Efforts Continue to Introduce Immunotherapy Into Earlier NSCLC Settings

Daniel Costin, MD

While the first-line setting of non—small cell lung cancer (NSCLC) drastically changed when the PD-1 inhibitor pembrolizumab (Keytruda) was granted FDA approval in October 2016 for metastatic patients, an ongoing trial could potentially give early-stage patients an immunotherapy option, as well.

The phase III ANVIL study is randomizing patients with stage IB to IIIA NSCLC to receive adjuvant therapy with nivolumab (Opdivo) following surgical resection and chemotherapy (NCT02595944). Investigators hope that the addition of immunotherapy will kill additional tumor cells still present even after these traditional treatment methods. Aside from this trial, researchers are also exploring PD-1/CTLA-4 combinations as first-line treatment in an effort to hit multiple immune targets.

“We know that these areas of checkpoint inhibition are like brakes on a car; there may be more than 1 brake,” says Daniel Costin, MD. “If we can block these areas at multiple sites, we can have much more effective therapy.”

OncLive: What is the current state of immunotherapy in lung cancer?

During the 2017 OncLive^® State of the Science Summit on Advanced Non—Small Cell Lung Cancer, Costin, who specializes in hematology and oncology at White Plains Hospital, lectured on checkpoint inhibition in the first- and second-line settings for patients with NSCLC. In an interview during the meeting, he shared insight on understanding the deeper biology of the immune system, the emerging research with immunotherapy, and the importance of managing associated adverse events.Costin: This is a very interesting time in cancer therapy because we now have introduction of immunotherapy into the treatment of our patients with very different cancers. Traditionally, patients who had locally advanced NSCLC were treated with chemotherapy. About 7 years ago, we had the first patients being offered checkpoint inhibition and we began to see that this was a major change and a breakthrough in the management of these patients.

In terms of checkpoint inhibition, the concept is to try to allow our own immune system to get rid of the cancer. Cancer cells can avoid our immune system through various checkpoints; they act almost like brakes. If we can somehow dislodge or unlock those brakes, we allow our own immune system to start attacking the cancer cells and to eradicate them.

The various new treatments that are now available are aimed at focusing on these particular areas where the brakes to our immune system exist. The 2 drugs that are now most commonly used in the forefront are the PD-1 antibodies nivolumab and pembrolizumab. There have been numerous important clinical trials that have brought these drugs to the forefront.

In addition, we also understand that checkpoint inhibition works in different areas of our immune system. New drugs that are aimed at antagonizing or blocking PD-L1 are now also being offered to patients and getting FDA approval. The future will likely hold combinations of checkpoint inhibition.

What about the first-line setting?

Over the last several years, the initial approach to using immunotherapy with checkpoint inhibition has primarily been in individuals with advanced NSCLC and disease that has progressed on primary chemotherapy. A lot of our initial clinical studies have shown that in these patients, when you compare immunotherapy with standard second-line chemotherapy, there were very dramatic responses and benefits. Many patients have shown prolonged survival and continue to show disease-free states at 12 months, 18 months, and even 24 months after starting therapy. We are seeing not just responses and prolonged progression-free survival, but improved overall survival and quality of life, as well. For second-line therapy, immunotherapy has become very much a standard of care. An interesting, important clinical question that exists now is, can we start to introduce immunotherapy as first-line therapy and should we be thinking about immunotherapy in patients with early-stage lung cancer?

Traditionally, those patients are treated with surgery followed by chemotherapy, but many of those patients still recur and will potentially die from their cancer. If immunotherapy works so well, can we start thinking about it in that setting? There are important studies addressing that. For nivolumab, there is a national study called ANVIL that is looking at men and women with early-stage lung cancer who have standard surgery followed by chemotherapy, if appropriate, followed by randomization with nivolumab or placebo.

That is a very important question because even in our patients with early lung cancer, we are still finding many patients with recurrences who are still susceptible to dying of their cancer.

What ongoing trials have the potential to change practice?

Another important question is maintenance therapy. We know that, for locally advanced NSCLC, chemotherapy followed by maintenance therapy benefits patients. Can we consider maintenance therapy with immunotherapy? There are ongoing studies that are addressing that. Those look to be having some challenges in accruing patients. We will see if they can give us the answer to that extremely important question. The ANVIL study is very important. Lung cancer is the number 1 cause of cancer death for men and women. Close to 1 out of every 4 individuals who die of cancer are dying of metastatic lung cancer, so that is a very important issue.

Some of our patients who have early-stage lung cancer may have a 40% to 50% likelihood of recurring and dying from the cancer. How could we introduce immunotherapy early on as a postsurgical and postchemotherapy treatment protocol to see if that can really make a huge difference?

What other challenges remain with immunotherapy?

The other important study regarding immunotherapy involves defining the proper signals and markers so we know when the best time to give immunotherapy is. We have some conflicting information depending on which drugs we are using, in terms of whether PD-L1 expression can predict whether a drug is useful or not and what is the greater likelihood of benefit. That is an area where we haven’t done as much as we should be doing to define that. Once we can, it will allow us to create much better pathways for our patients to ensure that they are getting immunotherapy at appropriate points of their disease, when immunotherapy can have the greatest positive impact. The most important challenges are finding where we can enter with a particular checkpoint inhibitor. We need to be able to have a consensus in particular situations where a patient presents with NSCLC, whether adenocarcinoma or squamous histology, or with 1%, 10%, or 60% PD-L1 expression. Can we have more consistent guidelines with regard to which are our best treatment modalities? What is the best time to do the treatment modality, and when can we introduce immunotherapy before chemotherapy or wait until after chemotherapy? How do we choose between the different immunotherapies? Is there any difference between the PD-1 antibodies nivolumab and pembrolizumab? Is it better to use a PD-L1 antibody, such as atezolizumab (Tecentriq)? Would that be a better option?

What do you hope that community oncologists took away from your lecture?

Also, we can combine our checkpoint inhibitors—such as a PD-1/PD-L1 antibody with a CTLA-4 antibody. Remember, those are the different brakes. We want to unleash those T lymphocytes against the cancer cells. At baseline, those T lymphocytes are going to have these 2 parking brakes on them. They can’t be activated unless we somehow block them. It makes good sense that if you have 2 forms of immunotherapy—2 drugs attacking the different parts of the pathway—you are going to have a much more effective treatment. The most important thing is that immunotherapy is becoming very much standard. Educating themselves on the different drugs is very important. Educating themselves on potential adverse events (AEs) related to drugs is crucial.

Fortunately, when you look at comparisons between chemotherapy and immunotherapy, most of the studies you will see show that 50% of patients will have significant AEs with chemotherapy and only about 10% will have significant AEs from immunotherapy. But, that small 10% can be very severe and potentially life-threatening.

While it’s certainly comforting to use a drug that 90% of our patients will do so well with, for every 10 patients there is 1 who is going to get very sick. You have to be prepared, have good resources, and prepare yourself and your entire team. The whole team needs to be aware of these potential AEs.