Is immunotherapy the wrong choice for some lung cancer patients?

Howard (Jack) West, MD, Founder and President

Amidst all of the glowing reports about immunotherapy for lung and many other cancers, it would be understandable for patients and physicians to be tempted to rush toward prioritizing immunotherapy as the first treatment strategy to pursue. In fact, a highly publicized trial called KEYNOTE-024 was just presented at the ESMO meeting in Copenhagen and demonstrated a significant improvement in progression-free and overall survival over standard chemotherapy doublet treatment as the first line approach for patients with high level expression of the PD-L1 protein on their tumor (about 30% of patients).  But there is also converging evidence that some patients are consistently less likely to benefit from immunotherapy -- specifically, those patients with an EGFR mutation and perhaps others with another "driver mutation" such as an ALK or ROS1 rearrangement.  This is an important issue to know, because I and some other lung cancer specialist colleagues see patients with one of these highly targetable lesions sometimes being mistakenly recommended immunotherapy over the optimal targeted therapy for their cancer, or patients deflect a recommendation for an EGFR or ALK inhibitor in favor of immunotherapy based largely or completely on the hype around the latest new idea in cancer treatment.

It is only in the last decade that we learned that patients with EGFR mutations, ALK rearrangements, ROS1 rearrangements, and perhaps other specific mutations can be the key "driver" of a lung cancer. Such markers are most typically seen in younger patients who often have little or no smoking history, and the idea is that these random developments can be sufficient to generate the chaotic, rapid cell growth and division of a cancer, even without just about any other mutation. This is in contrast to most lung cancers and many other kinds of cancer, which often develop as a product of a wide range of dozens to hundreds of mutations that collect over a long time, which is why so many cancers are associated with advancing age and exposure to various environmental toxins, most notably tobacco smoke for lung cancer. 

Though there are certainly differences among targeted therapies, these are now routinely recommended as first line treatment when we identify an EGFR mutation or ALK or ROS1 rearrangement after a patient is diagnosed with advanced NSCLC.  These oral medications are typically associated with a response rate of 60-75% and a better side effect profile than standard chemotherapy, which is still also of potential value but usually a deferred until after patients have exhausted the benefit of the more effective and better tolerated targeted therapy.  Though several immunotherapy agents have been tested compared with second line Taxotere (docetaxel) and have been shown to be more active and better tolerated for previously treated advanced NSCLC, these same trials have consistently shown that never-smokers show less benefit than smokers, and patients with EGFR mutations are a subset of patients who benefit a bit less from immunotherapy than from standard chemo (the differences aren't statistically significant, but they are conspicuous for being the only clinical variable that trends in the wrong direction from a benefit for immunotherapy).  Though smaller subgroups such as patients with an ALK or ROS1 rearrangement have never been looked at in these trials as a distinct subgroup, it has been hard for lung cancer specialists to identify a case of any such patient who has responded very dramatically and for a long time to an immune checkpoint inhibitor. We suspect that most or all patients with driver mutations are unlikely to be major beneficiaries of immunotherapy.

At the same time, there have also been reports of potentially increased toxicity, specifically pneumonitis (inflammation in the lungs) from a combination of the third generation EGFR inhibitor Tagrisso (osimertinib) with the immune checkpoint inhibitor durvalamab that has raised our concern about presuming that immunotherapy is always safe. 

Though we don't yet know as much as we'd like to about why immunotherapy seems to be relatively less active for patients with EGFR mutations and perhaps other driver mutations as well, I think it is related to the concept of "mutational load".  In addition to the probability of a good response to immunotherapy being associated with high levels of expression of the protein PD-L1, protein helps to decrease the reactivity of the immune system, on tumor cells, tumors that have a large number of individual mutations also often tend to respond better to immunotherapies.  I think of it simply as a "landscape" that has far more features for the immune system to recognize. The converse of this is that the tumors that are driven by a single very important mutation, often arising with very few other mutations, don't provide much for the immune system to recognize and go after.

Importantly, this isn't to say that someone with a driver mutation shouldn't receive an immune checkpoint inhibitor at some point. After all, these agents have tended to perform about comparably to standard second line chemotherapy. But that is a lower bar than standard doublet chemo and far less than the usually very impressive efficacy of the right targeted therapy for the right target, if we are fortunate enough to find one.  So please don't believe that immunotherapy is the right answer for everyone. The concept of precision medicine means that individual patients have different best treatments for them.  For those patients with an EGFR mutation at least, and very likely for other patients with other driver mutations, the best therapy by far is still likely to be their oral targeted therapy, and it would be a grave mistake to deflect that choice because they are swept by the tide of excitement for immunotherapy.

 

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