Durvalumab Success Signifies New Era in Stage III NSCLC

Edward S. Kim, MD

Findings from the phase III PACIFIC trial solidified the benefit of the PD-L1 inhibitor durvalumab (Imfinzi) in the treatment of patients with stage III non—small cell lung cancer (NSCLC), according to Edward S. Kim, MD.

In his lecture during the 2018 OncLive^® State of the Science Summit^TM on the potential use of immunotherapy for stage III locally advanced disease on Advanced Non—Small Cell Lung Cancer, Kim recapped the findings from the PACIFIC study of durvalumab and discussed the treatment of patients with stage III NSCLC.

“Durvalumab is a promising new therapeutic option in patients with stage III, locally advanced, unresectable NSCLC who have completed concurrent chemoradiotherapy, and [is] a new standard,” said Kim, chair, Department of Solid Tumor Oncology, Levine Cancer Institute.

Although 22% to 30% of patients have stage III disease at diagnosis, Kim said that this is a population that had previously been largely overlooked.

"Everybody was focusing on stage IV, and everyone was getting ‘seduced’ by the biomarkers, what might be the population, and what combinations worked better. [PACIFIC] sort of snuck up on folks," said Kim. "I don't think anyone thought these would be the results of this trial."

The standard of care for unresectable stage III disease has been concurrent chemoradiation, which has a median progression-free survival (PFS) of 8 to 10 months. Beyond that, there have been no major advances in this population until this study.

PACIFIC is a phase III, randomized, double-blind, placebo-controlled, multicenter, international study of patients with stage III, locally advanced, unresectable NSCLC who have not progressed following definitive platinum-based concurrent chemoradiotherapy. In the durvalumab arm, patients received 10 mg/kg of durvalumab every 2 weeks for up to 12 months.

The coprimary endpoints were PFS by blinded independent central review using RECIST v1.1 criteria, and overall survival. Secondary endpoints included overall response rate, duration of response, and safety and tolerability.

The median PFS was 16.8 months with durvalumab compared with 5.6 months for placebo (HR, 0.52; 95% CI, 0.42-0.65; P <.0001).

"You can see that the curves are very striking, it is basically a 3-fold difference in median at 5.6 versus 16.8. It is very compelling when you see [these] data with not even 12 months of immunotherapy," said Kim.

Overall survival data are still not mature.

The safety profile of durvalumab was favorable, with a comparable rate of grade 3/4 adverse events (AEs) between durvalumab and placebo (29.9% versus 26.1%). Of 475 patients treated with durvalumab, 73 (15.4%) had AEs that led to treatment discontinuations. The most frequent all-grade AEs were cough (35.4%), pneumonitis (33.9%), and fatigue (23.8%). Other all-grade AEs of note included pyrexia (14.7%) and pneumonia (13.1%).

"Everybody was pretty cautious about [AEs]. We know that there are safety issues and different side effects that occur with immunotherapy,” said Kim. “We don't see that much pseudoprogression; we don't see as many side effects as some of the [patients with] melanoma do."

Challenges in the treatment of stage III disease remain, as the EGFR-mutant population did not demonstrate benefit from treatment with durvalumab. Kim says that overall, patients with locally advanced NSCLC are still challenging to treat.

"We still have things that we are trying to figure out in EGFR-mutant patients and how immunotherapy fits in. We don't even understand how radiation and chemotherapy necessarily affect that population either," said Kim.

Other questions include the duration of durvalumab treatment, when to treat after completion of chemoradiation, and the role of combinations.

The success of durvalumab in the PACIFIC trial has made many in the community excited about the potential for other immunotherapy regimens in the treatment of stage III NSCLC.

A study of pembrolizumab (Keytruda), paclitaxel, carboplatin, and radiation therapy in patients with stage II-IIIB NSCLC is currently recruiting (NCT02621398). There is also a study of consolidation pembrolizumab following chemoradiation in patients with inoperable/unresectable stage III NSCLC that is ongoing (NCT02343952). Additionally, the NICOLAS study is investigating the combination nivolumab (Opdivo) with standard first-line chemotherapy and radiotherapy in locally advanced stage IIIA-B NSCLC (NCT02434081).

Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non—small-cell lung cancer. N Engl J Med. 2017;377(20):1919-1929 doi: 10.1056/NEJMoa1709937.