Five-Year Survival Outcomes From the PACIFIC Trial: Durvalumab After Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer

Abstract

Purpose: The phase III PACIFIC trial compared durvalumab with placebo in patients with unresectable, stage III non-small-cell lung cancer and no disease progression after concurrent chemoradiotherapy. Consolidation durvalumab was associated with significant improvements in the primary end points of overall survival (OS; stratified hazard ratio [HR], 0.68; 95% CI, 0.53 to 0.87; P = .00251) and progression-free survival (PFS [blinded independent central review; RECIST v1.1]; stratified HR, 0.52; 95% CI, 0.42 to 0.65; P < .0001), with manageable safety. We report updated, exploratory analyses of survival, approximately 5 years after the last patient was randomly assigned.

Methods: Patients with WHO performance status 0 or 1 (any tumor programmed cell death-ligand 1 status) were randomly assigned (2:1) to durvalumab (10 mg/kg intravenously; administered once every 2 weeks for 12 months) or placebo, stratified by age, sex, and smoking history. Time-to-event end point analyses were performed using stratified log-rank tests. Medians and landmark survival rates were estimated using the Kaplan-Meier method.

Results: Seven hundred and nine of 713 randomly assigned patients received durvalumab (473 of 476) or placebo (236 of 237). As of January 11, 2021 (median follow-up, 34.2 months [all patients]; 61.6 months [censored patients]), updated OS (stratified HR, 0.72; 95% CI, 0.59 to 0.89; median, 47.5 v 29.1 months) and PFS (stratified HR, 0.55; 95% CI, 0.45 to 0.68; median, 16.9 v 5.6 months) remained consistent with the primary analyses. Estimated 5-year rates (95% CI) for durvalumab and placebo were 42.9% (38.2 to 47.4) versus 33.4% (27.3 to 39.6) for OS and 33.1% (28.0 to 38.2) versus 19.0% (13.6 to 25.2) for PFS.

Conclusion: These updated analyses demonstrate robust and sustained OS and durable PFS benefit with durvalumab after chemoradiotherapy. An estimated 42.9% of patients randomly assigned to durvalumab remain alive at 5 years and 33.1% of patients randomly assigned to durvalumab remain alive and free of disease progression, establishing a new benchmark for standard of care in this setting.

Trial registration: ClinicalTrials.gov NCT02125461.

FIG 1.

CONSORT diagram. Study data collected up to the DCO date of January 11, 2021. Patients who completed 12 months of study treatment are those for whom the electronic case report form showed that they had received the maximum number of cycles of study treatment. ^aInformed consent received. ^bFour patients did not receive their assigned study treatment because of neutropenia (n = 1), worsening chronic obstructive pulmonary disease (n = 1), and patient decision (n = 2). ^cNine patients (durvalumab, n = 4; placebo, n = 5) who terminated the study because of patient decision have subsequently died; one additional patient (placebo arm) with missing termination reason has subsequently died. AE, adverse event; DCO, data cutoff.

FIG 2.

Updated (A) OS and (B) PFS (blinded independent central review) in the intent-to-treat population. The vertical dashed lines indicate yearly landmarks; the associated numerical values represent the OS and PFS rates at the landmark. OS was defined as time from random assignment until death from any cause. PFS was defined as time from random assignment to the date of the first documented event of tumor progression or death in the absence of disease progression. For PFS, patients who had not progressed or died at the time of the data cutoff were censored at the time of their last evaluable RECIST assessment; however, if the patient progressed or died after ≥ 2 missed visits, they were censored at the time of the latest evaluable RECIST assessment before the two missed visits. HR, hazard ratio; OS, overall survival; PFS, progression-free survival.

FIG 3.

Updated OS by prespecified and exploratory, post hoc subgroups. ^aHRs and 95% CIs were not calculated if the subgroup had < 20 events. ^bThree patients with missing WHO PS were included in the PS 1 subgroup. ^cThe other race category includes American Indian or Alaskan Native (n = 9), Native Hawaiian or Other Pacific Islander (n = 2), and Other (n = 1). ^dThe subgroup includes 35 patients with tumors harboring EGFR mutations and, on the basis of local testing, eight patients with tumors harboring ALK alterations. ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; HR, hazard ratio; NSCLC, non–small-cell lung cancer; OS, overall survival; PD-L1, programmed cell death-ligand 1; PS, performance status.

FIG 4.

Updated TTDM (blinded independent central review) in the intent-to-treat population. The vertical dashed lines indicate yearly landmarks; the associated numerical values represent the TTDM rates at the landmark. TTDM was defined as time from random assignment until the first date of distant metastasis or death in the absence of distant metastasis. HR, hazard ratio; TTDM, time to death or distant metastasis.

FIG A1.

Updated PFS (blinded independent central review) by prespecified and exploratory, post hoc subgroups. ^aHRs and 95% CIs were not calculated if the subgroup had < 20 events. ^bThree patients with missing WHO PS were included in the PS 1 subgroup. ^cThe other race category includes American Indian or Alaskan Native (n = 9), Native Hawaiian or Other Pacific Islander (n = 2), and Other (n = 1). ^dThe subgroup includes 35 patients with tumors harboring EGFR mutations and, on the basis of local testing, eight patients with tumors harboring ALK alterations. ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; HR, hazard ratio; NSCLC, non–small-cell lung cancer; PD-L1, programmed cell death-ligand 1; PFS, progression-free survival; PS, performance status.

FIG A2.

Updated OS by tumor PD-L1 expression level: (A) PD-L1 TC ≥ 25%, (B) PD-L1 TC < 25%, (C) PD-L1 TC ≥ 1%, (D) PD-L1 TC < 1%, (E) unknown PD-L1 status, and (F) PD-L1 TC 1%-24%. The vertical dashed lines indicate yearly landmarks; the associated numerical values represent the OS rates at the landmark. HR, hazard ratio; NE, not estimable; NR, not reached; OS, overall survival; PD-L1, programmed cell death-ligand 1; TC, tumor cell.

FIG A3.

Updated PFS (blinded independent central review) by tumor PD-L1 expression level: (A) PD-L1 TC ≥ 25%, (B) PD-L1 TC < 25%, (C) PD-L1 TC ≥ 1%, (D) PD-L1 TC < 1%, (E) unknown PD-L1 status, and (F) PD-L1 TC 1%-24%. The vertical dashed lines indicate yearly landmarks; the associated numerical values represent the PFS rates at the landmark. HR, hazard ratio; PD-L1, programmed cell death-ligand 1; PFS, progression-free survival; TC, tumor cell.

FIG A4.

Updated times to (A) first and (B) second subsequent therapy or death in the intent-to-treat population. The vertical dashed lines indicate yearly landmarks; the associated numerical values represent the TFST and TSST rates at the landmark. TFST was defined as time from random assignment to the start of the first subsequent anticancer therapy after discontinuation of study treatment, or death, whichever occurred earlier. TSST was defined as the time from random assignment to the start of the second subsequent anticancer therapy after discontinuation of study treatment, or death, whichever occurred earlier. HR, hazard ratio; TFST, time to first subsequent therapy or death; TSST, time to second subsequent therapy or death.