Experts Reflect on Unmet Needs in Patients With Lung Cancer

A roundtable discussion, moderated by Millie Das, MD, covered challenges, advances, and future directions for the diagnosis, treatment, and management of non-small cell lung cancer (NSCLC), as well as critical clinical trial data and updates from the 2024 American Society of Clinical Oncology Annual Meeting. Dr. Das was joined by Ticiana Leal, MD, Martin Dietrich, MD, PhD, and Kent Shih, MD.

In the third segment of the roundtable series, the panel discusses unmet needs in patients with NSCLC and what clinicians should consider when treating patients who lack driver mutations.

In the next segment, the panel discusses how to choose among treatment regimens for NSCLC.

—

Dr. Das: There are a number of unmet needs for our patients, particularly patients without driver mutations. I think we’re going to focus a little bit more on that patient population. I just wanted to open it up to really talk about, what do you perceive as being some of the unmet needs for these patients who don’t have driver mutations, where targeted therapies aren’t really an option? Kent, I’ll start with you.

Dr. Shih: I think the traditional high-risk patients we think about are probably squamous cell patients, PD-L1 low, PD-L1 zero-type patients, brain [metastases] patients, bulky disease, highly symptomatic patients, maybe elderly, poor performance status. Maybe that those don’t have the social support that they need. I think there are groups of patients that clearly do worse that probably need a little bit more.

Dr. Dietrich: I would agree. I think it’s a mix of clinical and molecular features, and obviously, the PD-L1 zeroes are the first obvious frontier. We are more and more interested in secondary mutations that are predicting responses or predicting against responses for treatment, KEAP1, STK11, p53, and others. I think this is going to be a much more multiplexed field then. We did it originally with sort of a PD-L1-centric worldview.

I think we also look at PD-L1 in sort of a short-sighted way by just having a high, low, and a negative assessment. I think there’s a much more granular usefulness for the biomarker. I think it’s a complex field to decide the right immunotherapy and when to escalate to combinations of either chemotherapy or chemotherapy [immuno-oncology (IO)] combinations.

Dr. Shih: Smart. Do you think there’s a sort of a sliding scale difference between a PD-L1 zero and a PD-L1, 1-5? Or is it a little bit more Boolean and a little bit more true/false?

Dr. Dietrich: Within the frame of the histological assessment, I think this may be a more gradual difference. I think the PD-L1 zero is a distinctly different histology than the lows. I don’t really know that there’s a big difference where the cutoffs would be, but I think the closer we get to 100%, the more IO efficacy we see for our PD-1 spectrum. Yeah, it has to be taken with a grain of salt, I know there’s variability between different tumor compartments and sort of the different assays and antibodies play a role. It’s not an easy marker to determine.

Dr. Das: Ticiana, any comments?

Dr. Leal: I agree with everything that’s been said. I think just to add more in terms of, as I’m thinking about the patients in my clinic and other unmet needs, I would say the patients that are categorized as non-small cell lung cancer, but the large cell neuroendocrine carcinomas, those are definitely a patient population that I think we still need to do a lot more in terms of clinical trials to really identify optimal therapies. Because a lot of times we extrapolate either towards non-small cell or towards small cell, and that is certainly a clinical challenge.

The other sort of high-risk histology that I’m seeing in my clinic are the SMARCA4 tumors, very aggressive, poorly differentiated sarcomatoid tumors that are presenting in clinic now. We’re really struggling to find the optimal therapies, because these are such resistant tumors to begin with. I think a lot needs to be done for these subsets of lung cancer that we’re identifying now—with our better diagnostic tools—that we hopefully will be able to in the future continue to address through clinical trials.

Dr. Das: I agree with all of your sentiments about the unmet needs. Some of the other things that I think about are patients who don’t have targeted mutations, we’re typically offering them immunotherapy, immunotherapy combinations or immunotherapy with chemotherapy, and patients usually will respond for some time.

But I think one of the major unmet needs is [addressing] what happens when these patients develop disease progression on immunotherapy. How do you overcome resistance? I know there are a number of clinical trials that are really seeking to answer this question, but we just don’t know. Then we always come back to single-agent chemotherapy. It’s usually docetaxel plus or minus ramucirumab. I think that’s one of the major unmet needs. A lot of the trials that are second-line trials are using docetaxel as the comparator arm and are surprisingly not beating docetaxel. So that I think is a problem, and I really hope that over the next few years, some of these trials are going to read out positive.

Then the other thing that I deal with is, I feel like on a very frequent basis, there are immune-related adverse events and [I’m] counseling patients about this. There was a great session at [the American Society of Clinical Oncology Annual Meeting] this year about how we counsel patients about the potential for immune-related toxicities so that they can understand, because it is confusing. We know that patients can develop autoantibodies that target any organ system of the body, and the severity can range from very mild to very severe and life threatening. How do you have these conversations with patients? These are things that I think about and continue to, I think, grapple with.

View the first segment of this roundtable series here.

View the second segment of this roundtable series here.