Immunotherapy Advances to Frontline in NSCLC, But More Work Remains

Ronald Natale, MD, medical director, Clinical Lung Cancer Program, assistant clinical professor, Cedars-Sinai

Ronald Natale, MD

While there has been an explosion of immune checkpoint inhibitors in the lung cancer treatment paradigm, greater research efforts are still needed to determine optimal biomarkers for immunotherapy response, explained Ronald Natale, MD.

Moreover, it is still a challenge to determine whether select patients should receive frontline checkpoint inhibitors alone or in combination with chemotherapy, yet cutoff points of PD-L1 expression have been helping to guide these treatment decisions in practice thus far, he added.

“PD-L1 testing helps us to select patients and enrich the population, but it is not a very good biomarker. For example, if you look at one of the KEYNOTE studies, in which pembrolizumab (Keytruda) was combined with chemotherapy and the randomization was stratified according to PD-L1 expression, there was a survival benefit even in patients with no PD-L1 expression,” said Natale. “There was also a benefit in survival in groups that had 1% to 49% and ≥50% PD-L1 expression.”

In an interview during the 2020 OncLive^® State of the Science Summit^™ on Lung Cancer, Natale, medical director, Clinical Lung Cancer Program, assistant clinical professor, Cedars-Sinai, expanded on the recent developments with immunotherapy in advanced NSCLC.

OncLive: How is immunotherapy currently being used in NSCLC? How has it evolved in recent years?

Natale: Over the last 2 years, it has evolved from its initial approval as second-line treatment in advanced stage IV NSCLC. In some randomized clinical trials both nivolumab (Opdivo) and pembrolizumab proved to be more effective than docetaxel, and immune checkpoint inhibitors have quickly moved into the first-line setting.

A group of studies were done with immune checkpoint inhibitors versus standard first-line chemotherapy. What those studies showed, at least in the case of pembrolizumab, was that for patients with a high tumor proportion score of PD-L1, which constitutes about 25% to 30% of the patient population, single-agent pembrolizumab was superior to standard platinum-based chemotherapy.

That was then followed by studies in patients who had any kind of PD-L1 expression, from 1% to 40% or ≥50%. It was confirmed that in patients with ≥50% PD-L1 expression, pembrolizumab was superior to standard first-line platinum-based chemotherapy in terms of OS. For patients with lower levels of PD-L1 expression, it was not superior; it was approximately equivalent.

In those studies, there was also an attempt to try to better define the cut-off point for when [PD-L1] expression gets to a level in which pembrolizumab might be superior to chemotherapy. For example, they looked at patients with ≥20% PD-L1 expression, and that group had better survival than patients treated with single-agent chemotherapy.

The studies with nivolumab all fell short. There was a trend towards improvement of OS either with a single-agent or combined with chemotherapy, but none of those reached statistical significance. There was an attempt to try to look for better biomarkers and tumor mutational burden (TMB), with a suggestion that in the absence of PD-L1 expression, TMB identified a subset of patients treated with nivolumab that proved beneficial. With further scrutiny, that did not hold up in a statistically significant manner.

When we get to the combination of these agents with chemotherapy, we begin to see some of the other immune checkpoint inhibitors used, such as atezolizumab (Tecentriq) and durvalumab (Imfinzi). In those randomized trials, there was a trend towards improvement in OS by combining the checkpoint inhibitor with chemotherapy, but it did not reach statistical significance. In the case with durvalumab, the number of patients in the study were on the low side compared with some of the larger clinical trials. It might have reached statistical significance if there were more patients, but it was a bit of an underpowered study.

When AstraZeneca looked at TMB in those studies, they did find an improvement in outcomes in patients who were treated with durvalumab and the CTLA-4 targeted drug tremelimumab. Again, it is a small subset analysis and a randomized clinical trial is needed to confirm. There is not a huge amount of interest [in this study], because we know combining an immune checkpoint inhibitor that targets PD-L1 with an agent that targets CTLA-4 results in a significant increase in toxicity.

Pembrolizumab has had a series of wins [in NSCLC] and showed an improvement in OS, all of which reached statistical significance. My conclusion is that all immune checkpoint inhibitors are not created equal. They have different targets and, even if they have the same target, they bind with different affinities to slightly different epitopes on those targeted molecules. They all have different pharmacokinetics and penetrations into tissue, all of which most likely affects efficacy. However, the efficacy depends on the setting because the results that we see in patients with advanced stage IV NSCLC do not translate across the board to every stage or other forms of lung cancer, such as small cell lung cancer.

For example, atezolizumab and durvalumab have demonstrated some significant improvements in outcome. We are in an era where we are still experimenting and looking at checkpoint inhibitors, and that [immunotherapy] combined with chemotherapy performs better than single-agent checkpoint inhibitors. Although, there are some patients who still do not want to receive chemotherapy for their lung cancer.

How has PD-L1 testing impacted clinical practice?

Overall, probably about 40% to 50% of patients with stage IV NSCLC actually benefit from an immune checkpoint inhibitor—in this case, pembrolizumab. PD-L1 can enrich a population, but there are still a lot of patients with low or no PD-L1 expression who do benefit [from checkpoint inhibitors].

TMB has not proven to be the answer to selecting patients [for immune checkpoint inhibitors], but I believe there is a subset of patients with TMB that will benefit [from this class of agents]. We need to do further research on biomarker selections for patients who we treat with immune checkpoint inhibitors.

TMB is a much more difficult test to perform than PD-L1 testing, which is an immunohistochemical stain. This is whole-exome sequencing of the tumor population versus the normal population. With the more genes you look at, the wider the net you cast, and the more data you collect. However, you are collecting an enormous amount of data that require some specialized modeling in order to understand.

We are also learning that, for example, the purity of the tumor and how much it is infiltrated with normal cells in the specimen can adversely affect the calculation of TMB burden and skew results. That may be the main reason why some of the TMB studies have not proven to be as predictive as we expected them to be. There are some refinements that are in progress that hold promise, but it will pose a more complex way of selecting patients.