LUGANO-MADRID – Durvalumab improves progression-free survival in patients with locally advanced, unresectable stage III lung cancer, according to late-breaking results from the phase III PACIFIC trial presented today at the ESMO 2017 Congress in Madrid (1) and published in the New England Journal of Medicine. (2)
About one-third of patients with non-small-cell lung cancer (NSCLC) have a stage III presentation. Standard treatment with platinum-based chemotherapy concurrent with radiation therapy gives a progression-free survival of about eight months and only 15% of patients are alive at five years.
PACIFIC is the first phase III trial to test an immune checkpoint inhibitor as sequential treatment in patients with stage III NSCLC who had not progressed following platinum-based chemotherapy concurrent with radiation therapy.
“There is evidence that synergy between radiotherapy and immunotherapy, such programmed death-ligand 1 (PD-L1) inhibitors, could increase the probability of response,” said first author Dr Luis Paz-Ares, chair, Medical Oncology Department, Hospital Universitario Doce de Octubre, Madrid, Spain. “We therefore explored the impact of PD-L1 inhibition after standard chemoradiation treatment.”
The PACIFIC trial compared sequential treatment with the PD-L1 inhibitor durvalumab versus placebo in patients with locally advanced, unresectable stage III NSCLC who had not progressed following platinum-based chemotherapy concurrent with radiation therapy.
The trial is being conducted at 235 centres in 26 countries, and Dr Scott Antonia from the Moffitt Cancer Center is the lead investigator. It included 713 patients who were randomised 2:1 to receive durvalumab 10 mg/kg every two weeks or placebo for up to 12 months. The co-primary endpoints were progression-free survival and overall survival.
Results from a pre-planned interim analysis at 14.5 months are presented today. The median progression-free survival was 16.8 months in the durvalumab arm compared to 5.6 months with placebo, with a hazard ratio of 0.52.
Paz-Ares said: “Durvalumab decreased the probability of disease progression of 48%. The improvement was consistent across all patient subgroups that were analysed.”
The secondary endpoints of time to death or distant metastasis and objective response rate were also improved overall and across subgroups with durvalumab compared to placebo. Overall survival data were immature and and will be analysed after a longer period of follow-up.
Treatment-related adverse events occurred in 68% of patients in the durvalumab group compared to 53% in the placebo group. The rate of immune-mediated adverse events was 24% with durvalumab and 8% with placebo. Severe pneumonitis (grade 3/4) occurred in 3.4% and 2.6% of patients on durvalumab and placebo, respectively. Treatment had to be discontinued due to pneumonitis in 6.3% of patients on durvalumab and 4.3% on placebo.
“Overall there was a slight increase in toxicity in the durvalumab arm but severe toxicity was similar between groups,” said Paz-Ares.
He concluded: “Durvalumab is a reasonably well tolerated treatment with a manageable safety profile that improved progression-free survival by 11 months. PD-L1 inhibition after chemoradiation appears to be a new option for patients with locally advanced, unresectable stage III lung cancer. It will be important to see the impact on overall survival after a longer follow-up.”
Commenting on the results for ESMO, Dr Pilar Garrido, head of the Thoracic Tumour Section, Medical Oncology Department, Ramón y Cajal University Hospital, Madrid, Spain, said: “PACIFIC is one of the largest clinical trials recruiting patients with unresectable stage III NSCLC. Giving durvalumab after finishing chemoradiation improved progression-free survival by three-fold compared to placebo, which is a clinically relevant benefit. The results for 12 and 18-month progression-free survival were also highly encouraging.”
“It is important to highlight the acceptable toxicity profile of durvalumab in this setting, with severe adverse events rates very similar between both arms,” she added.
Garrido continued: “Overall survival data are awaited, but the magnitude of progression-free survival benefit supports this combination as a new standard of care for unresectable stage III NSCLC patients who had no progression following standard care with platinum-based chemotherapy and concomitant radiotherapy.”
She concluded: “Further research is needed regarding the duration and timing of immunotherapy, the best regimen of chemoradiation to combine it with, and the selection of patients most likely to benefit based on predictive biomarkers.”
Notes to Editors
Please make sure to use the official name of the meeting in your reports: ESMO 2017 Congress
- Abstract LBA1_PR ‘PACIFIC: A double-blind, placebo-controlled Phase III study of durvalumab after chemoradiation therapy (CRT) in patients with Stage III, locally advanced, unresectable NSCLC’ will be presented by Dr Luis Paz-Ares during Presidential Symposium I on Saturday, 9 September 2017, 16:30 to 18:10 (CEST) in Madrid Auditorium.
