Research Efforts Strive to Overcome Osimertinib Resistance in EGFR+ Lung Cancer

Helena A. Yu, MD, discusses novel non–small cell lung cancer combinations and biomarkers that are under investigation in order to overcome osimertinib resistance

Osimertinib (Tagrisso) has become an established frontline treatment option for patients with EGFR-mutant non–small cell lung cancer (NSCLC) but overcoming resistance to the agent continues to be a challenge, according to Helena A. Yu, MD, who added that several trials are underway to combat this.

In April 2018 the FDA approved osimertinib as a first-line treatment for patients with NSCLC whose tumors harbor EGFR mutations was based on data from the phase 3 FLAURA study (NCT02296125). Results showed that frontline osimertinib reduced the risk of progression or death by 54% compared with the standard-of-care EGFR TKIs gefitinib (Iressa) and erlotinib (Tarceva).1

Since the agent’s approval, osimertinib has been adopted as a frontline standard of choice, according to Yu. With its widespread use, the issue of resistance has become more pronounced. Several studies have since launched to examine methods to overcome this resistance. One such effort of interest is the open-label multicenter, biomarker-directed, phase 2 ORCHARD trial (NCT03944772), which is examining the optimal treatment for patients with EGFR-mutated NSCLC, depending on their underlying resistance mechanism to frontline osimertinib.2

Additionally, in the early-phase CHRYSALIS study (NCT02609776), the combination of amivantamab (JNJ-61186372; JNJ-6372)plus lazertinib (previously, GNS 1480) demonstrated encouraging preliminary activity in patients with EGFR-mutated NSCLC who had relapsed following treatment with osimertinib.3

“There are a lot of new emerging ways to treat [patients with] EGFR-mutant lung cancer. Osimertinib has really moved the needle in the first-line setting,” said Yu. “I’m excited about some of these combinations with osimertinib to see whether we can help patients [achieve] disease control for longer and live longer with their metastatic disease. I also look forward to seeing learning more about some of the combination treatments that are based on patients’ acquired resistance alterations. Some really promising targeted treatments [are being examined] for all comers following osimertinib resistance.”

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on Lung Cancer, Yu, a medical oncologist at Memorial Sloan Kettering Cancer Center (MSKCC), discussed other novel combinations and biomarkers that are under investigation in order to overcome osimertinib resistance.

OncLive®: Could you start by speaking to the clinical significance of the FLAURA trial and the role of osimertinib in EGFR-mutated NSCLC?

Yu: In terms of what we use for the first-line treatment of patients with EGFR-mutant lung cancer, one of the defining studies was FLAURA. This study randomized patients to receive frontline osimertinib versus a standard-of-care TKI, which was either first-generation erlotinib or gefitinib. [Osimertinib led to] an improvement in both progression-free survival (PFS) and overall survival (OS) compared with the other 2 [agents]. Based on these data, osimertinib was approved by the FDA for use [in this patient population]. The majority of providers [have since] adopted that [agent] as their first-line treatment of choice.

An alternative combination approach was examined in the RELAY trial and resulted in another approved option in the frontline setting. Could you discuss this research?

If we don't go with the newer-generation EGFR TKI, one of the other treatment strategies would be to add something to the earlier-generation TKI. The 2 [approaches] that have been combined with EGFR TKIs are chemotherapy and VEGF inhibition. Earlier studies examined erlotinib plus bevacizumab (Avastin).

More recently, there was the RELAY study, which enrolled patients and gave them erlotinib with or without ramucirumab (Cyramza). Results showed an improvement in PFS, as well as OS. One thing to mention is that the trial did exclude patients with brain metastases; that's an important difference from FLAURA. Results [from RELAY] led to the FDA approval of the combination of erlotinib plus ramucirumab, making it another option for patients in the first-line setting.

Based on these data, are trials planned to combine newer-generative EGFR TKIs with VEGF inhibition?

That’s the natural way to go. Several studies are ongoing, but one to highlight is a soon-to-open ECOG study where we're looking at osimertinib versus osimertinib plus bevacizumab based on the RELAY study and other studies.

The other thing is, based on the FLAURA study and other studies, [is that we have seen] improvements with adding chemotherapy. Usually we use chemotherapy in the second-line setting, but we can also add it to the EGFR TKI. Again, we’ve seen improvements in PFS and OS [with this approach]. The ongoing FLAURA2 study is examining osimertinib versus osimertinib plus chemotherapy.

Are other osimertinib combinations under exploration? What are the challenges faced with osimertinib resistance?

The challenge with osimertinib combinations is we're finding osimertinib resistance to be much more diverse. When patients became resistant to erlotinib, half of them developed T790M, so it made sense to target T790M; that was how osimertinib was developed. However, with osimertinib, because we're seeing such diverse resistance, it's much harder to target a specific mechanism of resistance with combination therapy.

