In this episode of JCO Article Insights, host Dr. Ece Cali Daylan interviews author Dr. Jeffrey Bradley about the article, "Simultaneous Durvalumab and Chemoradiotherapy in Unresectable Stage III Non–Small Cell Lung Cancer" by Bradley, et al published October 13, 2025.

TRANSCRIPT

Dr. Ece Cali: Welcome to this episode of JCO Article Insights. This is Dr. Ece Cali, JCO Editorial Fellow. Today I'm joined by Dr. Jeffrey Bradley, Professor of Radiation Oncology at the University of Pennsylvania, to discuss the manuscript, "Simultaneous Durvalumab and Platinum-Based Chemoradiotherapy in Unresectable Stage III Non-Small-Cell Lung Cancer: The Phase III PACIFIC-2 Study."

The PACIFIC-2 study was a phase III, double-blind, randomized trial comparing the efficacy and safety of simultaneous durvalumab with concurrent chemoradiation followed by consolidation durvalumab to the concurrent chemoradiation followed by placebo in patients with unresectable stage III non-small cell lung cancer. The primary endpoint was progression-free survival by blinded independent central review. The secondary endpoints were overall response rate, overall survival, and safety.

Three hundred twenty-eight patients were randomized 2:1 to durvalumab and placebo, respectively. Unfortunately, this trial did not meet its primary endpoint. There were no statistically significant differences in PFS or OS. The frequency of adverse events was similar between the two arms. Grade 3 or higher adverse events were observed in 53% of the patients in the durvalumab arm compared to 59% of the patients in the placebo arm. Of note, the frequency of pneumonitis was similar in the two arms. Approximately 28% of patients in each arm developed pneumonitis, and about 5% of the pneumonitis observed in each arm was grade 3 or higher in severity. Treatment discontinuation rates secondary to the adverse events were higher in the durvalumab arm, 25% compared to 12%. Adverse events leading to treatment discontinuation and death were more frequently seen in the durvalumab arm during the first four months of the treatment, which corresponds to the simultaneous administration of chemoradiation and durvalumab.

Dr. Bradley, before we delve into the results, can you please explain the rationale for this study design and how this concept fits into the current treatment landscape?

Dr. Jeffrey Bradley: Yeah, this trial came on the heels of PACIFIC after there was a progression-free survival benefit showed in PACIFIC that in the locally advanced unresectable population that consolidation immunotherapy, in this case durvalumab, had a progression-free survival benefit. A number of us in the clinical trial space thought to add concurrent immunotherapy in addition to consolidation immunotherapy that that would also improve outcomes for patients. So a number of trials were launched to follow up of PACIFIC.

In this case, this is a phase III trial where the control arm was placebo. There was no overall survival results yet from PACIFIC, just a PFS benefit, and a number of countries across the world had not approved maintenance durvalumab in this space. So this trial looked at the experimental arm, which was concurrent immunotherapy, durvalumab, and chemoradiation followed by consolidation durvalumab versus placebo.

Dr. Ece Cali: And if we were to focus on the safety profile first, an increased pneumonitis risk was a theoretical concern when immunotherapy is given concurrently with radiation. Do we see any major differences in the safety profile between the two arms in this trial?

Dr. Jeffrey Bradley: No, and we were concerned about the addition of concurrent immunotherapy and chemoradiation, like you said, towards concern about increased pneumonitis rate, but we did not see increased pneumonitis in the experimental arm over placebo. And the grade 3 or higher, as you said, it was roughly 5%, more or less, in both arms, so we didn't see increase in pneumonitis toxicity with concurrent IO and chemoradiation.

Dr. Ece Cali: But interestingly though, despite the lack of significantly increased toxicity with durvalumab, unfortunately, administering immunotherapy simultaneously with chemoradiation therapy did not improve survival. Lack of superiority of this treatment regimen, as you mentioned, is further confirmed across multiple similar negative trial readouts such as ECOG-ACRIN 5181 and CheckMate 73L. Dr. Bradley, in your view, what are some potential explanations for why this strategy did not pan out in clinical trials?

Dr. Jeffrey Bradley: Regarding toxicity, let me go back and point out that we did see an increased number of immune-mediated adverse events. It was 34.7% in the concurrent immunotherapy arm versus 15.7% in the placebo arm. So that led to a higher number of discontinuations of immunotherapy which I think probably had an effect. So we didn't... there was an increased pneumonitis toxicity, but there were expected immune-mediated toxicities that caused people to stop giving immunotherapy. You can see that in the PFS curves. They were, you know, they crossed over after like a month, but initially there was lower PFS for the experimental arm, and then the experimental arm got better after we divided into four months, before four months and after four months.

Dr. Ece Cali: For one reason or another, it looks like the simultaneous administration did not really improve outcomes. We now know that simultaneously giving them another concurrent radiation should really no longer be pursued in clinical trials for this patient population. Can you share with our audience what strategies are being studied in this setting and what trials to watch out for in the future?

Dr. Jeffrey Bradley: Sure, I think when you add concurrent radiation to immunotherapy, there were more central tumors in this trial, I think you're killing lymphocytes and negating the effect of immunotherapy. So I think that's the smoking gun for this trial, for the ECOG trial, for the small cell trial that NRG reported, LU005, and other trials. So correct, I don't think there's any need to continue to pursue concurrent immunotherapy in this space of lung cancer.

But that's not to say there aren't many other trials that are either ongoing, have accrued and awaiting results, or being planned for the next phase of clinical trials. We have a trial within NRG Oncology called NRG-LU008. It's a randomized phase III trial that is using an SBRT boost to a peripheral primary and chemoradiation to the nodes, because the primary tumor is the one that fails more often than the lymph nodes, and that's compared to PACIFIC in the control arm.

PACIFIC-9 is another trial in the same line as the other PACIFIC trials. That one is using dual checkpoint inhibition versus the control arm being PACIFIC. So there are three arms in that trial, durva and oleclumab, durva and monalizumab versus the PACIFIC arm. And that trial is completed accrual, but we have no results from that study yet.

Johnson & Johnson has a trial open looking at a nanoparticle. That's a radiosensitizer where bronchoscopy is used to inject the primary tumor and the lymph nodes with a radiosensitizer. That's a randomized phase ll trial that's ongoing. It's got three arms, two different doses of this radiosensitizing drug and then a control arm without injection at all. The control arm is again the PACIFIC arm.

And then those of us within the NCI-based clinical trials evaluation program, CTEP, are proposing an intergroup trial that would compare induction chemo-immunotherapy followed by chemoradiation followed by maintenance immunotherapy versus PACIFIC in a phase III study. So I think there's other trials that are either completed, ongoing completed, or on the horizon to assess in this patient population.

Dr. Ece Cali: Yeah, we definitely have an unmet need to improve survival outcomes for stage III patients, and it's great to hear that there are so many efforts looking at different strategies to improve outcomes for these patients. 

Thank you so much, Dr. Bradley, for this informative discussion and for sharing your insights. Any last thoughts?

Dr. Jeffrey Bradley: Yeah, we need something, you know. PACIFIC was first reported in 2017, and we really haven't made progress in terms of changing that standard of care control for the last eight years. So we need progress in this area.

Dr. Ece Cali: Yep, definitely. Thank you so much for joining, Dr. Bradley. 

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