New Immunotherapy Regimens Aim to Build Upon Durvalumab in Locally Advanced NSCLC

Although durvalumab (Imfinzi) following concurrent chemoradiotherapy, which was examined in the phase 3 PACIFIC trial (NCT02125461), remains the standard of care, new immunotherapy-based regimens are being developed to offer additional treatment options for patients with locally advanced non–small cell lung cancer (NSCLC), according to Marina C. Garassino, MD.1

“The old version of the PACIFIC regimen is still the standard of care, but there are many new ‘tastes’ [of this regimen],” Garassino, the director of the Thoracic Oncology Program and a professor of medicine in the Section of Hematology/Oncology at The University of Chicago Department of Medicine in Illinois, said during the presentation during the 26th Annual International Lung Cancer Congress.

PACIFIC compared durvalumab with placebo for the treatment of patients with unresectable, stage III NSCLC who did not experience disease progression after concurrent chemoradiotherapy.2 Findings from the 5-year survival analysis of the study demonstrated that the median progression-free survival (PFS) in the investigational arm (n = 476) was 16.9 months (95% CI, 13.0-23.9) compared with 5.6 months (95% CI, 4.8-7.7) in the placebo arm (n = 237; stratified HR, 0.55; 95% CI, 0.45-0.68). The median overall survival (OS) values were 47.5 months (95% CI, 38.1-52.9) and 29.1 months (95% CI, 22.1-35.1), respectively (stratified HR, 0.72; 95% CI, 0.59-0.89).

Garassino emphasized that the benefit of durvalumab was also reflected in a real-world population, based on data from the observational PACIFIC-R study (NCT03798535).3 Patients who received durvalumab (n = 1154) achieved a median OS of not reached (NR; 95% CI, 46.3-not evaluable [NE]). The 2- and 3-year OS rates were 72.3% (95% CI, 69.7%-74.8%) and 63.2% (95% CI, 60.3%-65.9%), respectively. The median PFS was 24.1 months (95% CI, 20.2-27.8); the 2-year PFS rate was 50.1% (95% CI, 47.2%-53.0%), and the 3-year PFS rate was 42.2% (95% CI, 39.2%-45.1%).

Unpacking Data From Other PACIFIC-Based Regimens

In the phase 2 PACIFIC-6 trial (NCT03693300), the safety and efficacy of durvalumab were evaluated following sequential chemoradiotherapy in patients with stage III, unresectable NSCLC.4 Patients who received durvalumab (n = 117) achieved a median PFS of 10.9 months (95% CI, 7.3-15.6) and a median OS of 25.0 months (95% CI, 25.0-NE). “Patients were enrolled in this trial if they were not suitable for concurrent treatment,” Garassino commented. “The benefit was very visible, and the treatment was feasible.”

Garassino noted that there is no benefit in initiating immunotherapy with chemoradiotherapy. Findings from the phase 3 PACIFIC-2 trial (NCT03519971) showed that patients who received durvalumab in combination with chemoradiotherapy (n = 219) experienced a median PFS of 13.8 months (95% CI, 9.5-16.9) compared with 9.4 months (95% CI, 7.5-16.6) among those treated with chemoradiotherapy alone (n = 109; HR, 0.85; 95% CI, 0.65-1.12; P = .247).5

“There was a crossing of the OS curves that we believe was related to the higher number of adverse effects leading to [treatment] discontinuation with the PACIFIC-2 regimen vs chemoradiation,” Garassino commented.

Exploring Immunotherapy Regimens Beyond PACIFIC

In the phase 3 CheckMate 73L study (NCT04026412), investigators compared nivolumab (Opdivo) plus concurrent chemoradiotherapy followed by nivolumab with or without ipilimumab (Yervoy) vs the PACIFIC regimen.6 Patients in the investigational arm (n = 287) experienced a median PFS of 16.7 months (95% CI, 12.6-22.0) compared with 15.6 months (95% CI, 13.7-19.8) in the control arm (n = 318; HR, 0.95; 95% CI, 0.77-1.19; P = .6460).

The phase 3 GEMSTONE-301 study (NCT03728556) was a Chinese trial that evaluated the PD-L1 inhibitor sugemalimab vs placebo in patients with locally advanced, unresectable stage III NSCLC who did not experience disease progression after concurrent or sequential chemoradiotherapy.7 Data from the interim analysis of GEMSTONE-301 revealed that the median PFS in the sugemalimab arm (n = 255) was 9.0 months (95% CI, 8.1-14.1) compared with 5.8 months (95% CI, 4.2-6.6) in the placebo arm (n = 126; stratified HR, 0.64; 95% CI, 0.48-0.85; log-rank P = .0026).

The PD-1 inhibitor toripalimab (Loqtorzi) is being evaluated in patients with bulky unresectable stage III NSCLC in the phase 2 InTRist study (NCT05888402).8 Findings from InTRist presented during the 2025 ASCO Annual Meeting showed that patients who received toripalimab plus chemotherapy (n = 27) experienced a median PFS of NR (95% CI, NR-NR) compared with 12.4 months (95% CI, 8.0-NR) among those who received chemotherapy alone (n = 25; HR, 0.26; 95% CI, 0.08-0.81; log-rank P = .012). The 1-year PFS rates were 85.6% (95% CI, 71.6%-100.0%) and 54.5% (95% CI, 37.7%-78.7%).

