trials that are potentially targeting these different resistance mechanisms. At the 2019 ASCO Annual Meeting, we saw some responses in patients treated with a bispecific MET/EGFR antibody JNJ-372 as well as the HER3 antibody-drug conjugate U3-1402. Those are clinical trials to consider for those patients.

For patients withMETamplification, using a combination of EGFR- and MET-directed antibodies, which is being explored in the SAVANNAH trial, is a good option. For many patients who don't have a resistance mechanism identified today, chemotherapy or possibly chemotherapy plus immunotherapy remains the standard of care.

The data for chemotherapy and immunotherapy is still limited, with small numbers ofEGFR-mutant patients enrolled on the IMpower150 trial. Knowing that there may be a risk to reintroducing TKIs in patients who get them, I am cautious about using chemotherapy and immunotherapy and going back onto TKIs afterwards.

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). doi: 10.1093/annonc/mdz394.076.
2. Ramalingam S, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA.Ann Oncol. 2017;28(suppl_5). doi: 10.1093/annonc/mdx440.050.