Table 1.
Main clinical trials with tRT combinations in PDAC.
| Reference | Phase | Setting | N | Systemic Agents | RT Scheme | RT Timing/Immunotherapy | Primary Endpoint | Note |
|---|---|---|---|---|---|---|---|---|
| Clinical trials with published results | ||||||||
|
Lutz et al. 2011 [17] |
II | Adjuvant | 60 | GVAX (cancer vaccine) |
28 × 1.8 Gy (+ 5-FU) |
After 1st dose | mDFS: 17.3 mo. | |
|
Picozzi et al. 2011 (ACOSOG Z05031) [18] |
II | Adjuvant | 89 | Cisplatin-5FU + INFα2b |
28 × 1.8 Gy | At cycle 1 | OS at 18 mo.: 69% | Toxicity failure (95% grade ≥3) |
| Crane et al. 2011 [19] | II | Unresectable LA | 69 | Gemcitabine + Oxaliplatin + Cetuximab |
28 × 1.8 Gy (+capecitabine) |
After 4 cycles | 1y-OS: 66% | |
| Hardacre et al. 2013 [20] | II | Adjuvant | 70 | Gemcitabine + Algenpantucel-L (cancer vaccine) |
28 × 1.8 Gy (+ 5-FU) |
At 3rd dose | 1y-DFS: 62% | |
| Chan et al. 2016 [21] | I | Neoadjuvant R/BR/LA | 21 | Vorinostat (HDAC inhibitor) | 10 × 3 Gy | Day 1 | MTD | mOS: 13 mo. |
|
Brar et al. 2019 (abstract) [22] NCT02311361 |
Ib/II | Unresectable + nonresponder to chemotherapy | 51/65 | Durvalumab +/− Tremelimumab +/− |
1 × 8 Gy or 5 × 5 Gy |
Day 1 | Feasibility/Safety | Preliminary results |
| Cuneo et al. 2019 [23] | I | Neoadjuvant LA | 34 | Gemcitabine + Adavosertib (Wee1 inhibitor) |
25 × 2.1 Gy | At cycle 2 | MTD | mOS: 21.7 mo. |
| Murphy et al. 2019 [24] | II | Neoadjuvant LA | 49 | FFX + Losartan |
5 × 5 GyE (protons) or 10 × 3 Gy or 28 × 1.8 Gy (+capecitabine) |
After cycle 8 | R0 RR: 61% | mOS: 31.4 mo. mPFS: 17.5 mo. |
| Lin et al. 2019 [25] | Ib/II | Neoadjuvant LA | 11 | Gemcitabine-5FU-leucovorin + Oregovomab (anti-CA-125) + Nelfinavir mesylate |
5 × 8 Gy | At week 11 | mPFS: 8.6 mo. | Closed prematurely due to outdated chemotherapy |
|
Tuli et al. 2019 (abstract) [26] NCT03245541 |
Ib/II | Neoadjuvant LA | 18/30 | Gem-Np + Durvalumab |
5 × 6.6 Gy | Day 8 | Safety, PFS, RR | Preliminary results – mPFS: 14 mo., RR: 50% |
| Xie et al. 2020 [27] | I | M+ (2nd line) | 59 | Durvalumab + Tremelimumab | 1 × 8 Gy or 5 × 5 Gy |
Day 1 Day -3 to +1 |
Safety | ORR: 5.1% |
| Parikh et al. 2021 [28] | II | M+ (MSS) | 25 | Nivolumab + Ipilimumab |
3 × 8 Gy (photons or protons) | At cycle 2 | DCR: 20% | ORR:12% |
|
Poklepovic et al. 2021 (abstract) [29] NCT02349867 |
I | Neoadjuvant R/BR/LA | 22 | Gemcitabine + Sorafenib + Vorinostat |
28 × 1.8 Gy |
Concurrent | Recommended dose | Preliminary results |
| Rahma et al. 2021 (abstract) [30] | Ib/II | Neoadjuvant R/BR | 37 | Pembrolizumab +/− FFX | 28 × 1.8 Gy (+capecitabine) |
Concurrent | Safety/TILs density | Preliminary results–mOS: 27.8 mo. TILs: No difference |
|
Lee et al. 2021 (abstract) [31] NCT02648282 |
II | Neoadjuvant LA | 58 | FFX or Gem-Np + GVAX + Pembrolizumab |
5 × 6.6 Gy | In cycle 2, concurrent | DMFS: 9.7 mo. (NS) | |
|
Haldanarson et al. 2022 [32] (N064A Alliance) NCT00601627 |
II | Unresectable LA | 52 | Panitumumab (EGFR inhibitor) + Gemcitabine |
28 × 1.8 Gy (+ 5FU) |
Day 1 | 1 y-OS rate: 50% | OS and toxicity failure (88% grade ≥3) |
| Zhu et al. 2022 [33] | II | Post-op local recurrence (KRAS mut and PD-L1+) | 85 | Pembrolizumab + Trametinib | 5 × 7–8 Gy | 2 weeks before ICIs | mOS: 14.9 mo. | |
| Chen et al. 2022 [34] CHECKPAC | II | Refractory M+ | 84 | Nivolumab +/− Ipilimumab | 1 × 15 Gy (single lesion) | Day 1 | CBR: 37.2% for triple combination | ORR: 14% for the triple combination mOS: 3.8 mo. |
|
Lierman et al. 2022 [35] (PARC) |
