Building Off the Success Seen With Immunotherapy Strategies in NSCLC

Erminia Massarelli, MD, MS, PhD

Indicators like PD-L1 expression, tumor mutational burden (TMB), smoking status, and severity of symptoms all factor into the decision of whether an immunotherapy approach is optimal for a patient with non–small cell lung cancer (NSCLC), according to Erminia Massarelli, MD, MS, PhD. Moreover, novel combinations and cellular therapies are under exploration to improve responses to this modality and offer additional options to those who may be unresponsive, respectively.

“In NSCLC, the largest group of patients who respond to immunotherapy are usually those who have a high PD-L1 expression,” Massarelli said. “PD-L1 is basically the way the tumor escapes the immune system. The tumors that express the highest PD-L1 score, which is usually 50% or higher, are the ones that are most likely to escape the immune system by this kind of mechanism. Using anti–PD-1/PD-L1 [therapy] in these patients has been shown to be a winning strategy.”

To improve responses to immunotherapy, several innovative combinations are under investigation. For example, atezolizumab (Tecentriq) is being paired with the anti-TIGIT antibody tiragolumab as a potential first-line treatment for patients with stage IV NSCLC. Data from the phase 2 CITYSCAPE trial (NCT03563716) showed that the doublet resulted in a 43% reduction in the risk of disease progression or death vs atezolizumab alone (HR, 0.57; 95% CI, 0.37-0.90).

For those who are unresponsive to immunotherapy, cell therapies are also under exploration. These approaches may also serve as an option for patients who respond to immunotherapy with or without chemotherapy for a limited time and then progress, according to Massarelli.

In an interview with OncLive^® during an Institutional Perspectives in Cancer webinar on lung cancer,Massarelli, the co-director of the Lung Cancer and Thoracic Oncology Program, and an associate clinical professor in the Department of Medical Oncology & Therapeutics Research at City of Hope, shared key updates in immunotherapy and targeted treatment for patients with NSCLC.

OncLive^®: How do you navigate the use of immunotherapy in practice for your patients with NSCLC? What are some of the factors you consider when making decisions?

Massarelli: Of course, [those with] PD-L1 expression of 50% or higher are the ones who benefit the most [from this approach]; however, in the [group of patients who have a score that is] below 50%, those with intermediate expression, we know that it is not just PD-L1 but other indicators [we also need to pay attention to], like TMB. Usually, patients who have a significant smoking history are the ones who show the best response to immunotherapy. Some mutations that have been discovered are associated with immunotherapy resistance, such as STK11; this is kind of a controversial one, but some others [have also been identified]. We [still] have more to discover.

Usually, for patients with NSCLC [who are receiving treatment] in the first-line setting, if their PD-L1 expression is below 50%, they are treated with chemotherapy plus immunotherapy; that is the standard of care. However, regarding the combination of anti–PD-1 and anti–CTLA-4, we have seen that it is possible that some of the patients who have a lower expression of PD-L1 may respond to the [dual immunotherapy] combination.

What are some of the efforts being made to improve response to immunotherapy?

We always have to improve the responses and survival of patients with PD-L1 expression of 50% or higher, and that is why we are hoping that combination strategies, such as [with an] anti-TIGIT antibody, for example, will prolong the survival of these patients. However, we also have to significantly focus on the patients who do not respond to immunotherapy. It is very important to know the gene alterations that predispose patients not to respond to immunotherapy.

Several other factors [must be considered but] unfortunately, we do not know [too much about them]. For example, some operations of the immune system do not allow the T cells, the primary effector cells, of the immune system to recognize the cancer cells and go after them. I see an important role for cell therapy. With T-cell therapy, for example, we extract the T cells from the tumor, manipulate them in the lab, and then re-inject them into the patient; this makes them more powerful so that they can recognize the tumor.

Will cell therapies serve as an option for those who are not responsive to immunotherapy?

Cell therapy is important for patients who are not able to respond to immunotherapy. Also, some patients respond for a certain time to immunotherapy plus or minus chemotherapy and then, unfortunately, they progress. At that point, it is useful to consider these cell therapies. Of course, not everyone has the facilities needed to run these cell therapy trials. We are very fortunate at City of Hope to have an amazing Cell Therapy Department and so, we can run these complicated trials.

Do you typically wait for the results of next-generation sequencing to see whether a patient who has a suspected mutation actually has one before you pursue immunotherapy?

If the patient is asymptomatic or has a very low symptom burden, we usually tend to wait [for the results]— especially with never smokers, because there might be an actionable alteration for which there is a specific targeted therapy. However, in patients who have significant symptom burden—for example, those with a cough, or who are spitting up blood or are in pain—then we might not have time to wait.

Even if you do a liquid biopsy, it takes at least 1 week to get results back. Plus, once you prescribe the targeted therapy, it takes another week for the pharmacy to deliver the drug to the patient, so it [takes] at least 2, potentially 3 weeks. Patients who have significant symptom burden cannot wait. You can always start targeted therapy or add it later on. If there is an important symptom to [address], it needs to be [managed appropriately],

How do you anticipate that the field of targeted therapy will change with the emergence of newer agents like the KRAS G12C inhibitor sotorasib (AMG 510)?

We are in this world where we have multiple inhibitors that are attacking the same target. Everything is based on the data, and every medical oncologist is going to look at those data and use the [agents] that they feel most comfortable with. KRAS mutations [are found in] 25% of [patients with] NSCLC. KRAS G12C, for which we have specific inhibitors now, is [seen in] less [patients], but still about 15% [of cases]. We are talking about high numbers. We are talking about an important number of [patients with] NSCLC for whom we will soon, hopefully, have a new standard of care. Of course, as it happened with EGFR mutations, I foresee that these novel drugs will quickly move up to the first-line setting.

Reference

1. Rodriguez-Abreu D, Johnson ML, Hussein MA, et al. Primary analysis of a randomized, double-blind, phase II study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab (atezo) versus placebo plus atezo as first-line (1L) treatment in patients with PD-L1-selected NSCLC (CITYSCAPE). J Clin Oncol. 2020;38(suppl 15):9503. doi:10.1200/JCO.2020.38.15_suppl.9503