Oncology Data Advisor: Welcome to Oncology Data Advisor, I'm Keira Smith. Today, I'm joined by Dr. Mark Kris, who is the William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan Kettering Cancer Center. Dr. Kris will be sharing the updates that have occurred in metastatic squamous non–small cell lung cancer treatment during this past year.

Dr. Kris, thanks so much for being here today.

Mark Kris, MD: Hello, I'm Mark Kris. I'm a thoracic medical oncologist, and I work at Memorial Sloan Kettering Cancer Center here in New York. I'd like to update and refresh some thoughts about the treatment of squamous cell lung cancers in 2023.

Squamous lung cancers comprise approximately 25% of patients with non­–small cell lung cancer. It's the biggest group of patients other than the adenocarcinomas. I think where the diagnosis of lung cancer is moving now is that whenever you have a suspected case of lung cancer and you order a biopsy, you need to be absolutely sure that sufficient tissue is obtained—not just to diagnose cancer or diagnose lung cancer, but to allow a complete morphologic examination. That would include immunohistochemistry (IHC) tests for p40 or p60. These are measures for squamous cancer. Generally, tests would also be done to rule out adenocarcinoma, things like napsin or thyroid transcription factor 1 (TTF-1).

Then you need sufficient material to do an immunohistochemistry test. The one that really needs to be done on every suspected lung cancer would be programmed cell death ligand 1 (PD-L1). Lastly, you need to do molecular tests. Why do you need to do that? Even though we don't have a targeted therapy for squamous cell cancers, there are some rare cases where you can find a target. Epidermal growth factor receptor (EGFR) has probably been the one that's most explored. Importantly, you're now required to tell people they don't have anaplastic lymphoma kinase (ALK) EGFR. By people, I mean the approvals of the payors to get checkpoint inhibitors, which will be a standard of care for our patients with squamous cancers.

I think it's pretty important to make sure sufficient tissue is there for molecular testing. I would urge you to please work with the partners that you have that do the biopsies to get sufficient tissue and to order the comprehensive testing for morphology, for IHC, and for next-generation sequencing (NGS) regardless. You can't wait until the morphology and pathology are available. You need to get sufficient tissue and get these tests underway, because you'll get some information.

Once a patient has squamous cancer, again, the standard paradigms are about the same. For non-metastatic patients, you need to make sure of whether there's a role for surgery or not. For patients who are nonmetastatic, if they are not candidates for surgery—either because of fitness or because of resectability—you need to consider concurrent chemotherapy and radiation. In so doing, give drugs appropriate for squamous cancers. That would either be a taxane or gemcitabine with cisplatin or carboplatin, to be followed by a year of durvalumab in these patients that don't have drivers in their squamous cancer.

For people who have metastatic disease, the standard of care would be a combination of chemotherapy and a checkpoint inhibitor. We now have more checkpoint inhibitors available. Again, it's just very interesting—for the last checkpoint inhibitor approved for lung cancer, cemiplimab, there's a requirement now to make sure that the patient does not have EGFR, ALK, or in this case, ROS1 as well. You need to do these molecular tests even to just facilitate getting the approval for your patient. But the standard of care in 2022 upfront would still be cisplatin or carboplatin, probably a taxane—gemcitabine could also be used—and a checkpoint inhibitor, unless there's a contraindication to any of those things.

What's changed in the last year? One thing that I think has led to a major change is the consideration for neoadjuvant therapy. In the past, any patient with locally advanced cancer who would be a candidate for surgery, operable and resectable, would not necessarily receive neoadjuvant therapy. But there was an approval this year for chemotherapy plus nivolumab in patients who are candidates for neoadjuvant therapy and who don't have EGFR or ALK, and our squamous patients fall into that group. I think the use of neoadjuvant therapy and giving a checkpoint inhibitor in the neoadjuvant space, rather than waiting for adjuvant, makes a lot of sense. That's one approval in 2022, now available as a standard of care in 2023, that I think has changed therapy as well.

When you look at all the data for squamous cell, just as we talked about a year ago, while there is clear benefit from combination chemotherapy and a checkpoint inhibitor for patients with metastatic disease, the results in those patients are just not quite as good as they are in patients with adenocarcinoma. We continue to have this, I call it, treatment success gap for patients with squamous cancers. It doesn't mean that they can't benefit, but it does mean that the likelihood of response and better outcomes is smaller.

I think what that does is push us to look for new therapies for these patients, and there's a lot of research going on for that, but there isn't anything that is on the immediate horizon that would make sense where there would be an availability of another treatment. I think, firsthand, it's chemotherapy plus a checkpoint inhibitor unless there are contraindications, then additional chemotherapy if there is disease progression. These patients are candidates for ipilimumab and nivolumab, and dual checkpoint inhibition too, depending on PD-L1 status and depending on tumor mutational burden (TMB) status. That is something to be considered.

A couple other things—number one, if you have the diagnosis of squamous cell based on a tiny biopsy, the recommendation is to still do molecular testing on that, because on a tiny biopsy is not as certain that it is pure squamous cell. If it's a tiny biopsy—and the National Comprehensive Cancer Network (NCCN) guidelines say this as well—you should consider doing molecular testing if you have sufficient tissue on a tiny biopsy.

The last thing that we've seen—and this is an observation that we're still trying to sort out—is that in certain patients with EGFR-mutant cancers who receive osimertinib an an initial therapy, when some of them progress, in addition to having transformation to small cell lung cancer, some have had transformation to squamous cell lung cancer. It's not impossible that a patient with EGFR-mutant disease would indeed have squamous cancer. It's rarely seen at the time of diagnosis but can occur after treatment with osimertinib. In those patients where you are deciding treatment after progression on osimertinib, you really need to get tissue to rule out transformation to small cell or squamous, and to get the most comprehensive gene molecular testing.

To summarize in 2023 with squamous cancer, we have therapies, and we use multimodality therapy whenever that can be successfully employed. Neoadjuvant therapy is becoming more and more available and more and more useful. For me, it's my preferred treatment. If you have a patient with locally advanced disease where a chemotherapy or adjuvant immunotherapy is in their future, I would give the treatment neoadjuvant, so look for those.

About Dr. Kris

Mark Kris, MD, is the William and Joy Ruane Chair in Thoracic Oncology and Chief of the Thoracic Oncology Service at Memorial Sloan Kettering Cancer Center, where he specializes in the treatment of patients with lung cancer, thymoma, and mediastinal tumors. His research focuses on the identification of genetic targets to develop novel therapeutic strategies for patients with lung cancer. Dr. Kris has served as principal investigator or co-investigator of numerous clinical trials.

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Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of Oncology Data Advisor.