High-dose irradiation in combination with non-ablative low-dose radiation to treat metastatic disease after progression on immunotherapy: Results of a phase II trial

Abstract

Aim: To report early findings from a phase II trial of high-dose radiotherapy (HD-RT) with or without low-dose RT (LD-RT) for metastatic cancer.

Methods: Eligible patients had metastatic disease that progressed on immunotherapy within 6 months. Patients were given either HD-RT (20-70 Gy total; 3-12.5 Gy/f), or HD-RT + LD-RT (0.5-2 Gy/f up to 1-10 Gy total) to separate lesions, with continued immunotherapy. Radiographic response was assessed per RECIST 1.1 and Immune-Related Response Criteria (irRC). Primary endpoints: (1) 4-month disease control (DCR, complete/partial response [CR/PR] or stable disease [SD]) or an overall response (ORR, CR/PR) at any point in ≥10% of patients, per RECIST 1.1; (2) dose-limiting toxicity within 3 months not exceeding 30%. Secondary endpoint was lesion-specific response.

Results: Seventy-four patients (NSCLC, n = 38; melanoma n = 21) were analyzed (39 HD-RT and 35 HD-RT + LD-RT). The median follow-up time was 13.6 months. The primary endpoint was met for 72 evaluable patients, with a 4-month DCR of 42% (47% [16/34] vs. 37% [14/38] in HD-RT + LD-RT vs. HD-RT, P = 0.38), and 19% ORR at any time (26% [9/34] vs. 13% [5/38] in HD-RT + LD-RT vs. HD-RT, P = 0.27). Three patients had toxicity ≥grade 3. LD-RT lesion response (53%) was improved compared to nonirradiated lesions in HD-RT + LD-RT (23%, P = 0.002) and HD-RT (11%, P < 0.001). T- and NK cell infiltration was enhanced in lesions treated with LD-RT.

Conclusions: HD-RT plus LD-RT safely improved lesion-specific response in patients with immune resistant solid tumors by promoting infiltration of effector immune cells into the tumor microenvironment.

Keywords: Immunotherapy resistance; Low-dose radiotherapy; Metastatic cancer; Radioimmunotherapy; Salvage radiotherapy.

Figure 1.. Individual Lesion-specific Response.

Waterfall plot (per irRC) of (A) Low-dose-treated target lesions (complete plus partial response rate=53%) in patients receiving high + low dose cohort and (B) Nonirradiated target lesions in patients receiving high-dose RT (11% response rate). Only lesions that were stable or progressing before RT were visualized.

Figure 2.. Comparation of Lesion-specific Responses in Two Cohorts.

In the HD-RT+LD-RT cohort, the lesion-specific response of LD-RT lesions compared with nonirradiated lesions as an internal control was 53% vs 23% (P=0.002); LD-RT lesions from HD-RT+LD-RT cohort had significantly improved rates of lesion-specific responses when compared with nonirradiated lesions in the HD-RT cohort (53% vs 11%, P<0.001); No differences were noted between nonirradiated lesion-specific responses in the HD-RT+LD-RT and HD-RT cohorts (23% vs 11%, P=0.17). HD-RT: high-dose radiotherapy; LD-RT: low-dose radiotherapy.

Figure 3.. Low-dose Lesion Response and Immune Cell Infiltration.

(A) PET/CT prior to low-dose RT. Red circle identifies progressing neck lesion at the site of the pre-treatment biopsy. (B) Low-dose RT treatment plan to the neck lesion. (C) PET/CT one week after low-dose RT. Red circle identifies treated neck lesion at the site of the post-treatment biopsy. (D-G) Immune-cell infiltration by Multiplex Immunofluorescence microscopy of pre- and post-low-dose RT biopsies from the same lesion. (D) Immunofluorescence analysis of CD3⁺ (red) CD4⁺ (green) T cells pre- and post-low-dose RT. (E) Immunofluorescence analysis of CD3⁺ (red) CD8⁺ (pink) T cells pre- and post-low-dose RT. (F) Immunofluorescence analysis of CD56⁺ (yellow) NK cells pre- and post-low-dose RT. (G) Quantification of CD4⁺ T cells, CD8⁺ T cells and NK cells, and the percentages of changes pre-and post-low-dose RT.