rII | Inoperable PDAC | 68 | Gemcitabine +/− Cetuximab |
25 × 2.16 Gy | After 1 week | mPFS: 6.8 mo. | mOS: 14.2 mo. (NS) |
| Hewitt et al. 2022 [36] | III | Neoadjuvant BR/LA | 303 | FFX or Gem-Np +/− Algenpantucel-L | 28 × 1.8 Gy (+ 5-FU or capecitabine) |
After 6 doses | mOS: 14.3 mo. (vs. 14.9 for SOC) |
|
| Ongoing clinical trials | ||||||||
| NCT01072981 | III | Adjuvant | 722 | Gemcitabine +/−Algenpantucel-L | 28 × 1.8 Gy (+ 5-FU) |
At 3rd dose | mOS | Recruitment completed |
| NCT03767582 | I/rII | Neoadjuvant LA | 30 | Chemotherapy + Nivolumab + CCR2/5 dual antagonist +/− GVAX |
5 × 6.6 Gy | 2–4 weeks after chemotherapy and 2–3 weeks before ICIs | Safety/TILs response | Recruiting |
|
NCT04331041 |
rII | Neoadjuvant LA | 42 | FFX or Gem-Np +/− Defactinib (FAK inhibitor) |
5 × 10 Gy (MR-Linac) |
Day 1, concurrent | PFS | Recruiting |
| NCT04172532 | Ib/rII | Neoadjuvant LA | 24 | Pebosertib (DNA-PK inhibitor) | 5 × ?Gy | Day 1 | MTD, PFS | Recruiting |
|
NCT04106856
(SHAPER) |
I | Neoadjuvant BR/LA | 20 | Losartan | 15 × ?Gy | Day 14 | Toxicity | Recruiting |
| NCT02305186 | Ib/II | Neoadjuvant R/BR | 68 | Pembrolizumab | 28 × 1.8Gy (+ capecitabine) |
Concurrent | Number of TILs in resected tissue/Safety | Recruiting |
| NCT05411094 | I | Unresectable LA | 18 | Olaparib (PARP inhibitor) + Durvalumab |
NR | In cycle 2, concurrent | MTD | Recruiting |
|
NCT04247165
(LAPTOP) |
Ib/II | BR/LA/M+ | 40 | Gem-Np + Nivolumab + Ipilimumab |
3 × 8 Gy (MR-Linac) |
NR | Safety | Recruiting |
|
NCT03915678
(AGADIR) |
II | M+ solid tumors (including PDAC) | 247 | Atezolizumab + BDB001 (TLR 7/8 agonist) |
3–5 × 9–12 Gy | After 1st dose | ORR | Recruiting Basket trial |
|
NCT05116917
(INFLUENCE) |
II | M+ | 30 | Nivolumab + Ipilimumab + Influenza vaccine |
1 × 15 Gy | Day 1 | ORR | Recruiting |
| NCT05088889 | I | M+ | 10 | Nivolumab + Ipilimumab + |
3 × 8 Gy + 1 × 2 Gy for nonresponder |
Day 1 | ORR | Recruiting |
| NCT04361162 | II | M+ (MSS) | 30 | Nivolumab + Ipilimumab | NR (3D) | Week 1 of 1st cycle | ORR | Active, not recruiting |
| NCT04050085 | I | Refractory M+ | 6 | Nivolumab + SD-101 (TLR-9 agonist) |
5 × 6–10 Gy | Day 1 | Safety | Active, not recruiting |
| NCT03490760 | II | Refractory M+ | 39 | Durvalumab | 3 × 8 Gy | At week 5 | PFS | Active, not recruiting |
| NCT03161379 | II |
Neoadjuvant BR | 30 | Cyclophosphamide + GVAX + Nivolumab |
5 × 6.6 Gy | At 2nd dose | CD8 count (cell/ mm3) in the TME | Active, not recruiting |
|
NCT03563248
(SU2C) |
rII | Neoadjuvant BR/LA | 168 | FFX +/− Losartan +/− Nivolumab |
NR (SBRT) |
Concurrent | R0 RR | Active, not recruiting |
| NCT01595321 | I | Adjuvant | 19 | FFX + Cyclophosphamide + GVAX |
5 × 6.6 Gy | After 1st dose | Toxicity | Active, not recruiting |
| NCT04098432 | Ib/II | Neoadjuvant LA | 15 | FFX + Nivolumab |
4 × 8 Gy | Before ICI | PFS | Active, not recruiting |
RT = radiotherapy; CBR: clinical benefit rate; ORR: objective response rate; mOS: median overall survival; PFS: progression-free survival; DCR: disease response rate; GMCI: gene-mediated cytotoxic immunotherapy (aglatimagene besadenovec + valacyclovir); DMFS: distant metastasis-free survival; NS: not significant; TLR: toll-like receptor; MSS: microsatellite stable; LA: locally advanced; BR: borderline resectable; M+: metastatic; TME= tumor microenvironment; TIL = tumor-infiltrating lymphocytes; (R0) RR: (complete) resection rate; HDAC: histone deacetylase; FFX: FOLFIRINOX; Gem-Np: gemcitabine/Nab-paclitaxel.