Predicting the Future of Overcoming EGFR Resistance Mechanisms in NSCLC

Sukhmani K. Padda, MD

As research efforts prevail with encouraging therapies designed to overcome resistance to EGFR-directed therapies for patients with advanced non–small cell lung cancer (NSCLC), Sukhmani K. Padda, MD, noted that hope indeed exists for this patient populations.

“There may be strategies after a certain resistance that are going to be helpful across a diversity of mechanisms of resistance,” said Padda, director of thoracic medical oncology at Cedars-Sinai Medical Center. “There are other strategies that are going to be much more specific to the resistance profile in that patient's particular tumor.”

In an interview with OncLive® during the 22nd Annual International Lung Cancer Congress, a program hosted by Physicians’ Education Resource®, LLC, Padda discussed strategies to overcome EGFR resistance in patients with NSCLC.

OncLive®: Your presentation at this year’s congress focused on EGFR resistance mechanisms. Why is this an important topic of discussion for the community physician?

Padda: One of the first things I focused on was the type of EGFR resistance. Is it EGFR-dependent resistance? Has there been a second-site EGFR mutation that prevents binding of the drug? Is it an EGFR-independent mechanism of resistance? That means looking to see if a bypass track has been activated downstream of activation of pathways, such as MAPK or PI3K. Or, has there been histologic transformation, where the tumor can transform from adenocarcinoma to high-grade neuroendocrine or small cell lung cancer [SCLC]?

Unfortunately, with cancer, it's not always so simple [to identify] and sometimes these mechanisms of resistance co-occur with one another, and as each generation of targeted therapy gets better, the mechanisms of resistance also get much more diverse.

As an example, with earlier-generation TKIs like erlotinib (Tarceva) and gefitinib (Iressa), there was a dominant mechanism of resistance—EGFR-dependent resistance with development of T790M in 60% of tumors. However, with the third-generation drug osimertinib (Tagrisso), you see much more complexity and do not see a dominant mechanism resistance. When osimertinib is given in the second-line setting in the context of a T790M mutation, you can see evidence of an on-site EGFR mutation called C797S in about up to about 20% [of these cases].

However, if we move osimertinib into the first-line setting, that becomes even less frequent, only occurring in the single digits; some literature quotes around 7%. Then, there is a diversity of resistance mechanisms, from MET amplification being the second most common to activation of the MAP kinase pathway with acquired BRAF mutations, KRAS mutations, and PIK3CA mutations. Histologic transformation to SCLC seems to be potentially a more prominent mechanism of resistance to third-generation drugs.

There has been some data showing that combining a third-generation TKI with some sort of MET inhibitor for those patients has some probability of shrinking and controlling the tumor. An example of that was the combination of the third-generation drug lazertinib and a bispecific monoclonal antibody that hits EGFR and MET. Activity was seen in this group of patients who had been [previously] treated with EGFR-directed drugs. Moreover, that activity [was most prominent] in patients who had EGFR- or MET­-based resistance, [with an objective response rate of] 47%.

There may be a way for precision oncology even at the time of resistance. Another therapeutic is a small molecule inhibitor known as savolitinib [and was studied in combination] with osimertinib at the time of resistance with evidence of MET amplification. Again, there was a modest objective response rate of about 30%. You may be able to use your combination strategies at the time of resistance.

For EGFR-dependent resistance, one of the most challenging to treat is what is called the triple mutation. This is where the tumor has an EGFR-activating mutation as well as acquired T790M resistance and C797S resistance. Fourth-generation EGFR inhibitors are being developed. These are not TKIs; these are allosteric inhibitors. There is some hope, and now clinical trials are ongoing in that specific population.

What is your current approach to treating a patient who develops resistance to EGFR inhibition? How do you determine their next line of treatment?

One of the first things is to reassess the molecular profile of the tumor when it has progressed on osimertinib. With liquid biopsy, you can get an assessment of what's going on at all tumor sites throughout the body that are shedding their DNA into circulation. That's the first step, but the other step to consider is to reassess the molecular profile with tissue biopsy. This is even more important after osimertinib because the rates of histologic transformation seem to be reported at slightly higher rates and first- and second-generation drugs. You don't want to miss a transformation to SCLC, squamous cell carcinoma, or pleomorphic undifferentiated cancers. Tumor biopsy is often a part of that.

Secondly, we need to assess how the disease progression is occurring. Is it relatively limited, with only 1 or 2 sites are progressing, and the rest of the body is stable? In that case, one could consider continuing osimertinib. You could still interrogate the molecular profile, but you could continue osimertinib and consider a local approach of stereotactic radiation to take care of the misbehaving tumors. Some data suggest that you can get increased time on therapy with that approach.

