Locally Advanced NSCLC: Value of the PACIFIC Trial

Howard (Jack) West, MD:We need to carefully consider the eligibility for the PACIFIC trial, which was the first big sea change in how we treat patients with locally advanced non—small cell lung cancer. Patients with unresectable stage 3 non–small cell squamous or nonsquamous disease received at least 2 cycles of platinum-based chemotherapy and concurrent chest radiation. And then, patients who had not progressed or who had responded in terms of tumor shrinkage were then randomized within the next several weeks to start durvalumab or placebo in a 2:1 randomization in favor of durvalumab by two-thirds. This trial demonstrated not just a significant improvement in progression-free survival with durvalumab but also a highly significant benefit with a hazard ratio of 0.52.

Now, this was progression-free survival, not yet overall survival, but there were a few additional points. The first is that with the progression-free survival, I mentioned the hazard ratio of 0.52, but this was sustained while the patients were being followed at 12 and 18 months—a huge difference in progression-free survival that really suggested a high probability that this would lead to an improvement in survival. We’ve also seen an ESMO [European Society for Medical Oncology] presentation of PACIFIC and theNew England Journal of Medicinepaper that showed that time to distant metastases or death in the PACIFIC trial was significantly better in the durvalumab arm, also with a hazard ratio of 0.52. We’ve gotten a press release just in the last few weeks, in May of 2018, that PACIFIC achieved an overall survival benefit.

We haven’t seen the details of that at this time, but what we have seen is a not just statistically significant but also clinically significant, very striking improvement in progression-free survival. It’s sustained. It’s associated now with a significant improvement in time to distant metastases or death and, based on the press release, an improvement in overall survival. This is now FDA approved in early 2018 and a new standard of care for patients who are eligible for it.

The particular patient in our case had achieved stable disease but not a significant response. At the same time, she does not have high tumor PD-L1 expression, and we might wonder whether these factors could be associated with her not getting a benefit from durvalumab. But the PACIFIC trial demonstrates that patients like her do benefit quite significantly. In fact, in the PACIFIC trial, the patients who achieved stable disease after chemotherapy and radiation had a hazard ratio for PFS of 0.55, a very significant benefit there. There was also no difference in the progression-free survival benefit based on PD-L1. So, even though we’ve come to expect a greater benefit in the advanced disease setting, sometimes a big difference based on whether a patient has high PD-L1 or low PD-L1—in her particular case, she has a PD-L1 below the 25% cutoff that was used in the trial—they looked at less than 25% or 25% and higher, and both groups achieved a very comparable and highly significant benefit in PFS.

It’s not critical that you do the testing in this setting, because no matter what the result is, durvalumab is an appropriate answer. But if you do that and you find a lower level of PD-L1 of less than 25%—or even less than 1%, negative—that does not mean that this patient is not a candidate for consolidation durvalumab. These patients were in the group in PACIFIC that demonstrated a benefit. Even in the subset analysis, they benefited very comparably, essentially the same, as patients who had high-level PD-L1.

Transcript edited for clarity.

A 60-year-old Asian Woman With Unresectable, Locally Advanced NSCLC

• A 60-year-old Asian woman presents with complaints of chest pain and shortness of breath. She reports developing a persistent cough about 1 year ago, which she attributed to allergies. In the past month, she has “spit up” blood several times, which caused her to make the appointment.
• Her history includes:
  • Former smoker, quit smoking at age 35 when she became pregnant
  • Normal BMI, postmenopausal, no history of cardiovascular disease
  • No previous cancer history
• Evaluation and follow up testing reveal
  • Stage IIIA NSCLC in right bronchi: 3.5-cm tumor with pleural involvement and spread to mediastinal lymph nodes
  • WHO performance status 1
  • Histology: Squamous cell
  • Biomarkers:
    • EGFR,BRAF,ALK/ROS1negative
    • PD-L1 status: 10%
• After multidisciplinary evaluation, the patient was determined not to be a candidate for surgery, and completed chemoradiotherapy:
  • Carboplatin/paclitaxel doublet plus 55 Gy radiotherapy
  • Achieved stable disease without progression 14 days after completing treatment
  • Began treatment with durvalumab