Presentation and investigation
A 60-year-old nonsmoking female presented with mild cough in 2023. Apart from hypertension and a history of lung cancer in her father, she was physically fit with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0.
PET-CT in November 2023 showed a large mass of 6.7 cm in the right upper lobe of the lung, closely encroaching the chest wall and pleura, with multiple mediastinal lymph nodes (LNs) in stations 2R and 4R, 7R, 10R, and11R, and a small right supraclavicular node, consistent with N3 disease.1 (Figure 1A) Several small LNs were also noted in the left neck and axilla; these were speculated to be reactive, likely related to recent Streptococcus pneumoniae vaccination. Brain MRI was negative.
CT-guided biopsy revealed adenocarcinoma. Genetic testing (LCMAP) detected HER2 exon 20 insertion mutation, with no EGFR mutation identified. SP263 assay demonstrated PD-L1 expression of 0 percent. Her tumour markers were elevated, including CA-125 (200 U/mL), CEA (21.1 ng/mL), and CA 19-9 (187 U/mL). The patient was diagnosed with stage IIIC (T3N3) non-small-cell lung cancer (NSCLC) based on the 8th edition of American Joint Committee on Cancer (AJCC) staging manual.1
Treatment, response and tolerability
After a multidisciplinary meeting, the PACIFIC regimen (ie, chemoradiotherapy [CRT] followed by durvalumab consolidation) was recommended as first-line treatment, with HER2-targeted therapy reserved for metastatic disease.
From 11 December 2023 to 19 January 2024, the patient received six weekly cycles of platinum-based chemotherapy with paclitaxel and carboplatin, concurrently with radiotherapy (60 Gy), to cover the primary tumour and regional LNs.
Concurrent CRT (cCRT) was well tolerated. CT of the thorax on in February 2024 showed tumour shrinkage from 6.7 to 3.3 cm, with good response in all regional LNs. Levels of all tumour markers had also normalized (CA-125, 13 U/mL; CEA, 1.8 ng/mL; CA 19-9, 15 U/mL).
On 20 February 2024, 1 month after completing cCRT, intravenous durvalumab at 10 mg/kg Q2W was initiated per protocol as consolidation therapy for up to 12 months.
The patient experienced two types of immune-related adverse events (irAEs). She initially developed transient thyroiditis in March 2024, which progressed to hypothyroidism after 2 months. Low-dose thyroxine replacement was initiated in May 2024. In November 2024, after 8 months of durvalumab consolidation, CT showed new ground-glass densities in the left upper and lower lobes (outside the radiation field), suspected to be interstitial lung disease (ILD). The patient was asymptomatic (grade 1), but durvalumab was withheld for 1 month. As she remained clinically stable and asymptomatic, with no progression on follow-up CT scan of thorax, durvalumab was restarted, and 12-month consolidation was completed in February 2025.
The patient achieved complete response, with clearance of the primary tumour and all LNs. Restaging PET-CT in March 2025 showed no active disease, although there was a tiny lesion at the primary tumour site, which was most likely radiation-induced inflammation rather than tumour, as it showed progressive improvement over time. (Figure 1B) Her ECOG PS remained 0 with a good quality of life throughout treatment.
As of November 2025, the patient remained clinically well, with normal levels of biomarkers and no active disease. Follow-up brain MRI was negative, and PET-CT demonstrated further improvement of the small inflammatory lesion, with decreased size and tracer uptake. Thyroxine replacement continued. At the time of writing, the patient’s progression-free survival (PFS) and overall survival (OS) were ≥21 months and ongoing.
