Stage 3 Unresectable NSCLC: The PACIFIC Trial

Heather Wakelee, MD:The PACIFIC trial was a randomized phase III trial for patients who had unresectable stage 3 lung cancer who were treated with concurrent chemoradiation without specification of a chemotherapy regimen. And then, for those who were not progressing after completing the chemotherapy and radiation, they were randomized 2:1 to receive either durvalumab or a placebo. The study showed that the patients who ended up getting the durvalumab had a significant improvement in progression-free survival. We don’t yet have overall survival data, but the assumption would be that they would follow the progression-free survival, as they often do in studies.

The progression-free survival for the patients getting the durvalumab was in excess of 16 months. For those getting the placebo, it was less than 6 months. One of the criticisms of the trial was that the placebo group did seem to underperform historical controls. There are a lot of questions around that—some of which are around the high numbers who had weekly carboplatin/paclitaxel without any consolidation. Carboplatin/paclitaxel—we don’t really know the answers.

A nuance point from the trial is the fact that they did include patients who had either anEGFRmutation orALKtranslocation. The numbers were fairly small, but that group did not seem to not derive benefit. They did derive benefit but not quite as much as some of the other subgroups. There also did not seem to be a difference between the chemotherapy regimens that were utilized, but there are still more questions to be asked. However, with that trial result, the United States FDA did approve durvalumab in this setting. Patients who have completed chemoradiation, who have not progressed, are then randomized to get durvalumab.

One of the things that was looked at was, how long can you wait? I think as soon as you can start the durvalumab, as soon as the patient has recovered sufficiently, it’s time to go ahead and start it. It’s an every-2-week regimen. It’s up to 1 year of therapy.

One of the big concerns everyone had before the trial results came out was around toxicity, especially around the potential for pneumonitis, or inflammation in the lung. It turned out that those rates were relatively low and not significantly different between the patients getting placebo and those who got durvalumab. There were some risks for autoimmunity or immune-related adverse events. But, again, these were relatively low. So, we do feel this is a fairly safe approach.

With the PACIFIC trial, there were a lot of questions on different subgroups and whether there were any who weren’t going to benefit. At least from the data, as they were presented, there didn’t really seem to be any group that wasn’t benefiting. Those withEGFRmutations perhaps benefited less, but they still benefited. Also, those with the highest PD-L1 levels did seem to benefit a bit more. And again, it’s all progression-free survival. We don’t yet know about overall survival. So, those with the highest levels did seem to have more of a progression-free survival, but even those with low or no PD-L1 expression did seem to benefit as well.

Transcript edited for clarity.

• A 64-year-old man presented with shortness of breath and persistent cough of 18 months’ duration; recently, he has experienced chest pain, fatigue, and blood in his sputum. After consulting with his primary care physician, he was referred for oncology evaluation
• Patient history includes
  • Current smoker (1/2 pack day)
  • Hypertension
  • Acute MI at age 60
• Evaluation and follow up testing reveal
  • Non-small cell lung cancer in left lung and 2 lymph nodes (Stage IIIa)
  • WHO performance status: 1
  • Histology: adenocarcinoma
  • EFGR, BRAF,andALK/ROS1mutation status: wild-type
  • PD-L1 status: ≥25%
• He underwent multidisciplinary evaluation and was not a candidate for surgery; he was treated with chemoradiotherapy:
  • Concurrent carboplatin-paclitaxel doublet chemotherapy and radiotherapy (60 Gy)
  • Achieved partial response
• He had no disease progression 20 days after his last radiotherapy treatment, and began treatment with durvalumab