NSCLC: Initiating Second-Line Therapy

Benjamin P. Levy: The goals of therapy for second-line treatment are very similar to the goals of therapy for first-line treatment. It’s to improve survival, it’s to improve quality of life, it’s to lessen symptom burdens, and it’s to decrease shortness of breath and pain. I think that those are all very important goals. So, the goals for me don’t shift from first-line to second-line. l think when we’re making second-line decisions—I’ll say this throughout, and I’ve said it many times—treatment decisions have to be individualized. But, when you’re making those individualized decisions, they’re all in the context of improving survival, improving quality of life, and decreasing symptom burdens. I think those are the 3 things I really want to do no matter what agent or agents I’m using as second-line therapy.

When thinking about what treatment I’m going to use as second-line therapy after chemotherapy, importantly, we have to look at the patient’s performance status. You have to look at the pace of disease growth: how quickly this is growing. You have to look at the symptom burdens and the tumor burden. How symptomatic is the patient? What type of growth are we looking at? I would say performance status is critical, as well as the pace of disease and the patient’s symptoms.

Those are the things that I really look at. Again, we’re trying to improve quality of life here. We’re trying to extend life as well, so all of those things go into the calculations. It’s very important. These decisions are a little harder to make in the second-line than they are in the first-line. First-line patients are motivated. They want to get treated. When they get to second-line, you really have to think critically about what you’re going to do with these patients to help them improve their quality of life and extend their survival.

We’re starting to learn that aggressiveness of disease is a factor in making second-line decisions, and aggressiveness can be anything. I define aggressiveness as patients who really aren’t responding to first-line therapy, patients who come through the door and don’t have a driver mutation. You’re going to plan on giving them chemotherapy, but, after 2 or 4 cycles, that tumor continues to grow. That, to me, is aggressive. These patients generally need help right away with another agent that’s going to work quickly. And we see these patients. These patients are probably 25% to 30% of all our patients, without a driver who come in and progress quite rapidly.

This is the more aggressive tumor biology. It’s a chemo-refractory, or a frontline chemo-refractory, disease. Generally, at the end of 4 treatments, you know who these patients are. You know who these patients are by looking at their scans, but you can also look at them and see that they’re clinically deteriorating, and they need an action fast. There are a lot of different ways to define aggressiveness. You can define it on the scientific level in terms of the tumor mutation burden of the cancer, with some of the genetic underpinnings that may make it more rapidly growing. But, for me, clinically, these are patients who aren’t responding to first-line treatments.

I think this is a scenario that we have to look at carefully. It’s an easy decision for a patient who’s on 4 cycles of chemotherapy and who’s doing well. You just continue the maintenance strategy. It’s quite easy, and patients tend to derive a benefit from that. But for patients who are rapidly progressing, this is, I think, a special consideration that warrants a lot more thinking about what you’re going to do in second-line. You’ve got to look at the pace of disease. You’ve got to look at how the patient looks. You have to look at these scans and see how rapidly it’s growing, and then we have to go back in many of these cases and look at what the PD-L1 was up front. We can talk a little bit about how treatment makes life a little harder when making a decision. For me, all of these things go into individualizing second-line treatment decisions.

Looking at the side effects, one of the things that I want to optimize is quality of life for my patients in second-line. There’s no doubt that immunotherapy is better tolerated than chemotherapy. So, if I have a reason to use immunotherapy—and there are a lot of reasons to use it second-line, one of them being the side effects—then I’ll use it. I think it’s really important that we have these conversations with our patients. That said, not every patient is going to tolerate immunotherapy well, and not every patient can have immunotherapy.

There are patients who are obviously on steroids. They have autoimmune diseases. These patients can’t get immunotherapy. Immunotherapy works, it does, and there’s no one more excited about this new class of drugs and the combination strategies that are forthcoming than me. I’m very excited about this, but I think we have to be mindful of the toxicities. If a patient is doing well on chemotherapy and they then progress, and they’re hanging in there with their performance status, they’re an immunotherapy candidate. I think these are well tolerated drugs. We always have to look at drugs in the context of the survival advantage they provide, but at the same time, the toxicities they may have on the patient.