Expert Explains Successes, Challenges in Stage III Lung Cancer

Dustin M. Walters, MD

The heterogeneity of stage III NSCLC means there is not a one-size-fits-all strategy for patients. Rather, a multidisciplinary approach is required to optimally utilize the available tools of chemoradiation, immunotherapy, and surgery.

“We’ll have to figure out how to leverage all the benefits of all those therapies and time them appropriately [versus] a magic bullet or monotherapy that works well for these [patients],” said Dustin M. Walters, MD.

Exciting new data continue to expand the treatment options available for these multidisciplinary strategies. For example, following the readout of the PACIFIC trial, the use of durvalumab (Imfinzi) after chemoradiotherapy became a standard option in the treatment paradigm for patients with unresectable stage III NSCLC. Results of the study demonstrated an 11.2-month improvement in progression-free survival (PFS) with durvalumab versus placebo (16.8 vs 5.6; HR, 0.52; 95% CI, 0.42-0.65; P <.0001). The 18-month PFS rate was 44.2% compared with 27.0% in favor of the durvalumab arm.

Additionally, a clinical trial expected to open in October will examine the PD-L1 inhibitor in a phase II, single-arm study (NCT03589547). Patients with locally advanced stage III NSCLC will receive chemoradiation followed by concurrent durvalumab and consolidative stereotactic body radiation therapy. The trial has an estimated completion date of October 2025.

OncLive: What is the approach to treating stage III NSCLC?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Advanced Non—Small Cell Lung Cancer, Walters, assistant professor of Thoracic and Cardiovascular Surgery, University of Virginia Health System, provided perspective on the treatment landscape of stage III NSCLC.Walters: In general, stage III NSCLC is a pretty challenging disease. It's the most heterogeneous of all the stages that we deal with. Early-stage is very straightforward, and stage IV lung cancer is pretty straightforward. Stage III really necessitates a true multidisciplinary approach.

At the University of Virginia, that means a team of radiation oncologists, medical oncologists, surgical oncologists, radiologists, and pathologists. Everyone gets together, we discuss these patients, and we try to determine the best individualized treatment plan for them.

I looked at the context of the PACIFIC trial and how that changes the treatment landscape for stage III lung cancer. PACIFIC was a randomized phase III study that looked at patients who were surgically unresectable with stage III disease. About half of patients had stage IIIa disease and half had stage IIIb disease. It looked at the effects of durvalumab, which is a PD-L1 antibody on survival; it showed a pretty nice benefit in PFS. The overall survival data aren’t quite out yet.

What does the multidisciplinary approach at the University of Virginia look like?

Who is making sure that those approaches are carried out?

What is the role of chemoradiotherapy for these patients?

Is there potential for neoadjuvant immunotherapy?

What does the future hold for stage III disease?

Are these therapies going to be equal players?

A lot of folks have interpreted that trial [by questioning] the role of surgery moving forward. Most of us still think there is a pretty good role for surgery for these patients. The ultimate outcome is to cure these folks, and surgery will play a huge role, particularly for stage IIIa patients.We have a weekly tumor board that meets every Tuesday morning. We try to discuss every lung cancer case that is brought to all of our clinics, but certainly all of the very challenging cases. The cases are presented, and everyone gives their opinion. We come up with a consensus recommendation. It's really an individualized approach. We take everything into account, such as the stage of disease, the patient themselves, what they want, and what the options are. Based on that, we try to come up with as close of a consensus as we can.If it's one of my patients that I'm presenting, we'll discuss and come up with a consensus. I'll call the patient, and we will talk about what the different options are and what our recommendations are. Then we’ll decide, in conjunction with the patient, how to move forward.Certainly, for all stage III patients, chemoradiotherapy is one of the major parts [of treatment] regardless of whether they’re going to have surgery, durvalumab, or other therapy. For resectable patients, our typical approach is to give them induction chemoradiation, restage them, and then operate on them. For unresectable patients, they get definitive chemoradiation in conjunction with durvalumab.Absolutely. In fact, we just got approval for a clinical trial here at the University of Virginia. We expect it to open in the next 1 to 2 months. It's a phase II, single-arm study where folks are going to get induction chemoradiation with durvalumab. Then, they will get restaged, have surgery, and then get consolidation durvalumab for 1 year afterwards.It's going to be defining the real role of surgery, particularly in light of immunotherapy. Most of us at the University of Virginia—and most oncologists in general—will agree that the best approach is going to be some combination of chemoradiation, immunotherapy, and surgery.That is hard to say. I don't foresee any of those therapies being effective as monotherapy. The multimodality approach is going to be the best for these patients who need local control of their disease. The only options there are radiation and surgery. [Patients] also need systemic therapy because if they have metastasized to lymph nodes, we expect that they have micrometastases and circulating cancer cells.

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.