Evolving Approaches in Small Cell Lung Cancer - Episode 5

Future Directions in ES SCLC

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Panelists reflect on treatment considerations for asymptomatic brain metastases, progress in biomarker research, and frequency of administering checkpoint inhibitors.

Hossein Borghaei, DO, MS: Wade commented that he doesn’t think there are many people who wouldn’t be able to get immunotherapy. Stephen, you started your discussion by presenting the real-world data regarding patients who have PS2 [performance status 2] and brain metastases. Wade, if you have someone with extensive-stage small cell lung cancer and they’re in a hospital, just like Stephen suggested—which is what we see for the most part—and you have identified brain metastases, but they’re asymptomatic, what is your preferred method of treating these patients?

Wade Iams, MD: I would start patients with asymptomatic brain metastases on combination chemotherapy-immunotherapy and then address the brain metastases among the radiation oncologists. There is more of a push to consider SRS [stereotactic radiosurgery] for patients with small cell with brain metastases. Whereas, historically, whole brain radiotherapy had been a broad recommendation.

Institutionally and logistically, getting immunotherapy approved for an inpatient can be a hurdle. It has been an initiative that we’ve typically pursued to make that happen. That’s where working with our pharmacy and formulary colleagues has been instrumental. Ultimately, we don’t know for sure whether 1 dose of immunotherapy in cycle 1 as an inpatient is going to make a difference. But hypothetically, we would like to include it to maximize the immune response at the time of initial response.

Hossein Borghaei, DO, MS: Vivek, what do you do when you have somebody with brain metastases with this diagnosis?

Vivek Subbiah, MD: We would discuss it in a multidisciplinary group meeting. It’s individual case-based. I primarily focus on patients in clinical trials, so all these patients we discuss in the context of multidisciplinary care. I agree with Wade. It depends on the patient, insurance, how quickly we can get these agents approved, and the clinical condition of the patient. It’s individual discretion and discussion with every patient.

Hossein Borghaei, DO, MS: Stephen, you mentioned some potential new biomarkers and the transcription data that have come out, basically dividing small cell into 4 separate categories. Can you comment a little more about that and any other efforts you’re aware of regarding a potential biomarker for this disease predicting immunotherapy or chemotherapy, sensitivity resistance, or anything in that category?

Stephen Liu, MD: The transcription subset data are very intriguing. We’re looking at some heterogeneity in small cell. While we treat all small cell essentially the same, we know there are different behaviors. We all see this in our clinics. There are some patients who do quite well for a long time. When we look at some of these data presented early on from Charlie Rudin, [MD, PhD,] and John Heymach, [MD,] and then updated later with Carl Gay, [MD,] Triparna Sen, [PhD,] and Lauren Byers, [MD], there seem to be specific subsets based on expression of transcription regulators. These are useful, because while the original data are mostly based on RNA sequencing data, for a lot of these, we can detect these subtypes based on immunohistochemistry [IHC]. Not so much the inflamed group, which isn’t really the expression of a specific transcription regulator—more the absence—but we can check ASCL1, NEUROD, and POU2F3 with IHC, which is quick.

One of the challenges with biomarker development in small cell is that the tissue samples tend to be small, fine needle aspirates, cytologic specimens because it’s a central disease often diagnosed by bronchoscopy, or EBUS [endobronchial ultrasound], so we don’t have a whole lot of tissue. You don’t need a whole lot of tissue to make the diagnosis of small cell. It’s pretty characteristic under HNE [4-hydroxy-2-nonenal], but in order to do these biomarker studies, it’s hard to get these big chunks of tissue, which is how we made a lot of advances in non–small cell lung cancer.

It’s hard to get this tissue, and it’s a fulminant disease course. Patients can’t stick around too long, go back, and get repeat biopsies. They need to move forward with therapy. The natural history is not forgiving at all, so it’s difficult to rebiopsy. We have to make do with what we have. If you’ve got a frontline study that’s randomizing or stratifying by specific biomarker, you can’t wait a few weeks to get RNA sequencing data. You can’t wait a few weeks to get next-generation sequencing data. If IHC is quick, it’s possible, so it introduces that as a biomarker. There’s a lot of promise, but we still have a long way to go.

With that said, when we look at Impower133 and these transcription regulator subsets, we see that the inflamed subgroup seems to derive relatively more benefit and long-term survival with atezolizumab. But we see long-term survival in nearly all of the subgroups, with maybe the exception of POU2F3, that’s a pretty rare one. So we can’t use that to select patients. It’s not nearly ready for prime time. It’s encouraging, but there are a lot of challenges, including heterogeneity.

