Patients and Treatment

Table 1. Table 1. Baseline Characteristics, Stratification Factors, and Prior Therapy in the Intention-to-Treat Population.

Between May 2014 and April 2016, a total of 709 of 713 patients who underwent randomization (99.4%) received at least 1 dose of study drug as consolidation therapy (473 patients received durvalumab and 236 received placebo) (Fig. S1 in the Supplementary Appendix). Baseline characteristics were well balanced in the two groups (Table 1, and Table S1 in the Supplementary Appendix). The median age of all patients was 64 years, and the majority were men (70.1%) and current or former smokers (91.0%); 45.7% had a squamous histologic type of tumor. The previous use of chemotherapy was also well balanced between the two groups (Table S2 in the Supplementary Appendix); in addition, 25.8% of the patients in the durvalumab group and 28.7% of those in the placebo group had received induction chemotherapy before definitive chemoradiotherapy. The response to previous chemoradiotherapy was similar in the two groups (complete response, 1.9% in the durvalumab group and 3.0% in the placebo group; partial response, 48.7% and 46.8%, respectively).

According to the assessment of archived tumor samples obtained before chemoradiotherapy, PD-L1 expression of 25% or more on tumor cells occurred in 22.3% of patients (24.2% in the durvalumab group and 18.6% in the placebo group) and PD-L1 expression of less than 25% on tumor cells occurred in 41.0% of the patients (39.3% in the durvalumab group and 44.3% in the placebo group); 36.7% of the patients in both groups had unknown PD-L1 status (Table S3 in the Supplementary Appendix). EGFR mutations were observed in 6.0% of the patients (6.1% in the durvalumab group and 5.9% in the placebo group), whereas 67.3% of the patients’ tumors were EGFR-negative or wild-type (66.2% in the durvalumab group and 69.6% in the placebo group). The EGFR mutation status was unknown in 27.7% of the patients in the durvalumab group and 24.5% of the patients in the placebo group (Table S3 in the Supplementary Appendix). No significant (P<0.05) between-group differences were noted in either PD-L1 expression or EGFR mutation status.

As of February 13, 2017 (the data cutoff point for this interim analysis), 371 patients had disease progression (214 in the durvalumab group and 157 in the placebo group). The overall median follow-up was 14.5 months (range, 0.2 to 29.9). The median number of infusions received was 20 (range, 1 to 27) in the durvalumab group and 14 (range, 1 to 26) in the placebo group; 6.3% and 5.1% of the patients, respectively, were still receiving the study drug at the data cutoff point (Table S4 in the Supplementary Appendix). The median relative dose intensity was 100% in each group (range, 29 to 100 in the durvalumab group and 50 to 100 in the placebo group). Serum trough concentrations of durvalumab were similar at weeks 24 and 48 (177.00 and 189.00 μg per milliliter, respectively) (Table S5 in the Supplementary Appendix).

Efficacy

Figure 1. Figure 1. Progression-free Survival in the Intention-to-Treat Population. Shown are Kaplan–Meier curves for progression-free survival (PFS), defined according to the Response Evaluation Criteria in Solid Tumors, version 1.1, and assessed by means of blinded independent central review. Tick marks indicate censored observations, and vertical lines indicate the times of landmark PFS analyses. The intention-to-treat population included all patients who underwent randomization.

Median progression-free survival from randomization, as assessed by means of blinded independent central review, was 16.8 months (95% confidence interval [CI], 13.0 to 18.1) with durvalumab versus 5.6 months (95% CI, 4.6 to 7.8) with placebo (stratified hazard ratio for disease progression or death, 0.52; 95% CI, 0.42 to 0.65; two-sided P<0.001) (Figure 1). The 12-month progression-free survival rate was 55.9% (95% CI, 51.0 to 60.4) with durvalumab and 35.3% (95% CI, 29.0 to 41.7) with placebo, and the 18-month progression-free survival rate was 44.2% (95% CI, 37.7 to 50.5) and 27.0% (95% CI, 19.9 to 34.5), respectively. Progression-free survival results were consistent across all prespecified sensitivity analyses (data not shown), including results determined by investigator assessment (stratified hazard ratio, 0.61; 95% CI, 0.50 to 0.76; two-sided P<0.001).

Figure 2. Figure 2. Subgroup Analysis of Prognostic Factors for Progression-free Survival in the Intention-to-Treat Population. Progression-free survival was defined according to RECIST, version 1.1, and assessed by means of blinded independent central review. The hazard ratio and 95% confidence interval were not calculated for the complete response because this subgroup had less than 20 events. EGFR denotes epidermal growth factor receptor, and PD-L1 programmed death ligand 1.

