Expert Highlights Immunotherapy Use in Stage III NSCLC

Gary Schwartz, MD

The recent FDA approval of durvalumab (Imfinzi) in locally advanced unresectable stage III non—small cell lung cancer (NSCLC) marks a new era in the landscape, as the agent showed a significant improvement in progression-free survival (PFS) in a phase III trial.

The approval was based on the results of the PACIFIC trial that examined the PD-L1 inhibitor versus placebo. Results showed an improved median PFS of 11.2 months compared with placebo (16.8 vs 5.6 months; HR, 0.52; 95% CI, 0.42-0.65; P <.0001). The 12-month PFS rates were 55.9% versus 35.3%, and the 18-month PFS rate was 44.2% versus 27.0% for durvalumab and placebo, respectively.

In the trial, 473 patients were randomized to durvalumab and 236 were randomized to placebo. Chemotherapy use was similar between groups, with 25.8% and 28.7% receiving induction chemotherapy before definitive chemoradiotherapy, in the durvalumab and placebo groups, respectively. A higher objective response rate was observed in the durvalumab arm than the placebo arm (28.4% vs 16.0%; P <.001). Of the patients who had a response to durvalumab, 72.8% had a continued response at both 12 and 18 months compared with 56.1% and 46.8%, respectively, in the placebo arm.

OncLive: Can you highlight potential uses of immunotherapy for stage III locally advanced disease?

Which patients will benefit most from immunotherapy?

Can you speak to the impact of the PACIFIC trial?

Radiation therapy and immunotherapy are believed to have synergistic effects. Can you explain why?

What other combinations are being explored?

How is acquired resistance managed in patients who receive immunotherapy?

What should be kept in mind with regard to surgery in patients with locally advanced disease?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancers, Gary Schwartz, MD, of Baylor Scott & White Center for Thoracic Surgery, spoke about the significance of the PACIFIC trial and discussed expanding applications of immunotherapy for patients with stage III locally advanced disease.Schwartz: Immunotherapy is a very exciting topic right now, and we’ve seen incredible promise with it. We’re still trying to differentiate which agents to use and when to use them; that’s been really challenging. A particularly interesting topic for me is the stage III disease setting where we often give a combination of 3 or 4 different types of therapy. We’re still determining how this will pan out.We will [determine whether they will benefit from immunotherapy] based on the mutational analysis of their cancer biopsy and, often, [knowing how they responded] in the past to other kinds of treatment.The PACIFIC trial, which was just published in November 2017 in the New England Journal of Medicine, showed an incredible increase in disease-free survival and PFS. It more than doubled in patients with stage III lung cancer. These were patients who could not undergo surgery for a variety of reasons that are not specified in the trial, but are usually due to cancers that are surgically unresectable or patients who cannot tolerate surgery. Patients in that trial received either chemoradiation, which we considered definitive in that they were not going to have surgery afterward, or chemoradiation followed by immunotherapy. We did see incredible PFS benefit in those patients [who also received immunotherapy]. Of note was a slighter higher effect on the lung itself called pneumonitis. This is somewhat concerning overall, but it’s still too early to comment on.It’s actually a relatively old theory. The theory has been around for decades that if you target the primary tumor, you induce a necrosis of the tumor that will expose some antigens from the cells. This will heighten the immune system’s sensitivity to those proteins, allowing them to target lesions in other parts of the body. Immunotherapy can be thought of as priming the immune system so that radiation plus immunotherapy can help target cancer throughout the body, not just in the area of the body it’s going to radiate in. The effect is what radiation oncologists believe in. It doesn’t always happen, but we do think that we’ll see it more with combinations of radiotherapy and immunotherapy.The talk I gave looked at what we’re not doing yet, which is a combination of adding immunotherapy as an induction agent. I’m looking at whether a stage III lung cancer that would potentially be resectable after giving chemotherapy and radiation can have immunotherapy prior to surgery, as well. We’re also asking whether or not we should save immunotherapy for after surgery if the cancer comes back or if we should give them immunotherapy upfront. From a surgical perspective, those are the 2 most exciting applications of immunotherapy that can potentially make patients who couldn’t otherwise have surgery become surgical candidates or augment their surgery afterward with immunotherapy.That is always a potential issue, and it will depend on where the patient is in their treatment. If they’re given immunotherapy upfront and they develop resistance, you have to ask yourself whether that warrants surgery or not. If you use it after surgery or if surgery is not an option, then you’ll have to start looking at other agents.The most important thing, specific to stage III lung cancer, is not to rule out surgery. Historically, surgery didn’t play as large a role in stage III disease. Overall, it should, and with the introduction of immunotherapy, either in a neoadjuvant or adjuvant setting, it should definitely be considered more often.

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