Pending Molecular Testing Results in mNSCLC

Hossein Borghaei, DO:It is also important to discuss a couple of other points. We all deal with patients with lung cancer who unfortunately have a lot of comorbidities when they come into our clinic. Now this case, the patient had a really good performance status, not a lot of different issues. But the question always comes up that at least in some places, there is a long time between obtaining tissue and the patient is diagnosed and she sees a medical oncologist, typically. And then molecular testing is ordered in that visit, and it might be 3, sometimes 4 weeks unfortunately before we have the molecular data.

The question always becomes, do we wait for the molecular testing to come back, or do we just go ahead and start treatment, and which is better or not better? I’m going to make some general comments about that, with the understanding that obviously we practice in different settings. And patients’ well-being should come first above and beyond everything else.

But in my view, I think no patient with metastatic lung cancer should get treatment until we know the molecular profile. And by that I mean, next-generation sequencing is what we should do. Yes, we should have the PD-L1 [programmed death-ligand 1] as a potential biomarker to decide immunotherapy, chemotherapy plus immunotherapy in the absence of targetable lesions. But I think next-generation sequencing should be done on everyone. If a patient comes to my clinic rather asymptomatic, again very similar to the case that we presented here, and I get the sense that waiting another week or two is not going to be harmful to the patient, then my preference, of course with patients’ agreement and full acknowledgment of patients’ preferences and all that, is to wait for the molecular testing to come back. Because it has significant implication as far as tolerability of treatment and responsiveness and everything else. So my preference always is to wait until I have the molecular data before I decide which direction I want to go.

If I see a patient who’s a never-smoker, who comes to my clinic with metastatic lung cancer, I will try to talk to the patient about the importance of the molecular testing and waiting for the results. But if a patient is very symptomatic, then I would probably trigger treatment with chemotherapy alone without the use of immunotherapies because of the potential increased toxicity if a patient has anEGFRmutation or anALKtranslocation and requires targeted therapies. Again, if a patient is not symptomatic, I will wait for the testing. But if they are symptomatic, I would probably start with chemotherapy alone.

If I can wait, then I’ll get my results and let’s say I find aBRAFmutation, much like we have in this case, then my preference is to start with targeted therapy because it works well and because it is very well tolerated, and because it doesn’t really have as big of an impact on the quality of life of a patient because these are oral agents. Patients can take them at home. They are seen in the clinic periodically for toxicity assessment. They won’t have to come to an infusion room, hook up to an IV [intravenous drip] every 3 weeks or so. There is a lot that goes into the targeted therapies that we’re using from a convenience point of view, tolerability, clinical efficacy. I think the preference always is to start with targeted therapy when information is available.

I realize that it is hard for some patients to hear that they have metastatic cancer and that their doctor is not going to start treatment right away. But if we can manage to educate the patients and spend the extra time to say, “These are the reasons why we think we should wait until we have the next-generation sequencing,” I think it goes a long way. So again, using the clinical scenario is helpful. So a never-smoker, if you can wait, please wait.

If somebody comes in, a heavy smoker, has a lot of disease, you have to start something, you still have a possibility of having a targeted therapy. Smoking by itself does not exclude a patient from targeted therapies, but you have a little less likelihood. So in that patient who is in trouble, start with chemotherapy alone, wait for the molecular testing, and then decide whether you want to add the I/O [immunotherapy] or you want to switch back to targeted therapy, depending on the results. At least that’s the way I have been treating these patients.

Since we all realize the importance of finding patients with these rare mutations and the fact that sometimes waiting for the results of the tissue biopsy to come back could be complicated, could take several weeks, I think it’s important to realize that liquid biopsy can be a major asset in this setting. Liquid biopsy panels are easy to perform, a couple of tubes of blood sent to a specific center. And in general, based on the data that we’ve seen recently from multiple institutions and sources, the results of the liquid biopsy can become available a lot sooner than tissue, sometimes in a matter of a week or 10 days, which I think is potentially an important feature of the liquid biopsy that has to be emphasized.

Many of these panels are really good at detecting some of the more common mutations that we deal with—EGFR,andBRAF, and everything else. I think there should be serious consideration given to obtaining liquid biopsy panels on patients who walk into our clinics.

I think it’s also important to realize that again, more recent data suggest that if you do a combination of both liquid biopsy and tissue based NGS [next-generation sequencing], you can detect a higher percentage of patients with various mutations. Meaning that both the liquid biopsy panel and the tissue biopsy could have false negative rates, just because of the technical issues involved in testing. Therefore, at least in my clinic, I am revising my flow such that I do obtain both liquid biopsy and tissue biopsy and send for sequencing and for detection of these mutations on the majority of our patients. Again, because I think finding even another 5% to 10% of patients with both methods that could benefit from targeted therapies is important. That’s how I have decided to [treat] my patients and that’s how I interpret the data. Incorporating liquid biopsy into our practices could be very important.

With all of that in mind, I think we must come to the realization that we really have made significant progress in the treatment of patients with metastatic non—small cell lung cancer. Finding these driver mutations, finding the translocations that can be targeted with specific targeted therapies have been significantly important for our patients and for our practices. Patients respond well because their life is maintained. They have better survivals, or at least they have better clinical outcomes to the extent that we can determine. There are more and more of these mutations that are being found that are now targetable because we have better drugs. We have drugs that penetrate the blood-brain barrier for most of these patients.

These are significant improvements, but these would not have been possible, and our patients would not be able to benefit from it if we don’t perform the testing. So again, at the extent of sounding preachy, we must test our patients. Using liquid biopsy panels, using next-generation sequencing for tissue, streamlining the process so that the testing is reflexively done in all the centers are important aspects of detecting these mutations. For patients withBRAFmutations, particularlyBRAFV600E, I think use of targeted therapies, like we have discussed in this case, is significant and can have a significant clinical impact on the lives of our patients.

Yes, it comes at the cost of some toxicities that we discussed, particularly the squamous cell carcinomas of the skin that must be managed. But nonetheless, the results suggest that if a patient is diagnosed with having aBRAFmutation, targeted therapy is the way to go, at least as the initial step in this process. I would encourage you to improve the testing in your centers and try to detect these mutations, and take advantage of the great data that have been generated for the treatment of these patients.

Transcript edited for clarity.

Case: A 69-Year Old Man With MetastaticBRAFV600E—Mutated Metastatic NSCLC

Initial presentation

• A 69-year old man presented with a chronic dry cough and dyspnea on exertion
• PMH: history of hypercholesterolemia, medically treated; 20 pack-year smoking history, quit 6 years ago
• PE: decreased breath sounds on auscultation

Clinical workup

• Labs: WNL
• Chest X-ray showed a ~4-cm
• Chest/abdomen/pelvic CT showed a 3.7-cm solid pulmonary lesion in the right lobe, ipsilateral mediastinal and subcarinal lymph node involvement
• Bronchoscopy biopsy of the lung lesion and lymph nodes revealed lung adenocarcinoma
• Contrast-enhanced MRI of the head showed a small brain lesion
• Molecular and biomarker testing:
  • PD-L1 TPS 20%
  • EGFR-, ALK-,BRAFV600E+,ROS1-
• Stage T2aN2M1b; ECOG PS 0

Treatment and Follow-Up

• Patient started on dabrafenib 150 mg PO qDay BID + trametinib 2 mg PO qDay; achieved partial response
  • Patient developed intermittent grade 1 fatigue, which was tolerable; continued treatment
• Imaging at 3, 6 and 9 months showed sustained partial response