Advanced Lung Cancer: A Year in Review - Episode 15
Naiyer Rizvi, MD: The PACIFIC trial in unresectable stage III patients was a bit of a game-changing trial, showing that adding durvalumab versus placebo after chemotherapy and radiation therapy [RT] for unresectable stage III patients showed both PFS [progression-free survival] as well as survival benefit. Leora, talk to me about PACIFIC and your experience with it.
Leora Horn, MD, MSc: That is probably 1 of the most practice-changing regimens we’ve seen in lung cancer besides small cell, which we’ll talk about later. That was concurrent chemotherapy and radiation therapy followed by either placebo or durvalumab in patients with locally advanced disease who are not surgical candidates. When the trial first came out, there was a significant improvement in progression-free survival, almost a year. In the United States it actually led to the approval of durvalumab prior to the overall survival data, and then we saw last year that there was also a significant improvement in overall survival. There was also improvement in the incidence of distance disease in patients getting durvalumab, you know, particularly in the brain. We see a lot of patients with stage III disease. One of the areas of recurrence will be CNS [central nervous system], and there was a reduction in CNS metastases, so it has become a regimen where we prepare the patients up front. We don’t just tell them they’re going to get chemotherapy radiation and then say, “Oh, you’re going to get a year of therapy after.” We prepare them that you’re going to get this first and then you’re going to get your durvalumab after. I think where I’m hearing a lot of people, where it’s changed things, is their tumor board meetings. A lot of patients who are borderline resectable rather than trying to push the envelope of should we resect them where they’re switching over to definitive chemotherapy–radiation therapy followed by durvalumab? Although I will say that we still—if those patients are potentially resectable—do single-station N2. Our institution will resect those appropriate patients. The other thing it changed for our institution is we used to do carboplatin-paclitaxel weekly followed by consolidation carboplatin-paclitaxel, and that has fallen by the wayside. Patients are getting weekly paclitaxel, and they are going over to durvalumab after. We do not do the consolidation carboplatin-paclitaxel anymore.
Naiyer Rizvi, MD: Tim are you seeing more cases referred for chemotherapy-RT? Or are you seeing stage III patients a little earlier, fewer patients going to surgery, and more for chemotherapy-RT since the PACIFIC data?
Tim Kruser, MD: Leora’s statement was music to my ears. I make that argument at tumor board all the time that if we take someone to the operating room, we’re removing a component from their care that adds 3 years and 11% overall survival benefit with a hazard ratio of 0.69 or something. The decision to utilize surgery needs to really be evidence based. Right now there’s not really any evidence to suggest that incorporation of surgery in people who have stage III, IIIa, IIIb disease, is going to benefit them, whereas it does withdraw the durvalumab from their treatment package.
Naiyer Rizvi, MD: We didn’t see any statistically significant worsening of pneumonitis in the PACIFIC trial. What’s your experience? Do you feel like you’re seeing more pneumonitis? Do you feel like we need a CT [computed tomography] scan before they start the durvalumab? How do you approach when they get pneumonitis? Walk me through that a little.
Tim Kruser, MD: We actually just presented our data from Northwestern University and pooled with Washington University in St. Louis, looking at our real-world experience. Our grade 2 pneumonitis rate was 30%, which is a little higher than what they published in the PACIFIC cohort. But the PACIFIC cohort actually included grade 1, which was interesting, but it seems to be manageable. We looked at the rates of rebound pneumonitis if you restart after treatment with steroids, and importantly more than 80% of people who restarted did not have rebound pneumonitis upon reincorporation of durvalumab. So we see it. We manage it with steroids. The question is how long of a steroid taper we’ll use. Historically we’ve done 8 weeks. Both us and Wash U were using 4- to 6-week tapers, and it seemed to do fine by just dropping 1 dose of durvalumab and calming it down and restarting.
Leora Horn, MD, MSc: Naiyer, remember that in the PACIFIC trial you had to have a CT scan before you start durvalumab. So we all do CT scans after concurrent chemotherapy-radiation, because if patients have progressed, then they are not candidates for the durvalumab. The pneumonitis as well—it’s important for the physician who is looking at the scan to look where the pneumonitis is. When it’s in the radiation field, we’re a little less concerned about pneumonitis. In those patients who have these diffuse, patchy infiltrates, which we’ve seen several times, for those patients we don’t reintroduce the durvalumab. If they’ve got pneumonitis requiring steroids in bilateral lungs, that’s very different from the pneumonitis requiring some steroids in the prior radiation field.
Naiyer Rizvi, MD: That’s helpful, but Tim, you guys shoot beams from like all over the place, right? So you can get a radiation effect outside just where the tumor is, right?
Tim Kruser, MD: Our treatments are very precise. With IMRT [intensity-modulated radiation therapy], what you are pointing out is that historically that would have a swath of radiation fibrosis front to back, which is not currently what we’re seeing. But to Leora’s point, it still tends to be dominantly localized if it is radiation induced in the treated lobe. So reviewing that with your radiation oncologist, both in terms of the presentation and locality, to try to get the best guess as an attribution is important. Because if it is thought to be drug related, you’re going to be more hesitant to restart; whereas if it is radiation induced, it seems safe in most patients to reincorporate durvalumab.
Naiyer Rizvi, MD: When do you see the radiation pneumonitis? How soon do you feel comfortable starting the immunotherapy?
Tim Kruser, MD: In the series we looked at, all cases happened within 6 months. The mean time was 4½ months. It’s usually in that 3-, 4-, 5-month time frame that you’re seeing if it’s radiation induced. Again, as I said, we used to use 8 weeks of steroids because we weren’t withholding important therapy. We could be pretty prolonged with our steroid taper. Now that we know steroids are holding off an important treatment, we’ve gotten a little quicker with giving a steroid taper that’s more accelerated.
Transcript Edited for Clarity