How to Think About Second-Line Therapy in NSCLC

Mark G. Kris, MD


October 31, 2023

This transcript has been edited for clarity.

It's Mark Kris from Memorial Sloan Kettering. I have been thinking lately about treatments after initial therapy for non–small cell lung cancers, what people often call second-line therapy.

I think the first thought is that, for all the regimens that are available and tested, the results are clearly not as good as seen with first-line therapy. I'll get into some specifics in a second. That being the case, it's really important to make the best choice for first-line therapy.

The second thing that is absolutely critical is to very carefully assess when that first-line therapy has stopped working and whether there is a need for a new systemic therapy. We very often have these situations where there is an oligoprogression, and by treating a single symptomatic lesion, you may get the patient in a very good place and may continue initial therapy. Very often, there is inconsequential growth of the cancer.

For example, if there is a 21% increase in the size of a primary tumor that is not associated with any symptoms in a person who is living their life and is not having any severe side effects, you have to think long and hard about changing that therapy. I wouldn't even give a consolidative therapy there if they're really doing well. Obviously, consolidative therapies are a new therapy and they have their side effects with them as well.

Please think really carefully and weigh all factors, from the patient, the toxicity, and the benefit, before changing the initial systemic therapy. I would continue it as long as possible.

With second-line therapy, sadly, none of them have a huge benefit anywhere near what we see in first line. All the rates of response are well under 50%. Just getting into it, you're not going to shrink the cancer by more than 30% in the majority of patients, so you have to think long and hard about making that switch.

Second, our standard still remains docetaxel, and the numbers on docetaxel are really not great. It's about a 15% rate of response and a median survival of about 5 months. Now, by adding other RET drugs to docetaxel, you can achieve better results. By adding ramucirumab, for example, the response rate just about doubles and the duration of response and progression-free survival both go up by a few months.

For patients who have KRAS G12C, in the randomized trial that has been done so far, over docetaxel, you get, again, a doubling of response. For patients where response is important, you really double that response rate, but also you get an improvement in median progression-free survival by, again, 2-3 months. There is benefit there in terms of response and progression-free survival; however, it's not huge.

Please remember, if you're choosing to use docetaxel, to think about using alternative dosages and schedules. When you look at the course of a person treated with docetaxel over, let's say, a 6-month period, you often see that doses are held. When you look at the total dose, it's very similar to an every-2-week dose of a lower amount. I routinely give a 60-mg flat dose every 2 weeks.

I urge you to look at the progress of one of your patients over a 6-month period who was given the 75-mg dose. Many of those doses end up getting held. When all is said and done, you give a lower dose over that whole time from that 75-mg dose. Giving 35 mg/m2 or a 60-mg flat dose every 2 weeks, you end up getting almost exactly the same amount of docetaxel. There's really no convincing evidence that the higher dose is better. It's clearly harder on the patient.

I've shared some thoughts about second-line therapy. We really have to do better. Please make sure that your first-line therapy is the best you can give. Make sure you've gotten everything out of that first-line therapy and that it will be continued as long as possible, as long as you and the patient have concluded that there's benefit. When you do switch, try to give the most effective regimen that you have, which would be docetaxel with ramucirumab, or for patients with KRAS G12C, giving adagrasib or sotorasib at this point.

Mark G. Kris, MD, is chief of the thoracic oncology service and the William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan Kettering Cancer Center in New York City. His research interests include targeted therapies for lung cancer, multimodality therapy, the development of new anticancer drugs, and symptom management with a focus on preventing emesis.

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