Clinical Approach for Unresectable Locally Advanced NSCLC - Episode 4

Locally Advanced NSCLC: The PACIFIC Trial

April 16, 2018

Jyoti Patel, MD:There has been a significant shift and a leap forward in our understanding of how to treat stage 3 lung cancer, primarily because of the PACIFIC trial. And that trial was a study that enrolled over 700 patients and randomized them in a 2:1 fashion to receive durvalumab or placebo and after the completion of chemotherapy and concurrent radiation therapy.

In this study, which has been reported with the interim planned analysis, progression-free survival was significantly better with a hazard ratio of almost 0.5 with durvalumab consolidation therapy or for up to a year versus placebo. So, many fewer patients had recurrence of disease. We are awaiting overall survival analyses, but there are a lot of important factors in patients who received the durvalumab that make us quite optimistic that overall survival will also hit its primary endpoint. One of those is the time, the percentage of patients who had distance recurrence, as well as the percentage of patients who had CMS recurrence.

Now, the trial is sort of a real-world trial. Patients were treated from all over the world. The chemotherapy regimen and radiation were not strictly prescribed, so patients could have a range of radiation therapies and multiple chemotherapy regimens. What was required was that therapy was concurrent and that there was no consolidation therapy. So, because this was done in the rest of the world, up to one-quarter of patients had induction chemotherapy before radiation was started, which is a practice in Europe and in many places where radiation may not be as readily available initially. And then patients could start radiation or could start durvalumab very soon after completion of chemoradiation—up to 6 weeks afterward.

Because progression-free survival was adjudicated at the time patients were randomized, the progression-free survival in the placebo arm was 5.6 months versus 16.8 months in the durvalumab arm. That time of chemotherapy and radiation was not really counted, nor was that time that elapsed and up until 6 weeks until patients were entered on the trial, and so that number is probably larger. Regardless, it’s a huge magnitude of benefit with a large number of patients having no evidence of progression who received the durvalumab over placebo.

Certainly, there were many questions about safety with this regimen. We have, as a community, been nervous about pneumonitis after treatment with checkpoint inhibitors. And this regimen was really well tolerated in a population that we think is quite sick after chemotherapy and radiation. And in fact, pneumonitis rates were barely different between placebo and durvalumab, about 3% grade 3 in the durvalumab arm.

Patients tolerated therapy. There was a small number of grade 3 events, and it is important for us to look at are things like pneumonitis, which was at a very low level—in grade 3, about 3%—so patients did quite well. Given the impressive progressive-free survival, given the tolerability and the toxicity, many of us have brought this to our practice, even though overall survival results are not yet available.

Transcript edited for clarity.

  • A 63-year-old man presented to his PCP with intermittent cough and difficulty breathing on exertion
  • PMH: hyperlipidemia well-managed on simvastatin; hypothyroidism, managed on levothyroxine, COPD on inhalers
  • Recently quit smoking; has a 40-pack-year history
  • PE; intermittent wheezing; ECOG 1
  • Creatinine clearance, WNL
  • Imaging Studies:
    • Chest X-ray showed opacity in the lung right upper lobe
    • Chest CT revealed a 3.1-cm spiculated mass in the right upper lobe and 2 enlarged right mediastinal lymph nodes measuring 1.5 cm and 1.7 cm; moderate emphysema noted
    • PET confirmed the lung lesion and mediastinal lymphadenopathy without evidence of distant metastasis
    • Brain MRI was negative
  • Bronchoscopy with transbronchial lung biopsy and lymph node sampling revealed adenocarcinoma with positive nodes in stations 4R and 7; level 4L was negative
  • Genetic testing was negative for known driver mutations
  • Staging: T2aN2M0, stage IIIA
  • Based on the extent of mediastinal disease and emphysema, the patient’s cancer was deemed inoperable, and he was referred for consideration of concurrent chemotherapy and radiation
  • He underwent therapy with cisplatin/etoposide and concurrent thoracic radiotherapy
  • Follow-up imaging showed a partial response with shrinkage of the primary and nodal lesions