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Durvalumab reduces local, distant progression in non-small cell lung cancer
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Durvalumab extended the time to first progression and reduced the risk for local and distant progression among patients with unresectable stage III non-small cell lung cancer, according to an exploratory analysis of the phase 3 PACIFIC trial presented at American Society for Radiation Oncology Annual Meeting.
Further, the chest was the most common site of first disease progression, regardless of treatment received.
Earlier results from PACIFIC showed durvalumab (Imfinzi, AstraZeneca; n = 476) significantly extended PFS and OS compared with placebo (n = 237) among patients with unresectable stage III NSCLC without progression after chemoradiotherapy. Time to death or distant metastases also appeared improved among patients assigned durvalumab, and fewer patients in that treatment group developed new lesions.
“Based on these data presented over the last 2 years, durvalumab has received approval in many countries and the PACIFIC regimen — meaning the addition of durvalumab after concurrent chemoradiotherapy — has become the standard of care for unresectable stage III NSCLC,” Andreas Rimner, MD, radiation oncologist at Memorial Sloan Kettering Cancer Center, said during a press conference. “However, there were always questions regarding the detailed patterns of failure and disease progression in this trial.”
Thus, Rimner and colleagues further analyzed this trial population to characterize patterns of disease progression and sites of first progression.
A new, independent reviewer reevaluated patient scans to identify unequivocal new lesions, with those occurring within the lung parenchyma, chest wall and diaphragm categorized as intrathoracic lesions.
Study outcomes measures included the proportion of patients with progression or death, region of first progression, location and number of organs with new lesions, and number of new lesions at progression.
Results showed durvalumab reduced the incidence of first progression compared with placebo, regardless of region (45.4% vs. 64.6%). Specifically, fewer patients assigned durvalumab developed intrathoracic (36.6% vs. 48.1%), extrathoracic (6.9% vs. 13.1%), or both intrathoracic and extrathoracic (1.9% vs. 3.4%) lesions.
“It’s notable how the addition of durvalumab significantly decreased the distant progression of disease,” Rimner said in a press release. “With this type of cancer, you can achieve some control of the tumor within the lung, but it almost invariably comes back elsewhere in the body and there are limited options for what we can do. To have a treatment that truly reduces the rate of lesions developing distantly, and reduces the frequency of these distant lesions, is a major step forward and really improves the outlook for these patients.”
An evaluation of a subpopulation of patients with progression (durvalumab, n = 216; placebo, n = 153) revealed that the most common site of progression was intrathoracic in both treatment groups (80.6% vs. 74.5%).
Further, durvalumab improved the time to intrathoracic progression alone (25.2 months vs. 9.2 months; HR = 0.55; 95% CI, 0.43-0.7), extrathoracic progression alone (not reached in both groups; HR = 0.41; 95% CI, 0.27-0.63), and simultaneous intrathoracic and extrathoracic progression (not reached in both groups; HR = 0.48; 95% CI, 0.28-0.82).
Among patients with progression and new extrathoracic lesions (durvalumab, n = 42; placebo, n = 39), most patients had one (45.2% vs. 38.5%) or two (21.4% vs. 33.3%) lesions at first progression. Also, most new extrathoracic lesions occurred in one organ (95.2% vs. 94.9%), with the brain being the most frequent site (61.9% vs. 66.7%), followed by the liver (14.3% vs. 12.8%), bone (14.3% vs. 7.7%) and lymph nodes (7.1% vs. 7.7%).
“It is helpful to know that the cancer didn’t commonly come back in multiple different places,” Rimner said. “When cancer returns in just one or two areas, it can be amenable to aggressive local therapies. There is increasing evidence that local ablative therapies may further extend survival for these patients. We can’t say that this is definitively what should be done, as this trial didn’t address that question. But it’s highly suggested by several phase 2 studies and currently being investigated in ongoing phase 3 studies, including NRG-LU002.”
Rimner and colleagues plan to provide further detail on the specifics of the use of this combination.
“There is some speculation that an earlier start of durvalumab after chemoradiation might be associated with better survival,” he said. “There also are several other ongoing studies exploring the concurrent use of durvalumab in combination with radiation therapy in various forms.”
Overall, these data further establish durvalumab as standard of care in this setting, he added.
“I think it gives further credence to any doubters,” he said. “The addition of this immunotherapy drug following concurrent chemoradiation really needs to be implemented as the standard of care for these patients.” – by Alexandra Todak
Reference:
Rimner A, et al. Abstract LBA6. Presented at: ASTRO Annual Meeting; Sept. 15-18, 2019; Chicago.
Disclosures: AstraZeneca funded this trial. Rimner reports constant fees and research grants from AstraZeneca outside of this study. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Mohamed Abazeed, MD, PhD
This study assessed the patterns of disease progression in the two arms of the PACIFIC study, and the results show durvalumab clearly has an impact in both local-only and distant-only recurrence. The most substantial impact appears to be on distant recurrence. There was a 47% reduction in distant-only recurrence and a 24% reduction in local-only recurrence. Most patients recurred inside of the chest irrespective of treatment arm, suggesting that local radiation treatments need additional optimization.
As it relates to patterns of failure, when patients recur, a vast majority of them recur in an oligometastatic setting (fewer than five lesions). Interestingly, the most common site of progression was the brain. There has been prior suggestion that the brain constitutes an immune-privileged environment. These results appear to support that concept.
The authors suggest that time to progression was improved with durvalumab, and that is evident. Because more than 90% of patients had progression at five or fewer lesions, they suggested that stereotactic body radiotherapy may be beneficial with durvalumab. This is merely speculative based on the results of this study alone. Although some data are emerging that indicate an improvement in PFS by local ablative therapy in the setting of oligometastatic disease, the main driver of potential progression appears to be lack of control of the primary lesion. This suggests that any ablative therapy should incorporate the primary site and not merely distant-only disease.
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