PACIFIC Immunotherapy Data Open Research Opportunities in Stage III NSCLC

Drew Moghanaki, MD, MPH

Results from the phase III PACIFIC trial showed an improvement in overall survival with durvalumab (Imfinzi), leading to a new standard of care for select patients with stage III non—small cell lung cancer. Now, Drew Moghanaki, MD, MPH, is asking more questions as the community looks to the future of treatment for this patient population.

“Now that we see immunotherapy works so well on the back end after chemotherapy and radiation, the question becomes, ‘Should we be giving it earlier?’ To give 6 weeks of radiation and wait a few weeks and then start immunotherapy, [we might] be missing a window,” said Moghanaki, acting associate professor of radiation oncology at Winship Cancer Institute and section chief in the Department of Radiation Oncology at Atlanta VA Medical Center.

“There might be something else going on with immunotherapy's ability to start cleaning up tumor cells as the radiation chemotherapy is causing defects on the cells themselves. At the same time, we are still curious that immunotherapy might work best because of the cytoreduction upfront with radiation,” added Moghanaki.

In February 2018, the FDA approved durvalumab for the treatment of patients with unresectable, stage III NSCLC whose disease has not progressed following concurrent platinum-based chemoradiation, based on data from the phase III PACIFIC trial.

Results of the primary OS analysis showed that the PD-L1 inhibitor demonstrated a 32% reduction in the risk of death compared with placebo, which was a significant and clinically proven survival benefit in this patient population (HR, 0.68; 95% CI, 0.53-0.87; P = .0025).

In an interview during the 2019 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Moghanaki discusses the impact of the PACIFIC trial and future research in stage III NSCLC.

OncLive: Could you highlight the history and recent advances in stage III NSCLC treatment?

Moghanaki: [Radiation therapy] has been an integral part of treatment since the 1960s and over the ensuing half century, we've figured out how to incorporate chemotherapy into the paradigm. One of the first randomized trials in this field did observation versus radiation, and showed that radiation helps people live longer. It will be several decades later before we start adding chemotherapy.

Initially, we added chemotherapy before radiation. Later, we added chemotherapy [concurrently] with radiation. Then, we hit a plateau. For the last couple decades, we've been unable to move the needle. People try to add more chemotherapy after or before chemoradiation, but neither strategy has been able to [improve outcomes]. Enforcing more chemotherapy is just added toxicity [without] benefits.

Low and behold, immunotherapy drugs became available, which goes after modulating the immune system rather than attacking the tumor. Now, we deliver chemotherapy and radiation together. Then, the immune system comes in the back end and cleans up what chemotherapy and radiation has left behind. It's been interesting to see hypotheses that showed chemotherapy and radiation both upregulate PD-L1 and really set the stage for immunotherapy to work—maybe better than either treatment upfront.

Could you discuss the impact that the PACIFIC trial had on this specific lung cancer setting?

When the PACIFIC trial was first reported in 2017, it continued to have a lot of skeptics even though it was a double-blinded, randomized trial. I always say, “We should have a moment of silence for all the patients who sat in a chair every 2 weeks and received only placebo to give us the strongest level of evidence you could ever ask for in clinical research.”

When there was a progression-free survival gain, people still thought the overall survival curves would not separate because we've been burned so many times before in other trials. When the 2018 results came out in the New England Journal of Medicine, it was an ecstatic moment to see the needle move so much.

What's remarkable about PACIFIC is that the control arm continues to perform better versus historical control. Therefore, we know we have better staging and more accurate, precise radiation delivery that's less toxic than before. It has renewed hope for oncologists and patients. Now, if you have stage III disease—even IIIb disease—it's not time to pack up just yet. You still have a lot of gains to be held and a lot more life to live after treatment is over.

Because of the PACIFIC data, what research efforts are now ongoing?

There are so many questions. It's unfortunate that there could be more questions in the back end, but with so much research going on, the only solutions are going to be coming forward in the next several years. It's hard to predict what the next paradigm shift will be. It doesn't look like cytotoxic chemotherapies are going to have much of an additive role beyond what they currently do. Will immunotherapy ever replace cytotoxic chemotherapy? Those require the hard, difficult trials to compare appropriately.

We really need well-designed, placebo-controlled trials, such as the PACIFIC trial and other phase III trials, to know that we have a treatment that's better than what we used to do. Otherwise, you're going to have a study that will be debated and it will be difficult to persuade people to shift their practice.

How would you define the current prognosis for this patient population?

It's important to remember that not long ago, at stage IIIb disease, physicians would say, “The patient is not curable.” There are some patients with stage IIIb disease who I didn’t even treat because I didn't want to harm them—when I had very little evidence that my treatment would be beneficial for them, with or without chemotherapy. Today, when you look at the survival arms of the PACIFIC trial, if the patient has not progressed and they are about to get immunotherapy with durvalumab, there is a lot of hope to remain alive for several more years down the road.

Has the microenvironment in the tumor changed sufficiently with the immunotherapy? Is the body now in a different state to continue to fight any relapses or third relapses? There is still a lot to be known. We're looking forward to longer follow-up data. There will be an update soon and I can't wait to see the survival curves; I hope they keep diverging.

What are some ongoing trials in this space that you are excited to see the data of?

It's hard to know what studies are going to be reported in the next year. Generally, studies that I'm interested in are those that are using immunotherapy during chemoradiation for patients with stage III disease. It's a huge unanswered question. There are also some sequencing questions to ask as well. Should we start with immunotherapy before we deliver the first round of radiation or vice versa? These questions require a lot of resources, a lot of physician and patient commitment, and a lot of time. A lot of patients get diagnosed with this awful disease. Those are the questions that keep me up at night.

Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379(24):2342-2350. doi: 10.1056/NEJMoa1809697.