How would you treat a potentially resectable stage III lung adenocarcinoma with an EGFR mutation?

How would you treat a potentially resectable stage III adenocarcinoma with an EGFR mutation?
Do you consider any neoadjuvant therapy or proceed to surgery followed by adjuvant chemotherapy and osimertinib? 

This is a very challenging patient scenario that we face with some frequency and it truly is like a complicated puzzle. We have many pieces of the puzzle in front of us- however, we somehow need to put them in the right sequence to help our patients the best. Let’s start maybe with deconstruction of the case and clarifying the puzzle pieces we have at hand we need to position best.

Presumed case scenario might be a patient with a readily or less readily resectable primary lesion along with limited nodal involvement- e.g. single station N1 or N2 disease confirmed with bronch/EBUS. While information is not provided- let us presume a common EGFR mutation- exon 19 deletion or L858R for simplicity. Staging hopefully has been properly completed with PET/CT and brain MR- and on the side, we are glad to learn biomarker testing has been completed- with emerging new perioperative options, at minimum EGFR/ALK and PD-L1 testing should be done on all such patients.

So what do know for fact?

1. Resection alone is certainly suboptimal therapy- perioperative chemotherapy either pre or postop yields tangible survival benefits in such a patient.
2. Immunotherapy is likely of limited or no benefit at all looking at the sum of data available, including recent PACIFIC subset update (and quietly sidestepping the surprising PEARLS subset analysis here- editorial decision...)
3. EGFR TKI adjuvant therapy yields dramatic DFS benefits and (well, glad I did not write this piece earlier in the week)… as of 2 days ago now, we also know that this translates into an OS benefit. A stage 3 patient specifically has a lot to gain given the extremely high relapse rate noted on placebo arm of ADAURA study in this group.
4. EGFR TKI given neoadjuvantly has a much higher response rate than preop chemotherapy, however, this practically never translates to true pathological complete remissions.

Then maybe let’s look at the missing pieces of the puzzle

1. While based on the above, it seems we should try to come up with a treatment program offering both perioperative chemo and EGFR TKI therapy- osimertinib specifically, the proper sequence is completely unclear and will call for individualized decisions. Is the higher preop RR of the EGFR TKI desirable? Would it be better to stay more conventional and within FDA approval guidelines and offer preop chemo- surgery- then EGFR TKI or surgery- postop chemo- EGFR TKI?
2. How about thinking beyond? Since neither chemo nor TKI yields a significant path CR rate- are we better off combining the two based on the metastatic experience suggestive of potential synergy? The NeoADAURA study is assessing just that- and if available at site, might be the best option possibly.
3. Are there biomarkers we could incorporate into decision making? ctDNA clearance, MRD testing, etc?
4. Lastly, are there some patients where maybe, chemotherapy could be omitted and should duration of adjuvant osimertinib be truly 3 years? Recent updates of ADAURA seem to argue for studies extending duration of therapy beyond in light of flurry of recurrences as soon as osimertinib is stopped. This observation highlights the critical role of the dormant cancer cell compartment which we will need to understand better for larger benefits.

Well, enough said. Ultimately, we in consultation with our thoracic surgical colleagues and of course, even more importantly, close engagement with our patients will need to make a call. How important is a very high response rate for successful surgery? How much risk the patient is willing to take? Are there insurance barriers with treatment options in a less evidence-based sequence?

We as a multi-disciplinary treatment team just did make this tough call in an analogous case a few months ago- opting for the high RR of neoadjuvant osimertinib potentially allowing successful surgery in a borderline resectable case and then offering postop platinum doublet chemotherapy followed by adjuvant osimertinib to complete 3 years of therapy. Admittedly, this was just one of the listed paths we could have taken but so far so good for our patient- so maybe, this is a puzzle with many ways of yielding a good outcome? Well- the only way to find out is by playing!

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Tagrisso demonstrated strong overall survival benefit in the ADAURA Phase III trial for adjuvant treatment of patients with early-stage EGFR-mutated lung cancer (astrazeneca.com). 

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