PACIFIC Trial Changes Standard of Care in Stage III NSCLC

Adham Jurdi, MD

The PACIFIC trial proves that immunotherapy has an essential role in stage III non—small cell lung cancer (NSCLC); however, there are still unanswered questions surrounding the optimal sequence of checkpoint inhibitors and whether it is appropriate for patients with driver mutations, said Adham Jurdi, MD.

In the phase III study, consolidation immunotherapy with durvalumab (Imfinzi) significantly improved progression- free survival (PFS) and overall survival (OS) versus placebo in patients with stage III NSCLC who did not have disease progression after 2 or more cycles of platinum-based chemoradiation. Two-year OS rates in the durvalumab group were 66.3% compared with 55.6% for patients who were treated with placebo, according to updated data published in the New England Journal of Medicine.

Updated analyses regarding PFS were similar to those previously reported, with a median duration of 17.2 months observed in the durvalumab arm and 5.6 months in the placebo arm. Median time to death or distant metastasis was 28.3 months for patients treated with the PD-1 inhibitor versus 16.2 months for those who received placebo. For the trial, 713 patients were randomly assigned 2:1 to receive durvalumab intravenously, at a dose of 10 mg/kg, or matching placebo every 2 weeks for up to 12 months. Randomization occurred 1 to 42 days after the patients had received chemoradiotherapy.

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

OncLive: How has the PACIFIC trial changed the standard of care for patients with NSCLC?

What was the standard of care before the PACIFIC data?

In an interview at the 2018 OncLive^® State of the Science Summit™ on Lung Cancer, Jurdi, an assistant professor of medicine, medical director of hematology/ oncology, and medical director of Upstate Cancer Center Adult Hematology/Oncology at Upstate University Hospital discussed how the updated data from the PACIFIC trial have changed the standard of care for patients with stage III NSCLC.Jurdi: The updated data [reported in September 2018] from the PACIFIC trial were very exciting because they confirmed what we all were enthused about. Durvalumab, or checkpoint inhibitors, does/do have a benefit in stage III NSCLC after chemoradiation. Significant progress had not been made in this space for the past 10 to 15 years. We knew from last year that durvalumab improved PFS significantly compared with placebo after chemoradiation. When we saw that the OS data were on par with what we had hoped, [we were excited] because [this] changes the landscape. We do have a new standard of care right now, and this opens the door for further [use of] checkpoint inhibitors and immunotherapies in this setting. We have [nearly half a dozen other pivotal clinical trials underway].[Before the PACIFIC trial], the standard of care for most patients was concurrent chemotherapy with radiation. That would be given for about 6 weeks, and then most physicians would give 2 cycles of what is considered consolidation chemotherapy at a higher dose—usually carboplatin—with the idea of limiting micrometastatic disease.

PACIFIC does bring a longer treatment regimen for patients. They will have to come to the clinic and get infusions for a whole year. But in terms of toxicity, durvalumab was pretty well tolerated. There were some slightly higher adverse events compared with placebo, but we are seeing significant benefit in this population.

What are some of these ongoing trials?

[One] question [that needs to be addressed has to do] with patients who have EGFR mutations or other drivers. [These mutations] were presented in a small percentage [of patients] in PACIFIC, [but] we think there was a trend to improve outcomes with those who received durvalumab compared with patients who were given placebo. The numbers were not robust enough, however. These patients are still a question mark. We also would like to figure out if it is better to use checkpoint inhibitors upfront rather than in the later settings. There are clinical studies looking to answer all of these questions.One of them is the AFT16 trial, in which researchers are using a “sandwich” approach with immunotherapy. They are taking atezolizumab (Tecentriq) for 4 cycles as induction therapy and following that with chemoradiation—consisting of carboplatin/ paclitaxel for 2 cycles. After that, the patient will receive 1 year of adjuvant atezolizumab. This study is ongoing, and we are really excited [to see the data that will come out of it].

Is combination immunotherapy the future for these patients?

Another study is evaluating the addition of nivolumab (Opdivo) after chemoradiation compared with nivolumab plus ipilimumab (Yervoy). This is an immunotherapy doublet consisting of PD-L1 and CTLA-4 antibodies. These [data] will also be interesting.The short answer is that we do not know yet. We do know that immunotherapy certainly plays a role, but there will always be unanswered questions. One thing we need to be aware of is that the patients who had PD-L1 expression of <1% did not have much benefit from immunotherapy. Nothing much has changed for these patients, and we still need to investigate [what] future [treatment will look like] for them.

Antonia SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC [published online September 25, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1809697.