Strategies Evolve for Overcoming EGFR-TKI Resistance in NSCLC

Lyudmila A. Bazhenova, MD, sheds light on initial treatment approaches for patients with EGFR-mutant NSCLC and adapted therapeutic strategies at the time of progression.

Lyudmila A. Bazhenova, MD

Pending overall survival (OS) data from the phase III FLAURA trial, osimertinib (Tagrisso) may be the preferred frontline treatment for patients with EGFR-mutant non—small cell lung cancer (NSCLC), said Lyudmila A. Bazhenova, MD. However, treatment beyond progression on the agent will require more consideration, especially in the face of heterogenous resistance mechanisms.

Initial recommendations of the third-generation EGFR TKI in the frontline setting came after the results of the FLAURA trial, which showed a 54% reduction in the risk of progression or death versus first-generation EGFR TKIs erlotinib (Tarceva) and gefitinib (Iressa) in patients with EGFR mutations. In April 2018, the FDA approved the agent for patients with NSCLC who have EGFR exon 19 deletions or exon 21 L858R substitution mutations.

To ensure that the therapy is made available to patients, molecular profiling via tissue or liquid biopsy is needed, explained Bazhenova, who cautioned that a false-negative result can be expected in up to one-third of liquid biopsies.

Upon progression on osimertinib, patients, depending on the type of resistance pattern, can receive either chemotherapy, an earlier-generation EGFR TKI, or combination therapy. Although data from the phase III IMpower150 trial showed modest activity in a small subset of patients with EGFR or ALK mutations who received the combination of atezolizumab (Tecentriq), bevacizumab (Avastin), paclitaxel, and carboplatin (ABCP) versus BCP alone (HR, 0.54; 95% CI, 0.29-1.03),2 that too may become an option upon exhaustion of all appropriate targeted therapies.

“We need to prove beyond a doubt what the best treatment is for patients who have progressed on osimertinib,” stressed Bazhenova. “We need to have a more formal description of the efficacy for patients who developed other oncogenic drivers as resistance mechanisms. Right now, we have case series, case reports, and individual examples of using certain drugs for those patients, but they have not been well described.”

In an interview during the 2019 OncLive® State of the Science Summit™ on Non—Small Cell Lung Cancer, Bazhenova, medical oncologist, professor of clinical medicine, University of California, San Diego, shed light on initial treatment approaches for patients with EGFR-mutant NSCLC and adapted therapeutic strategies at the time of progression.

OncLive: How has the standard of care changed for patients with EGFR-mutant NSCLC?

Bazhenova: The standard of care for these patients has changed recently due to the results of the FLAURA study. The study compared a new, third-generation EGFR TKI osimertinib with the first-generation EGFR TKIs erlotinib and gefitinib. The study showed that osimertinib improved progression-free survival (PFS) compared with both first-generation EGFR TKIs. The OS data are not mature at this point, so we do not know if the third-generation TKI improves OS. However, the hazard ratio (HR) curves were respectable. With longer follow-up, I believe we might see a survival benefit. We have to test patients with stage IV NSCLC for EGFR mutations. Unless you test patients, you won’t know if there is a fairly effective treatment strategy available to them.

I also went over resistance to osimertinib [in my presentation]. We now have emerging data using cell-free DNA or liquid biopsy looking at resistance patterns to frontline osimertinib. There may be consequences on how we treat patients in the future based on the type of resistance patterns they have.

In addition, I showed the data on the lack of efficacy with single-agent PD-1/PD-L1 inhibitors in patients with EGFR mutations. There are published data showing that treatment-naïve patients who harbor EGFR mutations have no response to drugs like pembrolizumab (Keytruda), nivolumab (Opdivo), or atezolizumab and may, in fact, result in increased toxicity of pneumonitis. I also went over the data of other PD-L1 inhibitors for patients who have received them after progression on EGFR TKIs. I spent some time looking at the IMpower150 trial, which was the only frontline immunotherapy trial that allowed patients with EGFR mutations to enter. There is some hint of increased efficacy with the quadruplet regimen of carboplatin, paclitaxel, atezolizumab, and bevacizumab.

For symptomatic patients, is there enough time to test for EGFR mutations?

This is an excellent question. When we talk to our patients with stage IV lung cancer, we have to understand that some of them have a real medical or physical need to start treatment. In this situation, I certainly would not want to wait 3 weeks for the molecular testing results to come back. Therefore, I would just give the patient chemotherapy. I would not give them chemotherapy plus immunotherapy or immunotherapy alone, due to the potential risk of increasing pneumonitis if you sequence immunotherapy before TKIs. The data for pneumonitis risk are very limited.

