Progression of BRAF V600E+ Metastatic NSCLC

Joshua Bauml, MD:One of the things that’s really important for patients who are receiving molecularly directed therapy such as dabrafenib and trametinib is that at the time of progression, I personally always do another molecular interrogation to try to identify mechanisms of resistance. You can do that either through a tissue biopsy of something that’s growing or the use of circulating tumor DNA on a plasma assay….Many such assays…are available in the commercial space.

The reason…I do this from extrapolation from other targeted therapies is that we can sometimes identify mechanisms of resistance to target with combination treatment. This gets to be really complicated and, in all honesty, the early data…about mechanisms of resistance toBRAF-mutant non—small cell lung cancer that’s treated with targeted therapy have not revealed any specific target that we can really seek out.

So one could very reasonably argue: Why are you doing that additional test if there’s not an established line that you’re going to go to? And…my response…is that it’s important to remember that all of those studies…looking at mechanisms of resistance are really relatively small—and so it is not impossible at all that we are missing something in those theories. And so, I think that it is very reasonable to continue to look for mechanisms of resistance.

The other thing…I always do in patients who are progressing on targeted therapy is if they have oligoprogression, sort of focal progression, I…utilize something like stereotactic radiosurgery or another form of localized ablation to try to eradicate one particular site because mechanisms of resistance can develop in a heterogenous fashion when we’re using targeted therapy.

When one is doing reinterrogation of the molecular profile of a patient who is progressing on a targeted therapy, there are many approaches that one can use. You can use a tissue biopsy and then do next-generation sequencing assay off…that. Or, you can use a liquid assay and use circulating tumor DNA, from which you can also do a next-generation sequencing profile.

Now both of these have their advantages. Obviously, a blood test is a whole lot easier to do than putting a patient through a biopsy. There’s much less risk of adverse events. But the key thing…we must remember is that the sensitivity of a liquid biopsy, regardless of whether it’s done at diagnosis or at the time of progression, is not 100%. And so a positive liquid biopsy, if identified, is very useful. If you have a patient at diagnosis, you do a liquid biopsy that reveals aBRAFV600E mutation, you can act on that. The incidence of false positives is close to 0, and that is very reassuring.

In contrast, if you have a negative liquid biopsy, that is not illuminating at all. A negative liquid biopsy tells you nothing about the molecular profile. It does not show you that there is not a mutation-based mechanism of resistance. It just tells you that you were not able to pick one up. Whether that’s due to tumor shedding or lack thereof, or whether that’s due to just the overall tumor volume, there are many factors that can affect it. But the key thing is that if you find that the liquid biopsy is not revealing anything, you shouldn’t stop there.

Now at the time of progression on dabrafenib and trametinib, given the lack of an established path forward and a clear thing we’re looking for, I wouldn’t put a patient through a very risky biopsy—if something was growing in a dangerous location, I would not put them through a biopsy in that setting. But if there was something that was easily accessible and growing, I may be more tempted to try to interrogate that sort of lesion.

The other thing when you’re doing a tissue biopsy, though, is that you don’t want to biopsy something that is not growing. That is a waste of everyone’s time and energy because the thing that’s not growing does not have the mechanism of resistance that is driving progression. And so, as a result, putting the patient through a biopsy there exposes them to risk of the biopsy without the potential benefit of identifying the mechanism of resistance.

Transcript edited for clarity.

Case: A 62-Year-Old Woman With MetastaticBRAF^V600E-Mutated NSCLC

Initial Presentation

• A 62-year-old woman presented with a 4-month history of chronic cough, dyspnea, loss of appetite and weight loss
• PMH/SH: 25 pack-year smoking history, quit 12 years ago
• PE: Right-sided wheezing on auscultation

Clinical Workup

• Labs: WNL
• Chest/abdomen/pelvic CT showed a 2.5-cm solid pulmonary lesion in the left inferior lobe, ipsilateral peribronchial lymph node involvement and multiple small hepatic lesions
• Bronchoscopic biopsy of the lung lesion and lymph node revealed lung adenocarcinoma
• Contrast‐enhanced MRI of the head showed no evidence of metastases
• Molecular and biomarker testing: BRAF^V600E+,EGFR-, ALK-, ROS1-,PD-L1 0%
• Stage T1cN1M1c; ECOG PS 0

Treatment and Follow-Up

• Started on dabrafenib 150 mg PO qDay BID + trametinib 2 mg PO qDay; achieved a partial response
  • Patient developed intermitted nausea and vomiting, medically controlled
• Imaging at 3,6 and 9 months showed sustained partial response