Paz-Ares L, et al. ESMO 2017:LBA1_PR

Background

Most patients with locally advanced, unresectable non-small cell lung cancer (NSCLC) progress after concurrent chemoradiation therapy (cCRT), highlighting a need for novel therapeutic approaches in these patients. At the European Society of Medical Oncology (ESMO) 2017 Congress, interim results from a randomized phase III study evaluating durvalumab, an immune checkpoint inhibitor, in patients with stage III, locally advanced, unresectable NSCLC were presented.1

Study design

  • PACIFIC is a phase III, randomized, double-blind, placebo controlled, multicentre, international study investigating the anti-programmed death-ligand 1 [PD-L1] antibody durvalumab as consolidation therapy in patients with stage III, locally advanced, unresectable NSCLC without progression, following platinum-based cCRT.
  • Patients were randomized 2:1 to receive durvalumab or placebo up to 6 weeks post-cCRT.
  • The planned sample size was 702 patients.
  • Co-primary endpoints were progression-free survival (PFS) by blinded, independent central review (BICR) using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and overall survival (OS).
    • PFS was defined as the time from randomization to the first documented event of tumour progression or death in the absence of progression.
  • For PFS, this study has a ≥95% power to detect a hazard ratio (HR) of 0.67 with 458 events, using a two-sided 0.025 level log-rank test.
    • The interim analysis of PFS was planned after approximately 367 (80%) of events; however, the actual interim analysis was conducted after 371 events.
  • For OS, this study has a ≥85% power to detect an HR of 0.73 with 491 deaths, using a two-sided 0.025 level log-rank test.
    • This study currently remains blinded to OS until the final analysis, planned after the target number of deaths has been reached.
  • Key secondary endpoints included overall response rate (ORR) (per BICR), duration of response (DOR) (per BICR), safety, tolerability, and patient-reported outcomes.

Study Design

Key findings

  • Baseline characteristics were well balanced between arms.
  • In both arms, approximately 45% of patients were 65 years of age or older, 70% were male, 9% had never smoked, and 53% had stage IIIa disease.
  • PD-L1 expression on tumour cells was ≥25% in 24.2% of patients in the durvalumab arm and 18.6% of patients in the placebo arm.
    • PD-L1 status was unknown for approximately 37% of patients in each arm.
  • The best response to prior cCRT for patients in the durvalumab versus placebo arm, respectively, are as follows:
    • Complete response, 1.9% vs. 3.0%;
    • Partial response, 48.7% vs. 46.8%;
    • Stable disease, 46.6% vs. 48.1%; and
    • Progressive disease, 0.4% vs. 0%.
  • The median follow-up was 14.5 months (range: 0.2–29.9).
  • Completion of 12 months of treatment was reported in 42.7% of patients in the durvalumab arm and 30.1% in the placebo arm.
  • Study treatment was discontinued in 241 patients (51.0%) in the durvalumab arm and 153 patients (64.8%) in the placebo arm.
    • The most common reasons for discontinuation were adverse events (AEs) (durvalumab = 15.4% of patients; placebo = 9.7% of patients) and disease worsening (durvalumab = 31.3% of patients; placebo = 49.2% of patients).

Efficacy

  • At data cutoff, 214 patients in the durvalumab arm and 157 patients in the placebo arm progressed by BICR.
  • The median PFS from randomization was significantly longer with durvalumab (16.8 months, 95% CI: 13.0–18.1) versus placebo (5.6 months, 95% CI: 4.6–7.8; stratified HR = 0.52, 95% CI: 0.42–0.65; p <0.0001). (Figure 1)
  • The PFS benefit of durvalumab was seen across all subgroups analyzed (sex, age, smoking status, disease stage, histology, best response to cCRT, PD-L1 status, and epidermal growth factor receptor status).
    • For patients with ≥25% tumour cell PD-L1 expression, the HR in favour of durvalumab was 0.41 (95% CI: 0.26–0.65) compared to 0.59 (95% CI: 0.43–0.82) in patients with <25% tumour cell PD-L1 expression.
  • ORR was higher in the durvalumab versus placebo arm (28.4%, 95% CI: 24.28–32.89 vs. 16.0%, 95% CI: 11.31–21.59; p <0.001). (Table 1)
  • Patients in the durvalumab arm had a 1.78-fold greater probability of responding to treatment than patients in the placebo arm (relative risk = 1.78, 95% CI: 1.27–2.51).
  • The median DOR was longer in the durvalumab arm (not reached [NR]) compared to the placebo arm (13.8 months, 95% CI: 6.0–NR; HR = 0.43, 95% CI: 0.22–0.84). (Table 1)
  • The incidence of new lesions was more frequent in patients in the placebo arm (32.1%) compared to the durvalumab arm (20.4%).
    • The most frequent sites of new lesions in the durvalumab and placebo arms, respectively, were lymph nodes (5.7% vs. 11.4%), brain (5.5% vs. 11.0%), and lung (11.8% vs. 17.3%).
  • The time to distant metastases or death by BICR was prolonged in the durvalumab arm (23.2 months, 95% CI: 23.2–NR) compared with the placebo arm (14.6 months, 95% CI: 10.6–18.6; stratified HR = 0.52, 95% CI: 0.39–0.69; p <0.0001). (Figure 2)

Figure 1. PFS by BICR (ITT population)

Table 1. Antitumour activity by BICR (ITT population)

Figure 2. Time to distant metastasis or death by BICR (ITT)

Safety

  • Grade 3/4 all-causality adverse events (AEs) were reported in 29.9% of patients in the durvalumab arm and 26.1% of patients in the placebo arm.
  • AEs led to discontinuation in 15.4% and 9.8% of patients in the durvalumab and placebo arms, respectively.
  • In the durvalumab and placebo arms, respectively, any-grade treatment-related AEs occurred in 67.8% and 53.4% of patients and any-grade immune-mediated AEs occurred in 24.2% and 8.1% of patients.
  • The most frequent AEs occurring in >11% of patients in either treatment arm are presented in Table 2.

Table 2. Most frequent adverse events*

Key conclusions

  • Durvalumab demonstrated a statistically significant and robust improvement in PFS versus placebo at the planned interim analysis (HR = 0.52; p <0.0001; median improvement of >11 months).
  • PFS improvement with durvalumab was observed across all pre-specified subgroups.
  • Durvalumab demonstrated a clinically meaningful benefit in ORR (28.4% vs. 16.0%; p <0.001), with durable responses versus placebo (median DOR NR vs. 13.8 months).
  • Patients receiving durvalumab had a lower incidence of new lesions, including brain metastases, compared with patients receiving placebo.
  • The safety profile of durvalumab was consistent with that of other immunotherapies and with its known safety profile as monotherapy in patients with more advanced disease.
    • No new safety signals were identified.
  • The study remains blinded for OS.
  • Durvalumab is a promising new therapeutic option in patients with stage III, locally advanced, unresectable NSCLC who have completed cCRT.

Reference: 1. Paz-Ares L, Villegas A, Daniel D, et al. PACIFIC: A double-blind, placebo-controlled phase III study of durvalumab after chemoradiation therapy in patients with stage III, locally advanced, unresectable NSCLC. ESMO Annual Congress Abstracts 2017:LBA1_PR.