Discussion
According to the 2025 European Society for Medical Oncology (ESMO) guidelines, 1 year of durvalumab consolidation is recommended for patients with unresectable, EGFR–wild-type, stage III NSCLC who have not experienced disease progression after cCRT (level of evidence, I; grade of recommendation, A), including our patient. This high level of recommendation is based on the PACIFIC trial, which established durvalumab consolidation following cCRT as a standard of care.2
In the phase III PACIFIC trial, 713 patients with unresectable stage III NSCLC were randomized 2:1 to receive either durvalumab (10 mg/kg intravenously) or placebo Q2W for up to 12 months. The study drug was administered 1–42 days after the patients received cCRT.3
Exploratory survival analyses of PACIFIC demonstrated robust and sustained OS and durable PFS benefits with durvalumab. At 5 years, durvalumab consolidation improved both OS (42.9 vs 33.4 percent) and PFS (33.1 vs 19.0 percent) vs placebo in the intention-to-treat population.4
Durvalumab consolidation in patients with PD-L1 <1 percent?
An important question was whether to use durvalumab consolidation for our PD-L1–negative patient. Notably, durvalumab is the only immunotherapy recommended for post-cCRT consolidation in patients with unresectable stage III NSCLC, including those with PD-L1 expression <1 percent. Both the 2024 American Society of Clinical Oncology (ASCO) Guideline Rapid Recommendation Update and the 2025 Asian Thoracic Oncology Research Group expert consensus statement consistently recommend durvalumab consolidation after cCRT in patients with unresectable, EGFR- and ALK-negative, stage III NSCLC regardless of PD-L1 expression levels.5,6
In a real-world setting, the 5-year PACIFIC-R study (n=1,153) showed encouraging PFS and OS results with post-CRT durvalumab consolidation across subgroups, irrespective of PD-L1 expression levels.7 (Figure 2) This is consistent with the experience of our PD-L1–negative patient, who achieved a complete response to durvalumab after cCRT, with PFS and OS of ≥21 months.
Prespecified subgroup analyses of the PACIFIC trial also demonstrated durvalumab’s PFS benefit across PD-L1 expression levels.4 (Figure 3) Although there was no OS benefit in patients with PD-L1 expression <1 percent, the results may be limited by the relatively small number of patients in this subgroup (n=148) and by overperformance in the placebo arm, possibly driven by imbalances in prognostic baseline factors.4
In my clinical practice, PD-L1 testing is performed at diagnosis. The PACIFIC regimen may still be used even if tissue is inadequate for testing, since its PFS benefit is independent of PD-L1 expression. Of note, eligibility for the PACIFIC regimen requires that the patient shows no disease progression following CRT.
PACIFIC regimen or HER2-targeted therapy as 1L Tx?
Another question was whether to use the PACIFIC regimen or HER2‑targeted therapy as first-line treatment for our patient, who also harboured an uncommon HER2 exon 20 mutation present in approximately 2–3 percent of NSCLC cases.8 Since she had stage III (nonmetastatic) disease, and was relatively young and fit, a more radical treatment with cCRT and immunotherapy was suggested to improve the chances of survival and achieve a complete response. HER2-targeted therapy was reserved for metastatic disease.
Management of irAEs
As shown in our case, thyroid disorders (11.4 percent) and pneumonitis (10.7 percent) were common irAEs. Individual irAEs have different onset windows and can occur at any time.9 Regular and continuous monitoring with CT scans, chest X-rays, and blood tests is necessary to detect IrAE.
Overall, the safety profile of durvalumab is manageable.3 Patients should be educated to recognize and report possible AEs promptly.10 When detected early, most patients with irAEs recover with appropriate treatment. Delayed recognition of irAEs at grades 3–4 may necessitate discontinuation of durvalumab.
Conclusion
In conclusion, both PACIFIC-R and PACIFIC demonstrated encouraging outcomes with durvalumab consolidation after CRT in patients with PD-L1 expression <1 percent, supporting the use of durvalumab consolidation in a broad population of patients with unresectable stage III NSCLC who did not have disease progression after CRT.3,7
Patients with PD-L1 expression <1 percent should not be excluded from durvalumab consolidation, since individual outcomes can still be excellent. This is exemplified by our PD-L1– negative case, who initially had a partial response to cCRT and ultimately achieved a complete response with durvalumab consolidation.
