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ONCAlert | Upfront Therapy for mRCC

The Impact of the PACIFIC Trial and Updated Analysis

Targeted Oncology
Published Online:1:34 PM, Fri February 15, 2019

Mark A. Socinski, MD: The PACIFIC trial, a very important trial, evaluated patients with stage III, unresectable non–small cell lung cancer, who had undergone concurrent chemoradiation with platinum-based therapy. They received a radiation dose between 54 and 66 Gy. They could have received induction therapy. I think about 28% of patients did receive chemotherapy followed by concurrent chemoradiotherapy. After completion of chemoradiation, they had to have documented absence of disease progression. And within 6 weeks from the completion of concurrent chemoradiotherapy they were randomized to receive the control arm, which was a placebo, versus the investigational arm, which was durvalumab, delivered on an every-2-week basis for up to 12 months. And that was the design of the trial.

The endpoints of the trial were both progression-free survival as well as overall survival. And what we saw from this trial was, initially on the first analysis, a significant benefit in progression-free survival, and then subsequently at an updated presentation, a benefit in overall survival for the patients who were receiving durvalumab. Whether you want to call it consolidation durvalumab, or sequential durvalumab, or maintenance therapy, or whatever you want to call it, the delivery of a checkpoint inhibitor, durvalumab, following concurrent chemoradiotherapy led to significant improvements in progression-fee as well as overall survival.

The PACIFIC trial is an incredibly important trial, and the reason I say that is because we established, in really the decade of the 1990s, we established that giving chemotherapy, specifically platinum-based chemotherapy, with radiotherapy concurrently led to improved outcomes in stage III disease. And really what I mean by that is improved overall survival. However, once we established that the use of concurrent chemotherapy led to improved survival, there were really a number of trials looking at the next step. What could one do next? We looked at various targeted therapies. EGFR-directed therapy with cetuximab was not successful. We looked at dose escalation with radiotherapy, and that was not successful.

So I would say that for at least a decade, we really had no improvements in outcomes in stage III disease following concurrent chemoradiotherapy. Along comes the PACIFIC trial exploring the use of a checkpoint inhibitor, specifically durvalumab, an anti–PDL1 drug, after concurrent chemoradiotherapy, that showed an impressive benefit in progression-free as well as overall survival. So the combination of having that draught period where nothing changed, it led to some apathy about treating the disease—this is all we, this is the best that we could do. That was well over a decade of feeling it. Along comes PACIFIC, which if you visually see the progression-free and overall Kaplan–Meier survival curves, these are very impressive differences in these outcomes of survival.

In the PACIFIC trial, the initial data that we saw was based on progression-free survival. And that was very impressive. It really led to a change in the standard of care based on the progression-free survival. I think what was also very important in the initial presentation was the, what I call the poor man’s survival curve. What I mean by that is that data were presented that looked at the 2 outcomes in stage III disease that we are trying to prevent. What we’re trying to prevent is stage IV disease in death.

What we saw with the initial analysis was a curve that looked at patients with regard to time to first metastasis or to death. To me, that’s a poor man’s survival curve. That was highly statistically significant in favor of durvalumab. And at that point, even though we had officially just progression-free survival, I felt that the time to death, first metastasis curve, was compelling enough that there was no way that overall survival was not going to be significantly benefit.

Last September, at the World Lung Meeting [17th World Conference on Lung Cancer], we saw the update of the overall survival from the PACIFIC, with a hazard ratio of 0.68. The control arm showed a very impressive 28-month median survival, which was pretty much what one would expect in that population. And the median survival on the durvalumab arm has not yet been reached. And therefore I think this is, is not only statistically significant, this is clinically significant, it is practice changing, it is guideline changing, and it really offers patients a higher chance of cure.

When I see a patient with stage III disease, I say you have curable disease. Our goal is cure. When I see a patient with stage IV disease, I say you have treatable disease but you don’t have curable disease. The results of the PACIFIC trial suggest that we have the ability to cure more patients with stage III disease with the use of checkpoint inhibition following concurrent chemoradiotherapy than we did without checkpoint inhibition in that setting. So I think the PACIFIC trial really is a landmark, very important trial for the practice of caring for lung cancer patients.

