EGFR TKI Resistance Identified in a Patient with EGFR- and BRAF-Mutant Lung Adenocarcinoma

Brennan J. Decker, MD, PhD

Brennan J. Decker, MD, PhD

Osimertinib (Tagrisso) plays an important role in the treatment of patients withEGFRmutations. However, because this EGFR tyrosine kinase inhibitor (TKI) only works in patients harboring an EGFRmutation, the value of genomic testing continues to expand.

Following itsapproval in April 2018 for the frontline treatment of patients withEGFR-mutant non—small cell lung cancer (NSCLC), osimertinib continues to make an impact in the treatment landscape for lung cancers. This EGFR TKI quickly became the frontline standard of care in the United States based on data from the FLAURA trial.

Inthe randomized phase III FLAURA trial, osimertinib led to a median progression-free survival of 18.9 months versus 10.2 months with erlotinib (Tarceva) or gefitinib (Iressa) in patients with metastaticEGFR-mutant NSCLC, and the median overall survival was 38.6 months versus 31.8 months, respectively. Frontline osimertinib also reduced the risk of disease progression or death by 54% compared with erlotinib or gefitinib.

“It’s been a great breakthrough in terms of overall prognosis for patients who have these mutations, but the only patients that benefit are the ones that have that mutation,” said Brennan J. Decker, MD, PhD.

Although rare, patients that harbor theEGFRmutation as well as a second mutation, such as BRAF, will not benefit from osimertinib. Patients can progress rapidly on a targeted therapy, such as osimertinib, if a co-mutation is present. However, mutations are not looking for multiple mutations in patients, which can lead to a second mutation being missed. The identification of all mutations can be imperative in determining the appropriate treatment for patients with lung cancer.

In an interview withTargeted Oncology, Decker, a clinical fellow in the Department of Pathology at Brigham and Women’s Hospital in Boston, Massachusetts, discussed a real-life scenario of a patient with lung cancer who harbored both anEGFRand BRAFmutation. He highlighted the key takeaways of this case, which he presented at the 2019 Association for Molecular Pathology (AMP) Annual Meeting and Expo (AMP 2019).

TARGETED ONCOLOGY: Could you first discuss the value of identifyingEGFRmutations in patients with lung adenocarcinoma?

Decker:In lung adenocarcinomas, there are many different debilitating mutations that can lead to causing lung cancer. You can think of these as flipping on a switch that activates the cancer programming. One of the major breakthroughs in lung cancer therapies has been to identify those switches and identify ways that we could go about turning them off with medications. One of these molecular switches is the EGFR gene. EGFR is a signaling molecule, and when it is turned on abnormally, it leads to the cancer growing out of control. These therapies targetingEGFR[mutations] slowdown that signaling. It’s been a great breakthrough in terms of overall prognosis for patients who have these mutations, but the only patients that benefit are the ones that have that mutation. There are other such switches beyond EGFR. There are molecules called ALK, ROS1, and BRAF, and all of these things can be mutated and flip on the switch to cause any individual patient’s cancer.

TARGETED ONCOLOGY: Could you discuss the patient case you presented at AMP 2019?

Decker:Unfortunately for the patient that I presented, she had 2 of these switches. That is a very unusual phenomenon. Most patients only have 1 [mutation], so the traditional way that people look for these mutations that cause lung cancer is that they look for them 1 by 1. If you find 1 [mutation] that is positive, since it is very rare to have 2 of these switches flipped on at the same time, people stop looking. However, for this patient, since both the BRAF and EGFR genes were mutated and activated, the drug that targeted just the EGFR gene had no effect.

[Following identification of theEGFRmutation,] she started the medication, and most patients have a pretty nice response to osimertinib. However, she rapidly progressed and got worse. At that time, more complete genomic profile was done of her tumor, and this second mutation in the BRAF gene was uncovered. That led to a change in therapy that has been quite successful for her in the months since she made the switch. She has had a good response, she has been discharged from the hospital, and all of the metrics we use to measure her response look pretty good.

TARGETED ONCOLOGY: What is important to take away from this patient case?

Decker:This case is very illustrative of some of the deficits in the 1 by 1 strategy when looking for these mutations in the setting of lung cancer. It does strongly argue that a complete genomic profile is very valuable to lung cancer patients in general. We don’t know exactly what the frequency of these multiple mutations might be because we are not doing a good job of categorizing them upfront. Certainly, some of the patients that seem to fail the therapy, in fact, have additional activations,[but] because of the way we are looking at their tumors, [we are not catching them].

TARGETED ONCOLOGY: In what ways areEGFRand other mutations identified in lung cancer?

Decker:There are a number of different strategies. First, you can look for 1 thing at a time. At Brigham’s and Women’s Hospital, we have an assay that is very sensitive and looks for theseEGFRor BRAFmutations in little tiny bits of DNA that break off from the tumor and float around in the bloodstream. That’s called cell-free DNA testing. It can detect very small numbers of these mutation reads in the patient’s blood.

You can also look at the tumor as a whole, and the strategy people use is to look at either a panel of genes or many genes within the genome to characterize each 1 of them, all at the same time. That was the insight that was very valuable for this particular patient where we could look at both the EGFR gene and the BRAF gene to identify that the EGFR-targeted therapy alone was not likely to be of great use to her.

TARGETED ONCOLOGY: What sort of challenges do these testing strategies pose?

Decker:One thing we always run into in lung cancer diagnostics in particular is the biopsies tend to not be very high quality. They tend to be small, have a lot of immune cells that are coming in to fight the cancer, there is a lot of tissue reaction, and all of these things tend to dilute the amount of DNA that we can capture from any given biopsy. That is a major challenge for this all-at-once testing paradigm.

Some alternatives are doing gene panel testing in the plasma itself. That patient’s co-mutation status was determined because her initial biopsy was used up by this 1 by 1 testing strategy. By looking at a panel of genes in the circulation, we were about to identify this secondary mutation that was causing her treatment resistance.

TARGETED ONCOLOGY: How does identifying 2 mutations impact the treatment decisions for that particular patient?

Decker:In the case ofEGFRand BRAFmutations, they are actually in the same biological pathway. EGFR sits on the surface of the cell, and its usual job is to take signals from the outside of the cell and translate that to growth signals inside of the cell. Part of the translation is actually through the BRAF gene. You can think of it as EGFR is upstream of BRAF. If you have an activation of BRAF, turning off the upstream switch isn’t going to do anything to the signaling that is going on below because there is a second mutation that is activated in the BRAF gene.

What the clinicians [for this patient] did was went even further down in that pathway and said if we can’t target EGFR alone and we can’t target BRAF alone, what if we target BRAF and something that is even lower on this signaling pathway? That is a major challenge, identifying which medications and combinations are likely to be most effective, but when you have this linear sequence of signaling, you can infer which would be the best treatment option on that basis. We are working on building evidence as a community as to which combinations of mutations respond best to which combinations of therapies.

TARGETED ONCOLOGY: What are your final thoughts on this patient case?

Decker:I want people to learn that there are exceptions to this idea that these activations in lung cancer are mutually exclusive. In our patient, it was both anEGFRmutation and a BRAF