COMMENTARY

Therapy for Progressing Lung Cancer Not 'One Size Fits All'

Mark G. Kris, MD

Disclosures

February 07, 2019

Hello. This is Mark Kris from Memorial Sloan Kettering, continuing on the theme of the best management of patients with EGFR- and ALK-positive lung cancers. Clearly, giving the best drug up front and trying to add to it is our core strategy. Unfortunately, despite our best efforts, cancers do progress.

A critical question is, how do you decide when to intervene? Please be aware of the very large [amounts of] literature and multiple randomized trials of treatment past RECIST (Response Evaluation Criteria in Solid Tumors) disease progression. It has been shown that for the whole population of patients, folks tolerating a medication very well and minimally symptomatic can gain months to years of additional benefit without added toxicity or morbidity by continuing the tyrosine kinase inhibitor (TKI) despite disease progression.

I know that goes against everything we were taught. Many patients find it very hard when the CT report says their cancer is growing, and you recommend to continue the osimertinib or alectinib. Data have shown, particularly in the EGFR space, that that is the right thing to do for selected patients. You don't do it in everybody. When you do it, it's important to listen carefully to the patients and look for subtle changes in their condition that could suggest a transition to more symptomatic disease. See the patient more frequently—not so much to do more scanning, but to see and listen to them to detect changes in their clinical condition.

What is the most useful way of deciding when to change therapy? That is by the presence of symptoms. A patient who is symptomatic or poorly tolerating their therapy (again, a rarer problem for people on alectinib or osimertinib) is the patient in whom you have to think about changing therapy, where therapy past progression just does not make sense.

Another thing that might make you want to do it is an accelerating pace of disease. There are no data to guide you here. It's a gestalt that the disease has changed its pace and deserves a different strategy. The other thing is the emergence of a new disease site. New sites, more problematic disease, and potential for more symptoms would be signs to change.

Do you do a biopsy? I would whenever you can. You may find another target that could lead you to a more specific therapy targeting the resistance. For example, a C797S mutation may signal that the patient would be a candidate for a first-generation TKI. If you find a MET amplification, adding a MET inhibitor would be something you would consider. It's worth doing. But you cannot do it in every case. In addition to a tissue biopsy, you could use a cell-free DNA as a way of getting that information in an easier way.

Think about oligometastatic progression. Very often the progression is symptomatic. A growing primary tumor can be addressed by a local measure. In patients with by-and-large good disease control or very, very slow progression, treating an oligometastatic site is a strategy. Now that we have second-line therapies, we have that option open to us, but I would think that we would try to use the single best available therapy based on that patient's clinical course.

What do you do at the time of progression? If you find a target, you go after it. If you don't have a target, I think that the standard of care for most people, if there is not another targeted therapy that would be helpful, would be chemotherapy, probably plus pembrolizumab. That is an evolving area. There are clinical trials addressing that, but that is sort of the default answer here.

For osimertinib, there is not an obvious next TKI except, for example, a C797S-type mutation where a first- or second-generation TKI might be helpful. There are reports of benefits from other ALK drugs targeting the ALK kinase. I think the one that has probably been studied the most and with the most experience would be lorlatinib. It covers many of the mutations that occur at the time of acquired resistance, no matter what the prior ALK-targeted agent is. That drug is now in the approval process. It is not yet approved. It is available by an expanded access program.[Editor's note: This drug has since been approved.]

What about checkpoint inhibitors? The data to date suggest that their activity is limited. Even when PD-L1 is present, they seem to be of somewhat less benefit in patients with ALK- and EGFR-mutant lung cancers. It's not that they have no activity; they clearly do. Many patients have been helped by them. I think they would be our third choice after targeted therapies and after chemotherapy—then checkpoint inhibitors.

I've said over and over again that our jobs have gotten better but they have gotten harder. There are many more decision points. It's absolutely key, particularly in this progression space, to see patients, listen to them, and try to put together the best treatment plan based on the specific issues of that patient. It's not one-size-fits-all. Again, we can deliver so much more to our patients now.

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