Primacy of Front-Line Checkpoint Inhibitors in Non-Small Cell Lung Cancer

At the Great Debates & Updates in Lung Cancer meeting in New York, New York, Natasha Leighl, MD, FRCPC, FASCO, discussed the primacy of front-line checkpoint inhibitors in non-small cell lung cancer.

Transcript: 

Hi, my name’s Natasha Leighl, I’m from the Princess Margaret Cancer Center in Toronto, and I’m at the Great Debates & Updates in Lung Cancer here today. I was talking about the primacy of front-line checkpoint inhibitors.

It's been amazing that over the last 8 years, we've really seen checkpoint inhibitors involved in all phases of thoracic oncology from advanced lung cancer, maintenance therapy, now to early-stage, and also small cell and mesothelioma. Certainly, in the clinic when we're speaking with patients with advanced disease, PD-L1 still remains the key marker that we use to select which regimen and what to use in our patients with non-oncogene addicted lung cancer. For patients with high PD-L1, PD-L1 monotherapy really does remain the standard unless patients are never-smokers or have aggressive disease burden. We've learned a lot more about different measures like tumor glycolysis and using PET scans, but I think really clinical decision making and clinical assessment is still really important.

We're learning more about oncogene addiction and other genomic alterations. For example, we know that all of the different regimens we use work well in patients with KRAS mutations, whether it's anti-PD-1 monotherapy, PD-1 therapy plus chemotherapy, or adding CTLA-4 inhibitors. There's been a lot of data presented at conferences recently looking at the impact on outcomes with these different immune-based therapies, whether patients have single STK11 mutations, single KEAP1 alterations, or KRAS alterations and it's been a little confusing, on balance. Patients with KEAP1 alterations have had a poor prognosis, whether or not CTLA-4 based regimens improve that is unclear and should be explored further. STK11 is even more challenging. We just saw data published in KEYNOTE-42 where patients with STK11 alterations actually did better on single-agent checkpoint inhibitors than patients with STK11 wild-types. Clearly, even though that's something we associate with an immune desert phenotype, we still have a long way to go.

We're also learning a lot more about how well patients do at those very high levels of PD-L1 and lesser levels and I think that over time we're going to get a better understanding of what other factors we combine so that 50% isn't necessarily as low as we go, or that those patients with 50% to 70%, or 80%, or 90% that won't respond to single-agent could be identified for different combinations.

One of the key things that people are talking about or thinking about are how to incorporate CTLA-4 inhibitors. I think in particular, patients with PD-L1-negative disease, patients with squamous cell carcinoma, these are areas of interest, but you really have to make sure that patients can tolerate treatment. Certainly, some of our older patients, some of our less fit patients, you may still want to go with chemotherapy and anti-PD-1 treatment because this may be more manageable with more predictable toxicities.

On balance, a lot of progress, but still a lot of questions in clinic. PD-L1 really remains our guide with much more data on the way.

Source:

Leighl N. The Primacy of Front-Line Checkpoint Inhibitors in NSCLC. Presented at Great Debates & Updates in Lung Cancer; September 21-23; New York, NY.