Case 1: Immunotherapy in Locally Advanced NSCLC



Benjamin P. Levy, MD:Let’s talk a little bit about the PACIFIC trial. We’ve been waiting for a very long time to deliver a consolidative therapy, post—concurrent chemoradiation, that translates into an overall survival advantage. This has been attempted multiple times. We’ve had consolidation chemotherapy being looked at, and that was negative. We’ve had consolidation-targeted therapy looked at, and that was negative. This has been a welcome change with the PACIFIC trial, and this was a very straightforward design. Patients with stage III unresectable lung cancer who had received concurrent chemoradiation, were randomized 2-to-1 to durvalumab—a PD-L1 [programmed death-ligand 1] drug and an immunotherapy drug—versus placebo. Keep in mind that placebo was the standard of care at the time that this trial was designed and that therapy started to be delivered. Durvalumab was given every 2 weeks for up to a year.

We saw, initially, in aNew England Journal of Medicine[NEJM] publication last year, that there was a huge difference in progression-free survival [PFS]. You could drive a Mack truck through those curves. We were very encouraged by what we saw in the PFS, but we were all waiting around to see the OS [overall survival] advantage, and we weren’t able to get that until recently. We saw in OS advantage more recently—about 6 months ago in theNEJMpaper and also presented at World Lung [International Association for the Study of Lung Cancer 19thWorld Conference on Lung Cancer in Toronto—a meaningful difference in median overall survival, especially in 12-month and 24-month overall survival difference.

I think this has been practice changing. There has been an important look at key subgroups of patients in this trial that may have benefited more. Interestingly, when you look at PD-L1, there was a group of patients who did not benefit, and that was at less than 1% PD-L1. This led to Europe not approving immunotherapy for patients post—concurrent chemoradiation if the PD-L1 is less than 1%. In the US, the FDA approved it for all patients. Whether PD-L1 really makes a difference and saying whether we test in stage III, as well as if we use that information, is really yet to debate. I think for most of us, we end up giving immunotherapy for most patients.

The other interesting key subgroups…will layer into a question about the timing of scans. But if you are able to give the immunotherapy, the durvalumab, within 14 days after the completion of radiation, those are the patients who did better. That’s a little bit of a concern because we thought if we give immunotherapy right after radiation, there would be a pneumonitis concern. But we didn’t see that in the trial. So it’s really altered how we deliver. Usually, we give concurrent radiation, we do a scan, and then we follow these patients. If you want to go by the data, maybe there’s an opportunity to give immunotherapy within 14 days without even doing a scan and getting them going on therapy. You have up to 42 days to do it. The other key subgroup that we looked at wasEGFR-mutated lung cancer. They were allowed in the trial. This was a group that did not derive a benefit in overall survival, and we’ll talk aboutEGFRin the next case.

Finally, if you looked at toxicity, it was well tolerated. I think we were anticipating seeing a higher incidence of pneumonitis, and we didn’t see this. So this is clearly practice changing. Isabel, any thoughts on this? This clearly has changed your practice, I assume?

Isabel Preeshagul, DO, MBS:I think it has changed my practice for some patients, but it’s definitely a shared decision-making process that happens. I review the data with the patient. I talk about positives versus negatives for first going on immunotherapy. I also let them know that it’s not a binding contract. While it does call for durvalumab every 2 weeks for a year, I found that patients have still gained a benefit if they’ve ended up with some toxicity and had to come off after 6 months or even less.

Benjamin P. Levy, MD:The question is time. Do we need a year or not?

Isabel Preeshagul, DO, MBS:Right.

Benjamin P. Levy, MD:Can it be 6 months? I don’t think we know. Anshu, all radiation oncologists get very much involved. I don’t know if these are one-offs or not, talking about immunotherapy to patients post—concurrent chemoradiation.

Anshu K. Jain, MD:I have the fortune of working in a multidisciplinary clinic. We have patients seeing our medical oncologists and myself at the same time. I’d love to get involved with these discussions. I think that this trial, in particular, did a great job of making sure that there was a good QA [quality assurance] on the radiation plans, ensuring that those plans met those criteria in terms of V20 [volume of normal lung receiving at least 20 Gy], which is kind of what I was talking about a little bit earlier. I think that we all get involved in terms of the decision making about saying we anticipate that, in your case, this may be followed by immunotherapy as a maintenance for consolidation and treatment. We also often discuss the timing of post-treatment imaging as well.

Benjamin P. Levy, MD:Yeah. A great discussion, 1 case down.

Samuel Caughron, MD:Could I ask a question of the group?

Benjamin P. Levy, MD:Yes.

Samuel Caughron, MD:PD-L1 [programmed death-ligand 1] testing is relatively easy to perform. For its immunohistochemistry, we can get it back within 24 hours to 48 hours. Even though it may not be indicated, is it useful information to have if you have a patient with an 80% TPS [Tumor Proportion Score] versus a 5% or 2%?

Benjamin P. Levy, MD:I was giving you a hard time on the prior PD-L1 question. We test it on every phase III patient. The issue for me is that it may help me frame expectations on whether the drug will work, or how well it will work. If it’s greater than 80%, I do tell patients there’s a likelihood that this drug will further shrink your tumor. We don’t know this for the data, by the way. This is data-free zone. But if you look at the data, patients who had a higher PD-L1 had a more meaningful improvement in overall survival. The hazard ratios get smaller based on the PD-L1 cutoff. For an 80% TPS, I have a little more confidence. For the less than 1%, I’m a little more cautious on how quickly I follow and surveil them on whether the drug will work or not. But it’s still approved. I think it’s very meaningful. Isabel, I don’t know if you have any comments as a medical oncologist.

Isabel Preeshagul, DO, MBS:No. I think you bring a great point, Sam, and I echo Ben’s thoughts. I think I use it to guide my discussion with the patient and use it as an education point. For patients who are unsure about what decision to make and don’t really know which way to go, I don’t use it to scare them, but rather explain to them what their expectations may or may not be with this result. I found it to be very helpful, actually.

Transcript edited for clarity.

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