Table 2 Clinical trials of targeting posttranslational modifications combined with PD-1/PD-L1 blockade

Avelumab 800 mg IV q2w + Talazoparib 1 mg po daily

Phosphorylation

Locally advanced (primary or recurrent) or metastatic solid tumors

ORR: NSCLC 16.7%, TNBC 18.2%, HR(+), ERBB2(-), and DDR(+) BC 34.8%, platinum-sensitive, BRCA wild-type OC 20.0%, UC 15%, DDR(+) mCRPC 11.1%;

the most common ≥ grade 3 AEs: anemia 33.6%, thrombocytopenia 21.5%, and neutropenia 13.9%, 1 patient died due to acute respiratory syndrome.

NCT03330405,

nonrandomized controlled phase I, II study

Terminated,

223 patients

[150]

Nivolumab+

TPST-1120

Phosphorylation

Advanced renal cell carcinoma (RCC), cholangiocarcinoma (CCA), or hepatocellular carcinoma

ORR: 23%, TPST-1120 ≥ 400 mg bid ORR: 38%;

no grade 4/5 TRAEs or dose-limiting toxicities

NCT03829436,

open-label, dose-escalation phase I study

Completed, 39 patients

[149]

Nivolumab IV administration every 14 days for 10 doses starting 14 days prior to IMRT + Cetuximab 7 doses + IMRT 5 fractions per week for 7 weeks for a dose of 70 Gy

Phosphorylation

Advanced HNSCC

The tested regimens was safe

NCT02764593,

multiarm phase I trials

Completed,

10 patients

[147]

Durvalumab 1500 mg every 4 weeks for 8 cycles+

Cetuximab 400 mg/m² 1 week before RT start followed by 250 mg/m² weekly, for a maximum of 8 cycles

Phosphorylation

Locally advanced HNSCC

The median PFS, LRC and OS overlapped to

15 months, 1 and 2-year PFS rates: 77.7% and 58.3%;

one case grade 4 mucositis lasting for 14 days

NCT03051906,

single group, open-label,

phase I, II study

Terminated,

9 patients

[146]

Nivolumab or Pembrolizumab

+ Metformin

Phosphorylation

Solid tumor malignancies

DCR: 22%,

12-month OS: low CAIX/I 53%,

high CAIX/I 14.1%

NCT04114136,

randomized, parallel assignment, open label, phase II study

Recruiting

[159]

Pembrolizumab 200 mg IV on day 1 of each 21-day cycle + Niraparib 200 mg daily po

Phosphorylation

Advanced or metastatic TNBC or recurrent ovarian carcinoma (OC)

ORR: OC patients 18%, 10 patients with TNBC 21%, BRCA mutation TNBC 47%;

DCR: OC patients 65%,

23 patients with TNBC 49%, BRCA mutation TNBC 80%;

PFS: OC patients 3.4 months, TNBC patients 2.3 months, BRCA mutation TNBC 8.3 months; 8% immune-related AE in OC patients,

one TNBC patient death resulted from acute respiratory distress syndrome possibly related to treatment

NCT02657889,

single group, open-label,

phase I, II study

Completed,

9 patients with OC and 5 patients with TNBC in phase I,

53 patients with OC and 55 patients with TNBC in phase II

[151, 152]

Pembrolizumab2 mg/kg IV q3w + Erlotinib 150 mg daily po or Gefitinib 250 mg daily po

Phosphorylation

Unresectable or metastatic

Erlotinib: ORR: 41.7%, PFS: 19.5 months,

OS: not reached (NR);

Gefitinib: ORR: 14.3%, PFS: 1.4 months,

OS: 13.0 months,

grade 3/4 liver toxicity

NCT02039674, randomized, parallel assignment, open label, phase I, II study

Completed,

267 patients

[144]

Pembrolizumab 200 mg IV q3w + Cetuximab 400 mg/m² IV 1 week followed by 250 mg/

m² weekly, 3w

Phosphorylation

Recurrent/metastatic HNSCC

ORR: 45%,

the most common grade 3,4 treatment-related AE was 9% oral mucositis, and serious.

NCT03082534,

prospective, multicenter, open-label, nonrandomized, multiarm phase II trial

Active, not recruiting,

33 patients

[145]

Atezolizumab 1200 mg IV q3w + TPST-1120 1200 mg IV q3w+

Bevacizumab 15 mg/kg q3w

Phosphorylation

Advanced Liver Cancers

ORR:30%,

β-catenin mutation ORR: 43%, PD-L1 negative ORR: 27%

NCT04524871,

Phase Ib/II, open-label, multicenter, randomized umbrella study

Recruiting

[151]

Dostarlimab (TSR-042) 500 mg IV d1 + Niraparib 200 or 300 mg daily until PD or toxicity + Bevacizumab 15 mg/kg

Phosphorylation

Recurrent OC

ORR:17.9%, DCR:76.9%,

PFS: 7.6 months;

the most common grade ≥ 3 treatment-emergent adverse events (TEAEs) were hypertension (22.0%), fatigue (17.1%), and anemia (17.1%)

