NSCLC Management: Second-Line Options

Neal E. Ready, MD, PhD: When we look at second-line treatment for non–small cell lung cancer, it has changed with the recent approvals of frontline immunotherapy. Outside of patients with autoimmune disease, with an organ transplant, or some other contraindication receiving immunotherapy, most of our patients now are receiving some form of immunotherapy as initial treatment, unless they’re a non-squamous patient with a targetable mutation or fusion or other actionable alteration. I want to emphasize that, if you have a non-squamous lung cancer, we should be doing molecular testing, and oral therapy would be the first choice if you get an actionable alteration. The good news is we have better frontline treatment and patients are living longer, especially with the combination immunotherapies. The flip side of that is that we’re back to standard second-line regimens such as docetaxel or docetaxel with ramucirumab that we’re not that excited about.

This is one of our major areas of unmet need in non–small cell lung cancer. The goal is finding a way in the post-I/O setting to reignite the immune system and get additional prolonged immune responses, to continue to look for new molecular targets, and find ways to enhance the second-line chemotherapy options like docetaxel. The use of second-line therapy is more limited, but for a good reason that we have better initial treatments including immunotherapy, but the second-line setting now is really a challenge.

There’s clinical development now. There will be new immune options in the second line. We’re learning more about how cancers are able to evade the immune system. People will now get some form of I/O therapy first, and if the cancer progresses, then obviously if it was an initial response then it’s evaded the immune system somehow. There are a lot of ongoing scientific evaluations that let us understand is this down regulation of MHC-1 to evade the immune system? Is it local tumor effects with an increase in T reg cells or MDSCs [myeloid-derived suppressor cells]? Is it other changes in the tumor microenvironment? We are rapidly progressing to understand how immune evasion occurs, and there are a lot of pipeline therapies that are now available that will let us test different strategies for overcoming the secondary immune resistance.

That’s where things are headed, and the clinical trials are ongoing, so hopefully we’ll find some new strategies that will let us reignite the immune system in patients where progression has occurred and get secondary and tertiary immune responses that are helpful.

Stephen Liu, MD: When we look at second-line therapy, some of the big characteristics determining our approach are the prior treatment delivered, patient comorbidities, and performance status. When we look at performance status comorbidities, it drives the suitability of further therapy. Our role as an oncologist is not to see how much treatment we can deliver. It is to help patients. If patients have poor performance status or if they’re weak, I know they’re not going to derive the benefit from further therapy. In my effort, the best way to help that patient might be to focus on symptoms or more of a hospice-based approach. For patients who have a good performance status, there are an increasing number of options. Our previous second-line therapy had been docetaxel-based treatment, either alone or in combination with ramucirumab. It depends on what initial treatment was given. For example, if pembrolizumab alone or atezolizumab alone were given, or if dual checkpoint inhibitors such as nivolumab and ipilimumab were used in the frontline setting, my second-line regimen would really become platinum-based chemotherapy.

Now, whether to continue the checkpoint inhibitor in the setting of second-line platinum doublet chemotherapy is a question that the INSIGNA trial will look at to see if continuation of a checkpoint inhibitor beyond progression provides any value or only cost and toxicity. Right now, our standard approach after progressing on immunotherapy alone, either mono or dual checkpoint blockade, would be platinum doublet chemotherapy histology specific. If chemo immunotherapy were given continuously in our second-line option—really docetaxel-based treatment—we’re certainly always exploring clinical trials, novel immunomodulatory agents, and different strategies to really recapture those long-term benefits.

Transcript Edited for Clarity