Benjamin P. Levy, MD: Let’s discuss the risk of pneumonitis for patients on durvalumab post-chemoradiation. Dr Naidoo, I’ve heard you’ve done some work on pneumonitis before, so I’ll turn to you first. What is your take on the pneumonitis risk with immunotherapy, particularly durvalumab, post-concurrent chemoradiation? Is it any more risky to do that, independent of whether radiation is given or not?

Jarushka Naidoo, MBBCh: There have been a couple of presentations on this topic, led by Johan Vansteenkiste, MD, PhD, at the World Conference on Lung Cancer a couple of years ago, updated recently, and now there is a paper in press on this particular topic. I think we all expected that the pneumonitis rate with a consolidation immunotherapy approach after chemoradiation could be horrific, and I think we were all pleasantly surprised when it was not much of a departure from the placebo arm in the PACIFIC study.

I would say that the rates of pneumonitis are pretty encouraging, or not unacceptable, and are really a surprise in that regard. In many of these subset analyses looking at the rates of pneumonitis, we did see that patients of Asian ethnicity appeared to have higher rates of pneumonitis—patients with EGFR mutations—than what we might expect. There have been some subsequent real-world data that have been published showing that patients who receive higher doses of radiation, radiation that involves a greater proportion of the lung field than was included in the PACIFIC study, may also be at increased risk. I think these are all intuitive risk factors for the development of pneumonitis.

Touching on your other question regarding how we differentiate between RT [radiation therapy] and I/O [immune-oncology] pneumonitis, and what is the gray area in between, this is a hugely important area for us to understand a bit better. There are some assumptions and some barriers that are preventing advances in the area. In differentiating them just routinely at the moment, we understand that I/O pneumonitis can have a variety of radiographic appearances. It can be pretty esoteric in terms of its time to development—anywhere from 9 days to 19.5 months after the start of immunotherapy in our Journal of Clinical Oncology paper. RT pneumonitis is a bit more predictable in this sense. Also, it generally follows the curvature of the radiation field, whereas I/O pneumonitis is usually a bilateral phenomenon. That is something that we use in a colloquial sense, but certainly hasn’t been formally looked at and really does require a formal look in the stage III population.

I think the other thing to consider is we don’t know that pneumonitis can so cleanly segregate into I/O-related or RT-related cases, and there probably is a middle zone where both factors are coming into play in the development of that pneumonitis. We need to study that. The only data that have been published in that area was an abstract presented at AACR [the American Association for Cancer Research] looking at a 7-cytokine signature that was associated with pneumonitis in this setting. So I think those kinds of biomarker studies are very important to do. We did a BAL [bronchoalveolar lavage] study in patients who developed I/O pneumonitis and identified some immunologic signatures in the BAL. I think we need to have a low threshold for doing bronchoscopy and participating in these kinds of studies, in helping to understand who’s at risk for this very important toxicity.

Benjamin P. Levy, MD: Yes, I think it’s also important for future trial development. As you’re aware, Dr Naidoo, we’ve got some ongoing trials looking at immunotherapy given concurrently with definitive radiation. Soon, I think we’ll find out the optimal timing of immunotherapy. Is it consolidation? Can we safely give it with radiation? Can we do dual checkpoint blockade post-concurrent chemoradiation? I know you’ve been a part of some of these studies. Do you want to give some parting shots on the future trials for this?

Jarushka Naidoo, MBBCh: Sure. Again, I feel like my whole discussion today has been about believers and nonbelievers. But I think that’s where some of these concepts come from. Honestly, we don’t know about timing and optimal dose. This is something that has evaded us, in terms of a clear answer, when combining radiation with immunotherapy. It’s something that requires a dedicated study. Regarding the concurrent group, the believers obviously support the more is more approach—more treatment, more neoantigens. It’s the same sort of argument that we had on neoadjuvant immunotherapy. If you add chemotherapy, and then now if you add radiation, you increase that swell of neoantigens and potentially improve outcomes from immunotherapy. I think that’s the basis of the concurrent argument. But in the Salma Jabbour, MD, study that was highlighted recently, 69% of patients had grade 3 toxicity. So while it might be scientifically interesting, it might be very difficult to administer.

In terms of the consolidation approach, the Hoosier Oncology Group study randomized patients to nivolumab, or ipilimumab and nivolumab in the consolidation setting. Again, this showed a higher rate of toxicity for the combination arm. This is exactly what we expected. We are awaiting survival outcomes from that. And then the last study we know of looked at giving immunotherapy pre- and post-chemoradiation. This was a study of single-agent atezolizumab.

I think with all of these, we’re going to have to see the data in their entirety and balance these approaches. I do foresee that in the same way we have 9 options in first-line lung cancer now, we may have several options that we don’t have a clear comparator for. We will probably be having these similar discussions in the coming months or years.

Benjamin P. Levy, MD: Yes, an incredible time. Confusing, but what a gain for our patients to have these options. Who would have thought?

Transcript Edited for Clarity