However, if the disease is more disseminated, there is progression on multiple sites, or there is development of new lesion sites, you're generally thinking about switching therapies. In that scenario, that molecular profile testing could help to either guide a patient to a clinical trial, or consider some off-label combination strategies that have been published in the literature.

Finally, the other thing to look at is the status of the brain. We know one of the best qualities of osimertinib is how well it controls central nervous system (CNS) disease because of its pharmacokinetic profile. In the case of if systemic disease is progressing, but CNS disease is controlled, you would typically combine osimertinib and start new chemotherapy to control the disease in the body. Some data have been published showing that the combination seems relatively tolerable, and in my own experience, that's also what I've seen.

How is the use of liquid biopsy complementing or replacing standard tissue biopsy?

There are pluses and minuses of each of these approaches depending on the level of tumor burden. If all of the patient’s cancer is within the lungs, that may not be as good in terms of sensitivity of a liquid biopsy to detect resistance mechanisms, and a tissue biopsy may be more helpful there.

The other disadvantage of a liquid biopsy is that you're not able to look at the tumor under the microscope to see if there has been a change in how the tumor looks. If it is has transformed to a high-grade neuroendocrine type of tumor, that would dramatically change what you do for a patient in the subsequent setting.

In the molecular tumor board [at this conference] there are discussions, such as, “When do you consider tumor biopsy?” A couple of the points that were brought up that I agree with is, if the circulating tumor DNA shows no clear identified mechanism of resistance, that may be a time to pursue a tumor biopsy to make sure you're not missing something. Additionally, if the kinetics of the growth are fast, [one should] worry more about histologic transformation. However, there have been cases that don't progress very quickly where SLC was observed. None of these are, are perfect. In an ideal world, we would get information from both liquid and tissue biopsy.

What molecular markers do you envision will play a bigger role in future research efforts?

The diversity of resistance after osimertinib is complicated and it seems to be even more complex after being used in the frontline setting. It's going to be a tailored approach. If you've seen an acquired fusion, like RET or ALK, go after that. If you see acquired MET amplification, go after that. If you see C797S and if it's in the context of T790M, depending on how those 2 mutations are sitting on the DNA strands, you can even potentially combine osimertinib with an older-generation TKI like erlotinib and gefitinib.

There are also fourth-generation allosteric EGFR inhibitors that are emerging for the triple-mutant EGFR-positive lung cancers, along with C797S and T790M. One of the things to consider as this arena evolves is how to best inform oncologists who are treating these patients around the country.

At the 2021 ASCO Annual Meeting, we saw that the rates of testing in the frontline setting for metastatic lung adenocarcinoma are lower than what we want; they're around 50%. The proportion of patients we're missing who have actionable mutations are not necessarily getting matched with targeted therapies. However, something that is underestimated is when you do get genomic testing, [you need to interpret] the report. They're extremely complex. Education around performing testing is one thing, but the next step is to also think about what tools or resources we can provide oncologists around the country with, in terms of how to interpret these reports. That is challenging because of how quickly drug development is happening and all this technology that is allowing us to interrogate the tumors in these ways. It's great, but then there is a lag in terms of how to keep up with that information.

What combinations are ongoing that you're looking forward to the results of in EGFR-positive lung cancer?

Patritumab deruxtecan is a HER3 antibody-drug conjugate, and HER3 is not necessarily a resistance mechanism, but for patients with EGFR TKI resistance it's widely expressed; about 80% of patients will have evidence of HER3 expression by immunohistochemistry. It's an interesting target for these patients. They saw a good response rate in patients who had received prior osimertinib and platinum doublet chemotherapy, at around 40%. It really seemed to have an effect across the diversity of resistance mutations. That is an interesting and early observation for that therapy, and it will be notable if that plays out as more patients enroll.

You mentioned that fourth-generation EGFR inhibitors are emerging. How do you see that potentially impacting the treatment of these patients who are developing resistance?

The fourth-generation EGFR allosteric inhibitors are very exciting. They are a new class of EGFR drugs and they're not TKIs, monoclonal antibodies, or bispecific antibodies. These are really going to address that subset of patients with the problematic triple mutations. Fourth-generation drugs may be an avenue to really help those patients. There are EGFR-dependent mechanisms of resistance, but there are also other independent mechanisms of resistance and I'm curious to see what we'll see in terms of that.