At the ESMO Virtual Congress 2020 held 19-21 September, 2020, updated post-hoc findings from the PACIFIC Phase III trial confirmed that with a 4-year follow-up, durvalumab leads to a  sustained, clinically meaningful overall survival (OS) and progression-free survival (PFS) benefit in patients with unresectable, Stage 3 non-small cell lung cancer (NSCLC) who had not progressed following concurrent chemoradiation therapy (CRT) [1]. Physician’s Weekly interviewed Dr. Camille Hertzka, US Head of Medical Affairs Oncology at AstraZeneca, to discuss the implications.

The Phase III PACIFIC trial (NCT02125461) was a randomized, double-blinded, placebo-controlled, multi-center study (n=713) of durvalumab as a treatment in all-comer NSCLC patients, regardless of PD-L1 status, with unresectable, Stage 3 NSCLC whose disease had not progressed following concurrent platinum-based CRT. The primary endpoints of the trial were PFS and OS, and secondary endpoints included landmark PFS and OS, objective response rate (ORR), and duration of response (DoR). Initial results were published in The New England Journal of Medicine , which already showed that the OS primary endpoint indicated a survival benefit for durvalumab [2].

At ESMO 2020, Dr. Corinne Faivre-Finn, a lead investigator and Professor at The University of Manchester in the UK, presented the results from an updated post-hoc analyses at month 48, which set the median OS at 47.5 months for patients treated in the durvalumab arm as compared with 29.1 months in the placebo arm (HR, 0.71; 95% CI, 0.57-0.88), corresponding to an estimated four-year overall survival rate of 49.6% for durvalumab as opposed to 36.3% for placebo after CRT. Updated PFS data was similarly significant; patients on durvalumab had a median PFS of 17.2 months versus 5.6 months for the patients on placebo (stratified HR 0.55, 95% CI 0.44–0.67). PFS rates at 4 years were 35.3% for patients in the durvalumab arm versus 19.5% for the placebo arm.

Physician’s Weekly reached out to VP, Head of Oncology US Medical at AstraZeneca, Dr. Camille Hertzka, for more information: “We were really excited to present the long-term PACIFIC follow-up data at ESMO this year, and I think what was very exciting was to see that we were able to bend the survival curve – so very impactful data for us. PACIFIC had consistent benefit from durvalumab with a long term follow-up, in unresectable Stage 3 lung cancer.”

Most important impact of PACIFIC?

“PACIFIC is really important because a couple of years ago it was a total revolution for unresectable stage 3 lung cancer patients. It offered a completely new approach, namely that by adding durvalumab for up to a year after chemoradiation, one can improve PFS and OS, and it rapidly became the standard of care. Fast forward to today, most Stage 3 unresectable lung cancer patients are treated with this regimen. But having 4 year follow-up data is truly important because we are getting to a point where we really see this curve flattening in terms of both PFS and OS.”

“We would love to know from the start who those patients are who benefit for a very long time, but we lack that magical formula. What is really important, if you look closely at the OS benefits, you can see that half of the patients who are treated with durvalumab were still alive at 4 years. That means that even if it is not possible to identify exactly benefits most, the fact remains that half of these patients grew 4 years older, that is a very large number. What is most important in my mind, is that you could see that 35% of the patients had not progressed after taking durvalumab, as opposed to nearly 20% of the patients in the control arm. Keep in mind that the patients received a maximum of 1 year of durvalumab, yet a much higher number of patients have not progressed at 4 years. I am really looking forward to seeing the data next year, and year after year thereafter, to see if these patients will relapse. Of course, we hope for a potentially curative therapy. From the patient perspective this is very exciting, or if you have a friend or colleague who is under this regimen, the data showing that one out of two patients will be alive at least 4 years after treatment, living normal lives, is extremely exciting. That is the ultimate importance of this data.”

No biomarkers/subgroup analysis

“We looked at all the different pre-specified categories; age, gender, different backgrounds, different information around chemoradiation, different types of chemotherapy, and there was nothing that stood out. There were some subgroups, for example the EGFR mutated subgroup, where we had so few patients that it was very difficult to interpret the data. This is the first year where we have gathered potentially enough follow-up data with enough events in this group as well to potentially start to see something, but even here it was very difficult because the numbers were so small. That is the intrinsic challenge with this type of subgroup analysis. Perhaps with an even longer follow-up, a pattern may emerge as to why it would work so well in some people.”

Next steps?

“We are looking at many aspects, firstly; how can we improve this regimen in stage 3 unresectable lung cancer? PACIFIC 2 (NCT03519971) is looking at adding durvalumab at the same time as chemoradiation because what is happening is we know that a certain number of patients will relapse very early, and we also know that some patients will be too exhausted at the end of the chemoradiation to be able to receive durvalumab afterwards. Thus, by adding durvalumab at the same time as this regimen, we are seeing if we can increase the number of patients who can benefit from the overall treatment; we should results next year. The other study is LAURA (NCT03521154), with osimertinib which is going to look specifically at the EGFR segments. And then we have some other studies which are in early-stage durvalumab, such as the BR.31 study  (NCT02273375) that will look at adjuvant durvalumab in Stages 1-3 lung cancer that is resectable.”

  1. Faivre-Finn C, et al. Abstract LBA49. Presented at: European Society for Medical Oncology Virtual Congress 2020; Sept. 19-21, 2020.
  2. Antonia SJ, et al. N Engl J Med. 2018;379(24):2342-2350.