PACIFIC: Progression-Free Survival Increase in NSCLC

Julie Brahmer, MD:The PACIFIC trial was designed to see whether or not giving durvalumab after chemotherapy and radiation improves progression-free survival, as well as overall survival, compared with our standard of care, which is just observation after chemotherapy and radiation. In this trial, patients, after receiving concurrent chemotherapy and radiation—and the trial did allow induction chemotherapy, as well, in some patients—if they had a response or stable disease, were allowed to be randomized to either durvalumab or placebo. They would receive this treatment then every 2 weeks for up to a year. The great thing is that durvalumab in the consolidation setting does improve progression-free survival. We recently heard, at least by press release, it also improves overall survival.

This trial was very interesting and very timely. Being able to show that no matter what the subgroup was, patients did actually gain the benefit of receiving durvalumab. Durvalumab improved progression-free survival in almost every subgroup. Interestingly, and even in patients who had stable disease, it did help improve the time to progression as well. Also, the patients who are smokers or never smokers also gained the benefit in receiving durvalumab. Interestingly, while PD-L1 expression on tumors does seem to equate with response to therapy in the metastatic setting, the benefit to durvalumab was across all patients, no matter what their PD-L1 standing in their tumor was. Again, this equates to, as a whole group, patients’ being able to benefit from this type of treatment.

The PD-L1 level in patients’ tumors is not relevant in this setting because, in the PACIFIC trial, regardless of PD-L1 staining of the tumor at the time of diagnosis, patients actually were able to see an improvement in progression-free survival regardless of PD-L1 status; in the group of patients where we were unable to actually document PD-L1 staining, their PD-L1 status was unknown. Again, in this setting it really does not seem to matter what the initial PD-L1 status of the tumor was at the beginning. The thought is potentially that chemotherapy and radiation therapy may upregulate PD-L1 after treatment. Therefore, it may just not matter.

At this point, we don’t know whether tumor mutation burden or other biomarkers will increase the chance of benefiting from durvalumab, and we hope over time we’ll have more information about that in order to tease out whether or not there’s a particular group of patients that would be more likely to benefit from durvalumab, in this setting or not.

In the PACIFIC trial, patients were allowed to start on durvalumab anywhere between 1 and 42 days after finishing concurrent chemotherapy and radiation. We think the ideal time to be able to receive durvalumab is within the first 2 weeks, at least in this study. It seems that if the patients actually received durvalumab within 2 weeks of finishing up concurrent chemotherapy and radiation, that was the group of patients who benefited the most from durvalumab. Again, patients even could receive durvalumab after 42 days after finishing up concurrent chemotherapy and radiation. We’re not quite sure exactly why this benefit was seen within the first 2 weeks. Was it just because those patients were much healthier and could get started, or was it something else? We’re not sure.

Transcript edited for clarity.

Case: A 59-year-old Woman With Locally Advanced NSCLC

• A 59-year-old woman presents after referral from primary care for persistent cough and bloody sputum. She denies shortness of breath, says cough began last fall and she attributes it and the sputum to allergies.
• History:
  • 10-year smoking history, ages 15 to 25
  • Postmenopausal, BMI = 26 kg/m²
  • Basal cell carcinoma on chest and face, had 3 lesions removed 2 years ago
• Evaluation and follow up testing reveal stage IIIB NSCLC:
  • Radiograph shows 2 lesions in left lung (3.1 cm and 5.5 cm)
  • Fiber optic bronchoscopy identifies NSCLC
  • Endobronchial ultrasound reveals ipsilateral mediastinal lymph node involvement
  • WHO performance status 1
  • Histology: nonsquamous
  • Biomarkers
    • EGFRnegative,BRAFnegative,ALK/ROS1negative
    • PD-L1 status: >25%
• Laboratory findings:
  • WBC, renal function, hepatic function within normal ranges
• After multidisciplinary evaluation, the patient was determined not to be a surgical candidate
• She completed a weekly carboplatin/paclitaxel doublet therapy with concomitant radiotherapy (60 Gy)
  • Achieved partial response without progression 3 weeks later
  • Began treatment with durvalumab