PACIFIC Study Sets New Standard in Stage III NSCLC, Opens Door to Further Progress

Scott J. Antonia, MD

The phase III PACIFIC trial, which investigated concurrent chemoradiation therapy and consolidative therapy with durvalumab (Imfinzi) in patients with unresectable stage III non—small cell lung cancer (NSCLC), not only set a definitive standard of care in this setting but also laid the groundwork for future immunotherapeutic developments, explained Scott J. Antonia, MD, PhD.

“This has become the new global standard of care, and it’s exciting because we've tried for decades to make an advance in this setting. Nothing that we've done over the past couple of decades has done [what this trial has for the space],” said Antonia. “This is the first treatment strategy that has improved the overall survival and changed the standard of care for these patients.”

In addition to boasting a 2-year overall survival (OS) rate of 66.3% (95% CI, 61.7%-70.4%) with the PD-L1 inhibitor durvalumab versus 55.6% (95% CI, 48.9-61.8) with placebo (two-sided P = .005), the trial set the stage to explore PD-1 and CTLA-4 inhibition in a similar fashion.

For example, a phase I/II trial (NCT03663166) is now exploring the use of concurrent chemoradiation and ipilimumab (Yervoy) followed by consolidative therapy with nivolumab (Opdivo). The study, powered to assess progression-free survival (PFS) with the regimen, is expected to complete by March 2022.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Antonia, instructor in the Department of Medicine, Duke University School of Medicine, and member of Duke Cancer Institute, discussed the pivotal data that renewed interest in stage III unresectable NSCLC and anticipated data that are expected to advance the field even further.

OncLive^®: How have the data from the PACIFIC trial changed the standard of care?

Antonia: The PACIFIC trial enrolled patients who had locally advanced unresectable NSCLC of all histologies. Patients were treated with standard concurrent chemotherapy and radiation therapy. The patients who, at the end of that treatment did not have progressive disease, were randomized 2:1 to receive either durvalumab or placebo for 1 year.

The results were quite dramatic. Initially, we published the PFS data, which showed a clear splaying of the curves that was highly statistically significant. Those results have held up with the OS analysis. The median OS for patients in the durvalumab arm still has not been met compared with the expected median OS of patients who received chemotherapy and radiation therapy alone.

The standard of care for patients with unresectable locally advanced NSCLC is combined concurrent chemoradiation therapy followed by durvalumab as consolidation.

What is the role of immunotherapy in NSCLC? Are there any trials that have helped support this shift in the landscape?

We initially looked at immunotherapy in the advanced-stage setting. Those of us in the field were quite pessimistic that immunotherapy could ever have activity in NSCLC. It turns out that lung cancer is the second most immunogenic cancer other than melanoma. What is most exciting is that [this approach] not only improves median OS, but the responses can be durable and result in long-term survival. We've followed patients with metastatic disease who were treated in the [second-line or later-line] setting, and 15% of patients were alive at 5 years. We've clearly made an impact on the tail of the survival curve. Therein lies the enthusiasm behind this and why we are all very enthusiastic about moving it into the earlier-stage setting.

Are there any ongoing combinations under investigation that you're particularly excited about?

There are so many potential combinations. No other immunotherapeutic agent has the degree of single-agent activity that we see with anti—PD-1/PD-L1 agents. The only way that we're going to make the next leap is to develop combination immunotherapy. One part of the combination should be directed to the lymphoid compartment to increase the number of tumor reactive T cells, and the other should be a continued blockade of anti–PD-1 in the tumor microenvironment. A manifestation of a productive antitumor T-cell response within the tumor microenvironment is the secretion of gamma interferon on other inflammatory cytokines that are potent inducers of PD-L1.

We also have to better learn how to use biomarkers to select patients on clinical trials. In stage III NSCLC, we're interested in combining ipilimumab with radiation and chemotherapy when radiation is releasing tumor antigens in immunogenic fashion. If the anti—CTLA-4 agent has its principal impact on the lymphoid compartment, we reason that it will be a good combination to use in concurrent fashion. Our current trial is looking at the combination of an anti–CTLA-4 agent, chemotherapy, and radiation therapy followed by consolidative anti–PD-1 therapy.

Are there any concerns regarding toxicity with that approach?

Yes; there is an increased frequency of toxicities from combinations. However, the goal is to increase the cure rate. Whenever we think about whether or not some level of toxicity is tolerable, it has to be put into context. For example, [we need to think] about the clinical outcome that's possible. If the clinical outcome that is possible is increasing the cure rate, then we, as treating physicians, and, of course, patients, are more willing to accept an increased toxicity. The other point is that we've been using these drugs for a significant period of time. Now, the toxicities are becoming more predictable and are being caught at earlier stages; therefore, they are being managed effectively.

What unanswered questions do you hope will be addressed through ongoing research?

How do we make the next advance beyond PD-1 and CTLA-4 inhibitors? How can we understand which biomarkers to use to select patients for the proper combination of immunotherapy drugs for an individual patient?

There are biomarkers, such as PD-L1 expression within the tumor, tumor mutation burden, as well as T-cell or gamma interferon—expression signatures that correlate with clinical outcomes. However, these are [all] problematic because these are all physiologic mechanisms that the normal immune system uses to limit itself. They aren't fixed biomarkers; they're inducible biomarkers, which means that their expression is variable in time and space. Therein lies the difficulty that we've had in developing very good biomarkers. The biomarkers that we have enrich for patients who have a greater likelihood of responding or a greater likelihood of not responding, but they aren't absolute.

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.