Research Summary:
Unresectable, stage III non-small cell lung cancer (NSCLC) is treated with concurrent chemoradiotherapy (cCRT) followed by durvalumab for up to 12 months, which improves progression-free survival (PFS) and overall survival (OS) compared to cCRT alone. However, many patients receive sequential chemoradiotherapy (sCRT) rather than cCRT because of advanced age, frailty, comorbidities, concerns about toxicity, disease volume or location, or limited access to radiotherapy. In observational studies such as PACIFIC-R, a substantial minority of patients receiving durvalumab had previously received sCRT. Given that sCRT is generally associated with worse outcomes than cCRT, and the safety profile and survival data of durvalumab in this context was uncertain, the phase 2 PACIFIC-6 trial was designed to evaluate the safety and tolerability of durvalumab after sCRT in adults with unresectable, stage III NSCLC. Garassino et al1 provide updated safety data, including grade 3/4 adverse events possibly related to treatment (PRAEs), and updated survival outcomes after approximately 2.5 years of follow up.
PACIFIC-6 was a multicenter, open-label, single-arm, phase 2 trial. Adults aged at least 18 years with histologically or cytologically confirmed unresectable stage III NSCLC who had no evidence of disease progression after platinum-based sCRT were eligible. Patients were required to have an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 2. SCRT consisted of at least 2 cycles of histology-driven, platinum-based chemotherapy, followed by thoracic radiotherapy within 6 weeks of completing chemotherapy. Patients who had received cCRT, or sCRT with 2 or more concomitant cycles of chemotherapy and radiotherapy, or who had unresolved grade ≥2 toxicity from sCRT, were excluded.
Between April 16, 2019, to December 30, 2020, 117 patients were enrolled and treated. Median age was 68.0 years, 65.8% of patients were at least 65 years of age, 62.4% were male, and 88.9% were White. Most patients were current or former smokers (92.3%). ECOG PS was 0 in 40.2% of patients, 1 in 57.3%, and 2 in 2.6%. At baseline, 35.9%, 52.1%, and 11.1% of patients had stage IIIA, IIIB, and IIIC disease, respectively. Adenocarcinoma accounted for 53.8% of tumors and squamous cell carcinoma for 38.5%. Comorbidities were common: 98.3% of patients had at least 1 past or present comorbidity, most frequently vascular (59.0%), respiratory (53.0%), and metabolic disorders (51.3%). Carboplatin-based chemotherapy was used in 67.5% of patients. The majority (83.8%) received sCRT without any chemotherapy–radiotherapy overlap, whereas 16.2% had at least 1 overlapping cycle.
All 117 patients received at least 1 durvalumab dose. Median total treatment duration was 41.0 weeks, the median number of infusions was 9, and 23.9% of patients completed the full 24-month durvalumab course. Early discontinuation of durvalumab was most often due to disease progression (37.6%), AEs (26.5%), or patient decision (7.7%). Overall, 39.3% of patients received subsequent anticancer therapy, most commonly cytotoxic chemotherapy (31.6%) and radiotherapy (8.5%).
Regarding safety, 27.4% had grade 3/4 AEs, and 6.0% had grade 3/4 PRAEs. Pneumonitis was the most frequent PRAE (any grade 17.1%; grade 3/4 1.7%). Serious AEs occurred in 27.4% of patients, and serious PRAEs in 6.0%. Overall, 27.4% of patients discontinued durvalumab because of AEs; pneumonitis (10.3%), interstitial lung disease (2.6%), and radiation pneumonitis (2.6%) were the most common AE-related reasons for discontinuation. Cough, asthenia, dyspnea, diarrhea, fatigue, and pneumonitis were among the most frequent AEs of any grade, while pneumonia was the most common grade 3/4 AE (4.3%). Immune-mediated AEs occurred in 42.7% of patients, with 38.5% considered possibly related to durvalumab.
In terms of efficacy, median follow-up among patients censored for OS was 32.6 months. Median OS was 39.0 months, with 1-, 2-, and 3-year OS rates of 83.5%, 67.2%, and 56.5%, respectively. NSCLC-related deaths occurred in 35.0% of patients; median NSCLC-related survival was 41.8 months, and the 3-year NSCLC-related survival rate was 63.1%. Median follow-up for PFS among censored patients was 30.2 months. Overall, 64.1% of patients had experienced a PFS event. Median PFS was 13.1 months, and the 2-year PFS rate was 35.3%. The confirmed objective response rate was 20.5%, including complete response in 2.6% of patients and partial response in 17.9%.
PACIFIC-6 showed that consolidation durvalumab after sCRT was generally well tolerated and provided encouraging long-term survival and disease-control outcomes in adults with unresectable stage III NSCLC who were not treated with cCRT. Rates of grade 3/4 PRAEs were low and comparable to those reported with durvalumab after cCRT in PACIFIC, although the proportion of patients discontinuing durvalumab due to AEs was higher in PACIFIC-6, likely influenced by the longer potential treatment duration of up to 24 months and differences in patient characteristics. The median OS of 39.0 months and 3-year OS rate of 56.5% in PACIFIC-6 appeared favorable when considered alongside historical data for sCRT alone and the placebo arm of PACIFIC. Survival estimates suggest that this strategy could be a reasonable option when cCRT is not an option.
References
- Garassino MC, Khalifa J, Reck M, et al. Durvalumab after sequential chemoradiotherapy in unresectable stage III non-small-cell lung cancer-final analysis from the phase II PACIFIC-6 trial. ESMO Open. 2025;10(6):105071.