Lung cancer mortality rates have declined by more than 50% in men since 1990 and more than 30% in women since 2002. These declines in mortality are largely due to increases in smoking cessation. However, in recent years, clinical treatment advances, such as targeted therapies and immunotherapy, have accelerated the pace of lung cancer mortality rate declines.
Consolidation Durvalumab: ‘A New Benchmark’
The landmark PACIFIC trial is an example of one such noteworthy clinical advancement.1-3 Prior to the PACIFIC trial, the standard of care for patients with a good performance status and unresectable stage III non–small cell lung cancer (NSCLC) had been relatively stable, with first-line treatment consisting of platinum doublet-based chemotherapy with definitive-dose radiotherapy followed by observation. This treatment approach, however, continues to be associated with poor overall survival. The PACIFIC trial evolved this treatment approach for patients with stage III unresectable NSCLC, as it was the first study to demonstrate a survival advantage with immune checkpoint inhibitors in the curative-intent setting.
In the PACIFIC trial, patients with a World Health Organization performance status of 0 or 1 and any tumor PD-L1 status were randomly assigned 2:1 to receive durvalumab, administered once every 2 weeks for 12 months, or placebo after chemoradiotherapy, stratified by age, sex, and smoking history. Trial results in 2018 demonstrated an improvement in overall survival among patients who received consolidation durvalumab as compared with usual care.1,2
Now, in a recently published exploratory 5-year follow-up study by Spigel et al,3 summarized in this issue of The ASCO Post, the effect of consolidation durvalumab on the primary endpoint of overall survival was sustained among 709 of the 713 participants originally randomly assigned. Specifically, consolidation durvalumab remained consistently robust and effective in improving overall survival and had a durable effect on progression-free survival as compared with usual care alone. These results have established a new benchmark for standard of care among patients with unresectable stage III NSCLC.
What About Veterans Populations?
As with most immune checkpoint inhibitor studies, however, overall survival outcomes tend to be shorter in the real-world than those observed in the trials. In the PACIFIC trial, for example, populations with disproportionately higher rates of lung cancer were not as equitably represented, and therefore the benefit of this approach at 5 years of follow-up remains unclear. Veterans receiving care within the Veterans Health Administration, for example, have a greater burden of age-adjusted incidence of lung cancer than nonveterans, yet these populations were not included in the PACIFIC trial.
“We must overcome these decades-long structural barriers that continue to promote differential receipt of our advances in evidence-based cancer care.”— Manali I. Patel, MD, MPH, MS
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Veteran patient populations are unique in that they have higher rates of ongoing exposure to tobacco than nonveteran populations, experience greater burden of comorbidities (such as chronic obstructive pulmonary disease), and complications from social determinants of health. Questions remain as to the tolerance and adherence to durvalumab consolidation among these populations. In fact, one study of durvalumab consolidation among veteran populations found greater rates of durvalumab discontinuation due to toxicity and a less robust overall survival advantage as compared with the results from the PACIFIC trial.4 It is likely, therefore, that results at 5-year follow-up among veteran populations is also less robust.
Similarly, despite the higher incidence of lung cancer among non-Hispanic Black patient populations as compared with other populations, only 2% of participants in the PACIFIC trial identified as non-Hispanic Black. Although not unique to the PACIFIC trial, the low prevalence-to-participation ratio has grave implications on whether the survival advantage observed in the trial will result in equitable reductions in lung cancer mortality in the real world.
Applying These Results Outside the Trial Population
Although the enduring survival advantage of consolidation durvalumab is clear among the populations included in the -PACIFIC trial, multilevel factors influence the feasibility of applying these results routinely and equitably. For example, adverse effects and toxicities from treatment; financial burden including co-payments for treatment, travel needs, patient and caregiver time considerations; as well as other social factors such as child care and employment status strongly raise the issue of whether some patient populations can, in reality, even receive this evidence-based care. Such factors are necessary to consider in the quest to improve cancer survival equitably. For some patients, especially ones who may be experiencing greater financial burden or complications from social determinants of health, the survival advantage from 12-month consolidation treatment with durvalumab may not be enough to outweigh the opportunity cost of the impact on the lives of individual patients and their families.
How, then, can we sustain the results of the PACIFIC trial when applied more broadly outside of the trial population? Although the results from this study hold great promise for further decreasing lung cancer mortality rates, the hard question now is how to ensure equitable delivery of this evidence-based care. As novel therapeutics are developed and standards for lung cancer care evolve, there is great potential to worsen preexisting cancer survival disparities and widen disparity gaps due to differential and inequitable access and delivery of these clinical advances. Thoughtful trial designs, policies supported by funders and sponsors, as well as approval agencies such as the U.S. Food and Drug Administration, coupled with stakeholder-engaged interventions, such as partnering with community-based organizations, can help to ensure equitable delivery of evidence-based cancer care.
To confer the promising reduction in lung cancer mortality that the 5-year follow-up study of the PACIFIC trial reveals, we must overcome these decades-long structural barriers that continue to promote differential receipt of our advances in evidence-based cancer care. The onus truly is on all of us, including the scientific community, to thoughtfully consider these factors and to continuously advocate for multilevel solutions throughout and after the scientific process. Then great strides in survival advantage can translate from our trials to scale in the real world.
Dr. Patel is Assistant Professor, Division of Oncology, Stanford University School of Medicine, Staff Oncologist, VA Palo Alto Health Care System.
DISCLOSURE: Dr. Patel reported no conflicts of interest.
1. Antonia SJ, Villegas A, Daniel D, et al: Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med 377:1919-1929, 2017.
2. Antonia SJ, Villegas A, Daniel D, et al: Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med 379:2342-2350, 2018.
3. Spigel DR, Faivre-Finn C, Gray JE, et al: Five-year survival outcomes from the PACIFIC trial. J Clin Oncol 39(suppl 15):8511, 2021.
4. Sankar K, Bryant AK, Strohbehn GW, et al: Real world outcomes versus clinical trial results of durvalumab maintenance in veterans with stage III non-small cell lung cancer. Cancers (Basel) 14:614, 2022.
As reported in the Journal of Clinical Oncology by David R. Spigel, MD, of Sarah Cannon Research Institute/Tennessee Oncology, and colleagues, long-term follow-up of the phase III PACIFIC trial has shown maintained progression-free and overall survival benefits with consolidation durvalumab (a...