Title: Sequential chemo-durvalumab, reduced dose RT, and consolidation durvalumab for unresectable stage III NSCLC unfit for PACIFIC regimen (DEDALUS Trial)
Authors: Francesco Agustoni, Jessica Saddi, Diego Luigi Cortinovis, Stefano Arcangeli, Luca Sala, Catherine Klersy, Valeria Musella, Giulia Galli, Sabrina Borgetto, Giulia Maria Stella, Daniela Cicognini, Alessandra Ferrari, Paolo Pedrazzoli, Francesco Grossi and Andrea Riccardo Filippi.
Published in JNCI Cancer Spectrum, 2026
The PACIFIC regimen has become the standard of care for patients with unresectable stage III non-small cell lung cancer who are able to receive concurrent chemoradiotherapy followed by durvalumab. However, in daily practice, not every patient is fit enough for this approach.
Many patients with stage III NSCLC are older, have cardiopulmonary comorbidities, or are considered too vulnerable for full-dose concurrent chemoradiation. This creates a clinically important gap: how can curative-intent treatment be adapted for patients who are not candidates for the standard PACIFIC approach?
The DEDALUS trial was designed to address this question. The phase 2, open-label, multicenter study evaluated sequential chemo-durvalumab, reduced-dose hypofractionated thoracic radiotherapy, and consolidation durvalumab in patients with unresectable stage III NSCLC considered unfit for concurrent chemoradiotherapy.
Study Design
DEDALUS enrolled patients with unresectable stage IIIA–C NSCLC, regardless of PD-L1 status. Patients first received three cycles of chemotherapy with durvalumab. Those with complete response, partial response, or stable disease then proceeded to hypofractionated thoracic radiotherapy at 45 Gy over three weeks, delivered with durvalumab. This was followed by durvalumab maintenance for up to 12 months.
This design differed from the standard PACIFIC approach in two important ways. First, immunotherapy was introduced earlier, during the induction chemotherapy phase. Second, the radiotherapy dose was reduced from the conventional 60–66 Gy range to 45 Gy, aiming to maintain disease control while reducing toxicity in a more vulnerable patient population.
Patient Population
Between February 2022 and August 2024, 28 patients were screened and 25 were enrolled across three Italian centers. The study was stopped early because of low recruitment, below the planned sample size of 45 patients.
The enrolled population reflected a real-world, less fit group. Median age was 70.4 years, and most patients had baseline comorbidities. Cardiovascular disorders were common, and patients were selected specifically because they were considered unsuitable for concurrent chemoradiotherapy.
Safety Results
The primary endpoint was safety, measured by grade 3–4 possibly related adverse events within six months.
Seven of 25 patients experienced at least one grade 3–4 possibly related adverse event, corresponding to 28%. In total, 9 grade 3–4 possibly related adverse events were reported. Importantly, most were attributed to chemotherapy. Only one was considered immune-related, and none were attributed to radiotherapy.
No pneumonitis and no grade 5 adverse events were reported. This is clinically relevant, given the concern around thoracic radiotherapy combined with immunotherapy, especially in frail patients.
The authors also reported that quality-of-life measures were largely stable during treatment, with no major deterioration in most assessed domains.
Efficacy Results
Although the trial was not powered to draw firm efficacy conclusions, the early outcomes were notable.
In the intention-to-treat population, median progression-free survival was 13.2 months, and median overall survival was 17.5 months.
Among the 16 patients who reached the maintenance durvalumab phase, outcomes appeared more favorable. Median progression-free survival was 18.6 months, and median overall survival was not reached. However, these findings should be interpreted cautiously, because this subgroup included patients who had already tolerated and responded to earlier treatment steps.
Clinical Meaning
DEDALUS is not practice-changing, mainly because it was small, single-arm, and closed early. Still, the study raises an important clinical question.
For patients who are not fit for standard concurrent chemoradiotherapy, a less intensive but still curative-intent strategy may be possible. The combination of induction chemo-immunotherapy, reduced-dose hypofractionated radiotherapy, and durvalumab maintenance appeared feasible, with no radiotherapy-related grade 3–4 adverse events reported.
The study also supports the idea that treatment intensity in stage III NSCLC may need to be individualized. Rather than applying one standard regimen to all patients, future trials may need to define which patients can safely benefit from adapted strategies based on frailty, comorbidities, tumor response, immune status, and quality-of-life priorities.
Conclusion
The DEDALUS trial provides early evidence that sequential chemo-durvalumab followed by reduced-dose hypofractionated radiotherapy and durvalumab maintenance may be feasible for selected patients with unresectable stage III NSCLC who are unfit for the PACIFIC regimen.
The results require validation in larger comparative studies, but the trial adds useful data for a group often underrepresented in clinical research. Its main message is clear: for vulnerable stage III NSCLC patients, future progress may come not only from treatment intensification, but also from smarter, more personalized de-escalation.
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