Real-world data from the PACIFIC-R trial (NCT03798535) evaluating durvalumab (Imfinizi) following chemoradiotherapy in patients with stage III, unresectable non–small cell lung cancer (NSCLC) provide evidence supporting the agent’s efficacy in this population, solidifying its role as a standard-of-care treatment, according to Nicolas Girard, MD, PhD.
Study results showed that the median progression-free survival [PFS] was 21.7 months (95% CI, 19.2-24.5), which is higher than what was observed in phase 3 PACIFIC trial (NCT02125461) that provided the basis for the FDA to approve durvalumab in 2018 for patients with unresectable stage III NSCLC whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy.
“Not all eligible patients in the real-world setting are receiving durvalumab after completion of chemotherapy,” Girard said. “These data clearly confirmed the efficacy and demonstrate the safety of these treatments that are administered for a median duration of 11 months. This is a standard of care [and] we have multiple studies ongoing in this setting to [further] optimize the results.”
In an interview with OncLive®, Girard, professor of medicine at Versailles Saint Quentin University, Président elect of the International Thymic Malignancy Interest Group, medical oncologist, and head of the Curie-Montsouris Thorax Institute, discussed the observations from the real-world analysis of durvalumab after chemoradiotherapy in patients with stage III unresectable NSCLC.
OncLive®: What was the rationale for conducting this analysis?
This is an observational study of durvalumab after completion of chemoradiotherapy in patients with unresectable, locally advanced stage III NSCLC. The landmark study that demonstrated the effectiveness of durvalumab in this [patient population] is the [phase 3] PACIFIC trial, which enrolled 700 selected patients. [On this trial] patients received concurrent chemoradiotherapy, which is not standard practice because many patients…receive sequential chemoradiotherapy. For example, about 40% of patients in France [receive sequential chemoradiotherapy]. As such, we had to look at the real-world efficacy of durvalumab, and this was possible through expanded access programs for this drug.
We enrolled patients who initiated durvalumab as part of an expanded access program. Patients had to have unresectable, locally advanced NSCLC and completed chemoradiotherapy [with] no disease progression. [Any] PD-L1 status was acceptable. [There were] 1399 patients enrolled from 11 countries, and 290 hospitals. We had this large cohort of patients, first to confirm the effectiveness of durvalumab in terms of PFS and OS [overall survival], which were the primary endpoint of the study, but also to look at subgroups analyses.
The key findings of the PACIFIC-R study that I presented were that the real-world median PFS was 21.7 months, which is higher than the [PFS] reported in the landmark PACIFIC trial. It is infrequent that a real-world study does better than the clinical trial because the expectation is that [the] patients in a real-world setting [are] less selected [and] may have poor performance status. However, we [observed a] prolonged PFS here. This is a retrospective study, so we may have bias in the analysis of the PFS, especially regarding the time intervals between the imaging assessment for the patient. However, this is very important data because we confirmed the efficacy of durvalumab, which is a standard-of-care treatment for these patients.
What about the safety profile in the real-world study?
The safety profile was in line with that was reported in the PACIFIC study. The most frequent adverse effect was pneumonitis, which is complex to interpret in the setting of post-chemoradiotherapy and immunotherapy. Pneumonitis may be radiation-induced [or a result of] infection in patients with COPD. It could also be related to immunotherapy. [Pneumonitis] occurred in 18% of the patients, [was] usually mild or moderate in grade, and was managed with corticosteroids. Pneumonitis led to treatment discontinuation 9% of the patients. This is something we [observe] in our clinical practice [and] is in line with what is expected.
Did the results of this analysis come as a surprise to you?
We have had some surprises because in this cohort, because we were able to analyze key subgroups of patients based on PD-L1 status. [The data] that was interesting to see showed that patients with stage IIIA disease, or unlimited burden of the disease, are doing better than patients with stage IIIB disease. We were able to generate the figures for median PFS in those patients which was not the case in the PACIFIC trial.
The median real-world PFS for patients with stage IIIA disease with durvalumab was 23.7 months, which is very high. It is even higher than the PFS reported in surgical studies for patients with stage IIA disease. Patients who are receiving chemotherapy followed by durvalumab are classified as unresectable patients, but even if those patients do not go for surgery, the median real-world PFS is almost 2 years.
As a reminder, the last landmark trial on stage IIIA disease [was] the phase 3 LUNG ART trial [NCT00410683] which was updated during [the 2021 ESMO Congress]. The median DFS for patients with stage IIIA disease after surgery was only 22 months. Through PACIFIC-R, we are also discussing what is optimal management of patients with stage IIIA, locally advanced disease. We [still] have chemoradiotherapy followed by durvalumab as the standard of care, but we know that some patients are directed to surgical approaches. [This is] not usually sufficient [by itself] but can be combined with adjuvant or neoadjuvant therapies, or chemotherapy. We also have had results with immune checkpoint inhibitors in the perioperative setting. At the end of the day, we need to integrate all this data to decide on a personalized strategy for each patient.
What are your thoughts on ongoing studies, such as the phase 3 PACIFIC 2 trial [NCT03519971], which are evaluating more intensive treatment regimens?
This will be very interesting because, for these patients, if PACIFIC 2 shows benefit from the addition of durvalumab to chemotherapy and radiotherapy upfront, we will have 2 strategies [available to them]. Some patients will go for chemoradiotherapy and then for durvalumab in the absence of disease progression. It may [include] patients who [are not] eligible for immunotherapy upfront because of a need for high doses of steroids, or because of poor general condition. This is something that is still available.
Patients with smaller tumors [or] patients in a very good condition could go for durvalumab upfront in combination with chemotherapy and radiotherapy, and then continue durvalumab after this induction phase. We will have to look at the figures of these studies, but ultimately, this is not the same patient population. In PACIFIC, patients were randomized after completion of chemoradiotherapy. It was a highly selected population of patients without disease progression. We were able to complete chemoradiotherapy without major toxicity. In PACIFIC 2, all patients [will be randomized] including some patients who may progress during chemoradiotherapy. It is not very frequent, but it may happen.
We will have to see how the patients are responding to the PACIFIC 2 regimen, and what the survival and long-term survival of those patients will be. What we want with exposure to immune checkpoint inhibitors is the long-term survival, and this is what we expect. Once we give immunotherapy as early as possible in patients with lung cancer, we have a higher benefit.
Source: https://www.onclive.com/view/real-world-data-underscores-efficacy-of-durvalumab-in-nsclc