Transcript edited for clarity.

Mark A. Socinski, MD: The PACIFIC trial, a very important trial, evaluated patients with stage III, unresectable non–small cell lung cancer, who had undergone concurrent chemoradiation with platinum-based therapy. They received a radiation dose between 54 and 66 Gy. They could have received induction therapy. I think about 28% of patients did receive chemotherapy followed by concurrent chemoradiotherapy. After completion of chemoradiation, they had to have documented absence of disease progression. And within 6 weeks from the completion of concurrent chemoradiotherapy they were randomized to receive the control arm, which was a placebo, versus the investigational arm, which was durvalumab, delivered on an every-2-week basis for up to 12 months. And that was the design of the trial.

The endpoints of the trial were both progression-free survival as well as overall survival. And what we saw from this trial was, initially on the first analysis, a significant benefit in progression-free survival, and then subsequently at an updated presentation, a benefit in overall survival for the patients who were receiving durvalumab. Whether you want to call it consolidation durvalumab, or sequential durvalumab, or maintenance therapy, or whatever you want to call it, the delivery of a checkpoint inhibitor, durvalumab, following concurrent chemoradiotherapy led to significant improvements in progression-fee as well as overall survival.

The PACIFIC trial is an incredibly important trial, and the reason I say that is because we established, in really the decade of the 1990s, we established that giving chemotherapy, specifically platinum-based chemotherapy, with radiotherapy concurrently led to improved outcomes in stage III disease. And really what I mean by that is improved overall survival. However, once we established that the use of concurrent chemotherapy led to improved survival, there were really a number of trials looking at the next step. What could one do next? We looked at various targeted therapies. EGFR-directed therapy with cetuximab was not successful. We looked at dose escalation with radiotherapy, and that was not successful.

So I would say that for at least a decade, we really had no improvements in outcomes in stage III disease following concurrent chemoradiotherapy. Along comes the PACIFIC trial exploring the use of a checkpoint inhibitor, specifically durvalumab, an anti–PDL1 drug, after concurrent chemoradiotherapy, that showed an impressive benefit in progression-free as well as overall survival. So the combination of having that draught period where nothing changed, it led to some apathy about treating the disease—this is all we, this is the best that we could do. That was well over a decade of feeling it. Along comes PACIFIC, which if you visually see the progression-free and overall Kaplan–Meier survival curves, these are very impressive differences in these outcomes of survival.

In the PACIFIC trial, the initial data that we saw was based on progression-free survival. And that was very impressive. It really led to a change in the standard of care based on the progression-free survival. I think what was also very important in the initial presentation was the, what I call the poor man’s survival curve. What I mean by that is that data were presented that looked at the 2 outcomes in stage III disease that we are trying to prevent. What we’re trying to prevent is stage IV disease in death.

What we saw with the initial analysis was a curve that looked at patients with regard to time to first metastasis or to death. To me, that’s a poor man’s survival curve. That was highly statistically significant in favor of durvalumab. And at that point, even though we had officially just progression-free survival, I felt that the time to death, first metastasis curve, was compelling enough that there was no way that overall survival was not going to be significantly benefit.

Last September, at the World Lung Meeting [17th World Conference on Lung Cancer], we saw the update of the overall survival from the PACIFIC, with a hazard ratio of 0.68. The control arm showed a very impressive 28-month median survival, which was pretty much what one would expect in that population. And the median survival on the durvalumab arm has not yet been reached. And therefore I think this is, is not only statistically significant, this is clinically significant, it is practice changing, it is guideline changing, and it really offers patients a higher chance of cure.

When I see a patient with stage III disease, I say you have curable disease. Our goal is cure. When I see a patient with stage IV disease, I say you have treatable disease but you don’t have curable disease. The results of the PACIFIC trial suggest that we have the ability to cure more patients with stage III disease with the use of checkpoint inhibition following concurrent chemoradiotherapy than we did without checkpoint inhibition in that setting. So I think the PACIFIC trial really is a landmark, very important trial for the practice of caring for lung cancer patients.

Transcript edited for clarity.
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