NCT03574779,

randomized, parallel assignment, open label, phase I, II study

Recruiting,

41 patients

[157]

Durvalumab 1500 mg IV q4w + Olaparib 300 mg po bid

Phosphorylation

Recurrent endometrial cancer

ORR: 16%,

PFS:3.4months,

OS:8.0 months,

grade 3 TRAEs: 16%

NCT03951415,

single group assignment, open label, phase II study

Unknown status,

55 patients

[153]

Tislelizumab 2 mg/kg IV q3w + Pamiparib 20, 40, or 60 mg po bid

Phosphorylation

Advanced solid tumors

ORR: 20%,

PFS: 92 days,

OS: 388 days,

grade ≥ 3 TRAEs: 12% anemia, 6% elevated elevated aspartate aminotransferase concentrations, 6% elevated γ-glutamyltransferase concentrations, 6% autoimmune hepatitis. No fatal AEs.

NCT02660034,

nonrandomized, parallel assignment, open label, phase I study

Completed,

49 patients

[156]

Durvalumab 1.5 g IV q4w + Olaparib

300 mg po bid

Phosphorylation

Germline BRCA1-mutated or BRCA2-mutated(gBRCAm)metastatic BC, and OC

BC: PFS:8.2 months, OS:21.5 months,

OC: gBRCAm expansion doublet: PFS: 15.0 months, OS: immature, ORR:92.2%;

nongBRCAm doublet:

PFS: 5.5 months, OS:26.1 months, ORR:34.4%;

nongBRCAm triplet cohorts:

PFS: 14.7 months, OS:31.9 months, ORR:87.1%

NCT02734004, nonrandomized, single group assignment, open label, phase I, II study

Active, not recruiting,

BC:34 patients

OC: 114 patients

[154, 155]

Part A (after progression on a previous EGFR TKI): Durvalumab 3 or 10 mg/kg q2w + Osimertinib 80 mg daily;

Part B (first-line): Durvalumab 10 mg/kg q2w + Osimertinib 80 mg daily

Phosphorylation

EGFR-mutant lung cancer

Part A : ORR: 43%, DOR: 20.4 months;

Part B : ORR: 82%, DOR: 7.1 months,

PFS: 9.0 months;

35% interstitial lung disease overall

NCT02143466,

multicenter, nonrandomized, parallel assignment, open label, phase I study

Part A: active, not recruiting;

23 patients,

Part B: terminated,

11 patients

[189]

Avelumab (A) 10 mg/kg intravenously (IV) q2w + Palbociclib (P) 125 mg po daily (days 1–21 of each cycle) +

Fulvestran (F) 500 mg intramuscularly (IM) once on days 1

and 15 in cycle 1 and 500 mg IM once on day 1 of each

subsequent monthly cycle ;

P + F;

F

Ubiquitination

Hormone receptor-positive/HER2- Metastatic BC progressed on previous CDK4/6i and aromatase inhibitor therapy

PFS: A + P + F 8.1 months;

P + F

4.6 months;

F

4.8 months;

ORR: A + P + F 13%;

P + F

9%;

F

7.3%;

the most common grade 3/4 adverse event (AE) is neutropenia: A + P + F 49.1%,

P + F 32.7%,

F 0%

NCT03147287, randomized multicenter phase II PACE trial

Active, not recruiting,

220 patients

[169]

Avelumab 10 mg/kg IV q2w + Axitinib 3 mg po bid +

Palbociclib 75 mg po daily (7 days off/21 days on)

Ubiquitination

Advanced NSCLC (no EGFR, ALK, or ROS1 alterations; PD-L1 unrestricted; ≤2 prior therapy lines)

The clinical benefit rate:53%;

the most common grade 3/4 AE is neutropenia; one case grade 5 respiratory failure

NCT03386929,

WIN Consortium

multicenter phase I, II study

Terminated,

15 patients

[168]

Part A: SGN-2FF 1, 2, 5, 10, 15 g qd; 2 and 5 g b.i.d;

Part B: SGN-2FF 5 g b.i.d;

Part C: Pembrolizumab 200 mg IV + SGN-2FF 2, 5 g b.i.d

Glycosylation

Advanced solid tumors

Part A: 1/28 CR, 10/28 SD,

Part B: 2/2 PD,

Part C: 1/4 SD, 3/4 PD;

grades 2–5 thromboembolic events 16%(5/32)

NCT02952989.

open-label, multicenter, dose escalation, phase I study

Terminated, 46 patients

Part A 33 patients,

Part B 6 patients,

Part C 7 patients

[178]

Atezolizumab 1200 mg IV q3w +

Etoposide(EP) 100 mg/m² on days 1–3 + Carboplatin under the AUC of 5 mg/mL/min

Glycosylation

Untreated extensive-stage SCLC

ORR: 71.6%,

OS: 10.7 months,

PFS: 5.5 months,

serious AEs occurred in 29.9%

NCT04028050

multicenter, open-label, phase IIIb

Completed, 154 patients

[185]

