Immunotherapy Is Entering the Stage 3 Lung Cancer Landscape

Danielle Bucco

Imfinzi (durvalumab), a PD-L1 inhibitor, is being reviewed for a supplemental biologics license application (sBLA) by the Food and Drug Administration (FDA) for the treatment of patients with stage 3, unresectable non-small cell lung cancer (NSCLC). The sBLA is in light of positive progression-free survival (PFS) results from the phase 3 PACIFIC trial.

PACIFIC included 709 patients with stage 3 NSCLC who did not have disease progression after two or more cycles of platinum-based chemoradiotherapy. Patients were randomized to Imfinzi (473 patients) or placebo (236 patients).

The median PFS was 16.8 months with Imfinzi compared with 5.6 months for placebo. The objective response rates were 28.4 percent versus 16 percent, respectively.

“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, M.D.

In an interview with CURE at the 2017 State of the Science SummitTM 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 Imfinzi and other developments in the treatment of patients with stage 3 NSCLC.

Can you provide an overview of your presentation on immunotherapy for patients with stage 3 locally advanced lung cancer?

First, I discussed where we currently are with combination chemotherapy and radiation therapy for stage 3 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 3 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?

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… Imfinzi …was [administered] after completion of chemoradiation. It showed a significant benefit in PFS and we believe it will benefit overall survival (OS), as well.

Can you discuss the impact of the PACIFIC trial?

The results demonstrated an impressive PFS benefit of 20 percent. 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 3 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 3 treatment in the future.

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

This is just the beginning. Most of my talk involved discussing questions we still have for stage 3 disease, as well as earlier stages of disease and the role of immunotherapy. Imfinzi 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.

What challenges remain in the treatment of this patient population?

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 3 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. 

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 3 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.

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

Changes are not just occurring for stage 4 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 1, 2 and 3 disease. We need to take the successes that we have had in stage 4 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.

Is there anything else you would like to highlight?

We are already looking at changing stage 3 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 3 disease. There is a phase 3 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. 

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