A progression-free survival benefit with durvalumab was consistently observed across all prespecified subgroups, as defined according to patient demographic characteristics, baseline clinicopathologic features, and response to previous treatment (Figure 2). Additional nonprognostic factors are listed in Figure S2 in the Supplementary Appendix. Notably, the progression-free survival benefit with durvalumab was observed irrespective of PD-L1 expression before chemoradiotherapy (hazard ratio, 0.59 [95% CI, 0.43 to 0.82] for a PD-L1 expression level of <25% and 0.41 [95% CI, 0.26 to 0.65] for a PD-L1 expression level of ≥25%). A progression-free survival benefit was also evident in patients who had never smoked. The absence of corrections for multiple comparisons limits the extrapolations to particular subgroups.

The median time to death or distant metastasis was 23.2 months (95% CI, 23.2 to not reached) with durvalumab versus 14.6 months (95% CI, 10.6 to 18.6) with placebo (hazard ratio, 0.52; 95% CI, 0.39 to 0.69; two-sided P<0.001) (Fig. S3 in the Supplementary Appendix). In addition, the frequency of new lesions, as assessed by means of blinded independent central review, was 20.4% with durvalumab and 32.1% with placebo, with a lower incidence of new brain metastases with durvalumab (5.5% vs. 11.0%) (Table S6 in the Supplementary Appendix).

Table 2. Table 2. Antitumor Activity in the Intention-to-Treat Population.

The objective response rate, as assessed by means of blinded independent central review, was significantly higher with durvalumab than with placebo (28.4% vs. 16.0%; P<0.001) (Table 2); 16.5% of patients who received durvalumab and 27.7% of those who received placebo had disease progression (Table 2). The median duration of response was longer with durvalumab than with placebo (Table 2, and Fig. S4 in the Supplementary Appendix). Of the patients who had a response to durvalumab, 72.8% had an ongoing response at both 12 and 18 months as compared with 56.1% and 46.8%, respectively, of patients in the placebo group who had an ongoing response (Table 2). An analysis of overall survival was not planned at the time of this interim analysis of progression-free survival.

Safety

Table 3. Table 3. Adverse Events of Any Cause.

Adverse events of any cause and grade occurred in 96.8% of the patients who received durvalumab and 94.9% of the patients who received placebo (Table 3); grade 3 or 4 adverse events occurred in 29.9% and 26.1%, respectively. The most common grade 3 or 4 adverse event was pneumonia (in 4.4% of patients in the durvalumab group and 3.8% of patients in the placebo group). Discontinuation due to adverse events occurred in 15.4% of patients in the durvalumab group and 9.8% of patients in the placebo group, and serious adverse events occurred in 28.6% and 22.6%, respectively (Table S7 in the Supplementary Appendix). Death due to adverse events occurred in 4.4% of patients in the durvalumab group and 5.6% of patients in the placebo group (Table 3). Treatment-related adverse events are summarized in Table S8 in the Supplementary Appendix.

The most frequent adverse events leading to discontinuation of durvalumab and placebo were pneumonitis or radiation pneumonitis (in 6.3% and 4.3%, respectively) and pneumonia (in 1.1% and 1.3%). In patients who received durvalumab, as compared with those who received placebo, pneumonitis or radiation pneumonitis of any grade occurred in 33.9% and 24.8% and pneumonitis or radiation pneumonitis of grade 3 or 4 occurred in 3.4% and 2.6%; pneumonia of any grade occurred in 13.1% and 7.7%, and pneumonia of grade 3 or 4 occurred in 4.4% and 3.8%.

Adverse events of any grade that were of special interest, regardless of cause, were reported in 66.1% of patients in the durvalumab group and 48.7% of patients in the placebo group. The majority were grade 1 or 2, and events of grade 3 or higher were infrequent (in <10% of patients) in both groups. The most frequent adverse events of any grade that were of special interest with durvalumab versus placebo were diarrhea (18.3% and 18.8%), pneumonitis (12.6% and 7.7%), rash (12.2% and 7.3%), and pruritus (12.2% and 4.7%). Adverse events of special interest for which patients received concomitant treatment were reported in 42.1% and 17.1% of patients, respectively; treatments included glucocorticoids (in 15.2% and 6.8%), high-dose glucocorticoids (8.8% and 5.1%), endocrine therapy (11.6% and 1.3%), and other immunosuppressive agents (0.4% of both groups).

Immune-mediated adverse events of any grade, regardless of cause, were reported in 24.2% of patients in the durvalumab group and 8.1% of patients in the placebo group; grade 3 or 4 immune-mediated adverse events were reported in 3.4% and 2.6% of patients, respectively (Table S9 in the Supplementary Appendix). Treatments for immune-mediated adverse events included systemic glucocorticoids (in 14.3% of patients in the durvalumab group and 5.6% in the placebo group), high-dose glucocorticoids (8.2% and 4.3%), endocrine therapy (10.7% and 1.3%), and other immunosuppressive agents (0.4% of both groups).