Considerations for Therapy in Squamous NSCLC

Corey Langer, MD:The majority of our individuals with metastatic lung cancer, particularly squamous cell, have symptoms: two-thirds to three-quarters. This person is highly symptomatic. From the standpoint of squamous histology, we know that weekly nab-paclitaxel with carboplatin is superior to our more conventional Q3-week solvent-backed paclitaxel/carboplatin regimen, with response rates of over 40% compared to about 25% to 26% for the control arm. So, simply from a symptoms standpoint, I think nab-paclitaxel offers an advantage over conventional solvent-based paclitaxel.

From the standpoint of this individual’s age—she’s 70, so she just makes the cutoff—we have nested post hoc subset data that strongly suggest a survival advantage: 9 to 9.5 months’ advantage for nab-paclitaxel and carboplatin compared to solvent-based paclitaxel and carboplatin. And this is being looked at prospectively in additional phase II and phase III trials. Here, it may be a bit more debatable whether to actually order mutation testing. This individual is a past smoker. She has got squamous cell histology. The likelihood of having an actionableEGFRmutation orALKtranslocation orROS1translocation is probably under 5%, more likely on the order of 1% to 2%. She’s highly symptomatic. We really wait for those test results. So, while I would have ordered these tests, I highly doubt whether I would have waited for those results to come in. And we can even debate whether it makes sense, from a cost-efficacy standpoint, to routinely obtain mutation testing in individuals with a smoking history and squamous histology.

What do we do if and when the patient manifests disease progression in the current chemotherapy regimen? Well, we do have therapeutic options. Up until 2015, our standard approach was docetaxel alone or docetaxel combined with ramucirumab. The 2-drug combination, an angiogenesis inhibitor with docetaxel, has shown a survival advantage compared to docetaxel alone. And this included both nonsquamous as well as squamous histology. So, in contrast to bevacizumab frontline, where squamous cell was the contraindication, ramucirumab was FDA-approved specifically for individuals of this sort: squamous cell with disease progression on a platinum-based regimen.

More recently, there has been not 1, not 2, but 3 separate prospective phase III trials showing a survival advantage for checkpoint blockade over docetaxel, which is now our former standard. The first trial looked at nivolumab, specifically in squamous histology, compared to standard full-dose docetaxel at 75 mg/m². Q2-week nivolumab was clearly superior; it had a much higher response rate, nearly double, close to a 20% overall response rate. Progression-free survival was 50% better. And there was a 3.5-month improvement in median overall survival, with a near doubling of survival at 18 months and 2 years. Unprecedented data with incredibly promising hazard ratios andPvalues literally overnight. Nivolumab became our standard regimen in the second-line setting in individuals with advanced squamous cell whose disease had progressed on chemotherapy.

Nivolumab is not the only agent that’s available for use in this setting. KEYNOTE-010 was a phase III trial comparing 2 different doses of pembrolizumab in individuals with minimum PD-L1 expression levels of 1% or higher with standard docetaxel, and both pembrolizumab doses resulted in statistically significant—and, I’d argue, clinically meaningful—improvements in overall survival. And now we’ve seen data for atezolizumab, a PD-L1 inhibitor, as opposed to pembrolizumab and nivolumab, which are both PD-1 inhibitors. And here, too, compared to docetaxel in the OAK trial, a randomized phase III trial, once more we see a survival advantage that seems to be independent of either histology or PD-L1 level. So, it’s not a matter of whether to use checkpoint blockade in this setting; it’s a matter of which checkpoint inhibitor to institute. In this regard, there’s tremendous debate.

Transcript edited for clarity.

March 2017

• A 70-year-old female presents with shortness of breath and right-sided chest pain of 3 months’ duration
• She has a 25-year (1-pack/day) smoking history
• Chest X-ray revealed a pathologic fracture of the right 4th rib and a large right-sided pleural effusion
• CT scan confirmed the presence of a 3 cm spiculated mass in the right upper lobe, moderate right pleural effusion, and multiple lytic lesions in the spine and ribs
• Core needle biopsy of the lung mass was performed
  • Pathology showed poorly differentiated lung squamous cell carcinoma, p63+ and CK5/6+ with abundant cytokeratin
  • Genetic testing was negative for known driver mutations
  • PD-L1 testing by IHC showed expression in 20% of cells
• The patient received palliative radiation therapy to the rib
• Options for systemic therapy are under discussion