Dr Edward Garon on the Basics of Immunotherapy in Lung Cancer

Edward Garon, MD, MS, Professor at the David Geffen School of Medicine, University of California Los Angeles, provides an overview on the basics of immunotherapy for non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC), a topic he presented at the virtual 2022 Great Debates & Updates in Lung Cancers meeting.

In his presentation, Dr Garon discussed the latest immunotherapy breakthroughs and current research in the context of NSCLC and SCLC, with a primary focus on PD-1 and PD-L1 inhibitors. He also told attendees about the potential benefit of adding CTLA-4 inhibitors to PD-1 and PD-L1 inhibition.

Transcript:

Hello, I'm Edward Garon, and I am at the David Geffen School of Medicine, University of California Los Angeles (UCLA). I had the honor of speaking about the basics of immunotherapy.

Immunotherapy is in many ways a very exciting triumph in the field of lung cancer. Historically, lung cancer had not necessarily been a disease that was considered to be amenable to interventions that would alter the ability of the immune system to attack the cancer. I often joke that, historically, the people who had a focus on immunotherapy were relegated to the back corner of a poster hall because the ideas were interesting, but the results were unfortunately always poor.

That changed tremendously, of course, with the results from the PD-1 and PD-L1 inhibitors, which now have become a mainstay of care throughout lung cancer management. We have seen those agents move from initially previously treated non-small-cell lung cancer (NSCLC) now to be agents that are utilized for NSCLC and small-cell lung cancer, in almost all stages of these diseases. The outcomes have been very exciting.

Here at UCLA, we've started to have our first 10-year survivors from immunotherapy. We know from the KEYNOTE-001 study that approximately 15% of patients remain alive 5 years after the start of immunotherapy, which in many respects was unthinkable when the study initially launched.

One thing that obviously remains a focus of the field is how to select the appropriate patients. I gave my personal opinion, which is, imperfect as it may be, the PD-L1 biomarker has performed much better than people tend to give it credit for, that it had selected a group of patients that do better. In the KEYNOTE-001, approximately 25% of the patients, a little better than that even, were alive at 5 years from this group of patients, and that is certainly a reason for enthusiasm.

In addition to the PD-L1 biomarker, there is reason for enthusiasm about the TMB biomarker, which is also utilized in lung cancer. There are new biomarkers that people are trying to integrate, and this continues to be a very active area of research.

My personal hope, and one of the focuses of research for my group, is to look at more specific issues, perhaps being able to select based on neoantigens eventually, which will be the optimal patients for immunotherapy and those for whom they will have the optimal outcomes.

In addition, I focused on areas that I consider we were falling down as a group. One of those is an ongoing frustration of mine, which is the idea that all our subsequent studies are looking to add blindly a new agent to a PD-1 or a PD-L1 inhibitor. This has not to date led us where we want, and I outlined some of the reasons that I had some concerns around that. The agents that we have approvals for, along with a PD-1 or PD-L1 inhibitor, have generally been treatments we know to be effective, meaning that chemotherapy plus a PD-1 or PD-L1 inhibitor has been now a proven approach. Immunotherapy after modalities known to be of benefit, like surgery or chemoradiotherapy, also have been beneficial.

But our idea of looking to combine different immunotherapies has stumbled, in my opinion. There are, of course, approaches that combine a CTLA-4 inhibitor with PD-1 or PD-L1 inhibitors. To date, it has been difficult to evaluate the added benefit of that CTLA-4 inhibitor, and hopefully we will eventually have study designs that will allow us to truly determine what benefit the CTLA-4 inhibitor is adding and in which patients it may be adding benefit.

The other concern that I raised, which I think is significant, is the fact that these studies have tended to be designed to have blockbuster effects. When adding a new agent, the expectation is that this new agent is going to have a tremendous clinical effect, when, in fact, it is likely that the effects that will be seen are going to be in a subset of patients, which I think complicates our research to date.

In summary, I addressed the reasons for enthusiasm for this class of agents, but also some caution about some of the limitations of the way that we have been studying ways of advancing immunotherapy over the last several years.

Source

Garon, E. Basics of Immunotherapy in NSCLC. Presented at: Great Debates & Updates in Lung Cancers. Aug 24-26, 2022. Virtual.