“There was a [benefit] in PFS with the combination of chemotherapy and immunotherapy, compared with chemotherapy alone,” Garassino noted. “But we don’t have the results yet in terms of OS, and we need larger studies to [get more data].”

Durvalumab was examined in combination with multiple novel agents in the phase 2 COAST trial (NCT03822351).9 Findings from COAST revealed that patients who received durvalumab plus monalizumab (n = 62) or durvalumab plus oleclumab (n = 60) experienced a median PFS of 15.1 months (95% CI, 13.6-NE) and NR (95% CI, 10.4-NE), respectively. Comparatively, patients who received durvalumab monotherapy experienced a median PFS of 6.3 months (95% CI, 3.7-11.2); the HRs for PFS using the monotherapy arm as a reference were 0.42 (95% CI, 0.24-0.72) in the monalizumab arm and 0.44 (95% CI, 0.26-0.75) in the oleclumab arm. The 12-month PFS rates in the monalizumab, oleclumab, and durvalumab monotherapy arms were 72.7% (95% CI, 58.8%-82.6%), 62.6% (95% CI, 48.1%-74.2%), and 33.9% (95% CI, 21.2%-47.1%), respectively.

“[In COAST], we saw good PFS data for the combination arms, and there was also some benefit in patients with PD-L1–negative disease, which we haven’t seen with durvalumab only,” Garassino commented.

Garassino concluded her presentation by emphasizing that proton pump inhibitors (PPIs) should not be added to the PACIFIC regimen. Findings from a post-hoc analysis of PACIFIC showed that patients in the durvalumab arm who were exposed to PPIs (n = 185) experienced a median PFS of 10.7 months compared with 18.1 months among those who did not receive a PPI (n = 265; P = .017).10 “[These data] showed that adding PPIs can reduce the [efficacy] of immunotherapy, [but there] are still a lot of uncertainties,” Garassino said.

References

1. Garassino MC. Immunotherapy in locally advanced NSCLC: latest findings Presented at: 26th Annual International Lung Cancer Congress; July 25-27, 2025; Huntington Beach, CA.
2. Spigel DR, Faivre-Finn C, Gray JE, et al. Five-year survival outcomes from the PACIFIC Trial: durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. J Clin Oncol. 2022;40(12):1301-1311. doi:10.1200/JCO.21.01308
3. Filippi AR, Bar J, Chouaid C, et al. Real-world outcomes with durvalumab after chemoradiotherapy in patients with unresectable stage III NSCLC: Interim analysis of overall survival from PACIFIC-R. ESMO Open. 2024;9(6):103464. doi:10.1016/j.esmoop.2024.103464
4. Garassino MC, Mazieres J, Reck M, et al. Durvalumab after sequential chemoradiotherapy in stage III, unresectable NSCLC: the phase 2 PACIFIC-6 Trial. J Thorac Oncol. 2022;17(12):1415-1427. doi:10.1016/j.jtho.2022.07.1148
5. Bradley JD, Sugawara S, Lee KHH, et al. Durvalumab in combination with chemoradiotherapy for patients with unresectable stage III NSCLC: final results from PACIFIC-2.. ESMO Open. 2024;9(suppl 3):102986. doi:10.1016/j.esmoop.2024.102986
6. Peters S, Tan DSW, Gerber DE, et al. CheckMate 73L: Phase III study comparing nivolumab (N) + concurrent chemoradiotherapy (CCRT) followed by N ± ipilimumab (I) v CCRT followed by durvalumab (D) for previously untreated, locally advanced stage (stg) III NSCLC. IOTECH. 2024;24(suppl):100808. doi:10.1016/j.iotech.2024.100808
7. Zhou Q, Chen M, Jiang O, et al. Sugemalimab versus placebo after concurrent or sequential chemoradiotherapy in patients with locally advanced, unresectable, stage III non-small-cell lung cancer in China (GEMSTONE-301): interim results of a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2022;23(2):209-219. doi:10.1016/S1470-2045(21)00630-6
8. Wang Y, Wang J, Deng J, et al. The preliminary results of a randomized phase II trial evaluating induction toripalimab plus chemotherapy followed by concurrent chemoradiotherapy and consolidation toripalimab in bulky unresectable stage III non-small-cell lung cancer (InTRist). J Clin Oncol. 2025;43(suppl 16):8012. doi:10.1200/JCO.2025.43.16_suppl.8012
9. Herbst RS, Majem M, Barlesi F, et al. COAST: an open-label, phase II, multidrug platform study of durvalumab alone or in combination with oleclumab or monalizumab in patients with unresectable, stage III non-small-cell lung cancer. J Clin Oncol. 2022;40(29):3383-3393. doi:10.1200/JCO.22.00227
10. Brunetti L, Santo V, Pinato DJ, et al. Differential effect of proton pump inhibitors (PPIs) and antibiotics (ATB) on clinical outcomes from immunotherapy or placebo in patients with locally advanced, unresectable NSCLC who have not progressed following chemoradiation therapy (cCTRT): a post-hoc analysis of the PACIFIC trial. J Thorac Oncol. 2025;20(3):S129-S130. doi:10.1016/S1556-0864(25)00386-7