Paradigm Shift Still Leaves Unanswered Questions in Stage III NSCLC

Everett E. Vokes, MD

Results of the randomized phase III PACIFIC trial introduced a new standard of care with durvalumab (Imfinzi) after chemoradiation for patients with locally advanced, unresectable non—small cell lung cancer (NSCLC). However, following these data, questions remain regarding sequencing and what patient subsets best respond to the PD-L1 inhibitor, said Everett E. Vokes, MD.

In February 2018, the FDA approved durvalumab based on initial results from PACIFIC, which showed a 32% reduction in the risk of death compared with placebo in patients with locally advanced, unresectable NSCLC who have not progressed following concurrent chemoradiation (HR, 0.68; 95% CI, 0.53-0.87; P = .0025).¹ In July 2019, an updated analysis showed a 31% reduction in the risk of death versus placebo based on 3-year overall survival (OS) data from the trial (HR, 0.69; 95% CI, 0.55-0.86).²

"This is a new standard," said Vokes. "At this point, most investigators know this, but a patient with stage III disease getting chemoradiation should get consolidation durvalumab after."

Despite this paradigm shift, questions remain in this space regarding sequencing strategies.

“How does durvalumab apply to patients who are marginally resectable—who have surgery and then receive chemoradiation? What about patients who get chemoradiation followed by surgery?” questioned Vokes. “In terms of sequencing, the role of surgery is largely unknown.”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Lung Cancer, Vokes, the John E. Ultmann Professor of Medicine and Radiation Oncology, and physician-in-chief and chair of the Department of Medicine at University of Chicago Medicine, discussed remaining questions in stage III NSCLC following the PACIFIC results.

OncLive^®: How has the space of stage III NSCLC changed in recent years?

Vokes: Stage III NSCLC has a history of many years of sometimes successful work, followed by a long hiatus of stagnation. We know that combined chemoradiation with simultaneous administration of the 2 is standard of care. There are 3 regimens that can be used: cisplatin plus paclitaxel, cisplatin plus etoposide, and cisplatin plus pemetrexed. Beyond that, there was not a lot of progress.

It's interesting though that outcomes improve with PET staging. There is more precise establishment of the exact stage, which leads to better outcomes.

The PACIFIC trial is the next big innovation. It is fairly recent, but it is transformative in many ways. Patients received chemoradiation at their institution with whatever regimen they wanted to use. There was no quality control on the initial treatment.

Then, up to 42 days after chemoradiation, patients were randomized 2:1 to either receive durvalumab or placebo. The outcome was very dramatic. The progression-free survival is better for patients who received durvalumab compared with the group that received placebo. Similarly, OS is better.

[Durvalumab] is the new standard because 2 things can happen when a patient gets chemoradiation. They can fail locally or they can fail elsewhere. We don't have hard data on local control, but we do know that more patients responded and had additional shrinkage after they received durvalumab than after placebo. That hints that local control was improved.

Disease control was clearly improved as shown by various sites like the brain, bone, lung, or other. In each case, the recurrence rate is much lower. Overall, it is a successful trial and the new standard.

What are the unanswered questions prompted by the trial?

The trial has subset analyses, a number of which are of interest. For one, patients who received durvalumab early—within 2 weeks of stopping chemoradiation—seemed to do better. It could be that those patients have smaller tumors with less complications, but it may also mean that giving the drug early is important. You could make a theory around either one, so that needs to be tested.

The second question is regarding EGFR- or otherwise driver-mutated patients who were included in the trial. We don't know the role of targeted therapies in stage III NSCLC. In the PACIFIC trial, the group of patients with identified mutations was too small, so we don't have that analysis. It doesn't appear to be a worrisome outcome if you look at raw numbers, but technically we don't know.

Sequencing is also an unanswered question. If patients benefit from durvalumab after chemoradiation, should we give it during chemoradiation or in the neoadjuvant setting? We don't know those answers yet.

The PACIFIC trial paved the way for immunotherapy in stage III NSCLC. Are there other ongoing trials exploring this approach?

Currently, this trial is singular. No other trial is even close in terms of a randomized approach. Several key questions need to be answered moving forward. Should neoadjuvant chemotherapy be given? Should it be neoadjuvant chemoimmunotherapy? Should it be neoadjuvant immunotherapy? Should it be given concurrently? If so, what is the risk of severe radiation pneumonitis?

Those questions are being addressed in ongoing trials and so far, giving treatment early and giving treatment concurrently appears to be beneficial.

Are there any other approaches being investigated that you want to highlight?

There has been an interesting approach with metformin. There is epidemiological evidence that patients with diabetes who take metformin do better with lung cancer. Preclinical trials support giving metformin together with radiation in animal models as they appear to do better [with the combination].

NRG did a trial of chemoradiation with or without metformin. While the hypothesis was good, and the idea was great, the outcome was not supportive.

References

1. 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.
2. Gray J, Villegas AE, Daniel DB, et al. Three-year overall survival update from the PACIFIC trial. J Clin Oncol. 2019;37(15 suppl; abstr 8526). doi: 10.1200/JCO.2019.37.15_suppl.8526.