ONCAlert | Upfront Therapy for mRCC

Implications of Durvalumab Following PACIFIC Update

Targeted Oncology
Published Online:1:35 PM, Fri February 15, 2019

Mark A. Socinski, MD: In stage III disease, we’re very much interested in long-term outcomes. What I mean by that is the survival endpoints, whether it be progression-free survival PFS or overall survival, at the longer time points of 3, 4, and 5 years. The updated PFS curve with continued separation and pretty much the same numbers that we saw with the initial PFS curve, suggest that the impact of that year of checkpoint inhibition is durable, that we really are curing the patients we think that we’re curing, and these, this continued separation of those curves really reinforces that concept.

In terms of safety from the PACIFIC trial, I must say there were many of us who were potentially concerned about using a checkpoint inhibitor after chemoradiation. The most important concern that we had, I think, was in regard to the rate of lung toxicity. Obviously, pneumonitis is a common problem as a result of radiation, and we know that checkpoint inhibitors have a low rate of pneumonitis associated with them. And so the question from the PACIFIC trial was were you going to see an increased risk of pneumonitis given to modalities that do cause pneumonitis.

And just focusing on the pneumonitis to start with. I think, reassuredly, we saw that there was a little bit more pneumonitis on the durvalumab arm, but it was mostly grade 1 or 2. That if you look specifically at grade 3 or 4, which is severe or life-threatening toxicity, the overall rates on both arms—durvalumab and placebo—was about 3%. So there didn’t appear to be any difference between the 2 arms with regard to severe or life-threatening grade 3 or 4 toxicity. So that was very reassuring. If you step back and look at all the other toxicities, I think to summarize it in a way that’s important to clinicians is that there were no surprises with regard to the side effects of checkpoint inhibition.

We saw the typical things, the immune related side effects that you would typically see. I think all oncologists are used to giving checkpoint inhibitors in the stage IV setting. There was really nothing new in the stage III setting from what we knew from stage IV. The typical -itises that we thought would occur—dermatitis, hepatitis, colitis, these sorts of things—were pretty much as expected.

The one concern, again, as I mentioned was there going to be an increased risk of pneumonitis and, as I mentioned, slightly higher rates overall of pneumonitis. But in terms of severe life-threatening grade 3 or 4, really no difference. And relatively low rates of about 3%. So that was very reassuring with regard to the safety from the PACIFIC trial.

I think there’s no doubt in my mind that the results of the PACIFIC trial really bring us to a new standard of care in stage III disease in that the potential benefit in long-term survival and overall cure rates is so significant that the risks are really quite minimal in my opinion with regard to that thinking about the risk/benefits sort of thing. I think the investment, from the patient’s perspective, of committing to a year of therapy is not insignificant, but that investment does translate into a 32% reduction in the risk of death. That is very significant, and most patients with stage III non–small cell lung cancer, with a good performance status, their goal is to be cured. And when you say to them that they have a slightly greater than 30% reduction in the risk of death, that is significant to patients, and certainly the risk that we put them at with regard to use of checkpoint inhibition, I think, is minimal relative to that 30%, 30-plus percent reduction in the risk of death.

Transcript edited for clarity.

Mark A. Socinski, MD: In stage III disease, we’re very much interested in long-term outcomes. What I mean by that is the survival endpoints, whether it be progression-free survival PFS or overall survival, at the longer time points of 3, 4, and 5 years. The updated PFS curve with continued separation and pretty much the same numbers that we saw with the initial PFS curve, suggest that the impact of that year of checkpoint inhibition is durable, that we really are curing the patients we think that we’re curing, and these, this continued separation of those curves really reinforces that concept.

In terms of safety from the PACIFIC trial, I must say there were many of us who were potentially concerned about using a checkpoint inhibitor after chemoradiation. The most important concern that we had, I think, was in regard to the rate of lung toxicity. Obviously, pneumonitis is a common problem as a result of radiation, and we know that checkpoint inhibitors have a low rate of pneumonitis associated with them. And so the question from the PACIFIC trial was were you going to see an increased risk of pneumonitis given to modalities that do cause pneumonitis.

And just focusing on the pneumonitis to start with. I think, reassuredly, we saw that there was a little bit more pneumonitis on the durvalumab arm, but it was mostly grade 1 or 2. That if you look specifically at grade 3 or 4, which is severe or life-threatening toxicity, the overall rates on both arms—durvalumab and placebo—was about 3%. So there didn’t appear to be any difference between the 2 arms with regard to severe or life-threatening grade 3 or 4 toxicity. So that was very reassuring. If you step back and look at all the other toxicities, I think to summarize it in a way that’s important to clinicians is that there were no surprises with regard to the side effects of checkpoint inhibition.

We saw the typical things, the immune related side effects that you would typically see. I think all oncologists are used to giving checkpoint inhibitors in the stage IV setting. There was really nothing new in the stage III setting from what we knew from stage IV. The typical -itises that we thought would occur—dermatitis, hepatitis, colitis, these sorts of things—were pretty much as expected.

The one concern, again, as I mentioned was there going to be an increased risk of pneumonitis and, as I mentioned, slightly higher rates overall of pneumonitis. But in terms of severe life-threatening grade 3 or 4, really no difference. And relatively low rates of about 3%. So that was very reassuring with regard to the safety from the PACIFIC trial.

I think there’s no doubt in my mind that the results of the PACIFIC trial really bring us to a new standard of care in stage III disease in that the potential benefit in long-term survival and overall cure rates is so significant that the risks are really quite minimal in my opinion with regard to that thinking about the risk/benefits sort of thing. I think the investment, from the patient’s perspective, of committing to a year of therapy is not insignificant, but that investment does translate into a 32% reduction in the risk of death. That is very significant, and most patients with stage III non–small cell lung cancer, with a good performance status, their goal is to be cured. And when you say to them that they have a slightly greater than 30% reduction in the risk of death, that is significant to patients, and certainly the risk that we put them at with regard to use of checkpoint inhibition, I think, is minimal relative to that 30%, 30-plus percent reduction in the risk of death.

Transcript edited for clarity.
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