For example, giving a MET inhibitor plus osimertinib would be less helpful because, ultimately, only about 15% of patients develop MET amplification. Essentially, you would be targeting the wrong mechanism of resistance for the majority of patients. [Approaches] such as chemotherapy or VEGF inhibition, because they target general tumor biology, seem to be the best way to go.

At MSKCC and Dana-Farber Cancer Institute, we are also looking at dual EGFR inhibition, so using a third-generation TKI and an earlier-generation TKI. An ongoing study is evaluating osimertinib plus dacomitinib (Vizimpro) and osimertinib plus gefitinib in the first-line setting. The idea is to be able to prevent all the different acquired EGFR alterations that might [develop].

With regard to osimertinib resistance, does circulating tumor DNA (ctDNA) show promise in identifying resistance mechanisms?

There have been both ctDNA, as well as tumor tissue series, that have looked at resistance mechanisms to osimertinib; [these mechanisms] fall into 3 categories. [The first includes] acquired EGFR alterations that basically makes osimertinib not [as effective]; these include the acquired EGFR C797 or EGFR G724 and they are seen with some frequency. Then, there are off-target resistance mechanisms, which [includes the] upregulation of bypassing link pathways; that’s the MET amplification and acquired ALK fusions or RET fusions. The cancer then finds other ways around the EGFR signaling inhibition. Thirdly, what we're seeing more with osimertinib is histologic transformation, so cancers that were previously adenocarcinoma transformed to squamous cell lung cancers or small cell lung cancers; those cancers are really only identified on tumor tissue. If you have a suspicion for that, or if there isn't another mechanism of resistance identified on plasma, at this point, a tissue biopsy might be the most proven way to go.

In practice, what are some of the factors that you're considering when choosing treatment following osimertinib resistance?

You have to look at the patient in front of you. Is the patient symptomatic? Do they have a high burden of disease? Is it very indolent progression where things are only changing by a few millimeters in 1 or 2 sites? If so, you might want to just continue the EGFR inhibitor for a period of time. If there is oligoprogression, where most of the disease remains controlled on osimertinib but there are a few sites that have some growth, one could think about radiation or some kind of local treatment to growing areas and then continuing osimertinib.

However, if someone is symptomatic or the disease is significantly progressing, my standard practice is to [do a] biopsy to see whether there are potential resistance mechanisms that we can treat with targeted therapy and to rule out histologic transformation. If not, then I would proceed with chemotherapy.

Could you speak to the ORCHARD study and the hope for this research?

That study is of interest because it's targeting different mechanisms of resistance. [In ORCHARD,] patients [are biopsied] after first-line osimertinib and then treated based on those biopsy results. We have a cohort of [patients who have a] MET amplification and they’re receiving the MET inhibitor savolitinib with osimertinib. If [a patient has an EGFR] C797S [mutation], then they’ll receive osimertinib plus gefitinib. [The trial is] also addressing emerging resistance mechanisms. [For example], if [a patient] has a RET fusion, we're going to be treating you with osimertinib plus selpercatinib (Retevmo). That's a neat way to really personalize treatments, to try to target the mechanism of resistance in an individual patient's tumor. Those are all really exciting combinations.

If possible, it's always better to look at a patient's individual molecular results after a biopsy and to try to tailor treatment based on any alterations observed. However, if there are none [to be detected], there are a few possible treatments that we're looking at post osimertinib. [In a] more recent update from the 2020 ESMO Virtual Congress, [we saw] amivantamab, which is a bispecific MET/EGFR antibody and lazertinib, which is a third-generation EGFR TKI. That combination was looked at immediately after osimertinib and did look promising both from a response rate, as well as time on treatment perspective. That's one [combination] to keep our eyes on.

The second [agent] is patritumab deruxtecan (U3-1402), which is a HER3 antibody-drug conjugate. That [agent] was looked at after TKI and chemotherapy, but also appeared to be promising, with a reasonable response rate and time on treatment. We look forward to further data to confirm these early results.


  1. Soria JC, Ohe Y, Vansteenkiste, et al. Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer. N Eng J Med. 2018;378:113-125. doi:10.1056.NEJMoa1713137
  2. Yu H, Goldberg S, Le X, et al. ORCHARD: a phase II platform study in patients with advanced NSCLC who have progressed on first-line osimertinib therapy. J Thorac Oncol. 2019;14(10):s647. doi:10.1016/j.jtho.2019.08.1366
  3. Cho BC, Lee KH, Cho EK, et al. Amivantamab (JNJ-61186372), an EGFR-MET bispecific antibody, in combination with lazertinib, a 3rd-generation tyrosine kinase inhibitor (TKI), in advanced EGFR NSCLC. Presented at 2020 ESMO Congress; September 19-September 21, 2020; Virtual. Abstract 1258O.