To many, the recent FDA approval of a combination of chemotherapy and concurrent immunotherapy for the vast majority of patients with advanced (metastatic) non-squamous non-small cell lung cancer (NSCLC) probably seems like a great idea. This approval was based on the more favorable results for the combination of the IV immunotherapy agent Keytruda (pembrolizumab) every 3 weeks along with first line carboplatin and Alimta (pemetrexed) as a the chemo backbone, compared to the same chemotherapy alone, in a relatively small randomized trial of 123 patients, called KEYNOTE-021g. The “g” part refers to this actually being just one portion of a much larger trial comparing chemo to the same chemo with Keytruda. The other arms haven’t panned out as favorably.

Importantly, when we talk about the arm of patients getting chemo combined with immunotherapy, we aren’t talking about improving survival. Instead, we’re talking about prolonging the time before patients showed significant progression of their cancer on scans, which leads us to switch to a new treatment. This “progression-free survival”, or PFS, was the primary goal of the trial, though the gold standard of what we should really want from our treatments is improvement in how long patients live. There’s a bit of a favorable trend for that, but that’s all. There was also a significant improvement in the fraction of patients who show major shrinkage of their cancer when Keytruda is added to chemotherapy.

Still, even if survival isn’t improved, the results seem promising enough, so what’s not to like?

First, there’s plenty of reason to doubt that this trial would appear as good if you took out the patients who we know can do very well with immunotherapy alone. About 28-30% of patients who are tested for PD-L1 expression, a predictor of probability of benefit from immunotherapy such as Keytruda, have what we define as high level PD-L1, with 50% or more of their tumor cells staining for this protein on a special pathology test that is routinely done now in just 1 day at the time a patient is initially diagnosed. These patients now typically receive Keytruda alone and have a nearly 50% chance of a very prolonged response.  They are likely to be major drivers of the benefit seen in the entire KEYNOTE-021g trial, and for them, chemotherapy alone is no longer the appropriate standard comparison.  The question is whether they should have chemo added to Keytruda, and this trial can’t answer that. But the bigger question is whether, if you take out this nearly 1/3 of patients on the trial who shouldn’t be in it, would the overall study look good for the whole group? Very likely not.

You might ask why should the patients with high PD-L1 expression not just get chemo, too? Yes, it’s certainly possible they might do better, but it’s definite that they’ll have more side effects.  And for many patients who respond to immunotherapy without chemo, they can respond very well for a year or even many years – we don’t even know how long is possible. If you can get those great results without chemotherapy, why would you just dump on chemo gratuitously? Part of the big promise of immunotherapy has been to be able to avoid the challenges of chemotherapy with a different approach, so adding it in the patients most likely to do well without it seems very questionable.

Then there’s the other 70% of patients with low or no PD-L1 expression. These patients may still benefit from immunotherapy, but far fewer will. For them, chemotherapy alone is likely more effective as a first line therapy, and essentially all of the patients eligible to get a chemo/Keytruda combination should be candidates for immunotherapy in the second line setting after they progress on chemo.  With good care, nearly all should get their opportunity to benefit from chemo and then immunotherapy.  On the KEYNOTE-021g trial, 3 of every 4 patients assigned to initial chemotherapy received Keytruda or a very similar drug after their cancer progressed, but that means that 1 in 4 did not. While you have to expect that there will always be a small amount of drop-off if patients decline, that should be 5-10% at the most.  Having a quarter of the patients never get immunotherapy reflects less than ideal care and makes the arm getting chemo alone as first line therapy look worse than they should if they receive the kind of cancer care I deliver.

You might ask, “what’s the harm in giving all of your most effective therapies up front, together?”.  This strategy does ensure that a patient at least gets access to the best drugs and doesn’t miss any opportunities, but it has several drawbacks. First, you end up delivering a combination of the side effects of chemotherapy and immunotherapy at the same time. The added side effects from immunotherapy are usually modest, but the side effects with more agents is certainly greater. More importantly, if patients get into trouble with side effects on a chemo/immunotherapy combination, it can become difficult to disentangle which side effects are from which agents compared with giving fewer drugs at a time. This can be like trying to juggle too many balls at once and then just dropping all of them. If patients run into major issues with side effects on this kind of regimen, we may need to stop all drugs for a while and then test by adding back one at a time to see if we can isolate which treatment is causing which problems. 

By the same token, if treatment is working and a patient’s cancer is shrinking, you can’t know what is actually doing the heavy lifting, and which drug(s) are just adding side effect risks and cost to ongoing treatment. The KEYNOTE-021g trial allows for patients to get a combination of Alimta and Keytruda together every 3 weeks until progression.  We know that patients can do well for years, and now they will likely be receiving two of the most expensive drugs in lung cancer, at a total cost of about $25,000 per month, but it’s very likely that ONLY ONE of those two drugs is actually still helping, while the other is just adding potential for cumulative side effects, along with major ongoing costs.

By favoring a sequential approach for most patients, we can actually know the side effects and benefit of the specific treatments we’re giving, rather than give everything at once and have no idea which drugs are helping and which ones are harming someone.

Finally, combining your first two lines of therapy together leaves you with far more limited options once the cancer progresses on this treatment approach. It isn’t necessarily better to use all of your big guns up front and be left with very little after that. There may be more sense in using as little as needed to stay ahead of the cancer at a given time, leaving more options for later.

I don’t mean to say that the combination of chemotherapy with Keytruda is a poor choice for everyone. For a minority of patients, specifically those in whom we can’t reliably anticipate that they’ll still be doing well after progressing on first line therapy to receive and potentially benefit from second line therapy, I would favor giving the treatments together up front and not worrying about which is the driver of the benefit we hope to see. That’s a small minority of patients with a very high “tumor burden” (the overall amount of viable cancer in the body) and/or patients whose cancer shows a pattern of rapid progression just over the (usually relatively short) time of a patient’s work-up that diagnoses advanced cancer.

For most patients, however, I favor pacing our treatments over time.  In the meantime, we can expect that in just a few months we will be getting results of much bigger studies to better clarify the benefit of chemo/immunotherapy over chemo followed by immunotherapy for most patients.  Until that time, I see no reason to rush into a very front-loaded attack for patients who don’t need it.