A Randomized Phase 2 Study of Pembrolizumab With or Without Radiation in Patients With Recurrent or Metastatic Adenoid Cystic Carcinoma

Treatment of Cancer with Radio-Immunotherapy: What We Currently Know and What the Future May Hold

“…The benefit of adding metastasis-directed radiotherapy to immunotherapy has been the subject of a number of comparative phase I/II trials, the designs and results of which are summarized in Table 2. These studies represent a variety of histologies, including NSCLC [36][37][38][39], melanoma [38], HNSCC [40], and adenoid cystic carcinoma (ACC) [41]. With the exception of the report by Curti et al in which patients received interleukin-2 (IL-2) three days after treatment with either 20 Gy or 40 Gy given in 20 Gy fractions [38], patients in these studies were treated with an anti-PD-1/PD-L1 agent [36][37][38][39][40][41].…”

“…With the exception of the report by Curti et al in which patients received interleukin-2 (IL-2) three days after treatment with either 20 Gy or 40 Gy given in 20 Gy fractions [38], patients in these studies were treated with an anti-PD-1/PD-L1 agent [36][37][38][39][40][41]. Patients treated with radiotherapy in these studies were largely treated with radiotherapy doses of 24-30 Gy given in 3-5 fractions [36,37,40,41], with exceptions in the study reported by Welsh et al, in which patients were treated with 48 Gy in four fractions if deemed clinically feasible (n = 19) and otherwise received 45 Gy in 15 fractions (n = 21) [39], and the previously described study reported by Curti et al Among patients treated with radiotherapy in these studies, radiotherapy was delivered before [38], following [36,37,41], between cycles [40], and concurrently [39], relative to ICB. Despite the differences among these studies, a similarity exists in that all failed to demonstrate significant improvements in ORR, PFS, and OS with the addition of radiotherapy to immunotherapy [36][37][38][39][40][41].…”

“…Patients treated with radiotherapy in these studies were largely treated with radiotherapy doses of 24-30 Gy given in 3-5 fractions [36,37,40,41], with exceptions in the study reported by Welsh et al, in which patients were treated with 48 Gy in four fractions if deemed clinically feasible (n = 19) and otherwise received 45 Gy in 15 fractions (n = 21) [39], and the previously described study reported by Curti et al Among patients treated with radiotherapy in these studies, radiotherapy was delivered before [38], following [36,37,41], between cycles [40], and concurrently [39], relative to ICB. Despite the differences among these studies, a similarity exists in that all failed to demonstrate significant improvements in ORR, PFS, and OS with the addition of radiotherapy to immunotherapy [36][37][38][39][40][41]. It is of note that, in an unplanned, pooled analysis of the studies by Theelen et al and Welsh et al, patients treated with radiotherapy had improved PFS (4.4 vs. 9.0 months, p = 0.045) and OS (8.7 vs. 19.2 months, p < 0.001) [42].…”

“…While clinical studies investigating radio-immunotherapy in patients with metastatic disease have largely failed to demonstrate improved outcomes compared to treatment with immunotherapy alone, a number of factors may explain these results. Although comparative studies investigating the addition of radiotherapy to immunotherapy have been negative regardless of whether a single [36,37,40] or multiple metastases [38,39,41] were targeted with radiotherapy, it is of note that all of these studies have required at least one metastasis to be remain unirradiated. In contrast to these studies, in a non-randomized prospective study of NSCLC patients with ≤ 4 metastases (93% had ≤ 2 metastases and 61% had one metastasis) reported by Bauml et al, locally ablative therapy to all sites of distant metastasis in combination with pembrolizumab yielded impressive gains over historical outcomes, including a two-year PFS of 56% among patients metachronous disease [43].…”

Tumour-Infiltrating Lymphocytes (TILs) and PD-L1 Expression Correlate with Lymph Node Metastasis, High-Grade Transformation and Shorter Metastasis-Free Survival in Patients with Acinic Cell Carcinoma (AciCC) of the Salivary Glands

“…In general, expression of PD-L1 is correlated with tumour response to immune checkpoint inhibition, but the applied immunohistochemical antibodies, scoring systems and cut-offs for positivity vary greatly. In salivary gland cancers, response rates to therapies including immune checkpoint blockade have been limited, but partial responses in individual patients were observed [30][31][32][33][34]. Therefore, the objective of this study was the comprehensive analysis of TILs and PD-L1 expression in correlation to clinico-pathological parameters including long-term follow-up in a well-characterized single institutional cohort of AciCCs of the salivary glands.…”