Updates in Immunotherapy for Advanced Thoracic Malignancies - Episode 8

Treatment Options in Small–Cell Lung Cancer

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Suresh Ramalingam, MD: Where does PD-L1 expression stand in small-cell lung cancer? Is this something you test in your routine clinic? Martin, let me ask you that question and then have Christine chime in as well.

Martin Dietrich, MD, PhD: That’s the million-dollar question. We don’t have any biomarkers. I used to be more aggressive about sequencing small-cell lung cancer, and my experience was surprising to me, that a large portion of small-cell lung cancer is actually TMB [tumor mutational burden] low as well. They have hallmark mutational changes in the retinoblastoma and the TP53 gene but are sufficient in mouse models and in humans to actually lead to a small-cell transformation in the right neuroendocrine precursor cell. It’s not surprising that despite the typical heavy-smoking background, there’s very little efficacy.

I don’t have any biomarker answer for you. This is typically a very difficult-to-biopsy lung scenario if they have them, and we just have to basically go back, and some of that work has been done, to look at that 10% benefiting population and the long-term surviving or long-term benefiting population, that may be different whether up front or in the long-term maintenance setting. But for most patients, the vast majority of benefit is driven still by carboplatin. There’s not a big difference between the platinum agents. This is more to allow for international enrollment where cisplatin is more frequently used than in the United States, in the palliative setting.

We’re far away from finding 1 true biomarker that would characterize PD-L1 or PD-1 benefit in the population, and the trials overall look so interchangeable. One of the things that was interesting for durvalumab and that makes me spring toward the CASPIAN regimen is the difference regarding whole-brain radiation as an intervention, where it was more optional. This will be 1 of the trial design changes. But overall, the hazard ratios and the outcomes are almost interchangeable between the 2 trials.

Suresh Ramalingam, MD: Thank you. Christine, a not-infrequent clinical scenario is you’re on the consult service, and you’re asked to see a patient diagnosed newly in the hospital. It turns out to be small-cell lung cancer, and there is a need for a clinical reason to start the patient on treatment right away. How do you approach that situation?

Christine Bestvina, MD: The way I have handled this is to give cycle 1 of chemotherapy inpatient, and just add in the immunotherapy with cycle 2. We’re not sure exactly how that would change the long-term outcome of the patient, but certainly for practical reasons, just to get the patient started on treatment, get some chemotherapy in their system, and then have the flexibility to add the immunotherapy and go through the insurance approval process in a more calm setting as an outpatient is something that has served me well.

Suresh Ramalingam, MD: Thank you. When we give this chemotherapy-immunotherapy approach, all these trials have used the I/O [immuno-oncology]as a maintenance treatment after they complete chemotherapy. Is that something you all routinely do in the clinic?

Firas Badin, MD: No. We did a very large study, CheckMate 451, nivolumab and nivolumab-ipilimumab as a maintenance treatment after platinum doublet. I thought it was going to give us some hope for our patients; unfortunately, that study came back negative. For a patient who gets started on triplet, whether durvalumab or atezolizumab-platinum doublet, I tend to keep them on maintenance treatment like the study design. But I’m going to give the survival advantage the 25% or 30% reduction in risk of death, and I tend to do the same thing they’ve done on the trial. I tend to keep my patients on a single agent, either atezolizumab or durvalumab, as a maintenance treatment.

Suresh Ramalingam, MD: Thank you. Steve, when you talk about I/O agents in patients with small-cell lung cancer, where we see paraneoplastic syndromes, is there any change in the tolerability profile of the chemo–I/O combination for small cell compared with what we see in non–small cell lung cancer?

Stephen Liu, MD: Not that I’ve seen. Patients with severe paraneoplastic syndromes were excluded from those registrational studies. We don’t have clear answers there. If someone had a myasthenic crisis, for example, it probably wouldn’t be likely to give that patient immunotherapy across the board. But endocrine paraneoplastic syndrome is common in small-cell lung cancer. Really we haven’t seen any worsening. A lot of times the course of those conditions mirrors that of the cancer itself. Once you get a response, those can improve. I haven’t seen any difference in tolerability. It was something we were concerned about, but I haven’t seen evidence to point me in that direction.

Transcript Edited for Clarity