Biopsies to Understand Resistance to Frontline Treatment in EGFR+ Lung Cancers

Thomas E. Stinchcombe, MD.

It is known that patients with EGFR-positive lung cancers can develop resistance to frontline agents that are found to be effective for their treatment, and resisting these drugs leads to disease progression. Experts believe that performing biopsies on patients to determine their resistance prior to prescribing treatment is essential.

“The value of biopsy at the time of disease progression [is important] to understand the molecular evolution of these tumors,” said Thomas E. Stinchcombe, MD.

Since osimertinib (Tagrisso) has become the standard-of-care (SoC) for treatment of patients with EGFR-mutant lung cancer in the first-line setting and is sometimes used in patients with other alterations like RET-rearrangements, understanding the mechanisms of resistance to osimertinib is an area of active research. The main purpose of some of the research around osimertinib is to develop another therapy from which patients can derive benefit once they are identified as having resistance to frontline SoC and other tyrosine kinase inhibitors (TKIs), such as erlotinib (Tarceva), gefitinib (Iressa), and afatinib (Gilotrif).

In an interview with Targeted Oncology, Thomas E. Stinchcombe, MD, professor, Medicine, Duke Cancer Institute, discussed resistance testing to aid treatment of patients with lung cancer. He also discussed the shift from tissue to liquid biopsy.

TARGETED ONCOLOGY: Can you provide an overview of your presentation? When does resistance testing really help patients?

Stinchcombe: I think the resistance testing has really been the forefront, and I think an example is the first-line EGFR TKIs with erlotinib, gefitinib, and afatinib to discover the T790M resistance mutation. Then the development of osimertinib, which now has become the frontline drug, has shown an example of the value of biopsy at the time of disease progression to really understanding the molecular evolution of these tumors. I think with that success, we're really trying to apply it to other areas of targeted therapies. Specifically, I think the ones on mind are post osimertinib progression, post-TKI progression and the mechanisms of resistance. I think we’re starting to see in our other subgroups that we've seen the acquired resistance mutations becoming the mechanisms to resistance to target therapies. I think there's 2 parts. For 1, we have to understand the mechanism resistance, and second, we have to develop a therapy that that will benefit them when we have identified it. I think it's an area of rapid evolution; some paradigms are probably established where you can do a biopsy and you change your therapy based on that, but other ones are still in the research phase or need to be validated in larger cohorts before we can define them as standard of care.

TARGETED ONCOLOGY: What is some of the research that is going on with resistance testing?

Stinchcombe: With resistance testing, there's sort of 2 common paradigms. One is the tumor biopsy. I think most of us sort of grew up with the tumor biopsy, but these are logistically difficult in terms of scheduling, sometimes the tissue quantity is not sufficient to do the next-generation sequencing, and then some patients don't have disease that is amenable to tumor biopsy either with progression in the brain with a new brain metastasis would be 1 example, or just anatomically, they can't be biopsied.

I think we're in a transition point where we're now moving more to the liquid biopsy for our circulating tumor DNA, and that's great because it sort of avoids some of the delays associated with the biopsy and the inconvenience and risk to the patient. However, I think like any technology, we're still in the formative phase that we have to make sure that the sensitivity and specificity, which are pretty well established, but also the positive negative predictive value, are really well established. That is the Quantum Leap we need to do and move away from the historic sort of tumor biopsy

TARGETED ONCOLOGY: What benefits are resistance testing providing to patients?

Stinchcombe: We have sometimes seen that some patients will transform from a non–small cell lung cancer to a small cell lung cancer, and that is a different therapy, a different prognosis and a major event. It's clear that people with RB1 and P53 alterations are at high risk for this transformation, and that would be 1 situation where they can do a biopsy.

Second, we have really promising clinical trials. I think more and more of these trials are requiring a biopsy at the time of progression so that they really know the molecular disease status at the time of enrollment. I think it's justifiable to do a biopsy if you have a clinical trial in mind. What the field wants to avoid is just doing biopsies as a fishing expedition and getting a bunch of results that you can’t act on and then you've put the patient through procedure or a delay, and I think we really need to think strategically as we roll this out.

TARGETED ONCOLOGY: What would you say is the key takeaway from your presentation?

Stinchcombe: The key takeaway is that there is a role for biopsy at the time of resistance, particularly for the targeted therapies, but this should really be used for judiciously and really thought of carefully before doing it. We don't want to just apply it randomly. I also think it's important that we do our clinical trials. Some of the preliminary evidence that that we've seen can be really validated and become standard of care.

TARGETED ONCOLOGY: Do you recommend resistance testing at every relapse?

Stinchcombe: Every relapse is different in terms of the patient, in terms of the disease, whether it's ALK- or EGFR-positive disease, behavior, and the future treatment options, so I don't think we can give a generic recommendation across all situations at this time. I think that there are select patients where it is very valuable.

TARGETED ONCOLOGY: What sort of criteria are you looking for when evaluating patients for retesting for resistance testing?

Stinchcombe: I am looking for things such as a small cell transformation, or maybe if I have a specific clinical trial in mind, maybe if there's ambiguity about whether this is truly progression or not, so there is a lot of clinical trial criteria that you have to factor in. This is why I think oncology is getting more complex. Historically, we did chemotherapy first, chemotherapy second, and maybe chemotherapy [thereafter], but now I think we're starting to understand the diversity of this disease.

TARGETED ONCOLOGY: Is the creation of resistance testing impacting the way that physicians sequence treatment?

Stinchcombe: Ideally, we'd like really a much more personalized treatment. I think we're on the cusp of that right now, but we really need to make some refinements and make it clear that they were benefiting patients. I also think that this is very tied to the current drug development. There are some very promising agents that are in development, and we need to make sure that those trials complete accrual, and the drugs are available widely.