Practice-Changing PACIFIC Trial Opens Road for Immunotherapy in Stage III NSCLC

Edgardo S. Santos, MD, FACP, FCCP

The incorporation of immunotherapy has been a practice-changing modality to the stage III non—small cell lung cancer (NSCLC) armamentarium for patients whose disease has not progressed following concurrent platinum-based chemoradiation, said Edgardo S. Santos, MD, FACP, FCCP.

"The magnitude at this moment cannot be measured because the median overall survival (OS) has not been reached," Santos explained. "However, we know with chemoradiation, the median survival is around 28 to 29 months. On the 3-year update, we are already 10 months ahead of that at 38 months, and that is on the lower confidence interval." 

The FDA initially approved durvalumab (Imfinzi) in this patient population in February 2018. In results of a primary OS analysis, 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).¹

Three-year follow-up results showed that the data were consistent with the initial 2-year findings (HR, 0.69; 95% CI, 0.55-0.86).²  Moreover, 57% of patients on durvalumab were alive (95% CI, 52.3%-61.4%) compared with 44% of those who received placebo (95% CI, 37.0%-49.9%) at the 3-year mark.

"It is very encouraging because, perhaps, we can cure a good percentage of patients that we couldn't before," Santos said. "The 5-year survival for patients with stage III disease is around 15% to 20% and we hope to significantly increase that percentage." 

In an interview during the 2019  OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Santos, a medical oncologist of internal medicine at Boca Raton Regional Hospital, discussed data from the PACIFIC trial and how it has changed the standard of care for this patient population.

OncLive: What is the latest in stage III NSCLC treatment?

Santos: The PACIFIC trial basically changed the standard of care for patients with stage III NSCLC. For the first time, we have consolidation therapy, durvalumab, which is a type of immunotherapy given after the patient finished concurrent chemoradiation. Chemoradiation has been the standard of care for the last 25 years.

During this period of time, we have done several clinical trials, but we have failed to improve the OS beyond what we saw with chemoradiation until the PACIFIC data, which proved a patient can live longer without progression. Then, at the 2018 ASCO Annual Meeting, the positive OS data were presented. 

More importantly, the 3-year OS update presented in June 2019 are very impressive. Median OS has still not been reached for the patients who received durvalumab. It is strikingly good news. 

Aside from PACIFIC, what other trials are important in this space?

The PACIFIC trial has established the new standard of care. Patients with stage III disease with good performance status and an ability to tolerate radiation therapy should receive concurrent chemotherapy and radiation followed by durvalumab for 1 year. 

With that, the idea is to improve. There are several ongoing clinical trials that includes, for example, combining immunotherapy with radiation concurrently followed by immunotherapy; giving immunotherapy at the time of induction followed by chemoradiation and then more immunotherapy; and giving immunotherapy prior to chemoradiation, followed by chemotherapy and immunotherapy. It varies tremendously.

All  efficaciou s immunotherapies in lung cancer are being studied in that kind of equation including durvalumab, pembrolizumab (Keytruda), nivolumab (Opdivo) and ipilimumab (Yervoy). Specifically, in one study, ipilimumab is given with radiation then followed by nivolumab as a consultation. Also, atezolizumab (Tecentriq) is being explored in a lot of ongoing clinical trials with chemotherapy and radiation therapy. 

Are there any thoughts as to which checkpoint inhibitor or immunotherapy agent would be most beneficial to this patient population?

The others [have shown success] in the metastatic setting with similar efficacy and adverse events. In that setting, we know that, for example, second-line pembrolizumab, nivolumab, and atezolizumab show an OS benefit.

In stage III NSCLC, I predict that there is no superiority among those immunotherapy agents; however, durvalumab [started] the roadmap in terms of improving cure in this patient population. 

Since pembrolizumab's expanded indication for PD-L1 ≥1%, does that apply here?

That's a good question. The FDA approved pembrolizumab for patients with PD-L1 tumor proportion score ≥1%, and that population includes inoperable stage III disease and cannot receive definitive radiation therapy. 

In a patient who cannot receive concurrent chemoradiation, the patient has the option to receive single-agent pembrolizumab. Meanwhile, their tumor has an expression of PD-L1 expression ≥1%. 

How would you define the role of chemotherapy in this space?

There is still a role for chemotherapy, even in the presence of immunotherapy. Sometimes the tumor itself is not very immunogenic. It may have a low PD-L1 expression, low tumor mutational burden, or is not microsatellite instability—high. [Typically], these biomarkers tell us whether a patient is going to do well on immunotherapy or not. When these biomarkers are not present, chemotherapy plays an important role. 

Studies such as the KEYNOTE-189 trial for nonsquamous cell disease and KEYNOTE-407 for squamous cell disease were positive, even in patients without PD-L1 expression, so chemotherapy is important in that specific setting. 

Also, unfortunately, immunotherapy is not for everyone. If a patient has an autoimmune disease, such as Crohn's disease or ulcerative colitis, and they are receiving an active immunomodulator, we don’t recommend immunotherapy for those patients because those diseases can have a bad flare. In those cases, chemotherapy plays an important role in those patients. 

References

1. 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.
2. Gray JH, Villegas AE, Daniel DB, et al. Three-year overall survival update from the PACIFIC trial. J Clin Oncol. 2019;37(suppl; abstr 8526). doi: 10.1200/JCO.2019.37.15_suppl.8526.