Significant Impact of PACIFIC Trial in Locally Advanced NSCLC Still Seen at 3-Year Follow-Up

July 23, 2019

Article

The results of the phase III PACIFIC trial made a significant impact on the treatment landscape for locally advanced non−small cell lung cancer when both the progression-free survival and overall survival results were announced separately.

Jhanelle Gray, MD

The results of the phase III PACIFIC trial made a significant impact on the treatment landscape for locally advanced non−small cell lung cancer (NSCLC) when both the progression-free survival (PFS) and overall survival (OS) results were announced separately. Now with 3 years of follow-up, updated results from the PACIFIC trial continue to show a significant improvement in outcomes with the use of durvalumab (Imfinzi) in patients with unresectable, stage III NSCLC who do not progress on chemoradiotherapy.¹

“For unresectable stage III NSCLC, previously, the 5-year survival rates were about 15% to 30%. The PACIFIC trial has changed the standard-of-care treatment for our patients by moving immunotherapy into the consolidation setting following completion of concurrent chemotherapy and radiation therapy,” said Jhanelle Gray, MD, the lead study author, on the updated findings presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, in an interview withTargeted Oncology.

At 3 years, 57% of patients receiving durvalumab were still alive compared with 43.5% of patients in the placebo arm.

“One of the key take-home messages here is that over 50% of patients were still alive at 3 years,” added Gray, the director of clinical research in the Department of Thoracic Oncology at H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida. “We have not seen results like this in the past and I think it represents a significant milestone in unresectable stage III lung cancer.”

The randomized, double-blind, international, phase III PACIFIC trial enrolled 713 patients with stage III locally advanced, unresectable NSCLC who had not progressed after at least 2 cycles of concurrent platinum-based chemoradiotherapy. The patients were randomized 2:1 to receive either durvalumab (n = 476) or placebo (n = 237) as consolidation treatment. The primary endpoints of the trial were PFS and OS.

In the preliminary results of the trial,2 a significant difference was noted in PFS between the 2 arms, with 16.8 months seen in the durvalumab arm compared with 5.6 months in the placebo arm (stratified HR, 0.52; 95% CI, 0.42-0.65;P<.001). At 12 months, the PFS rate was 55.9% versus 35.3% in the durvalumab and placebo groups, respectively.

Further findings demonstrated that durvalumab significantly prolonged OS compared with placebo (stratified HR, 0.68; 99.73% CI, 0.47-0.997;P= .0025), although the median OS had not yet been reached in the durvalumab arm.3 At 24 months, the OS rate was 66.3% in the durvalumab group versus 55.6% in the placebo group (2-sidedP= .005).

The updated results presented at the ASCO meeting represented a median of 33.3 months of follow-up (range, 0.2-51.3) and 45 new OS events since the primary OS analysis.1 The median OS still had not yet been reached in the durvalumab arm compared with 29.1 months in the placebo arm (stratified HR, 0.69; 95% CI, 0.55-0.86).

The durvalumab arm was also significantly favored in terms of OS across a number of exploratory subgroups, especially amongst non-smokers and patients who had a shorter time from chemoradiotherapy to randomization.

After treatment discontinuation, 43.3% of patients in the durvalumab group went on to receive subsequent therapy compared with 57.8% from the placebo group; of these patients, 9.7% and 26.6%, respectively, went on to receive immunotherapy.

PD-L1 Expression and Further Research

The median time to the first subsequent therapy or death was 21.2 months in the durvalumab group compared with 10.4 months in the placebo group (HR, 0.58; 95% CI, 0.47-0.71). Further, the median times to second subsequent therapy or death were 30.2 and 17.8 months, respectively (HR, 0.61; 95% CI, 0.49-0.75).Of the subgroups analyzed for OS, the updated results included a post-hoc analysis of patients’ response to treatment based on their PD-L1 expression. This analysis was requested prior to the European Medicines Agency’s approval for durvalumab as a treatment for patients with stage III unresectable NSCLC, which was limited to patients with PD-L1 expression ≥1% on tumor cells.

In the post-hoc analysis, patients with PD-L1 ≥1% showed a hazard ratio of 0.59 (95% CI, 0.41-0.83) favoring durvalumab, whereas patients with PD-L1 <1% showed a hazard ratio of 1.14 (95% CI, 0.71-1.84) favoring placebo.

Gray explained toTargeted Oncologythat due to the trial design of enrolling patients after completion of chemoradiotherapy, there was no guarantee of sufficient tissue availability in the diagnostic specimen (pre-chemoradiotherapy specimen) to allow for PD-L1 testing. Also, due to the time period in which the trial was initiated, PD-L1 expression was not tested at enrollment. Additionally, post-chemoradiotherapy biopsies may likely have yielded significant necrosis and mandating these would have presented concerns.

She noted that as PD-L1 is a heterogeneous biomarker, positive PD-L1 expression does not necessarily confirm benefit with immunotherapy. As such, she suggested that treatment with durvalumab regardless of PD-L1 expression should be a shared decision between the oncologist and patient. Future research is needed to clarify this question.

“Many more research studies are underway [based on the results of the PACIFIC trial]. This trial answered a lot of questions. It also generated new research questions about what our next steps are,” Gray said.

She mentioned that several trials are ongoing, or planned, including one examining whether immunotherapy could be given concurrently with chemoradiotherapy for patients with stage III disease, if immunotherapy could be given to patients who are not candidates for concurrent chemoradiotherapy and instead require sequential treatment, and if chemotherapy could be removed from the equation entirely. She also suggested that these approaches could then be studied in earlier stages of disease if positive results are seen.

“Currently, the standard of care is the PACIFIC trial design. As we look to further improve outcomes for our patients battling unresectable stage II lung cancer, durvalumab as consolidation therapy, should now be the control arm of these future trial designs,” Gray commented.

References

Gray JE, Villegas AE, Daniel DB, et al. Three-year overall survival update from the PACIFIC trial.J Clin Oncol. 2019;37(suppl; abstr 8526). ascopubs.org/doi/abs/10.1200/JCO.2019.37.15_suppl.8526.
Antonia SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Durvalumab after chemoradiotherapy in stage III nonsmall-cell lung cancer.N Engl J Med. 2017;377(20):1919- 1929. doi: 10.1056/NEJMoa1709937.
Antonia SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC.N Engl J Med. 2018;379(24):2342-2350. doi: 10.1056/NEJMoa1809697.