Several days ago, I posted an initial discussion of my arguments in favor of PD-L1 testing before recommending second line treatment for advanced non-squamous NSCLC, including my favoring Taxotere (docetaxel) over Opdivo (nivolumab) for most patients with no expression of the biomarker PD-L1 on their tumor cells.

After having had further discussions with colleagues about the data and the challenges in interpreting the optimal treatment in this setting, I am inclined to soften my view that Taxotere is quite likely to be the superior second line therapy for most patients without PD-L1 expression.  Specifically, I/we should bear in mind that response rate and PFS probably make Opdivo look less favorable than the actual reality, because at least some true beneficiaries in terms of survival may fail to have a response or even have progression by our standard (so called RECIST) criteria but actually have "pseudoprogression" of immune cells infiltrating around the cancer and making measurable disease look bigger or even have new nodules appear, an appearance that will technically be called progression on scans and not a response, but which precedes a real benefit for the patient. The OS curves on the Opdivo vs. Taxotere trial in non-squamous NSCLC still show the "IPASS-like" pattern of two populations within -- one doing somewhat better with chemotherapy and one doing better with Opdivo -- but PD-L1 isn't necessarily optimal to discriminate between them.

I still believe that the goal should be to try to give the best and ideally most cost-effective therapy at a given time to every patient, and PD-L1 status can help with that. I also think it's important to ensure that every patient, regardless of PD-L1 status, gets their opportunity with an immune checkpoint inhibitor, ideally while they have a pretty good performance status.  I wouldn't come down saying that it's critical for patients to undergo PD-L1 testing, at least not now.  But I think it will very likely become necessary before these checkpoint inhibitors move into the first line setting, which I anticipate will only for PD-L1 positive patients.

A final point to make: It was only just called to my attention that the FDA-approved dose for Keytruda is 2 mg/kg IV every 3 weeks, which is established for melanoma but was NOT the dose in which the 45% response rate was demonstrated in patients with NSCLC. In fact, all of those patients (actually only 61 with PD-L1 staining >50%) received 10 mg/kg IV every 2 or 3 weeks (no difference in efficacy between 2 and 3 week administration).  So we're left either taking on faith that it's just as good to give 1/5th the dose that was actually tested and looked so favorable in NSCLC patients, or we prescribe the evidence-based dose for lung cancer at a cost that is 5 times the already high price for Keytruda (matched at 2 mg/kg every 3 weeks to be comparable to that for Opdivo at 3 mg/kg every 2 weeks).  THAT'S A BIG PROBLEM: I'm not going to be inclined to charge a patient or insurer $60,000/month giving Keytruda at the dose that actually showed a benefit, nor am I going to give the FDA approved dose that doesn't have the evidence to support strong activity in lung cancer.  This is a situation that isn't tenable, so I expect something will change soon.