Table 1 Important clinical trials of TIME-targeted therapies that have achieved results in recent years

Immune checkpoint inhibitor

 NCT03404960 [31]

combined with PARP inhibition

Ib/II2

platinum-sensitive advanced pancreatic cancer (n = 91)

niraparib plus ipilimumab versus niraparib plus nivolumab

6-month PFS rate was 59.6% for niraparib plus ipilimumab, and 20.6% for niraparib plus nivolumab

 NCT03565991 [32]

IIb

advanced BRCA1/2-altered or ATM-altered solid tumors (n = 200) including pancreatic cancer

avelumab and talazoparib

The confirmed ORR was 26.4% (42 patients, including 9 complete responses [5.7%]) in the BRCA1/2 cohort and 4.9% (2 patients) in the ATM cohort

 NCT02309177 [33]

combined with chemotherapy

I

advanced pancreatic cancer (n = 50)

nivolumab, nab-paclitaxel, and gemcitabine

mPFS and mOS were 5.5 and 9.9 months, respectively

 NCT02879318 [34]

II

metastatic PDAC (n = 180)

gemcitabine and nab-paclitaxel with or without durvalumab and tremelimumab

the combination immunotherapy did not improve survival among the unselected patient population (p = 0.72) immunotherapy group (p = 0.02)

 NCT03104439 [36]

combined with radiotherapy

II

microsatellite stable PDAC (n = 25)

radiotherapy on ipilimumab plus nivolumab

DCR of patients was 20% (5 of 25; 95% CI, 7–41%), and reached 29% (5 of 17; 95% CI, 10–56%) after receiving radiotherapy

 NCT02704156 [37]

II

locally recurrent pancreatic cancer after surgical resection (n = 170)

SBRT plus pembrolizumab and trametinib versus SBRT plus gemcitabine

mOS of 24.9 months (95% CI, 23.3–26.5) for SBRT plus pembrolizumab and trametinib, compared with 22.4 months (95% CI, 21.2–23.6) for SBRT plus gemcitabine (hazard ratio, 0.60; 95% CI, 0.44–0.82; p = 0·0012)

 NCT02866383 [38]

II

refractory metastatic PDAC (n = 84)

SBRT/nivolumab/ipilimumab versus SBRT/nivolumab

clinical benefit rate of 37.2% (95% CI, 24.0–52.1%) for SBRT/nivolumab/ipilimumab versus 17.1% (95% CI, 8.0–36.0%) for SBRT/nivolumab

 NCT02704156 [39]

II

PDAC patients characterized by mutant KRAS and positive immunohistochemical staining of PD-L1 and documented post-operative local recurrence (n = 170)

dose escalation of SBRT plus pembrolizumab and trametinib versus SBRT plus gemcitabine

SBRT/pembrolizumab/trametinib had longer OS compared with SBRT plus gemcitabine, but did not reach statistical significance (median: 15.1 vs. 12.4 months, HR 0.67 [95%CI 0.43–1.04]; p = 0.071)

 NCT04258150 [40]

combined with IL-6 blockade and radiotherapy

II

refractory pancreatic cancer patients with intolerance to gemcitabine- or fluorouracil-containing regimens (n = 26)

pilimumab, nivolumab, and tocilizumab combined with SBRT

Five patients (19%; 95% CI, 7–39) achieved a stable disease. mPFS was 1.6 months (95% CI 1.4–1.7), and mOS was 5.3 months (95% CI 2.3–8.0)

 NCT02734160 [60]

combined with TGF-β inhibitor

Ib

recurrent/refractory metastatic pancreatic cancer (n = 32)

galunisertib plus durvalumab

1 patient had partial response, 7 had stable disease, 15 had objective progressive disease. DCR was 25.0%. mOS and mPFS were 5.72 months (95% CI: 4.01 to 8.38) and 1.87 months (95% CI: 1.58 to 3.09)

 NCT03098160 [203]

combined with prodrug that alleviates hypoxia

I

Advanced solid tumors (n = 22) including pancreatic cancer

evofosfamide plus ipilimumab

Of 18 patients with measurable disease at baseline, 3 (16.7%) achieved partial response and 12 (66.7%) achieved stable disease

Other approaches targeting lymphocytes

 NA [53]

TCR-T

NA

one patient with progressive metastatic pancreatic cancer

infusion of autologous T cells that clonally express two allogeneic HLA-C*08:02-restricted TCRs targeting mutant KRAS G12D

overall partial response rate was 62% at one month, and 72% at 6 month

 NCT02436668 [70]

BTK inhibition

III

PDAC (n = 424) of stage IV diagnosis ≥ 6 weeks

ibrutinib plus nab-paclitaxel/gemcitabine (arm A) versus placebo plus nab-paclitaxel/gemcitabine (arm B)

no significant difference in OS between arm A versus arm B (median of 9.7 versus 10.8 months; P = 0.3225). PFS was shorter for arm A compared with arm B (median 5.3 versus 6.0 months; P < 0.0001). Overall response rates were 29% and 42%, respectively (P = 0.0058)

Targeting myeloid cells

 NCT01413022 [81]

CCR2 inhibition

Ib

borderline resectable or locally advanced PDAC (n = 47)

PF-04136309 plus FOLFIRINOX

16 of 33 patients receiving FOLFIRINOX plus PF-04136309 who had undergone repeat imaging achieved an objective tumor response, with local tumour control achieved in 32 patients

 NCT02713529 [79]

