For EGFR- and ALK-Driven Lung Cancers, Use 'Best Drug First'

Mark G. Kris, MD


February 07, 2019

Hello. This is Mark Kris from Memorial Sloan Kettering, speaking to you today about a topic we have discussed many times: treatment of patients with epidermal growth factor receptor (EGFR)- and anaplastic lymphoma kinase (ALK)-driven lung cancers. I'd like to talk about the current status of therapy and next steps for how we can do more for our patients with those diseases.

We are amazed by the magnitude and the duration of the benefits we have seen with targeted therapies in our patients with these drivers. The emergence of alectinib and osimertinib have changed the field and have become the standard of care for initial therapy.

First, they are the obvious choice because of their effectiveness. The progression-free survival of standard first-line therapy followed by alectinib or a standard first-line therapy followed by osimertinib is as good or better than either drug given up front alone. You get an excellent disease-free time and you do so without the intervening difficult issue of progression. We start with the best drug first, and these are clearly the best drugs.

The second important point is that both of these treatments have been shown to cut down the incidence of central nervous system (CNS) metastases compared with the first-generation drugs in their respective diseases. Brain metastases are devastating. They impart a worse outcome, and preventing them is extraordinarily important for the patient and for us to control the patient's disease.

The third thing is tolerability. Yes, all of these agents have side effects. Clearly the adverse effects of an alectinib or osimertinib are less than their first-generation counterparts. For benefits to patients, the cutting down of CNS metastases, and better tolerability, these are our drugs of choice.

Are they good enough? They're not good enough. Unfortunately, none of these therapies lead to cure. I challenge oncologists to look for things we can add to these agents, not at the time of relapse but before relapse happens. Relapse is devastating for us and even more so for our patients. We want to try to prevent that.

Strategies include the use of anti-angiogenesis agents, particularly bevacizumab, which is best proven in the EGFR space. A recent presentation at the American Society of Clinical Oncology meeting said that in the EGFR space, adding in chemotherapy not at progression but while the first tyrosine kinase inhibitor (TKI) is being given can improve overall outcomes.[1] The use of other local therapies [is an option for] those patients with oligometastatic disease. There is evidence, admittedly a small amount of evidence, that for patients with one, two, three, or four metastatic sites, doing a definitive local therapy at the time of maximum benefit from the TKI is helpful, and I urge you to think about that for the patient where that sort of strategy makes sense. My rule of thumb is that good control of the disease about a year into the treatment is the time when you would want to consider adding in a local therapy before relapse.

The other strategy that is currently under study and would be available would be to add other drugs to the TKI. There is at least laboratory evidence that adding a first-generation or second-generation TKI to osimertinib can improve outcomes, and that would be another consideration to think about. Give the best drugs up front. Think about ways we can augment their benefit. Think about newer strategies to do that.

In my next talk we will discuss what to do when the cancer does start to grow again despite our best efforts.


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