Immunotherapy with radiotherapy extends survival in early-stage NSCLC
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Key takeaways:
- Stereotactic ablative radiotherapy plus immunotherapy improved 4-year EFS by 62%.
- Female sex and treatment with nivolumab appeared associated with longer EFS.
Stereotactic ablative radiotherapy with immunotherapy significantly improvement EFS among patients with early-stage, treatment-naive or lung parenchymal recurrent node-negative non-small cell lung cancer, according to study results.
Stereotactic ablative radiotherapy (SABR) with immunotherapy may be a new treatment option vs. SABR alone for this patient population, but further research is necessary, researchers wrote in The Lancet.
Rationale and methodology
“[SABR] has been standard of care for medical inoperable stage I or stage II node-negative NSCLC,” Joe Y. Chang, MD, PhD, FASTRO, director of SABR in the department of radiation oncology at The University of Texas MD Anderson Cancer Center, told Healio. “Although local control in the irradiated lesion has been higher than between 90% and 95%, recurrence of regional lymph node — other lobe or distant — or secondary lung cancer could be up to 40% if patients survive more than 5 years. To reduce disease recurrence and increase cure rate in this patient population, and to test the hypothesis of synergistic interaction of SABR and immunotherapy interaction in early-stage NSCLC, we initiated this phase 2 study in 2016.”
The open-label, randomized phase 2 trial compared SABR alone vs. SABR plus immunotherapy. The analysis included 141 patients treated at three hospitals in Texas.
Chang and colleagues randomly assigned patients 1:1 to SABR with or without four cycles of nivolumab (Opdivo, Bristol Myers Squibb) dosed at 480 mg once every 4 weeks, with the first dose on the same day as or within 36 hours after the first SABR fraction.
Four-year EFS served as the primary endpoint.
Median follow-up was 33 months.
Findings
Results of the per protocol analysis showed a significant improvement in 4-year EFS with SABR plus immunotherapy compared with SABR alone (77% vs. 53%; per protocol population HR = 0.38; 95% CI, 0.19-0.75; intention-to-treat population HR = 0.42; 95% CI, 0.22-0.8).
Results of Cox univariable analysis showed treatment with nivolumab and female sex appeared associated with longer EFS (P < .05).
Researchers observed no grade 3 or higher adverse events associated with SABR. However, 15% of participants experienced grade 3 immunologic adverse events associated with nivolumab.
Researchers acknowledged study limitations, including the small size of the study cohort, the fact it was not double-blinded or placebo-controlled, and the fact masked independent central review of imaging had not been used.
In addition, the study did not have adequate statistical power to address the efficacy of the SABR plus immunotherapy regimen among patients with EGFR mutations or other oncogenic drivers for which targeted treatments are known to be effective in the metastatic setting, researchers wrote.
Implications
The findings suggest immunotherapy should be considered as an option for patients with early-stage NSCLC who have been treated with SABR for curative intent, Chang told Healio.
“Our findings also support the concept that ablative radiotherapy is needed to initiate radiotherapy-mediated immune stimulation. It opens the door for further optimization of combined immunotherapy with radiotherapy in both early-stage and metastatic NSCLC,” Chang said. “We and others have been working on phase 3 randomized studies to validate SABR plus immunotherapy results.
“The impact of PD-L1 status and molecular profiling, such as EGFR and ALK targetable gene mutations, should be considered for future studies,” Chang added. “In the meantime, our team has been working on immunologic biomarkers to explore immunologic mechanisms and clinical/biologic/radiomic AI modeling to guide future studies and clinical practice. More specifically, we are trying to identify who will benefit the most from additional immunotherapy and who may not need it in this patient population.”
Overall, the trial represents a milestone for pursuing effective and safe therapies for patients with early-stage NSCLC and isolated local recurrence, Eric Brooks, MD, MHS, assistant professor in the department of radiation oncology at University of Florida, wrote in an accompanying editorial.
"The study limitations offer pause, but it adds to the evidence base and offers ongoing lessons about lung cancer antitumor immunity,” he wrote.
References:
- Brooks ED. Lancet. 2023;doi:10.1016/S0140-6736(23)01464-2.
- Chang JY, et al. Lancet. 2023;doi:10.1016/S0140-6736(23)01384-3.
For more information:
Joe Y. Chang, MD, PhD, FASTRO, can be reached at jychang@mdanderson.org.
Perspective
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Kevin Stephans, MD
This trial by Chang and colleagues is extremely important and, with additional confirmation, could change the standard of care for patients with medically inoperable stage I NSCLC from SABR alone to SABR with immune therapy.Compared to much longer consolidation courses, such as the PACIFIC trial regimen for stage III disease, the finding of a substantial benefit to just four cycles of immune therapy will be much more practical in the treatment of patients with medically inoperable stage I NSCLC who — given a combination of age and comorbidities — often have difficulties with transportation, frequently place high value on simplicity of treatment, and may decline more extensive or intensive treatment courses. With the delivery of the first course essentially concurrently with SABR, patients only have to return for three additional infusions after completion of SBRT. The benefit of nivolumab was also seen across essentially all subgroups. Although larger tumor size is typically correlated with recurrence, more than half of patients in this trial had tumors less than 2 cm but still derived benefit on subgroup analysis. Similarly, PD-L1 status was less than 1% for more than 40% of trial participants, but yet this subgroup also appeared to derive benefit. Few patients with EGFR mutations, and none with ALK or other driver mutations, were enrolled, so potential benefit in this subgroup remains unknown (and notably suggested detriment in PACIFIC).
Although this trial is extremely promising, several large phase 3 studies testing combinations of immune check-point inhibitors (eg, PACIFIC 4, KEYNOTE-867, SWOG/NRG S1914) with SABR are ongoing, and additional data are needed to absolutely define the standard of care for this patient group. The magnitude of the benefit seen by Chang and colleagues is substantial and would represent a very significant step forward in the care of medically inoperable stage I NSCLC.
References:
Spigel DR, et al. J Clin Oncol. 2022;doi:10.1200/JCO.21.01308.
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