Updates in Systemic Therapy for Non-Metastatic Lung Cancer - Episode 10

PACIFIC Trial in Stage 3 NSCLC

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Benjamin P. Levy, MD: Let’s move on to the final section, where we will discuss the role of immunotherapy in unresectable stage III disease. We’ve talked about the role of targeted therapy in the adjuvant setting and the role of neoadjuvant immunotherapy in the resected setting. But in the unresected setting, even for cure, we’ve obviously got new treatment paradigms that have evolved over the past 2 years. We have an FDA approval for durvalumab based on the PACIFIC data.

The PACIFIC trial has been presented multiple times. It has been published twice in the New England Journal of Medicine, once for the PFS [progression-free survival] end point and then for an OS [overall survival] end point. We’ve all attended these historical meetings in which we showed up in person. It was presented at ASCO [American Society of Clinical Oncology Annual Meeting] and at the World Lung World Conference on Lung Cancer in Toronto in 2018, and we have some data from ESMO [European Society for Medical Oncology Congress]. Dr Leal, do you want to talk about the PACIFIC data at high level, and then share some updates from ESMO too?

Ticiana Leal, MD: Yeah, definitely. It is great to have this update regarding the 4-year survival for the PACIFIC data. It’s very encouraging. It brings with it a lot of optimism for patients with resectable stage III non–small cell lung cancer, especially if you compare it with historical controls. We had 5-year overall survival rates, despite multiple randomized phase 3 trials, of about 10% to 15% at best.

The PACIFIC trial was a phase 3 trial that randomized patients after completion of concurrent chemoradiation with at least 2 cycles of platinum-based chemotherapy to durvalumab every 2 weeks or placebo. The initial report was an improvement in progression-free survival. The hazard ratio was 0.52. There was an improvement in overall survival, with a hazard ratio of 0.68. As you said, it’s been presented multiple times, and the good thing about having the updates is that it’s been reassuring to see that the data are holding up, and we’re seeing consistent improvements in PFS over time, as well as OS.

This leads us to think that at the 5-year overall survival update, perhaps we’re actually going to be talking about cure rates. Are we curing patients with stage III disease with consolidation durvalumab?

The update now is a 4-year OS update. We have a median follow-up of 34 months with durvalumab. This is the first time there is a median overall survival in the durvalumab arm. We’re seeing a PFS of 17.2 months vs 5.6 months, with a hazard ratio 0.55. We’re seeing an overall survival benefit as well—a median of 47.5 months vs 29.1 months and a hazard ratio 0.71. There are really impressive results.

The tolerability of durvalumab has been well known to all of us, and it is well demonstrated in the trial. It really is a game changer, and it is reassuring to see these updated 4-year overall survival updates.

Benjamin P. Levy, MD: Great summary. How do you put this data into clinical practice? I’ll put you on the spot. The PACIFIC trial did not allow consolidation chemotherapy, which we were generally doing; at least I was for some patients. A third of patients got induction chemotherapy, which no one really ever does, at least in our institution, or at least until recently. Which chemosensitization regimen are you generally using for these patients? Do you always start durvalumab right after the radiation is done, or do you give consolidation treatment?

Ticiana Leal, MD: One of the things I think about, even seeing this update, is that half the patients were alive at 4 years. When I start a patient on concurrent chemoradiation, I think about how I get them to the finish line. How do I get them to durvalumab? I want to make sure we don’t rock the boat during chemoradiation with extra toxicity. In general, I’ve preferred to use the carboplatin-paclitaxel regimen on a weekly basis during radiation. There are patients for whom I may alter the regimen for 1 reason or another. Say somebody has really bad neuropathy. If I feel they can’t handle Taxol, I may change the regimen. This is all based on comorbidities and certain clinical characteristics of that patient. But in general, I favor carboplatin-Taxol with concurrent radiation.

I have gotten away from using consolidation chemotherapy. I don’t think we have strong data for that. We did that in select patients because we had intuitively thought that more is better. But really, we have not seen that pan out in phase 3 clinical trials. So I don’t use consolidation chemotherapy. I am happy to let that go, and so are patients. That added toxicity and might take patients away from being able to get to the consolidation with durvalumab, which is really the main goal. That seems to be the main treatment that has really improved survival and outcomes for patients.

Benjamin P. Levy, MD: Yeah. Are there any differences in how the rest of you manage the chemosensitization regimen and the timing of durvalumab for patients, or is that generally what everybody is doing—weekly carboplatin-paclitaxel with radiation, followed by durvalumab within 2 to 4 to 6 weeks after the completion of radiation?

Jarushka Naidoo, MBBCh: On the PACIFIC trial, a specific chemotherapy regimen wasn’t necessarily mandated. I do use carboplatin-paclitaxel, as Dr Leal explained. I also use platinum-pemetrexed for patients with adenocarcinoma because it is very well tolerated. I am less of a fan of the classic SWOG regimen. I’ve been burned a number of times with that regimen. However, there are purists who use it and use it well, and there would be no reason not to use that regimen. But generally, patients do find it to be a tougher regimen.

In terms of the timing of beginning durvalumab, there was a lot of discussion regarding optimizing the timing—a change in the protocol to allow for a wider window in commencing treatment. It changed our paradigm slightly, in requiring a scan to rule out progression. Beforehand, this was something we weren’t necessarily doing until later. The timing has become more of an issue and requires us to have seamless communication with our radiation oncology colleagues. That might change the workflow for many oncologists in settings where they don’t have real-time access to their radiation oncologists.

Benjamin P. Levy, MD: Are there any other thoughts on the management of this, in how we apply these data into clinical practice?

Ravi Salgia, MD, PhD: The every-2-week dosing is a bit tougher for patients, in regard to coming in each time. Of course, we look forward to the q4 week dosing. The other question always becomes, why only 1 year? Should it be 2 years? Is it going to be 3 years? Or is it going to be 6 months vs a year? All those are important questions. We want to make it as palatable for patients as having a great overall survival but make it as less chemotherapy, less immunotherapy, less surgery, less whatever we can get away with by not having this toxicity. Those are all important questions as we go forward. But this is 1 of the first landmark studies that has revolutionized our practice.

Benjamin P. Levy, MD: Great point, Dr Salgia. Receiving 1 year of durvalumab treatment, every-2-week dosing vs every-4-week dosing, and in this era of the coronavirus pandemic, what treatment considerations are there in terms of how you’re timing this and how long you’re going to give it?

Ravi Salgia, MD, PhD: Yeah, that’s very nerve-racking, right? Our colleagues at Memorial Sloan Kettering Cancer Center published a beautiful paper in terms of cancer discovery, and there are a lot of other papers out of China and other institutions as well. We’re very worried about the coronavirus pandemic. You have this acute lung injury that can happen with COVID-19 [coronavirus disease 2019]. You can experience pneumonitis with immune checkpoint inhibitors. At what point do you worry about concomitant infections? It’s very clear that you have to be able to be cognizant of the pandemic, try to test your patients as best as you can, or at least have symptom checks. Then stick to the regimen, because that’s what FDA has approved. At the same time, for those who get COVID-19, I’m not necessarily sure we should give them this immune checkpoint inhibition. That data is not really out there to help us, and we need to be able to gather more information.

Benjamin P. Levy, MD: It’s a lot of medicine as an art and not a science with COVID-19, in trying to understand timing, frequency, and monitoring of patients. That’s a whole other discussion for a whole other time.

Transcript Edited for Clarity