However, if you look at the data [from Aaron Lisberg, MD, of UCLA Medical Center], 1 of 7 patients treated with TKIs after pembrolizumab developed pneumonitis; that’s essentially 14%, which is higher than I would expect with osimertinib by itself. It is hard to know if this is a true finding or not, but I prefer not to risk [patients developing] pneumonitis. If the patient develops pneumonitis from TKIs, then unfortunately we have to stop treatment.

However, many patients don't have a physical need to start therapy, they have an emotional need to start therapy. As a physician, it is very important for us to reassure the patient that it is OK to wait 3 weeks for the molecular studies if their tumor is not posing too many symptoms. You can always do a liquid biopsy, which comes back in about 7 to 10 days, in California. However, with a liquid biopsy, you also have to be aware of false-negatives. If you send the liquid biopsy out and it comes back with an EGFR mutation, it's perfectly fine to start treatment and not wait for the tissue to come back. If the liquid biopsy did not show an EGFR mutation, you want to follow that with a tissue biopsy, especially for patients who are nonsmokers or who have other phenotypical characteristics suggestive of an EGFR mutation, as 30% of liquid biopsies come back with a false-negative.

How do you approach sequencing beyond osimertinib?

I start with osimertinib and treat until progression. There are 3 types of progression. You can have a localized progression somewhere in the body, a localized progression in the brain, or you can have more of a systemic progression. I do not stop osimertinib if my patient has a localized progression and is otherwise doing well. That means that they’re not losing weight, they’re not losing energy, and they’re not having new severe pain in more than 1 part of the body. In that situation, I would use local therapy to the progressing lesion and continue osimertinib.

Could you expand on some of the signals with immunotherapy in EGFR-mutant lung cancer?

Traditionally, immunotherapy has not been very effective in patients with EGFR-mutant lung cancer, especially as tested in the second-line setting after failing a platinum-based doublet. IMpower150 is the only trial that allowed patients with EGFR mutations who have failed all available EGFR TKIs to enter and receive a quadruplet with immunotherapy. In that study, the HR seems to be better in patients with EGFR mutations who received the quadruplet as compared with carboplatin, paclitaxel, and bevacizumab. It’s the only trial that we have right now that gives us a hint of efficacy. There are additional trials underway looking at different chemotherapy combinations. Pemetrexed is better tolerated by our patients than paclitaxel, so there are trials looking for patients with EGFR mutations after progression on an EGFR TKI. These patients will be randomized to receive a pemetrexed-based platinum doublet plus immunotherapy and bevacizumab versus the pemetrexed doublet plus bevacizumab.

What are the next steps to take in this field?

When osimertinib was developed, we did studies [versus chemotherapy] and proved that it is the best treatment for patients who developed T790M. Those types of studies need to be done, comparing a first-generation EGFR TKI versus chemotherapy for patients with C797S mutations.

We need to better understand what the best chemotherapy is for our patients who develop resistance to TKIs and we need to come up with better immunotherapy strategies. It is clear that checkpoint inhibitor monotherapy is probably not the best strategy for those patients. We [are looking] into combination immunotherapy, such as vaccines with PD-L1 inhibitors or cell therapy plus PD-L1 inhibitors. All these things need to be examined further.


  1. 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, abstr LBA_PR). doi: 10.1093/annonc/mdx440.050.
  2. Socinski MA, Jotte RM, Cappuzzo F, et al. Overall survival (OS) analysis of IMpower150, a randomized ph 3 study of atezolizumab (atezo) chemotherapy (chemo) ± bevacizumab (bev) vs chemo + bev in 1L nonsquamous (NSQ) NSCLC. J Clin Oncol. 2018;36(suppl 15; abstr 9002). doi: 10.1200/JCO.2018.36.15_suppl.9002.


If the patient has more of a systemic progression, indicated by rapid growth in more than 1 site, I would recommend doing a post-progression biopsy. You can find a mutation called C797S on a post-progression biopsy, which could potentially resensitize your patient to first-generation EGFR TKIs—in which case, you could use either gefitinib or erlotinib as second-line therapy. I've seen BRAF mutations as a resistance mechanism to osimertinib, and I have successfully treated my patients with an approved BRAF combination of TKIs. I've seen MET amplification and have tried using MET inhibitors for those patients. There are clinical trials for patients who develop MET amplification, one of which is called SAVANNAH. That trial is open at many institutions, in which patients receive a combination of osimertinib and savolitinib.