New Paradigms for Treatment of Locally Advanced NSCLC - Episode 9

Improving Care in Locally Advanced NSCLC


Mark Kris, MD: I think we have some consensus here. We’re going to use this regimen and move forward. But, what’s the next step here? How are we going to do an even better job with patients? Is there a role for these drugs in patients who are not getting concurrent chemoradiation because of a side effect, severe neuropathy, for example? Is there a role for patients who are not getting a chemotherapy regimen? Because of poor functional status, they would only get radiation.

Walter J. Curran Jr., MD: I’d love to see some trials look at consolidation durvalumab after some sort of radiation course for people who are medically impaired. We’ve only done a fair job, at best, in doing those kinds of trials because there’s such heterogeneity. And some of the poor performance status is due to burden of disease. Some of it is coexisting conditions, and they’re multiple. I’d love to see a trial where we look at adjuvant durvalumab with either radiation, alone, or a very attenuated course of concurrent chemotherapy with radiation. We’ve really made no real progress with those patients. The main progress that I’ve seen, that radiation oncologists have demonstrated in such patients—a more hypofractionated regimen of radiation is doable with good symptom management. There is not too much toxicity. So, doing hypofractionated radiation, some sort of chemotherapy, and adjuvant durvalumab—I’d love to see that tested.

Mark Kris, MD: But, we have these patients who ultimately face metastatic disease. This is the biggest risk to their life and health. Wouldn’t it make more sense to give the durvalumab or other immune checkpoint blockers with the radiation?

Walter J. Curran Jr., MD: Yes. That’s now being looked at in a number of studies. A couple of institutions and groups are looking at this—bringing it in with the concurrent chemoradiation. One of the tough things about that, Mark, as you said, is that concurrent chemoradiation is tough. And is there toxicity?

Mark Kris, MD: I’m talking about adding a second modality to those patients who aren’t going to get chemotherapy.

Walter J. Curran Jr., MD: Absolutely. I agree with that.

Mark Kris, MD: Substituting.

Walter J. Curran Jr., MD: I absolutely agree with that.

Mark Kris, MD: I think that’s a real opportunity to move forward. Do you think that any side effects of the immune drugs are enhanced by radiation? Or, conversely, are there any radiation-enhanced side effects that are worsened by durvalumab or other checkpoint blockade inhibitors?

Walter J. Curran Jr., MD: The data is still coming out in phase I studies. The studies that I’ve seen do not show a dramatically worsened toxicity. But, until the studies are done, I don’t think we can answer that.

Mark Kris, MD: OK. Jyoti, for those patients who are candidates for concurrent therapy, can we do a better job with the systemic therapy, with the radiation?

Jyoti D. Patel, MD: Absolutely. I think we still have a long way to go. Again, bringing immunotherapy up during chemoradiation…

Mark Kris, MD: I’m sorry, I don’t mean with the immunotherapy. We’re talking about chemotherapy. Are all chemotherapies the same? Is it generic? Is that a place in which we should be investigating? Is there a better chemotherapy?

Jyoti D. Patel, MD: Three decades later, it’s hard for me to say, “Yes, there’s a substantial difference.” There are little differences, right? Certain regimens may be more tolerable. And so, you may be able to get the full dose of radiation in. Patient preference—certainly. But my sense is that there’s not going to be a significant difference between different chemotherapeutics. I don’t think one is more of a radiation sensitizer than another. It’s really about the systemic disease. As we have more patients with oncogene-driven tumors, with stage III disease, targeting those with radiation may be important. TKIs with chemotherapy and radiation may still be of interest.

Mark Kris, MD: That was my next question. Let’s say you found an EGFR exon 19 deletion. What would you do? Let me throw that case out to you. EGFR exon 19 deletion—you knew it on day 1. What would you do?

Jyoti D. Patel, MD: It’s stage 3 disease, and it’s still curative.

Mark Kris, MD: But it’s inoperable and unresectable.

Jyoti D. Patel, MD: Still, curative intent with chemoradiation. And so, I would probably treat that patient with cisplatin, pemetrexed, and radiation. In this trial, 5% or 6% of patients had EGFR mutations. With that small number of patients, it looks like there’s a benefit seen with durvalumab. So, in the absence of negative trials, I would treat that patient with durvalumab afterwards.

Mark Kris, MD: I would say that we have to be careful—extrapolating from what we know in stage IV disease to earlier stage disease. Again, I’ll throw out the example in the neoadjuvant space. I don’t think anybody would have expected the rate of pathological response to be double of that with chemotherapy, in people who are getting checkpoint blockers in the setting of neoadjuvant therapy.

Jyoti D. Patel, MD: Even in never-smokers, we’ve seen that, right?

Mark Kris, MD: They have. We’ve seen it in never-smokers. EGFR-mutant cases. It’s sort of a different ball game. So, you have to be careful with that. Would you ever give an EGFR-TKI to 1 of these patients? What about after they finish their durvalumab?

Jyoti D. Patel, MD: Is that 2019? We’ll have some more data by then.

Transcript Edited for Clarity