Immunotherapy Emerges in Stage III NSCLC Treatment Landscape

John Heinzerling, MD

The FDA is currently reviewing a supplemental biologics license application for the PD-L1 inhibitor durvalumab (Imfinzi) for the treatment of patients with stage III, unresectable non—small cell lung cancer (NSCLC), based on positive progression-free survival (PFS) results from the phase III PACIFIC trial.

PACIFIC included 709 patients with stage III NSCLC who did not have disease progression after 2 or more cycles of platinum-based chemoradiotherapy. Patients were randomized to durvalumab (n = 473) or placebo (n = 236).

The median PFS was 16.8 months (95% CI, 13.0-18.1) with durvalumab compared with 5.6 months (95% CI, 4.6-7.8) for placebo (HR, 0.52; 95% CI, 0.42-0.65; P <.001). The objective response rates were 28.4% versus 16%.0, respectively (P <.001)

“Our hope is that we can offer treatment for earlier stages of disease and can increase the cure rates for these patients,” said John Heinzerling, MD.

OncLive: Can you provide an overview of your presentation on immunotherapy for patients with stage III locally advanced lung cancer?

In an interview with OncLive at the 2017 State of the Science Summit^TM on Advanced Non—Small Cell Lung Cancer, Heinzerling, a radiation oncologist in the Department of Radiation Oncology at the Levine Cancer Institute, discussed the impact of durvalumab and other developments in the treatment of patients with stage III NSCLC.Heinzerling: First, I discussed where we currently are with combination chemotherapy and radiation therapy for stage III disease. I reviewed the progress that has been made in the last 15 years.

I explained why immunotherapy might play a potential role in the treatment of patients with stage III disease. How does it integrate with radiation therapy and how have we seen it provide a potential benefit for other stages of lung cancer along with other malignancies?

Can you discuss the impact of the PACIFIC trial?

Do you think the success that we have seen with durvalumab is an indicator for upcoming immunotherapy agents in this stage?

What challenges remain in the treatment of this patient population?

We obviously want data-driven discussions, so I mainly talked about the recent data presented in the New England Journal of Medicine on the PACIFIC trial. [In] this trial…durvalumab…was [administered] after completion of chemoradiation. It showed a significant benefit in PFS and we believe it will benefit overall survival (OS), as well.The results demonstrated an impressive PFS benefit of 20%. That is something we assume would progress to an OS benefit. Based on those results, it has gotten a lot of publicity very quickly with the presentation and publication in September 2017. It has now been included in the national guidelines for stage III treatment and is being integrated into clinics. This is a fast turnaround from a result to integration into the clinic. It will become a standard part of stage III treatment in the future.This is just the beginning. Most of my talk involved discussing questions we still have for stage III disease, as well as earlier stages of disease and the role of immunotherapy. Durvalumab is given either in the maintenance setting or the adjuvant setting, but there are other trials looking at giving some other drugs earlier, concurrently integrating with radiation. As we saw in the PACIFIC trial, there seems to be even more potential benefit the earlier we give the drug.The first thing that must be looked at is improving the efficacy and outcomes. Secondly, we need to focus on toxicity. Historically, we added chemotherapy to radiation concurrently for the treatment of stage III disease. Although this did increase survival and efficacy, it also increased toxicity. It would be ideal if we could add immunotherapy in a way that might increase efficacy and decrease toxicity.

What future approaches do you envision being developed in this area?

Is there anything else you would like to highlight?

We know that adding immunotherapy tends to be less toxic than cytotoxic chemotherapy, so we are looking to replace some of the aspects of cytotoxic chemotherapy within stage III treatment or give it in a way that may reduce the toxicity from radiation. We might not need to use as much radiation or we can administer it to certain locations. There are many opportunities to use immunotherapy to our advantage in a smart and sophisticated way.Changes are not just occurring for stage IV disease. We have a lot of work to do in earlier stages of disease. That is going to become more important as CT screening becomes nationwide for lung cancer. We are just starting to see CT screening being adopted in more clinics. We know it is going to shift the patient spectrum from dominant stage IV disease to what we hope is dominant stage I, II, and III disease. We need to take the successes that we have had in stage IV disease with targeted agents and immunotherapy and utilize them earlier. Hopefully, we will see results since we are going to see more of those patients now.We are already looking at changing stage III treatment within the Levine Cancer Institute. One of the ways, from a radiation perspective, is reintroducing dose escalation into the equation with the thought process that high-dose radiation like stereotactic body radiation therapy is a more immune-stimulating type of radiation. It may be more proactive in a setting where we are [using] immunotherapy in stage III disease. There is a phase II trial that we are very excited to launch within Levine Cancer Institute and it is enrolling very well. We are looking forward to seeing data from that trial.

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