Hossein Borghaei, DO, MS: Well said. Thank you. Those are really important aspects of caring for patients with metastatic small cell that we need to keep in mind. Anne, I have 1 final question for you. In the 2 randomized studies we talked about, the checkpoint inhibitor in question was given every 3 weeks in one and every 4 weeks in the other. Do you see any major difference between the frequency of administration of the checkpoint inhibitors?

Anne Chiang, MD, PhD: No. Actually, can I speak to the biomarker question?

Hossein Borghaei, DO, MS: Sure. Go ahead.

Anne Chiang, MD, PhD: It’s important for people to realize that PD-L1 in small cell is different from in non–small cell. If you look at tissue microarray studies that have been published in the literature, you’ll have one that has 92 specimens that are all 0% PD-L1–positive in the tumor. In fact, for the KEYNOTE-028 trial, they had to expand that definition of positivity to include not only the tumor cells, but the macrophages and the TILs [tumor-infiltrating lymphocytes] to get a combined positive score [CPS] of roughly 40%. And then when you looked at the ones who were positive, they showed a higher response rate of about 35% vs 6%. It’s a different story. It’s not just PD-L1 on the tumor. It’s the microenvironment that’s important. That’s where the tissue is important, because we’re going to have to be able to understand what it is that allows those checkpoint inhibitors to help make a response.

With respect to the frequency, the pandemic has showed us a lot about frequency of administration. During COVID-19, a lot of institutions, ours included, went to an every-6-week administration of pembrolizumab. For atezolizumab, we’ve been doing every 4 weeks. I don’t think the frequency of administration is going to make a big difference.

With regard to our inpatients who are diagnosed with small cell, it’s positive that the pharmaceutical industry went to CMS [Centers for Medicare & Medicaid Services], and the inpatient use of checkpoint inhibitors for extensive-stage small cell is something that will now be reimbursed to some extent. Making that happen within your own hospital, through whichever formulary and so forth, is important. We’re still working on that. We don’t know whether those 1 to 2 extra doses are going to make a difference, but the general approach toward this disease has been to try to use all your guns up front because we think that’s probably our best chance at affecting and improving these patients’ survival.

Stephen Liu, MD: If I can clarify what Anne said; anything about the biology and making care better, I agree with. But we shouldn’t be using PD-L1 today to select because, in KEYNOTE-604, they looked at the CPS, and there was no difference between 1% greater or negative. It’s…for PD-L1, but it’s not yet ready for use.

Hossein Borghaei, DO, MS: That was going to be my question. Is anybody checking for PD-L1 at this point to make a treatment decision? I’m not.

Anne Chiang, MD, PhD: It’s not reimbursed right now.

Hossein Borghaei, DO, MS: There’s no clinical utility for it. It’s not just a matter of reimbursement. There are no data to support its use. I don’t think it matters whether it’s reimbursed at this point, because what are you going to do with the data? It’s the same thing with TMB [tumor mutational burden] in small cell as far as I’m concerned. Outside of a clinical trial or a research question, there really isn’t a role for any of these biomarkers right now. Unfortunately, we’re left not knowing who truly benefits from these drugs and who doesn’t. Wade, where do you think we’re heading? How do you see the treatment landscape changing in the coming years?

Wade Iams, MD: One of the most ambitious and I hope ultimately fruitful hypotheses is linking the combination of our transcription factor-defined subsets in areas of opportunity. With extensive-stage small cell lung cancer, I would argue that’s the maintenance setting. Once we have a response with platinum doublet and immunotherapy, can we identify how to best capitalize and consolidate those gains with a subset-directed therapy? Dr Byers, in one of her most recent papers, articulated that very well in the conclusion. We have a way to go, but one of the biggest ambitions in extensive-stage disease is trying to consolidate gains in the maintenance setting.

Hossein Borghaei, DO, MS: Do you see any new treatment options coming down that we should expect to see or would be effective in the frontline setting?

Wade Iams, MD: The biggest item I’m monitoring is the consolidated checkpoint inhibitor in limited-stage small cell lung cancer. There’s nothing immediately in the next 6 to 12 months that I’m anticipating in the extensive stage frontline setting. There’s maintenance PARP inhibitor use, which will be interesting to see. It’s not subset-selected, but it will be interesting to see how those data play out.

Hossein Borghaei, DO, MS: Thank you for this great discussion.