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O PEN J O UR NAL • W I NT E R 2 0 18 - 31 -
15%, respectively. Dose-intense thoracic radiotherapy, consolidative chemotherapy, and surgical resection of residual disease have not
improved survival in randomized trials.
The PACIFIC trial was a phase III prospective randomized blinded placebo-controlled trial evaluating durvalumab, a PD-L1
blocking IgG1 monoclonal antibody as adjuvant therapy. 713 patients were treated on 2:1 randomization every 2 weeks for one
year post standard chemo-radiation. Durvalumab is one of several immune checkpoint inhibitors, targeting the PD-1/PD-L1
interaction between tumor cells (expressing PD-1) and cytotoxic T-lymphocytes (expressing PD-L1). The interaction abrogates
T-cell cytotoxicity and immune checkpoint inhibitors can reactivate T-cell cytotoxicity. Pembrolizumab, nivolumab, and atezolizumab
have already been approved for treatment of metastatic nonsmall cell lung cancer as first-line therapy (pembrolizumab, restricted
to high PD-1 tumor expression) and second-line therapy (pembrolizumab for any level of PD-L1 expression or nivolumab and
atezolizumab independent of PD-L1 expression). These immune checkpoint inhibitors have shown improved response rates,
progression-free survival and overall survival compared to standard chemotherapy. The PACIFIC trial targeted a previously
unstudied population of patients with stage III nonsmall cell carcinoma (median age 64, 70% male, 53% stage IIIA and 45%
stage IIIB, 45% squamous cell and 54% non-squamous cell, 91% previous or active smokers). The results showed a statistically
significant benefit for treated patients in progression-free survival (16.8 months vs 5.6 months), 12-month progression-free survival
(55.9% vs 35.2%), 18 month progression-free survival (44.2% vs 27.0%), median time-to-death or distant metastases (23.2
months vs 14 months). High-grade toxicity occurred in 30% of patients treated with durvalumab compared with 26% placebo, the
incidence of pneumonitis was low in treated patients (3.4% vs 2.4%), and there were no treatment-related toxic deaths. All subgroups
of patients derived benefit on forest plot analysis and the benefit was independent of PD-L1 expression or histology. Interestingly, the
small group of nonsmokers (64 patients) derived the greatest benefit (HR 0.29), contrary to the theory that tumors in smokers with a
higher number of neoantigens are more immunogenic and therefore more responsive to immune checkpoint inhibitors.
The accompanying editorial by Drs. Naiyer Rizvi and Solange Peters noted that the progression-free survival of nearly 17 months in
treated patients, one year longer than placebo, is unprecedented and that the overall survival benefit should be positive on subsequent
analysis. Since chemotherapy and radiotherapy promote immunogenic cell death of tumor cells by activating dendritic cells and
enhancing androgen presentation, the editorialists speculate that the sequencing of chemo-radiation before blockade of the PD-1/
PD-L1 pathway may have more general applicability across cancer therapy.
The PACIFIC trial highlights the success of clinical research performed at the ECHO center and The William W. Backus
Hospital. Most of the participating cancer centers were large academic institutions worldwide. 14 patients were screened and 5
patients were enlisted on the PACIFIC trial at the ECHO center, ranking ECHO as the fourth highest accruer in the U.S. The
ECHO center was acknowledged in the supplementary author section of the NEJM.
Clinical research will distinguish the William W. Backus Hospital as an institution promoting
cutting-edge clinical research inaddition to excellent clinical care, and should be encouraged
throughout the spectrum of clinical care.
-Dennis Slater, MD