Durvalumab in Stage III Lung Cancer: 'An Important Advance'

Zosia Chustecka

October 17, 2017

YOKOHAMA, Japan — New data from the PACIFIC study of durvalumab (Imfinzi, AstraZeneca) in patients with unresected stage III non-small cell lung cancer (NSCLC) show that the drug is well tolerated and does not affect quality of life.

In fact, some symptoms, such as dysphagia and alopecia, improved, most likely because of resolution of toxicities related to the prior chemoradiotherapy that all patients received.

These new patient-reported outcomes, a secondary endpoint of the trial, add to the recently reported efficacy results showing that durvalumab significantly improved progression-free survival (PFS) compared with placebo. The median PFS was 16.8 months with durvalumab vs 5.6 months with placebo (hazard ratio, 0.52; P < .0001).

"This is an important advance," commented Michael Boyer, MD, clinical professor of medicine at the University of Sydney, Australia.

Numerous previous trials have attempted to improve outcomes in this patient population, and all have failed. Researchers contemplating new trials must have felt as if they were banging their heads against a brick wall, Dr Boyer said. Now, a few bricks have fallen away and blue skies are visible beyond.

Dr Boyer was speaking at a plenary session here at the 18th World Conference on Lung Cancer (WCLC), acting as a discussant for the new data on patient outcomes from the PACIFIC trial, which had just been presented.

The efficacy data, which were the primary endpoint, had been presented a month ago at the European Society for Medical Oncology annual meeting and were simultaneously published online in the New England Journal of Medicine.

At that time, lung cancer experts welcomed the new results enthusiastically, as reported by Medscape Medical News. While overall survival results are now eagerly awaited, the magnitude of PFS benefit supports durvalumab as a new standard of care for patients with unresectable stage III NSCLC who had no progression after standard care with platinum-based chemotherapy and concomitant radiotherapy, commented Pilar Garrido, MD, PhD, head of the Thoracic Tumour Section of the Medical Oncology Department at Ramón y Cajal University Hospital, Madrid, Spain.

Since then, several lung cancer experts have commented that this trial changes the treatment paradigm because it shows — for the first time — that an immunotherapy is beneficial at an earlier stage of lung cancer. These patients had locally advanced unresectable stage III NSCLC. All the previous trials with immunotherapy in lung cancer (pembrolizumab, nivolumab, atezolizumab) have been in later-stage disease: advanced and metastatic NSCLC.

Dr Boyer provided the human context for this in his discussion — these patients with locally advanced stage III NSCLC are potentially curable, he said.

At present, about 15% of this patient population is still alive 5 years after treatment.

Numerous attempts have been made to improve upon the results achieved with standard-care chemoradiotherapy, he said. Clinical trials have compared sequential and concurrent chemotherapy and radiation but found no difference between the two. The RTOG 0617 trial in 2014 looked at increased radiotherapy dose but found only increased toxicity. Other trials looked at adding more chemotherapy before or after chemoradiotherapy (Cancer and Leukemia Group B in 2007, and Hoosier Oncology Group  in 2008), adding another chemotherapy to cisplatin (pemetrexed in the PROCLAIM study in 2016 and docetaxel in 2010), or adding targeted agents (cetuximab in RTOG 0617 in 2008 and gefitinib in the Southwestern Oncology Group S0023 trial in 2008). Another approach was the use of tecemotide vaccination after chemoradiotherapy (in the START trial in 2014).

But all of these trials failed to improve the outcomes for these patients.

That's why Dr Boyer considers the durvalumab results as "an important advance in the management of unresectable stage III NSCLC."

"For the first time in a long time, there was a significant improvement in outcomes," Dr Boyer commented.

Median PFS with durvalumab was 11 months longer than with placebo, about a 20% improvement, he said. Overall survival results are now anticipated — they should be reported in the coming months, he said.

The new data showing no impact on quality of life are important, he said, because "we want to ensure that the gains achieved in survival are not countered by adverse events."  

The quality-of-life data were presented at the WCLC meeting by Rina Hui, MD, from the Westmead Hospital and the University of Sydney in Australia.

In the PACIFIC trial, symptoms, physical function, and global health status/quality of life were evaluated on the European Organisation for Research and Treatment of Cancer QLQ-C30v3 questionnaire and its lung cancer module, QLQ-LC13, she explained. These were completed at baseline and weeks 4 and 8, and then every 12 weeks until disease progression.

The results show no change from baseline in most symptoms. A clinically relevant improvement in dysphagia and alopecia was reported at 48 weeks in both the durvalumab and the placebo groups. This is likely to reflect resolution of the toxicity from the chemoradiotherapy that all patients received (they were enrolled in the trial with 6 weeks of undergoing chemoradiotherapy), Dr Hui commented. In addition, reports of improvement in appetite loss and other pain favored durvalumab.

Dr Hui concluded that adding durvalumab to chemoradiotherapy "did not compromise quality of life." 

Durvalumab, a checkpoint programmed cell death ligand 1 inhibitor, is not yet approved for use in lung cancer, although the manufacturer has said it will be submitting the PACIFIC data to regulatory authorities. At present, the drug is approved for use in urothelial carcinoma.

The PACIFIC trial was sponsored by AstraZeneca. Dr Hui reports receiving advisory board fees from AstraZeneca, Merck Sharp & Dohme, and Novartis; speaker honorarium from Merck Sharp & Dohme; and accommodation expenses from Roche. Dr Boyer reports research funding and/or honoraria paid to his institution from Bristol-Myers Squibb, Merck, AstraZeneca, Amgen, Pfizer, Genentech/Roche, and Peregrine Pharmaceuticals.

18th World Conference on Lung Cancer (WCLC). Abstracts PL 02.02 (Dr Hui) and PL02.03 (Dr Boyer). Presented October 17, 2017.

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