Durvalumab With Concurrent Chemoradiation Misses PFS End Point in Unresectable Stage III NSCLC

Concurrent administration of durvalumab (Imfinzi) and platinum-based chemoradiation failed to significantly improve progression-free survival (PFS) over chemoradiation alone in patients with unresectable stage III non–small cell lung cancer (NSCLC), missing the primary end point of the phase 3 PACIFIC-2 trial (NCT03519971).¹

Data from an initial safety analysis indicated that the toxicity profiles for durvalumab and chemoradiation generally aligned with what has previously been reported with the agents. However, an increased rate of infection was observed in the concurrent treatment period for the durvalumab arm.

“While the PACIFIC-2 trial results did not show what we hoped, the PACIFIC regimen remains the standard of care [SOC] for patients with unresectable, stage III NSCLC,” Jeffrey D. Bradley, MD, vice chair of Proton Therapy & Technology Development at Penn Medicine in Philadelphia, Pennsylvania, stated in a press release. “As a community, we will take insights from these results to advance future research.”

It is known that that the global SOC for this patient population is platinum-based chemoradiation followed by durvalumab based on findings from the phase 3 PACIFIC trial (NCT02125461). With PACIFIC-2, investigators set out to determine whether concurrent administration of durvalumab and chemoradiation could address those who progress or discontinue treatment during chemoradiation and therefore are not candidates for the PACIFIC regimen.

The randomized, double-blind, placebo-controlled, multicenter, international study enrolled patients with histologically or cytologically confirmed NSCLC who had locally advanced, unresectable disease.² Patients were required to have a World Health Organization performance status of 0 or 1, at least 1 measurable lesion that did not receive prior irradiation, and a life expectancy of 12 weeks or more at the time of randomization.

If they received prior or current treatment such as radiation, investigational drugs, chemotherapy, durvalumab, and monoclonal antibodies, or others, they were excluded. They could not have prior exposure to immune-mediated treatment, nor could they have a history of allogeneic transplantation, active or previous autoimmune or inflammatory disorders, or uncontrolled intercurrent illness. Other exclusion criteria included a history of another primary malignancy, active infection, having mixed small cell and NSCLC histology, and a known allergy or hypersensitivity to any of the agents on the trial.

Study participants (n = 328) were randomly assigned 2:1 to receive durvalumab at a fixed dose of 1500 mg or placebo every 4 weeks starting at the beginning of definitive chemoradiation.¹ Patients received 1 of the following platinum-based SOC chemotherapy regimens by investigator discretion: cisplatin plus etoposide, carboplatin plus paclitaxel, pemetrexed plus cisplatin, or pemetrexed plus carboplatin.² Durvalumab or placebo was continued as consolidation treatment following chemoradiation until progressive disease.¹

In addition to PFS serving as the trial’s primary end point, key secondary end points included overall survival (OS), objective response rate, OS at 24 months, complete response rate, duration of response, disease control rate, time from randomization to second progression, time to death or distant metastasis, presence of antidrug antibodies for the durvalumab combination, health-related quality of life, and pharmacokinetics.

PACIFIC-2 was conducted in 88 centers throughout 20 countries.

“Our goal with the PACIFIC-2 trial was to address a remaining unmet need for patients in this setting by introducing immunotherapy even earlier and concurrently administering [durvalumab] with chemoradiotherapy,” Susan Galbraith, executive vice president of Oncology R&D at AstraZeneca, added in the press release. “While today’s results did not reach statistical significance, we will learn from this trial, and we remain committed to improving patient outcomes by expanding the benefit of immunotherapy to lung cancer patients across treatment settings.”

References

1. Update on the PACIFIC-2 phase III trial of Imfinzi concurrently administered with platinum-based chemoradiotherapy in unresectable, stage III non-small cell lung cancer. News release. AstraZeneca. November 14, 2023. Accessed November 14, 2023. https://www.astrazeneca.com/media-centre/press-releases/2023/update-on-pacific-2-phase-iii-trial-for-imfinzi.html
2. Study of durvalumab given with chemoradiation therapy in patients with unresectable non-small cell lung cancer. ClinicalTrials.gov. Updated September 21, 2023. Accessed November 13, 2023. https://clinicaltrials.gov/study/NCT03519971