Squamous Cell Histology in NSCLC: Targeted Approaches

Mark Socinski, MD:Squamous carcinoma does behave a little differently than nonsquamous. Squamous is a very predictable spread from the primary tumor to the lymph nodes to elsewhere. The common areas of spread of squamous are adrenal gland, liver, bone, and the brain can be involved like it was in this case; however, that’s unusual. Probably less than 10% of initially diagnosed patients with squamous will have the presence of brain metastases. That’s probably half the rate that we see in nonsquamous non—small cell lung cancer. For nonsquamous, which is principally adenocarcinoma, you don’t necessarily have this predictable spread from the primary tumor to the lymph nodes to elsewhere. You can have a primary tumor, no nodal involvement, and have brain metastases. That’s a common presentation of nonsquamous, particularly adenocarcinoma. That would be highly unusual in squamous carcinoma. Squamous tends to be a more local regional disease in the chest before it metastases.

The patient at the time of diagnosis was found to have 2 lesions. So, that’s a limited number of lesions. They were relatively small, and they were relatively asymptomatic. I think in this day and age, we would like to avoid whole brain radiotherapy because of its potential toxicity. So, I actually think this patient would have been a very good candidate for stereotactic radiosurgery because of the limited number of metastatic sites, their relatively small size, and the fact that he was asymptomatic.

The role of molecular testing in patients with squamous histology stage 4 disease I would say is in evolution. Most current guidelines do not recommend routine testing in squamous. There are a couple of exceptions in squamous where I would do the typical molecular testing that we do in the nonsquamous population, where there’s doubt about the exact histologic diagnosis or where there’s maybe mixed histologies. Occasionally, you see squamous histology in a patient who doesn’t have a smoking history or has a very remote-like smoking history. And I would test those patients. In the patient that is a heavy smoker, may be continuing to smoke with squamous, I think guidelines would say the likelihood that you’re going to find anything is so remotely low that routine molecular testing is not recommended in that group of patients. There’s one exception. I don’t know if I would call this molecular testing, but PD-L1 testing is important, and we know in this case that the patient was PD-L1—negative.

There are several studies ongoing that are looking at potential targets in squamous. We don’t see the typical targets in squamous like we see in nonsquamous. So, for instance, where we have FDA-approved therapies forEGFRmutation—positive patients,BRAFmutation—positive,ALK-andROS1-translocated patients, we all have FDA-approved targeted therapies for those patients. Those molecular abnormalities are very uncommon to exceptionally rare in squamous patients. So, there may be other targets that may be of importance. However, we’re still waiting for a proof of concept, so to speak. So, the role of targeted therapy in squamous plays much less of a role than it does in nonsquamous.

Transcript edited for clarity.

• A 72-year old male presented with dyspnea, weight loss, chronic cough, fatigue, and back pain
• PMH: current non-smoker for the past 10 years with 40-year (1-pack/day) smoking history, COPD, controlled on LABA/LAMA/ICS; hyperlipidemia controlled on atorvastatin
• Chest CT scan showed a 3.5-cm nodule in the upper lobe of the left lung
• MRI of the brain revealed lesions in the left cerebellum and left frontal lobe
• 99mTc bone scan showed increased uptake in the L1 vertebra and eighth rib
• ECOG PS=1
• Pathologic diagnosis of biopsy under bronchoscopy was squamous cell carcinoma
• IHC: PD-L1 expression in 0% of cells
• Patient was started on gemcitabine/cisplatin
• Brain metastases treated with stereotactic radiotherapy
• At 6 months, patient reported worsening fatigue
• Follow up MRI scan showed no evidence of new brain metastases
• CT scan showed new lesions in the right lung and liver
• Patient was started on atezolizumab; ICS medication for COPD was discontinued
• Patient reported decreased appetite, which resolved following implementation of self-management techniques