Radiotherapy fails to improve effectiveness of checkpoint inhibitors for solid tumors
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Key takeaways:
- The addition of SBRT to immune checkpoint inhibitors did not improve PFS for individuals with advanced solid tumors.
- Investigators reported a similar ORR regardless of treatment assignment.
The addition of stereotactic body radiotherapy to immune checkpoint inhibitors failed to significantly extend survival among individuals with advanced solid tumors, results of the randomized phase 2 CHEERS trial showed.
The findings, published in JAMA Oncology, revealed numerically longer PFS and OS among those who received the experimental combination regimen. However, the differences did not achieve statistical significance compared with those who received immune checkpoint inhibitor monotherapy, the investigators noted.
Background
Despite their status as a breakthrough therapy, immune checkpoint inhibitors induce durable responses in less than one-fifth of individuals who receive them, according to Mathieu Spaas, MD, of the radiation oncology department at Ghent University Hospital, and colleagues.
Attempts to combine immune checkpoint inhibitors with other treatment modalities have improved outcomes in some cases, but often while compounding treatment-related toxicity, they added.
“SBRT has the potential to neutralize active tumor sites in a noninvasive and relatively atoxic manner,” the researchers wrote. “Moreover, preclinical and early clinical data suggest that hypofractionated radiotherapy ... could synergize with modern immunotherapy by inducing immunogenic cell death, whereby cytotoxic T lymphocytes are primed and activated due to a sudden release of tumor antigens. This, in turn, could theoretically instigate a systemic antitumor immune response — more commonly referred to as the abscopal effect — meaning the benefit of SBRT could extend beyond the so-called oligometastatic state.”
Methodology
The open-label, multicenter CHEERS trial explored whether the addition of SBRT to immune checkpoint inhibitors could improve treatment outcomes compared with immune checkpoint inhibition alone for individuals with advanced solid tumors.
The study included 96 adults (mean age, 66 years; 79% women) with locally advanced or metastatic melanoma, renal cell carcinoma, urothelial carcinoma, head and neck squamous cell carcinoma, or non-small cell lung carcinoma treated at one of five hospitals in Belgium between March 2018 and October 2020.
Three-quarters of the study cohort had three or more tumor lesions and 68% received at least one line of therapy prior to enrollment.
Investigators randomly assigned study participants in a 1:1 ratio to receive standard therapy with PD-1/PD-L1 inhibitor monotherapy (control arm; n = 51) or an immune checkpoint inhibitor plus SBRT (experimental arm; n = 45).
The radiotherapy regimen included a dose of 3 × 8 Gy to a maximum of three lesions before the second or third immune checkpoint inhibitor cycle, depending on the frequency of administration.
PFS served as the study’s primary endpoint. Secondary endpoints included OS, objective response rate, local control rate and safety.
Median follow-up was 12.5 months (range, 0.7-46.2).
Key findings
The study did not meet its prespecified primary endpoint, with investigators reporting median PFS of 2.8 months in the control group compared with 4.4 months in the experimental group (HR = 0.95; 95% CI, 0.58-1.53).
Researchers observed no statistically significant difference in OS, with a median OS of 11 months in the experimental group compared with 14.3 months in the control group (HR = 0.82; 95% CI, 0.48-1.41).
ORRs appeared similar between the groups, with a 22% response rate in the control group vs. 27% in the experimental group.
Spaas and colleagues noted a “higher than expected” localized control rate of 75% for irritated lesions among patients in the experimental group.
Seven study participants in the experimental group did not finish the full radiotherapy regimen due to disease progression (n = 5) or intercurrent illness (n = 2).
Investigators reported similar rates of any grade treatment-related toxicities in the control group (79%) and the experimental group (78%). Eighteen percent of participants in both groups experienced grade 3 or higher treatment-related toxicities.
No treatment-related deaths occurred during the study.
Clinical implications
“While the addition of subablative multisite stereotactic radiotherapy to [immune checkpoint inhibitor] monotherapy failed to result in any clinically meaningful abscopal effect in a diverse and largely polymetastatic patient population, the findings suggest it is safe to combine both treatment modalities in this context and offer important insights for future trial design,” Spaas and colleagues wrote. “Recent evidence suggests that treating all active disease sites with higher radiation doses in a selected patient population may be a more promising strategy to optimize systemic disease control.”
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