CSF1R inhibition

II

Adult solid tumors (n = 116) including pancreatic cancer

AMG 820 plus pembrolizumab

safety profile was favorable but did not meet the predefined efficacy threshold

 NCT02880371 [80]

Ib/II

Advanced solid tumors (19 in phase Ib, 57 in phase II) including PDAC

ARRY-382 plus pembrolizumab

One PDAC patient had partial response in phase Ib. One PDAC patient had a partial response lasting 2.4 months in phase II

 NCT02588443 [85]

CD40 activatioin

I

resectable PDAC (n = 16)

selicrelumab

For selicrelumab-treated tumors, 82% were T-cell enriched, compared with 37% of untreated (P = 0.004) and 23% of chemotherapy/chemoradiation-treated (P = 0.012)

 NCT03214250 [86]

Ib

untreated metastatic PDAC (n = 30)

Sotigalimab and gemcitabine plus nab-paclitaxel, with or without nivolumab

The combination was tolerable. Responses were observed in 14 of 24 DLT-evaluable patients

 NCT03214250 [87]

II

metastatic PDAC (n = 105)

sotigalimab/nivolumab/chemotherapy

sotigalimab/nivolumab/chemotherapy arm did not show a meaningful improvement in 1-year OS rate (41.3%, P = 0.223, n = 35) compared to nivolumab/chemotherapy (57.7%, P = 0.006, n = 34) and sotigalimab/chemotherapy (48.1%, P = 0.062, n = 36)

 NCT03013218 [95]

CD47 block

I

Advanced solid tumors (n = 110) including pancreatic cancer

Evorpacept alone and in combination with pembrolizumab or trastuzumab

Evorpacept in combination with pembrolizumab or trastuzumab exhibited safety and preliminary antitumor activity

 NCT01896869 [125]

GVAX

II

metastatic PDAC (n = 82)

GVAX and ipilimumab

mOS was 9.38 months (95% CI, 5.0–12.2) for test group and 14.7 months (95% CI, 11.6–20.0) for control group (HR, 1.75; P = 0.019)

 NCT02243371 [125]

II

metastatic pancreatic cancer (n = 93)

cyclophosphamide/GVAX followed by CRS-207 with (Arm A) or without nivolumab (Arm B)

mOS in Arms A and B were 5.9 (95% CI, 4.7–8.6) and 6.1 (95% CI, 3.5–7.0) months, respectively, with an HR of 0.86 (95% CI, 0.55–1.34)

 NCT00727441 [128]

II

resectable PDAC (n = 87)

GVAX alone (arm A), GVAX/intravenous cyclophosphamide (arm B), GVAX/oral cyclophosphamide (arm C)

Arm A had a trend toward longer mOS (35.0 months) than that (24.8 months) in the historical controls. Arm C had a significantly shorter DFS than Arm A

 NL7432 [116]

DC vaccine

I

resected PDAC (n = 10)

allogeneic lysate-DC vaccination

No vaccine-related serious adverse events were observed. Seven patients have not experienced disease recurrence or progression at a median follow-up of 25 months (15–32 months)

Targeting CAFs

 NCT03307148 [172]

ATRA

Ib

advanced, unresectable PDAC (n = 27)

gemcitabine, nab-paclitaxel and ATRA

mOS of 11.7 months (95%CI, 8.6–15.7)

 NCT02826486 [164]

CXCR4 inhibition

II

metastatic PDAC (n = 37 in cohort 1, n = 22 in cohort 2)

BL-8040, pembrolizumab and chemotherapy

ORR is 21.1%, with confirmed ORR of 13.2%. mPFS is 3.8 months and mOS is 6.6 months. DCR of 34.5% in cohort 1, ORR and DCR of 32% and 77% in cohort 2

Targeting ECM

 NCT01839487 [189]

hyaluronan depletion

II

previously untreated metastatic PDAC (n = 279)

PEGPH20 plus nab-paclitaxel/gemcitabine (PAG) versus nab-paclitaxel/gemcitabine (AG)

median PFS is 9.2 months with PAG versus 5.2 months with AG (HR, 0.51; 95% CI, 0.26 to 1.00; P = .048)

 NCT01959139 [191]

Ib/II

untreated metastatic PDAC (n = 138)

PEGPH20 plus mFOLFIRINOX versus mFOLFIRINOX

PEGPH20 plus mFOLFIRINOX has a significant increase in grade 3–4 toxicity without prolonging mOS (odds ratio, 2.7; 95% CI, 1.1 to 7.1)

 NCT02715804 [190]

III

untreated, metastatic, hyaluronan-high PDAC (n = 494)

PAG versus AG

mOS of 11.2 months for PAG versus 11.5 months for placebo plus AG (HR, 1.00; 95% CI, 0.80 to 1.27; P = .97); mPFS is 7.1 months versus 7.1 months (HR, 0.97; 95% CI, 0.75 to 1.26])

 NCT01821729 [193]

angiotensin II receptor inhibition

II

previously untreated locally advanced unresectable pancreatic cancer (n = 49)

FOLFIRINOX, losartan, and chemoradiotherapy

margin-negative resection rate of 61%

 NCT02546531 [197]

FAK inhibition

I

Advanced treatment refractory pancreatic cancer (n = 20 in refractory cohort, n = 10 in maintenance cohort)

defactinib, pembrolizumab, and gemcitabine

mPFS and mOS were 3.6 and 7.8 months for refractory cohort, and 5.0 and 8.3 months for maintenance cohort