Diagnosis of Locally-Advanced Squamous NSCLC

Corey Langer, MD:This is an 81-year-old gentleman who presents to his physician with cough, hemoptysis, and fatigue requiring increasing rest during the course of the day. Past medical history is reasonably unremarkable. He has a history of hypercholesterolemia, which is controlled on a statin, and hypertension, which is well controlled on a calcium channel blocker. So, this gentleman has no history of smoking. He’s quite active. He continues to play golf several times a week, he drives, and he’s fully independent and maintains all his normal activities of daily living. Chest x-ray and CT show a cystic mass in the left upper lobe, as well as lymphadenopathy in the left hilum and both mediastinal nodes. PET/CT confirms these findings, showing fairly marked FDG uptake in the lung mass and in lymph nodes. Bronchoscopy and transbronchial lung biopsy are performed, and path confirms grade 3 squamous cell carcinoma of the lung. Genetic testing, in light of his never-smoking history, is performed, and this is completely negative, with no evidence of an oncogenic driver. PD-L1 testing by IHC shows expression in 65% of cells. The individual was started on treatment with pembrolizumab, with follow-up imaging at 3 months showing stable disease.

After about 5 months on immunotherapy, unfortunately, the patient was hospitalized with a seizure. At the same time, he reports increasing fatigue and cough over the preceding month. CT confirms enlargement of the primary mass in the left upper lobe. Brain MRI confirms multiple small intracranial metastases. He is started on whole brain radiation. Immunotherapy is discontinued, and the patient is actually started on a 2-drug chemotherapy combination: carboplatin/nab-paclitaxel and nanoparticle albumin-bound paclitaxel.

So, this gentleman presents with locally advanced squamous cell carcinoma of the lung. Technically, this individual has stage 3B disease; bilateral mediastinal nodes would confirm N3 disease. The primary tumor presumably is at least a T1 or T2. Historically, we would usually treat such an individual with concurrent chemoradiation—a platinum-based regimen—either weekly paclitaxel/carboplatin or etoposide cisplatin combined with 6 to 7 weeks of full dose RT (radiation therapy), a minimum dose of 60 gray. We can see cure rates in selected individuals approaching 20% to 25% in that cohort now. There are some individuals, for one reason or another, who are not appropriate for radiation because the field may be too large, there may be additional nuances in a case such as this, or there may be satellite lesions or contralateral intrapulmonary metastases that make full-dose curative chemoradiation inappropriate. If we assume that to be the case here, then the choice of treatment, pembrolizumab—based on the level of PD-L1 expression—is quite reasonable and certainly would be my first choice, assuming we had ruled out a curative approach with chemoradiation.

At this point, I think PD-L1 testing is standard, but clearly, in metastatic or stage 4 disease or in individuals who have recurrent disease, we can debate whether it should be standard or not in stage 3 or stage 3B non—small cell. But an individual with noncurable disease, who has the expression levels of 50% or higher, is well served by frontline checkpoint blockade by immune modulator, in this case, pembrolizumab, which has clearly shown a survival advantage compared to standard chemotherapy in this setting.

Now, it’s intriguing. This gentleman has squamous cell carcinoma, which almost always, but not always, is associated with the smoking history. And yet, he was a never-smoker. Had he been a heavy smoker, now with squamous cell, I’m not so sure I would have ordered molecular testing. Next-generation sequencing takes 2, 3, or 4 weeks minimum to turn around. We would end up delaying our intervention based on this waiting period, and the likelihood of actually harboring a mutation in the setting of the smoker probably would be less than 1% to 2%. But in a never-smoker, regardless of histology, I think it is reasonable to obtain mutation testing or molecular testing and look for actionable molecular aberration. I would guestimate that the rate of mutations in that group, the never-smokers, even with squamous cell would be on the order of about 10% to 15%. So, it’s a perfectly reasonable option.

Transcript edited for clarity.

November 2016

• An 81-year-old male presents to his physician with symptoms of cough, hemoptysis, and fatigue requiring frequent rest during the day
• PMH includes hypercholesterolemia, controlled on simvastatin and hypertension, controlled on a calcium channel blocker; mild osteoarthritis
• He has no history of smoking
• The patient is physically active and plays golf several days per week
• CT of the chest revealed a solid cystic mass in the left upper lobe and lymphadenopathy in the left hilar and bilateral mediastinal nodes
• PET/CT imaging showed 18F-FDG uptake in the lung mass, left hilar and both mediastinal lymph nodes
• Bronchoscopy and transbronchial lung biopsy were performed
• Pathology showed grade 3 squamous cell carcinoma of the lung
• Genetic testing was negative for known driver mutations
• PD-L1 testing by IHC showed expression in 65% of cells
• The patient was started on therapy with pembrolizumab
• Follow up imaging at 3 months showed stable disease

April 2017

• After 5 months on immunotherapy, the patient was hospitalized after having a seizure. He reported worsening fatigue and cough for 1 month
• CT showed increased size of the left upper lobe pulmonary mass
• Brain imaging showed several small intracranial lesions
• WBRT was started
• Immunotherapy was discontinued and the patient was started on carboplatin and nab-paclitaxel