Patient Scenario: Navigating Molecular Testing Dilemmas in Metastatic NSCLC

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Charu Aggarwal, MD, MPH: With that, I think it’ll be nice to go through a patient profile because both you and I see patients such as this as either new patient consults or referrals from the community. I think this may highlight a few nuances that are critical in the management of these patients. So I’ll walk through our 64-year-old [man] who presented first to his primary care doctor with fatigue, shortness of breath, and weight loss, about 12 pounds over the last month, but no real change in eating habits, and past medical history of hyperlipidemia, anxiety, hypertension, slightly limited in performance status due to this persistent fatigue, but overall still able to do all activities of daily living. So I’ll say [an ECOG] performance status of 1.

Physical examination was pretty unremarkable except for a few expiratory wheezes, liver function, renal function, and complete blood counts were normal. Imaging, a CT scan of the chest revealed a 6-cm mass in the left upper lobe. With further workup, a CT scan of the abdomen showed liver metastases. So [a] CT-guided biopsy was performed [on] this left upper lobe mass that confirmed a nonsquamous, non–small cell lung cancer [NSCLC] with an adenocarcinoma histology. Further confirmation with imaging revealed stage 4, metastatic nonsquamous NSCLC. This patient was symptomatic, fatigued, short of breath, and due to testing availability, the patient didn’t actually go ahead and receive molecular genotyping. The patient promptly initiated chemoimmunotherapy with cemiplimab, pemetrexed, and carboplatin. I’ll stop here and ask you, for this patient profile, would you agree with this treatment decision, and tell me how you would have approached this patient differently?

Melina E. Marmarelis, MD:It pains me a little bit to see this, but it happens. This happens and I think looking through surveys of doctors in particular one of the main reasons people don’t get molecular testing is they feel an urgency to get started on treatment and that is [a real issue]…. We see that in clinic. We see it with our very symptomatic patients, so I understand that pressure. I think in an ideal world, at the time of biopsy, tissue molecular testing would be initiated either by a reflex pathway meaning that the physician actually doesn’t need to place that order which can make things go a little bit faster.

Or even if the physician does need to place the order at the first visit, that’s at least in process. There are limitations there that can take a lot of time. It can take several weeks and sometimes you don’t have several weeks to wait. So that’s where liquid biopsy, just a blood test really comes in. That has a very quick turnaround time of 7 to 10 days depending on the test that’s ordered and so you can, especially in the metastatic setting with a heavy high burden of disease, usually get a lot of the molecular information from a liquid biopsy.

If I had seen this patient as a new patient [and] they had no molecular testing, I would have drawn a liquid biopsy that day, initiated the tissue testing in the background, and then hoped to get the answer before starting treatment. The risk is that if you start immunotherapy and then have to switch to one of the targeted therapies, there can be increased toxicity. So if I felt that that patient really needed to start treatment right away, I would start with chemotherapy alone and hold back on the immunotherapy until the molecular testing comes back, even though that’s hard. It’s so hard. And then wait for that testing to come through. We see this, though, because immunotherapy is out there. It’s so exciting and patients want to start that right away, but I think the counseling and the patience part of it is actually one of the harder parts.

Charu Aggarwal, MD, MPH: Absolutely. I want to touch on a couple of things that you highlighted; one is that molecular testing is important. We know that it’s important, but we recognize that it’s arduous to get it done. Tissue is often not available, or you have no idea whether or not it’s going to be adequate, even if it’s available. So, it may be there, but we don’t know what the DNA content looks like. It may be a very small biopsy specimen. Then you’re left waiting for weeks without knowing whether or not you’re going to get an answer. I think that’s where liquid biopsy really comes in with the ability to offer you an answer within 7 to 10 days.

But, again, we have to recognize that liquid biopsies also have their shortcomings. It’s not an absolute test. There can be situations where there is no shedding, and there is a lack of an actionable alteration does not always mean that the test has been performed accurately. So there is a lot of room for interpretation, and…something that we are actively performing in our program is [that] education around interpretation of results. So a nondetectable test is not a negative test. It’s just a nondetectable test and should be followed up.

The second thing that I would highlight is that, as you said, Melina, it’s so important that if you are in critical need to start treatment, to start with chemotherapy alone. And we sometimes find ourselves in a situation where we do have to start treatment where, let’s say, liquid biopsy comes back with a “not detectable” or there’s not enough ctDNA [circulating tumor DNA] shed and the tissue biopsy is still in progress for sequencing. I think it’s totally OK to start with chemotherapy. But I think worrying about the consequences of starting immunotherapy and then having to switch to targeted therapy are not inconsequential and should be weighed seriously.

Transcript edited for clarity.