- Antonia S.J., Villegas A, Daniel D, et al. Durvalumab after Chemoradiotherapy in Stage III Non–Small-Cell Lung Cancer. N Engl J Med. DOI: 10.1056/NEJMoa1709937
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PACIFIC: A double-blind, placebo-controlled Phase III study of durvalumab after chemoradiation therapy (CRT) in patients with Stage III, locally advanced, unresectable NSCLC
L. Paz-Ares1, A. Villegas2, D. Daniel3, D.V. Baz4, S. Murakami5, R. Hui6, T. Yokoi7, A. Chiappori8, K.H. Lee9, M. de Wit10, B.C. Cho11, M. Bourhaba12, X. Quantin13, T. Tokito14, T. Mekhail15, D. Planchard16, H. Jiang17, Y. Huang17, P.A. Dennis17, M. Özgüroğlu18
1Medical Oncology, Hospital Universitario 12 de Octubre, CiberOnc, Universidad Complutense and CNIO, Madrid, Spain, 2Medical Oncology, Florida Cancer Specialists, Fleming Island, FL, USA, 3Sarah Cannon Research Institute, Tennessee Oncology, Chattanooga, TN, USA, 4Medical Oncology, Hospital Universitario Virgen Macarena, Seville, Spain, 5Thoracic Oncology, Kanagawa Cancer Center, Yokohama, Japan, 6Medical Oncology, Westmead Hospital and the University of Sydney, Sydney, Australia, 7Thoracic oncology, Kansai Medical University Hospital, Hirakata, Japan, 8Medical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA, 9Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Korea, Republic of, 10Hematology and Oncology, Vivantes Klinikum Neukoelln, Berlin, Germany, 11Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea, Republic of, 12Medical Oncology, Centre Hospitalier Universitaire de Liège, Liège, Belgium, 13Medical Oncology, CHU Montpellier and ICM Val d'Aurelle, Montpellier, France, 14Internal Medicine, Kurume University Hospital, Kurume, Japan, 15Hematology and Medical Oncology, Florida Hospital Cancer Institute, Orlando, FL, USA, 16Medical Oncology, Gustave Roussy, Villejuif, France, 17Immuno-oncology, AstraZeneca, Gaithersburg, MD, USA, 18Internal Medicine, Istanbul University Cerrahpasa School of Medicine, Istanbul, Turkey
Background: Most patients (pts) with locally advanced, unresectable non-small cell lung cancer (NSCLC) progress despite concurrent chemoradiation therapy (cCRT). Here we report interim results from a global, Phase 3 study (NCT02125461) of the anti-PD-L1 durvalumab as consolidation therapy in Stage III pts without progression following platinum-based cCRT.
Methods: Pts with a WHO performance status 0/1 (any PD-L1 status) who received ≥2 cycles of platinum-based cCRT without progression were randomized (2:1) 1–42 days post-cCRT to receive durvalumab 10 mg/kg IV Q2W or placebo for up to 12 months, stratified by age, sex, and smoking history. Co-primary endpoints were progression-free survival (PFS; blinded independent central review, RECIST v1.1) and overall survival (OS). Secondary endpoints included 12- and 18-month PFS rates, objective response rate (ORR), duration of response (DoR), time to death or distant metastasis (TTDM) and safety.
Results: Between May 2014 and April 2016, 713 pts were randomized of whom 709 received consolidated treatment (durvalumab, n=473; placebo, n=236). Baseline characteristics were well balanced. As of Feb 13, 2017 (data cutoff), median follow-up was 14.5 months. 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). 12- and 18-month PFS rates were 55.9% versus 35.3% and 44.2% versus 27.0%, respectively. ORR was higher (28.4% vs 16.0%; P<0.001) and median DoR was longer (not reached vs 13.8 months) with durvalumab consolidation therapy. Median TTDM was longer with durvalumab (23.2 vs 14.6 months; stratified HR 0.52, 95% CI, 0.39–0.69; P<0.0001). OS data were immature at the time of interim PFS analysis. Comparing durvalumab with placebo, grade 3/4 adverse events (AEs) occurred in 32.0% and 27.8%; most common was pneumonia (4.4% vs 4.3%). 15.4% and 9.8% discontinued due to AEs.
Conclusions: Durvalumab demonstrated significant and clinically meaningful improvement in PFS, which was supported by secondary endpoints, and was well tolerated. Durvalumab is a promising therapeutic option in this setting.
Clinical trial identification: NCT02125461 (April 25, 2014)
Legal entity responsible for the study: AstraZeneca
Disclosure: L. Paz-Ares: Dr. Paz-Ares has received consultancy fees from AstraZeneca, Bristol-Myers Squibb, Merck Sharp and Dohme, Pfizer, Roche, Lilly, Boehringer Ingelheim, Novartis, and Ariad.
A. Villegas: Dr. Villegas has received speaker honoraria from Celgene, Alexion, and Bristol-Myers Squibb.
R. Hui: Dr. Hui has received advisory board fees from AstraZeneca, Merck Sharp and Dohme, and Novartis, and a speaker honorarium from Merck Sharp and Dohme.
A. Chiappori: Dr. Chiappori has received speaker honoraria from Genentech, Merck, Takeda, Novartis, Pfizer, Boehringer Ingelheim, and Celgene, and research support from Novartis and Bristol-Myers Squibb.
M. de Wit: Dr. de Wit has received a speaker honorarium from AstraZeneca.
T. Mekhail: Dr. Mekhail has received a speaker honorarium and research support from AstraZeneca.
D. Planchard: Dr. Planchard has received advisory board fees from AstraZeneca, Bristol-Myers Squibb, Merck Sharp and Dohme, Pfizer, Novartis, Roche, Lilly, and Boehringer Ingelheim.
H. Jiang: Dr. Jiang is a full-time employee of AstraZeneca with stock ownership.
Y. Huang: Dr. Huang is a full-time employee of AstraZeneca with stock ownership.
P.A. Dennis: Dr. Dennis is a full-time employee of AstraZeneca with stock ownership.
All other authors have declared no conflicts of interest.
Keywords: durvalumab, locally advanced NSCLC, chemoradiation, immunotherapy