Clinical Data on Consolidation After Chemoradiotherapy

In the PACIFIC trial, patients with unresectable stage III disease who were non-progressive after chemoradio- therapy, were randomised to receive either the PD-L1 antibody durvalumab (10 mg/kg)  intravenously  every 2 weeks for a year or placebo in a 2:1 fashion. Patients must have received at least two cycles of platinum-based chemotherapy concurrent with radiotherapy [54–66 Gray (Gy)]. As chemoradiotherapy was not part of this multi- national trial, there was big variation with about 20 dif- ferent chemotherapy regimens used—713 patients were randomised and 709 received the assigned treatment. PFS was 17.4 months with durvalumab as compared to

5.6 months with placebo (HR 0.51; 95% CI 0.41–0.63), measured from randomisation after chemoradiotherapy. Two-year survival was 66.3% in the durvalumab group compared to 55.6% with placebo (p = 0.005). The HR for death was 0.68 (p = 0.0025). In an exploratory analysis, it could be shown that benefit in terms of OS is restricted to patients with a PD-L1 expression ≥ 1%, whereas those without PD-L1 expression had a detrimental effect. The HR for death was 0.53 (95% CI 0.36–0.77) for patients with PD-L1 ≥ 1% and 1.36 (95% CI 0.79–2.34) for PD- L1-negative patients, respectively. Although this analysis was not stratified, the approval of durvalumab is restricted to PD-L1-positive patients in the EU.

Three-year survival was 57% (95% CI 52.3–61.4) with

durvalumab compared to 43.5% (95% CI 37.0–49.9) with placebo. The HR for PD-L1-negative patients is still in favour of the placebo arm (HR 1.14, 95% CI 0.71–1.84) [41]. A total of 30.5% of the patients in the durvalumab group and 26.1% of those in the placebo group had grade  3 or 4 adverse events of any cause; 15.4% and 9.8% of the patients, respectively, discontinued the trial regimen because of adverse events. There was a slightly higher rate of grade 3/4 pneumonitis for durvalumab (3.4 vs 2.6%) [42, 43].

In a smaller single-arm Phase II study, the PD-1 inhibi- tor pembrolizumab was given to 92 patients after chemo- radiotherapy. Primary endpoint was the time to metastatic

disease or death (TMDD). The hypothesis was that this time will increase to 18 months compared to 12 months achieved in historical controls. Secondary endpoints were OS, PFS, and toxicity. Median TMDD was 22.4 (95% CI 17.9–not reached) months; PFS was 17.0 (95% CI 11.9–not reached) months, and OS was not yet reached (95% CI

22.4 months–not reached). Two-year survival was 61.9% (95% CI 48.1–73.0). MPR was not reported in this trial.

Grade 3–5 pneumonitis developed in 6.5% of patients. No other grade 3 or higher immune-related adverse events occurred [44]. The results of these two trials are quite simi- lar in terms of survival. The rate of pneumonitis is slightly higher under pembrolizumab compared to durvalumab. This could be due to chance; however, a meta-analysis of trials in patients with metastatic disease showed a higher rate of severe pneumonitis with PD-1 inhibitors compared to PD-L1 inhibitors (4% vs 2%, p = 0.01) [45]. This could still be due to chance or reporting bias, as many included studies of PD-L1 inhibitors were not fully published. However, there is a potential benefit of PD-L1 inhibitors as they do not inter- fere with the PD-1/PD-L2 axis involved in anti-inflammatory processes in the lung [46]. Of course, larger trials are needed to clarify or reject this hypothesis.