Anna Chalmers, MD, discusses the PACIFIC trial and how its impact continues to change the treatment paradigm in stage III non-small cell lung cancer.
Anna Chalmers, MD
The non—small cell lung cancer (NSCLC) paradigm is evolving as researchers look to build on the momentum of the phase III PACIFIC trial, in which durvalumab (Imfinzi) improved survival in patients with stage III disease, said Anna Chalmers, MD.
"We are seeing a lot of changes coming and better outcomes for these patients," said Chalmers. "Unfortunately, they historically had very poor outcomes. We are slowly getting better, but we have a long way to go."
The PACIFIC trial explored the role of durvalumab for patients with locally advanced, unresectable NSCLC after chemoradiation. Results of the primary overall survival (OS) analysis showed that the PD-1 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).
These data not only changed the standard of care for this patient population, but they opened the door to potential concurrent chemoradiation and immunotherapy combinations.
"In stage III lung cancer, [we are] looking at combining immunotherapy in earlier settings, doing immunotherapy prior to chemoradiation, and even looking at whether we can omit chemotherapy all together for these patients and still have the same survival benefit that we see with the PACIFIC data," Chalmers said.
In an interview during the 2019 OncLive® State of the Science Summit™ on Non—Small Cell Lung Cancer, Chalmers, a clinical instructor in the Division of Oncology and an investigator at Huntsman Cancer Institute, University of Utah, discussed the PACIFIC trial and how its impact continues to change the treatment paradigm in stage III NSCLC.
OncLive: Could you expand on the PACIFIC data and how they have impacted treatment decisions?
Chalmers: The PACIFIC trial randomized patients  2:1  to durvalumab or placebo. Patients had to have completed chemoradiation within 42 days of the start of treatment. Patients were randomized based on age, smoking status, and sex.
PACIFIC showed a significant OS benefit, even at 3 years, which held across all subgroup analysis with some exceptions. There was a very small number of patients with  EGFR-mutated disease, so it is difficult to say what it means. The benefit still held, however, for smoking status and age.
The one controversial aspect at this point is PD-L1 status. Patients were stratified based on PD-L1 expression ≥25% or PD- <25%. Europe [regulatory authorities] requested a post-hoc analysis of ≥1% PD-L1. That analysis did not show a benefit for patients who had no PD-L1 expression; therefore, the approval in Europe is for patients whose tumors are PD-L1 positive. In the United States, we treat patients regardless of PD-L1 status, but it is an open question. It should be noted that not all patients on trials had tissue to test for PD-L1.
Are there any  next steps being taken to evaluate that?
There are a lot of the trials moving forward and it is one of the things we are going to look at. At this point in terms of the PACIFIC trial, the tissue has been tested. It is a question that future trials are going to look at.
Were there any other unanswered questions that arose from the PACIFIC trial that we need to dive more deeply into?
For a lot of people, one of the unanswered questions is in terms of patients with EGFR or ALK mutations. It is a significant patient population for us in Utah because we have more nonsmokers. Do those patients truly benefit?
From what we know in the single-agent, metastatic setting for those patients, immunotherapy does not have a significant effect.
Do we expect a benefit in earlier-stage disease? The biology of earlier-stage NSCLC might be slightly different in terms of immunotherapy, but we also don't want to do harm with these agents.
What are some of the other novel immunotherapy approaches that are under investigation in this setting?
There are a lot of immunotherapy trials out there. Many of the other PD-1/PD-L1 drugs including atezolizumab (Tecentriq), pembrolizumab (Keytruda), nivolumab (Opdivo), and ipilimumab (Yervoy) are being looked at as well.
Many of them are doing similar studies with consolidation after chemoradiation in stage III NSCLC. Others are trying to get immunotherapy involved earlier [in sequencing] either prior to chemoradiation or during chemoradiation. Also, there are definitely trials of omitting chemotherapy all together for patients who have high PD-L1 expression.
What are the data that are supporting moving immunotherapy up? Are there any specific data that come to mind that lead us to believe this is the right approach?
From the PACIFIC trial, we know that when patients received immunotherapy within 14 days of randomization, they had a better hazard ratio for OS as opposed to after 14 days.
Part of the rationale for using immunotherapy after chemoradiation is this idea of the abscopal effect and the immune modulating effects of radiation with immunotherapy. We do know some data from the stage IV setting showing that perhaps there is an additive of doing them together. Therefore, it makes biologic and rational sense to use it [concurrently] with radiation.
With all of these immunotherapeutic approaches emerging, what are some strategies that are being investigated to eliminate chemotherapy from the equation?
People are going about this in a very rational fashion. At this point, I don't think anyone is saying we can eliminate chemotherapy for everyone. The SPRINT trial is looking at stratifying people on their PD-L1 status and right now, we are using that as our biomarker. Patients with high PD-L1 status will be placed on immunotherapy and radiation alone and those without will go on to get standard of care.
Where should future research focus in terms of immunotherapy?
There are many unanswered questions. When do we bring in immunotherapy? Is it just as consolidation? Should we bring immunotherapy in earlier, even before chemoradiation? Also, for how long? There are studies looking 2 years of treatment as opposed to just 1 year. Is longer going to be better?
A not insignificant portion of the population will still progress while they were on consolidation therapy for that year. Who are those patients and how can we best identify them? There may be patients who are not benefitting from consolidation immunotherapy or others in whom we need to do something more than just consolidation immunotherapy.
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.