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Radiation improves outcomes with pembrolizumab for metastatic lung cancer
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The addition of stereotactic body radiotherapy after progression on pembrolizumab prolonged PFS among patients with metastatic non-small cell lung cancer, according to results of a prospective phase 2 study presented during the plenary session of American Society for Radiation Oncology Annual Meeting.
These findings suggest that SBRT “reinvigorates” the immune system to induce responses in patients, according to Allison M. Campbell, MD, PhD, resident in the department of therapeutic radiology at Yale New Haven Hospital.
“We know that we need more therapies for patients with metastatic NSCLC; we also know that immunotherapy activates the immune system to attack cancer,” Campbell said during a press conference. “In rare cases, adding radiation to immunotherapy has been shown to result in therapeutic synergy, meaning that when we give high-dose radiation to patients on immunotherapy, some tumors that were not targeted by the radiation can shrink, known as the ‘abscopal effect.’”
To evaluate this effect, Campbell and colleagues assessed whether high-dose radiation in a few fractions to a single tumor site would reinvigorate an immune response among patients who progressed on anti-PD-1 immunotherapy with pembrolizumab (Keytruda, Merck).
The study included 56 patients with metastatic NSCLC and at least two disease sites — one for treatment, and at least one for measurement. Fifty of these patients had not been treated previously with immunotherapy and received pembrolizumab during the study.
Researchers administered high-dose radiation in three or five fractions to one disease site in 22 patients — 21 of whom completed both treatments — after they progressed on pembrolizumab. Sixteen of these patients experienced disease progression during the study, and six had progressed at enrollment and received upfront SBRT.
Median follow-up from the time of enrollment was 15.2 months (95% CI, 10.7-19.3).
When researchers looked at response outside the radiation field, they determined three patients achieved a partial response or stable disease that lasted for at least 1 year.
“We did observe responses that occurred outside the radiation field,” Campbell said. “Keep in mind that all of these patients had progressed on immunotherapy at the time of radiation.”
Two patients (10%) achieved a partial response that persisted for longer than 1 year, and the overall disease control rate was 57%.
Median PFS for all patients after SBRT was 4.1 months (95% CI, 2.1-6.5). Researchers observed a trend toward longer PFS among patients who were PD-L1 positive, but this did not reach statistical significance (6.5 months vs. 2.4 months).
Researchers also evaluated the presence of tumor-infiltrating lymphocytes (TILs) in tumor biopsies taken prior to treatment on study. Results showed that patients with more T cells in the tumor biopsy, with TIL scores of 2 to 3, had longer median PFS than those with TIL scores of 0 to 1 (6.7 months vs. 2.2 months).
Further, patients with any immune-related adverse event experienced longer median PFS than those without these events (6.5 months vs. 2.2 months).
When researchers looked at T cells in the peripheral blood, they identified T-cell subsets that differed among excellent vs. poor responders. For one, CD8-positive effector memory cells appeared enriched among patients with long-lasting partial responses. Also, CD4-positive regulatory cells were more common among patients with poor responses to SBRT.
“The bigger picture here is that there are signatures in the peripheral blood that are promising avenues for future identification of people who will respond well to SBRT combined with immunotherapy,” Campbell said in a press release.
Researchers plan to validate these findings in a larger population.
“We are starting to see that the combination of immunotherapy and radiation is safe and there are some hints that for certain patients, radiation might be an important option when immunotherapy no longer curbs disease progression,” Campbell said. “Our study lays the groundwork for a phase 3 randomized trial, which is the gold standard for changing guidelines and clinical practice.” – by Alexandra Todak
Reference:
Campbell AM, et al. Abstract 74. Presented at: ASTRO Annual Meeting; Sept. 15-18, 2019; Chicago.
Disclosures: Campbell reports no relevant financial disclosures. Please see the abstract for all other authors’ relevant financial disclosures.
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Mohamed Abazeed, MD, PhD
This is a phase 2 study designed to examine whether SBRT after progression on anti-PD-1 therapy can improve systemic response rates. Fifty-six patients were enrolled; 16 experienced disease progression and were deemed suitable for SBRT. Results showed a PFS improvement with SBRT. This is not surprising because it is well-established that SBRT can control disease that is targeted by treatment. Therefore, assessment of PFS for a modality that ablates all contemporaneous and metachronous sites of disease represents circular logic. It is important to assess the systemic disease control rate (ie, complete response, partial response and stable disease), which was 57.14%. The study was not powered to detect an OS difference.From a translational correlation perspective, there appears to be an association between higher tumor-infiltrating lymphocyte score and improvement in PFS. However, given the limited numbers, that should be considered speculative.
This study suggests that local ablative therapy can extend PFS. There is a controversy about whether PFS is the right endpoint for ablative therapy in the oligometastatic setting. Some argue that other outcomes like OS and/or quality of life are the appropriate outcomes to assess the utility of this intervention. The rejoinder by some in the radiation oncology community is that there are many drugs that are approved on the basis of PFS alone. Although true, the drug studies are designed to assess the activity of a new or repurposed drug. We already know that SBRT is locally effective; therefore, other outcomes ultimately are needed to truly assess the efficacy of this approach.
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