Expert Highlights Ongoing Trial Evaluating Durvalumab Efficacy, Safety in Real-World Setting

Nicolas Girard, MD

Nicolas Girard, MD

Durvalumab (Imfinzi) consolidation has become the standard of care for patients with locally advanced unresectable stage III non—small cell lung cancer (NSCLC) following chemoradiotherapy, based on data from the phase III PACIFIC trial, in which overall survival (OS) and progression-free survival (PFS) were significantly improved with the PD-1 inhibitor compared with placebo.

The international, observational PACIFIC-R trial, led by by Nicolas Girard, MD, is currently recruiting patients to evaluate the efficacy and safety of durvalumab in a large, real-world population following chemoradiotherapy, which will allow investigators to closer evaluate different subgroups of patients.

“PACIFIC enrolled [approximately] 700 patients, but it still may not be sufficient to study very specific subgroups of patients. The point is that real-life data clearly, and probably better, reflects routine clinical practice,” said Girard.

In the phase III PACIFIC trial, 713 patients were randomized to either durvalumab or placebo. Results showed the median PFS was 17.2 months versus 5.6 months, respectively. At 24 months, the OS rates were 66.3% in the durvalumab arm and 55.6% in the placebo arm.

Both arms experienced adverse events (AEs) of any grade; grade 3/4 AEs were more common among patients who received durvalumab versus placebo (29.9% vs 26.1%), pneumonia being the most common (4.4% vs 3.8%, respectively). In the durvalumab arm, AEs led to discontinuation in 15.4% of the patients compared with 9.8% in the placebo arm.

These data served as the basis for the FDA approval of durvalumab in February 2018 for the treatment of patients with locally advanced, unresectable stage III NSCLC who have not progressed following chemoradiotherapy.

In an interview withTargeted Oncologyduring the European Lung Cancer Congress, Girard, professor at the Institut Curie in Paris, France, discussed the importance of evaluating durvalumab in a real-world setting. In addition, he highlights other questions that remain unanswered in this area, as well as the role of immunotherapy in patients with NSCLC.

TARGETED ONCOLOGY:How was PACIFIC-R designed and what was the rationale to conducting this research?

Girard:PACIFIC-R is a real-life study, so it’s a retrospective collection of data from patients who did receive durvalumab as a consolidation treatment for unresectable stage III NSCLC. PACIFIC-R actually aims at validating, in a real-world setting, the data from the PACIFIC trial that demonstrated the benefit of durvalumab consolidation in this situation. Given the benefit in terms of PFS and OS, which is highly significant and led to a change in the standard of care for these patients, an expanded access program (EAP) for durvalumab was set up just a few weeks after the presentation of the data.

Now we have many patients treated as part of the EAP worldwide with more than 4000 patients treated in more than 40 countries, so we have many patients who did receive durvalumab, but we need to see who those patients are. Some of the patients will be exactly the same as those that were enrolled in the PACIFIC trial, but we will identify a new population of patients. We will have the ability to study some other subgroups of patients, such as elderly patients, patients with performance status (PS) 1 or even PS2, patients who did receive sequential chemoradiotherapy, and patients who did receive different chemotherapy regimens. This is a great opportunity to increase our knowledge, and at the end of the day, to better select our patients or future patients for this strategy.

We will also be able to have prolonged follow-up of the patients because PACIFIC aims to capture 5-year OS for those patients. We will be able to understand the patterns of recurrence in the patient who presents with disease recurrence after exposure to chemoradiotherapy plus durvalumab. We will be able to understand what the treatment patterns for those patients are.

So far, we are treating patients who are presenting with disease recurrence after chemoradiotherapy, similar to metastatic patients. Here, we will have patients that have already been exposed to immunotherapy, so what is the efficacy of chemotherapy? We may be able to re-challenge those patients with immune checkpoint inhibitors at some point, but what is the best strategy? This kind of question has not been addressed in clinical trials so far. The PACIFIC-R data will be able to provide some information.

TARGETED ONCOLOGY:Why is generating real-world evidence so critical for this particular therapy?

Girard:Generating real-world evidence is the key now for any situation because we have the clinical trials, but usually in clinical trials, we have selected populations based on inclusion or exclusion criteria. We can study some subsets of patients but not that many because the number of patients is usually limited, even in this study.

PACIFIC enrolled 700 patients, but it still may not be sufficient to study very specific subgroups of patients. The point is that real-life data clearly, and probably better, reflects routine clinical practice. We know as physicians that the more patients we treat, the better we are with a new treatment strategy. Collecting those real-life data, in the end, will increase the experience of everyone very quickly because we will have access to a cohort of more than 1000 patients who have received durvalumab, and there will be questions that we have that can be answered by those data.

We always need to find the balance between the clinical data from clinical trials and what we are doing in our routine practice when we treat the patient in the hospital. The real-life data is in between these 2 things. Then we can have a better sense of how we select the patients and treatment strategies that are associated with a benefit from any treatment strategy.

TARGETED ONCOLOGY:What are some additional unanswered questions that remain in the field of stage III unresectable NSCLC?

Girard:There are multiple clinical trials ongoing with immunotherapy during chemoradiotherapy with the concurrent approach. There are some trials that are also evaluating optimized maintenance with additional treatment in addition to the new standard of care of durvalumab. We also need to better understand the patterns of chemoradiotherapy because there are specific patients that are enrolled after completion of chemoradiotherapy. If we integrate chemotherapy into the clinical trials in combinations, it would also be a way to better understand how to optimize chemoradiotherapy.

One major question in the field is now that we have durvalumab consolidation therapy, how do we treat disease recurrence? In my experience, I see many patients who are presenting with oligoprogressive disease either during durvalumab or after completion of durvalumab. This is something that was not that frequent before we had durvalumab consolidation, so maybe if we are changing the pattern of recurrence, then we are very pragmatic when we have oligoprogressive disease that we can apply focal treatment with either stereotactic body radiotherapy or surgery. Some patients also present with systemic progression, so we need to apply systemic treatment, but which one and what would be the efficacy? We have many questions here. In PACIFIC-R, we provide some answers, but we also need clinical trials.

TARGETED ONCOLOGY:When you look at the overall treatment landscape for NSCLC, what are some trends that you see emerging?

Girard:Immunotherapy is clearly a new standard of care. Immunotherapy is replacing chemotherapy in the late-line setting and in some patients as a first-line treatment. Now we are moving to combination, so chemotherapy plus immunotherapy in the first-line setting. We are now in the setting of integrating immunotherapy in nonmetastatic tumors, as in PACIFIC with locally advanced disease, but maybe soon it will be in the perioperative setting for early-stage NSCLC. We have some data suggesting that neoadjuvant immunotherapy may lead to a high rate of complete pathological response that may be associated with prolonged survival.

Immunotherapy is everywhere in all stages of the disease, and right now we have to go back to late lines of treatment. Once patients will be exposed to immune checkpoint inhibitors along the initial treatment, the first-line treatment, what can we do after the failure of first treatment? How do we better select the patients for new immunotherapy strategies to personalize immunotherapy? This is one of the key questions.