Table 1

Clinical studies on combining or sequencing RT and anti-CTLA-4 checkpoint inhibition in melanoma

Author(s) (year)ICI agentStudy designnRT targetRT typeCohorts/
comparators
RT timingOS (median)PFS (median)ResponseBenefit of
combination/
sequencing
Anti-CTLA-4
Knisely et al (2012)30 IpilimumabRetrospective77BrainStereotactic (SRS)Two cohorts: RT+ICI (n=27); RT (n=50)Sequential (RT before ICI, n=11; RT after ICI, n=16)6.7 months (all patients); 21.3 months (RT+ICI) vs 4.9 months (RT), p=0.04NRNRYes (RT+ICI superior to RT; OS)
Barker et al (2013)31 IpilimumabRetrospective29Various, non-brainVarious (stereotactic and conventional)Single cohort (RT+ICI); no comparatorConcurrent9.0 months (RT within 16 weeks after start of ICI); 39.0 months (RT later than 16 weeks after start of ICI)5 months (RT within 16 weeks after start of ICI); 39 months (RT later than 16 weeks after start of ICI)NRNA
Mathew et al (2013)32 IpilimumabRetrospective58BrainStereotactic (SRS)Two cohorts: RT+ICI (n=25); RT (n=33)Concurrent5.9 months (all patients); 6 months OS 56% (RT+ICI) vs 46% (RT), p=nsNRLocal tumor control (brain) 65% (RT+ICI) vs 63% (RT), p=nsNo (local tumor control; OS)
Silk et al (2013)33 IpilimumabRetrospective70BrainVarious (stereotactic and conventional)Two cohorts: RT+ICI (n=33); RT (n=37)Sequential (RT before ICI, n=21; RT after ICI, n=12)18.3 months (RT+ICI) vs 5.3 months (RT), p=0.0022.7 months (RT+ICI) vs 3.3 months (RT), p=0.55NRYes (RT+ICI superior to RT; OS); SRS+ICI superior to WBRT+ICI
Chandra et al (2015)34 IpilimumabRetrospective47VariousVarious (stereotactic and conventional)Single cohort (RT+ICI); no comparatorConcurrent28.0 monthsNRLesion response in hyperfractionated (81%) vs hypofractionated (52%) RT, p=0.014NA
Kiess et al (2015)35 IpilimumabRetrospective46BrainStereotactic (SRS)Three cohorts on different timings: RT before ICI, n=19; RT concurrent to ICI, n=15; RT after ICI, n=12Concurrent or sequential (RT before ICI, n=19; RT concurrent to ICI, n=15; RT after ICI, n=12)1-year OS RT before (56%) vs concurrent (65%) vs after (40%) ICI, p=0.0081 year regional recurrence RT before (64%) vs concurrent (69%) vs after (92%) ICI, p=0.003NRYes (RT before or concurrent to ICI superior to RT after ICI; PFS, OS)
Tazi et al (2015)36 IpilimumabRetrospective31BrainStereotactic (SRS)Two cohorts: RT+ICI, n=10 (brain metastases); ICI, n=21 (no brain metastases)Concurrent or sequential16.5 months (RT+ICI) vs 24.5 months (ICI), p=0.93NRNRNo (OS)
Twyman-Saint Victor et al (2015)37 IpilimumabProspective, phase 1 (NCT01497808)22Various, non-brainStereotactic body radiationSingle cohort (RT before ICI); no comparatorSequential (RT before ICI)10.7 months3.8 monthsBOR 18% (18% PR, 18% SD, 64% PD)NA
Hiniker et al (2016)38 IpilimumabRetrospective22Various, including brainVarious (stereotactic and conventional)Single cohort (RT+ICI); no comparatorConcurrent13.8 months6.5 monthsBOR 27% (14% CR, 14% PR, 27% SD, 45% PD)NA
Qian et al (2016)39 IpilimumabRetrospective54BrainStereotactic (SRS)Three cohorts: RT concurrent to ICI, n=19; RT before/after ICI, n=19; RT concurrent and sequential, n=16Concurrent or sequential (RT before/after ICI)19.1 months (RT concurrent to ICI) vs 8.0 months (RT sequential to ICI), p=0.086NRNRNA
Qin et al (2016)40 IpilimumabRetrospective88Various, including brainVarious (stereotactic and conventional)Two cohorts: RT+ICI, n=44; ICI, n=44Sequential (RT before ICI, n=20; RT after ICI, n=24)17.9 months (RT+ICI) vs 24.8 months (ICI), p=0.67NRNRNo (OS)
Theurich et al (2016)41 IpilimumabRetrospective127Various, including brainVarious (stereotactic and conventional)Two cohorts: RT+ICI, n=45; ICI, n=82Concurrent or sequential23.3 months (RT+ICI) vs 10.5 months (ICI), p=0.0028NRBOR 58% (RT+ICI) vs 39% (ICI), p=0.05Yes (RT before, concurrent to, or after ICI superior to ICI; BOR, OS)
Koller et al (2017)42 IpilimumabRetrospective101Various, including brainVarious (stereotactic and conventional)Two cohorts: RT+ICI, n=70; ICI, n=31Concurrent19.0 months (RT+ICI) vs 10.0 months (ICI), p=0.015.0 months (RT+ICI) vs 3.0 months (ICI), p=0.20BOR 37% (RT+ICI) vs 19% (ICI), p=0.11; CR 26% (RT+ICI) vs 7% (ICI), p=0.04Yes (RT+ICI superior to ICI; BOR, OS)
Patel et al (2017)43 IpilimumabRetrospective54BrainStereotactic (SRS)Two cohorts: RT before ICI, n=20; RT, n=34Sequential (RT before ICI, n=20)1 year OS: 37.1% (RT before ICI) vs 38.5% (RT), p=0.84NR1 year intracranial control: 12.7% (RT before ICI) vs 29.1% (RT), p=0.59NA
Minniti et al (2019)44 IpilimumabRetrospective45BrainStereotactic (SRS)Single cohort (RT before ICI, n=45); no comparatorSequential (RT before ICI)14.7 months6.0 months (intracranial PFS)NRNA
Knispel et al*IpilimumabRetrospective596Various, including brainVarious (stereotactic and conventional)Two cohorts: RT+ICI, n=150; ICI, n=446Sequential (RT before ICI)6.8 months (RT before ICI) vs 9.6 months (ICI), p=0.61 (adjusted for confounders)2.8 months (RT before ICI) vs 3.1 months (ICI), p=0.74 (adjusted for confounders)BOR 9% (RT before ICI) vs 13% (ICI), p=0.20 (adjusted for confounders)No (BOR, PFS, OS)
  • Published clinical studies on RT and ICI are presented with their outcomes in terms of tumor response and patient survival. Only studies investigating a cohort >20 patients are shown.

  • *Data of the present study.

  • BOR, best overall response; CR, complete response; ICI, immune checkpoint inhibition; NA, not applicable; NR, not reported; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; RT, radiotherapy; SD, stable disease; SRS, stereotactic radiosurgery; WBRT, whole brain radiotherapy.