Stage IIIA Unresectable NSCLC After Chemoradiotherapy - Episode 5

Durvalumab Consolidation in NSCLC: The PACIFIC Trial

Mark A. Socinski, MD:In this particular patient, we have evidence from the CT [computed tomography] scan that there’s no evidence of disease progression. The patient has no contraindication to checkpoint inhibition. Yes, I would recommend durvalumab for 1 year in this particular patient based on the results of the PACIFIC trial. The results of the PACIFIC trial show a very robust impact on both progression-free survival [PFS] as well as overall survival [OS]. And I think that benefit in overall survival is the most important endpoint. Certainly there were no major issues with regard to the safety of using durvalumab in this setting, the PACIFIC trial that would make me worry about doing such a strategy in this patient.

The PACIFIC trial evaluated patients with stage III unresectable non—small cell lung cancer who had received concurrent chemoradiation, received a dose of radiation between 54 and 66 gray, and got through the treatment. They could have had induction therapy, but they had to demonstrate that following this treatment, that they had no evidence of disease progression. And they had to be randomized within 6 weeks from completion of chemoradiotherapy to either durvalumab as the investigational arm for 1 year versus placebo. The results of that trial showed, in terms of the coprimary endpoints of progression-free as well as overall survival, a very significant benefit in both PFS as well as overall survival. The hazard ratio for overall survival was 0.68, suggesting a 32% reduction in the risk of death as a result of this. So I think that this is an important trial. It was a practice-changing and guideline-changing trial.

Based on the initial analysis of the PACIFIC trial, which really was initially just progression-free survival, it showed an impressive benefit in progression-free survival and led to incorporation into the NCCN [National Comprehensive Cancer Network] guidelines as a category 2A. And I think that in and of itself led to many clinicians changing their standard of care and incorporating it based on the 2A recommendation. With the updated PFS, as well as the overall survival advantage where there was a significant hazard ratio for 0.68 and an impressive difference in overall survival, the NCCN updated its recommendation to a category 1, which means that there was general consensus that this was a new standard of care. And I agree with that. In fact, if I were on the NCCN, I probably would have voted with the initial PFS to give it a category 1. But I wasn’t involved in those discussions. However, I think given the overall survival benefit that we saw, that the category 1 recommendation is appropriate based on that PACIFIC data.

The significance of the PACIFIC trial, and the reason I believe that it is truly practice-changing, is when you look back at the history of stage III disease. When I started in this business, the standard of care in stage III disease was radiation alone. In the mid-1980s to early 1990s, we began to add chemotherapy to radiation. And whether you gave chemotherapy before as induction or gave it as concurrent therapy, it was better than radiation alone. We determined in the 1990s that to give concurrent chemoradiation led to better outcomes and better survival compared to giving chemotherapy followed by radiation. So concurrent was better than sequential treatment.

Once we established concurrent chemoradiotherapy as the standard of care—we’re now talking roughly in the early 2000s—a number of ideas were tried but nothing actually changed the overall survival benefit. And so we had more than a decade where we made no advances in stage III disease, despite real efforts in new ideas to try to improve the outcomes. And so I think that after that drought of more than a decade, when you have the results that we saw in the PACIFIC trial on both PFS and OS, in my opinion, with relatively little toxicity or no new toxicity, this was truly practice-changing and was embraced by the lung cancer thought-leader community.

That message needs to get out to all community oncologists because this is an opportunity to offer a patient a much higher chance of being cured by the addition of immunotherapy following a well-done concurrent chemoradiotherapy in those patients that are eligible for immunotherapy. So I think it really is truly practice-changing. There are very few trials that you can say really impact the standard of care. I think this is much more impactful than many things that we’ve seen over the past decade or so.

Transcript edited for clarity.


Case: A 52-Year-Old Male With Stage IIIA NSCLC

Initial presentation

  • A 52-year-old man presented with a 15-lb weight loss and worsening dyspnea
  • PMH: HTN
  • SH: Computer programmer; Smoked a pack/day for 30 years; Quit smoking 2 years ago; Married with 4 kids
  • PE: Unremarkable

Clinical workup

  • Imaging:
    • Initial CT showed a 5-cm left upper lobe mass with aortopulmonary window and left paratracheal adenopathy measuring up to 2.5 cm
    • Subsequent PET scan showed activity in the left upper lobe mass and all nodal areas
    • No extrathoracic disease was identified
    • MRI showed no brain metastases
  • Mediastinal sampling: EBUS was performed and documented squamous carcinoma in the left paratracheal lymph nodes
  • Staging: T2N2M0
  • ECOG PS 1
  • Multidisciplinary tumor board deemed his tumor unresectable due to multistation N2 disease

Treatment

  • Concurrent cisplatin/etoposide with external-beam radiotherapy
  • Repeat CT 4 weeks after completion of concurrent chemoradiotherapy showed a PR with no new sites of disease