Bunn Reviews Neoadjuvant/Adjuvant Approaches for Patients With Lung Cancer

Paul A. Bunn, Jr, MD

In early-stage patients with lung cancer, surgery is known to cure some patients, but not all. While the use of chemotherapy in either the neoadjuvant or adjuvant setting has been shown to improve 5-year survival by 5%, this is still a small number, says Paul A. Bunn, Jr, MD.

Researchers are now aiming to find a treatment that can improve the cure rate in either the neoadjuvant or adjuvant setting. Targeted therapies, for instance, have been investigated, but did not result in a survival benefit. Ongoing trials are currently investigating tyrosine-kinase inhibitors (TKIs)  in the neoadjuvant setting. While Bunn says he is not optimistic that patients will be cured with TKIs, these therapies can be used to find why some cells persist, identify biomarkers, and increase the complete response (CR) rates.

There are preclinical data to support the use of immunotherapy alone in the neoadjuvant setting, but there is currently no data from randomized trials. Ongoing trials are investigating immunotherapy as an adjuvant treatment after surgery with chemotherapy and in the neoadjuvant setting before surgery.

In an interview withTargeted Oncologyat the 19^thAnnual International Lung Cancer Congress, Bunn, professor in the Division of Medical Oncology at the University of Colorado Cancer Center, discussed the potential approaches with neoadjuvant or adjuvant therapies for curing patients with lung cancer. He also shares his own opinions on which approaches might be best.

TARGETED ONCOLOGY:Can you begin by giving us an overview of your presentation?

Bunn:The goal of treating early-stage patients is to cure them. Surgery cures some patients, but not a minority of patients with early-stage disease, such as stage I, stage II, and select stage IIIA patients. It's been shown that chemotherapy given before surgery in the neoadjuvant setting or after in the adjuvant setting improves the 5-year survival rate by only 5%. That's clinically meaningful and statistically significant, but it's small. It also means to benefit 1 patient, you have to treat 20. Obviously, we would like to do more to cure more patients, and there are a number of studies that have looked at ways of doing that.

One way is to give targeted therapy to patients who have a mutation-activating mutation. Unfortunately, thus far, the trials that have been done have not shown any advantages in overall survival or cure rate, maybe a prolongation of progression-free survival, but not a survival advantage. This is probably because they don't kill enough cancer cells.

We are trying to do some neoadjuvant trials with TKIs to see why some cells persist. Ordinarily, if you look at their mutation in the beginning and then at the time of surgery, there are persisting cells. We can try to find out why they persist, so we can make a combination. It would be important to know why they persist, for 1 reason or 10 different reasons. If there's more than 10, there's no way that we will ever get combinations, but hopefully, we can identify some combinations.

Another approach besides chemotherapy has been to look at immunotherapy. We don't have any randomized trial results yet with immunotherapy, but there are ongoing trials, both as an adjuvant [treatment] after surgery with chemotherapy, and also some neoadjuvant trials, some of which are giving immunotherapy alone before surgery. There are some large randomized trials now that are giving chemotherapy and immunotherapy before surgery.

In preclinical studies, there's some pretty good evidence that it's actually better to do it before surgery because there's a big tumor burden, a lot of neoantigens, and so, preclinical studies suggest that immunotherapy would work better in the neoadjuvant setting before surgery. However, there are randomized trials going on, and the hope is that we will cure more patients by adding immunotherapy to standard surgery and chemotherapy.

TARGETED ONCOLOGY:Looking at neoadjuvant immunotherapy or TKIs, what kind of data have we seen so far?

Bunn:There are some data with immunotherapy alone first. There have been 2 studies that have been presented. One was nivolumab (Opdivo) with 39 patients. There was a major pathologic response in 43%, which is expected to be 10% or less with chemotherapy. There was a study that looked at atezolizumab (Tecentriq), where there was about 1/3 of response, although that study is still going on. It's a trial with 180 patients.

There's some evidence that immunotherapy by itself would be better than chemotherapy. There are also preliminary results from a phase II trial in Europe that gave chemotherapy and immunotherapy first. The complete pathologic response was over 50% in that trial, but these are preliminary results from ongoing trials. It is encouraging, but the results should be taken with a grain of salt.

TARGETED ONCOLOGY:Were you surprised by the findings with adjuvant TKIs?

Bunn:One of the things that people forget about is things that happened in the past. When you get cancer, you've got a billion cells. If you kill 99% of them, that's impressive and a lot of cells, but there's still 10 of the 10 cells left. If you look at curves in people that are getting TKIs, all the responses are in the first month, and then they are stable after that. Not having a CR means that at best, you're killing 2 logs of cancer cells. You wouldn't predict with killing 2 logs of cancer cells that you would cure people, even if you add it onto surgery. You might delay the time until they get worse, but you're not going to improve their overall survival. That's what the studies show so far.

That being said, that's pretty limited. There are a large number of ongoing randomized trials. I'm not too optimistic that they're going to cure more patients, arguably, because you just don't kill enough cells with TKIs.

TARGETED ONCOLOGY:What are some other strategies we are currently seeing?

Bunn:Again, there's some evidence that even withALKorEGFR