Some Oncogene Drivers Impact Efficacy of Durvalumab Consolidation in Stage III NSCLC

The standard of care for patients with unresectable locally advanced (stage III) non-small cell lung cancer (NSCLC) is definitive chemoradiotherapy (CRT) followed by 1-year durvalumab consolidation in patients who achieve disease control after CRT. This is based on the results from the PACIFIC trial in which durvalumab consolidation improved both progression-free survival (PFS) and overall survival (OS) in patients with unresectable, stage III NSCLC. In this trial, baseline testing for PD-L1 expression or for oncogenic alterations was not mandatory, and thus was not extensively performed. However, subgroup analysis indicated survival benefit across all prespecified groups except among a small number of patients with known EGFR, ALK alterations or those with PD-L1 expression of ≤1% on tumor cells. Whether all patients benefit from durvalumab consolidation continues to be uncertain. Some data indicate that patients with EGFR-mutated NSCLC may gain less benefit from durvalumab consolidation while experiencing a greater risk of immune-related adverse events (AEs).

Recently, the European Journal of Cancer published two retrospective studies that provide an important insight into potential biomarkers that may impact the efficacy of durvalumab consolidation after CRT in locally advanced NSCLC. The first study included 551 patients, of whom 113 received durvalumab consolidation. The investigators evaluated how baseline PD-L1 expression and the density of CD8-positive tumor-infiltrating lymphocytes (TIL) before CRT impacted the efficacy of CRT followed by durvalumab consolidation versus CRT alone. They found that both PD-L1-positive expression ≥ 1% and the high density of CD8-positive TILs (TILHigh 100/mm2) were significantly associated with longer median PFS in patients treated with CRT followed by durvalumab, but not in those receiving CRT alone. In patients with EGFR mutations or ALK rearrangements there was no significant difference in PFS in those who received durvalumab consolidation and those who did not (9.9 months vs 14.0 months, P = 0.77).

In the second study, investigators assessed median PFS and OS of patients treated with durvalumab consolidation after CRT in the context of oncogenic drivers (EGFR/BRAF/KRAS mutations and ALK/ROS1 rearrangements). Of 323 total patients, 43 patients had one oncogenic driver. Among them, 26 had KRAS mutations (of which 8 were G12C), 8 had EGFR mutations (of which 6 were del19/ex21), and 5 had BRAF mutations (of which 4 were V600E). Additionally, 4 patients had ALK rearrangements. PD-L1 was positive in 87% of patients with oncogenic drivers. In the whole cohort, the median PFS was 17.5 months and the median OS was 47 months. The investigators saw no statistically significant differences in the median PFS between patients with driver genomic alteration and patients without them (14.9 months vs. 18 months; P = 1.0). However, when they analyzed different genomic alterations separately, patients with KRAS mutations derived the greatest benefit (the median PFS was not reached) while those with the EGFR mutations and ALK rearrangements had the shortest median PFS (8.1 months and 7.8 months, respectively). In patients with oncogenic drivers, median PFS was not correlated with PD-L1 expression. OS rate in patients with genomic drivers at 18 months was 93.4%, but OS data were immature for a biomarker-guided subgroup analysis.

In their conclusions, the authors noted that the presence of some genomic drivers may limit the activity of durvalumab consolidation in stage III unresectable NSCLC, and that more research is crucial to better identify patients who will benefit from immunotherapy in this setting. In an accompanying editorial, the authors highlight that both studies ‘’strongly stress’’ the importance of genomic profiling in all stages of NSCLC. They also pointed out study limitations including small subgroups, limited follow up, and the retrospective nature of the data. Nevertheless, they stated: ‘’Although in many countries patients are selected to receive consolidation durvalumab based on PD-L1 expression of the tumor, the strongest markers that predict no benefit are the positive testing in oncogenic drivers, other than KRAS-mutation, especially EGFR-mutant NSCLC. Testing for these alterations before CRT initiation should therefore become standard of care in stage III NSCLC when consolidation durvalumab is considered.”

Shirasawa M, et al. Eur J Cancer.2022;162:1-10.
Riudavets M, et al. Eur J Cancer. 2022 Mar 17. [Online ahead of print].
De Ruysscher D, et al. Eur J Cancer. 2022 Mar 17. [Online ahead of print].