Nondriver Lung Adenocarcinoma: Treatment Considerations

Heather Wakelee, MD:For patients with adenocarcinoma of the lung, about 10% of all patients will have anEGFRmutation, maybe 5% to 7% or 8% are going to have anALKtranslocation, and about 2% are going to have aROS1mutation. Those are the 3 that, if we find a mutation, we know that starting with the targeted drug is going to be better than starting with chemotherapy. We have randomized phase III data forEGFRandALKmutations showing us that. For theROS1mutation, it’s a little bit less clear, but it has become a standard practice.

However, patients with adenocarcinoma of the lung could haveMET exon 14skipping mutations,BRAFmutations, orHER2translocation mutations. I’ve personally had patients in my practice with all of those less common driver mutations, where we found it and have been able to give them other treatment options with targeted approaches that we wouldn’t have had if we didn’t know. So, I personally think it’s important to test all patients with adenocarcinoma for a list of about 20 genes now that could be potentially actionable. For patients with squamous histology, it’s less likely that we’ll find those. But in my patient population, which is a lot of patients who have very light or no smoking history and a lot of patients who are Asian, we’re finding those driver mutations even in squamous at times.

There’s also the issue of misdiagnosis. You can get a small piece of tissue that looks squamous, but really, if you looked at a bigger piece, you would see it’s mostly adenocarcinoma. So, it’s important not to exclude testing unless there’s really a reason not to. If there’s really not enough tissue or the patient has a heavy smoking history and a squamous histology, it’s not necessarily worth repeating the biopsy, at least early on, because the risk from the biopsy is probably a little bit higher than the potential likelihood of finding something that’s going to change the practice.

But if a patient comes in and they have never really been tested, they didn’t have much tissue, they have a very light or no smoking history, or they have adenocarcinoma, your likelihood of finding something that might change your treatment options is going to be 25%, 30%, or 40%. So, it’s really important to push to get that testing done.

I think the fact that she had the PD-L1 testing and she had the molecular testing is really important. I want to emphasize that, because we are still seeing—even in the United States—patients like this coming in and not getting that testing done, and that really limits our ability to know what to do next. In her case, they didn’t help guide us to anything other than chemotherapy, but it was good to know that those were tested and negative. And then, the decision for a platinum doublet was perfectly reasonable.

This patient had her PD-L1 testing done at the time of her diagnosis, assuming it was with a 22C3 assay that would have allowed her to get pembrolizumab if the level had been over 50%. I do believe that, for all patients with metastatic lung cancer, it’s really important to do that testing now. We know that about 30% of all patients with lung cancer will have a PD-L1 expression level of greater than 50% at the time of diagnosis, again using the 22C3 assay. If that is found and a patient does not have anEGFRorALKmutation, we know that starting them with pembrolizumab can lead to a higher response and actually improve survival versus starting with a platinum doublet. So, it’s really critical that we do that testing for all of these patients.

Transcript edited for clarity.

• A 70-year-old Caucasian female presented with mild dyspnea and no chest pain.
• She has also experienced recent, rapid weight loss (>10 pounds in 1.5 months) without any changes in her diet or exercise pattern.
• She gave up smoking 7 years ago (2 packs per day for 35 years).
• Her medical history is unremarkable:
  • A few years ago, she was diagnosed with gastroesophageal reflux disease that was clinically and endoscopically confirmed.
  • She has no history of cancer in the family.
  • Her cardiac workup is negative.
• Her PS by ECOG assessment was 0.
• Chest x-ray showed a 2.5-cm lesion in her right lower lobe.
• CT scan of the chest and abdomen confirmed the presence of the lung mass in addition to numerous bilateral nodules, all about 5 to 9 mm, in the right upper and lower lobes and the left upper and lower lobes, as well as enlargement of hilar lymph nodes. In addition, 3 small nodules were seen in the liver, measuring 1 to 2 mm.
• PET/CT imaging showed 18F-FDG uptake in the lung mass, left hilar lymph nodes, and liver.
• MRI of the brain was negative for intracranial metastases.
• A core biopsy of the lung nodule was performed:
  • Its morphology and molecular phenotype (TTF-1-positivity) supported a diagnosis of lung adenocarcinoma.
  • Mutational testing showed absence of driver mutations (i.e., was negative forEGFR, ROS, andALK).
  • PD-L1 testing showed PD-L1 expression of 35%.
• The patient was diagnosed with stage IV metastatic NSCLC.
• The patient was started on therapy with a chemotherapy doublet and bevacizumab (Avastin).
• At her next follow-up 2 months later, her CT scan showed the right lung mass to be stable, with no new lesions. She has improved symptomatically.