Pembrolizumab 200 mg IV day1 + Etoposide 100 mg/m² on days 1–3, q3w

Glycosylation

Extensive-stage SCLC

Pembrolizumab + EP: ORR 70.6%, twelve-month PFS estimates 13.6%;grade3/4 AEs: 76.7%, AEs led to death: 6.9% ;

Placebo + EP: ORR 61.8%, twelve-month PFS estimates 3.1%,

grade3/4 AEs: 74.9%, AEs led to death: 5.4%;

NCT03066778,

randomized, double-blind, phase III KEYNOTE-604 study

Completed,

453 patients,

pembrolizumab + EP 228 patients,

placebo + EP 225 patients

[183]

Atezolizumab 1,200 mg IV d1

+Carboplatin 5 mg/mL/min + Etoposide 100 mg/m² IV, days 1–3, q3w

Glycosylation

Untreated extensive-stage SCLC

Atezolizumab group : OS:12.3 months, PFS:5.2 months,

DOR: 4.2 months;

placebo group: OS:10.3 months,

PFS:4.3 months,

DOR: 3.9 months

NCT02763579,

double-blind, placebo-controlled, phase III trial

Completed, atezolizumab group 201 patients, placebo group 202 patients

[186]

SCLC cohort: Tislelizumab 200 mg + Etoposide + Platinum q3w

Glycosylation

Advanced/metastatic lung cancer

SCLC cohort :

ORR: 77%,

PFS: 6.9 months,

OS: 15.6 months,

NCT03432598,

multicenter, open-label, phase II study

Completed,

54 patients

[188]

Serplulimab 4.5 mg/kg q3w + Carboplatin+

Etoposide

Glycosylation

Extensive-stage SCLC

ORR:80.2%,

OS: 15.4 months,

PFS: 5.7 months,

TRAEs: grade ≥ 3 82.5%

NCT04063163,

randomized, parallel assignment, double-blind, phase III study

Unknown status,

585 patients

[189]

Avelumab 800 mg IV q2w + Talazoparib 1 mg po daily

Phosphorylation

Advanced BC

\

NCT03964532, multi-institutional pilot phase I, II TALAVE trial

Active, not recruiting

\

Avelumab + Bempegaldesleukin (NKTR-214) + Talazoparib

Phosphorylation

Metastatic castration-resistant PC

\

NCT04052204,

phase I, II study

Terminated

\

Nivolumab + Rucaparib

Phosphorylation

OC, ovarian epithelial cancer, fallopian tube cancer, adenocarcinoma of the appendix

\

NCT03824704,

open label phase II, 2-stage, 2-cohort trial

Terminated

\

Nivolumab + Metformin

Phosphorylation

Stage III-IV NSCLC

\

NCT03048500,

single group,

open-label,

phase II study

Unknown status

\

Nivolumab or Pembrolizumab + Recombinant human EGF-rP64K/montanide ISA 51 Vaccine

Phosphorylation

Advanced NSCLC or HNSCC

\

NCT02955290,

nonrandomized, parallel assignment, open label, phase I, II study

Recruiting

\

Atezolizumab+

Olaparib

Phosphorylation

Locally advanced unresectable or metastatic non-HER2-positive BC

\

NCT02849496

randomized, crossover assignment, open label, phase II trial

Active, not recruiting

\

TSR-042 1000 mg IV d1, q6w + Niraparib 100 mg daily

Phosphorylation

First-line treatment of stage III or IV nonmucinous epithelial OC

\

NCT03602859,

randomized, parallel assignment, triple (participant, care provider, investigator), phase III trial

Active, not recruiting

\

TSR-042 + Niraparib

Phosphorylation

Metastatic or recurrent endometrial or oOC

\

NCT03651206, randomized, parallel assignment, open label, phase II, III, study

Active, not recruiting

\

TSR-042 500 mg IV q3w (cycle 1-4)

1000 mg q6w (cycle 5 until PD or toxicity, up to 27 months) + Niraparib Weight ≥ 77 kg (kg) and platelet count ≥ 150,000/microliter (µL) at baseline: 300 mg daily; others: 200 mg daily

Phosphorylation

Platinum resistant OC

\

NCT03955471,

single group assignment, open label, phase II, III, study

Terminated, 41 patients

\

Durvalumab + Olaparib

Phosphorylation

IDH mutated glioma

\

NCT03991832,

nonrandomized, parallel assignment, open label, phase II, study

Recruiting

\

Sintilimab 1200 mg q3w + Metformin 1000 mg

bid from day20

Phosphorylation

Extensive-stage SCLC

\

NCT03994744,

open-label, single-arm, phase II study

Unknown status,

68 patients

\

PDR001 + Ribociclib

Ubiquitination

Metastatic HR + BC or metastatic OC

\

NCT03294694,

nonrandomized, parallel assignment, open label, phase I study

Terminated,

33 patients

\

PDR001 + Ribociclib

Ubiquitination

NSCLC, HNSCC, ESCC, GC, CRC

\

NCT04000529,

nonrandomized, parallel assignment, open label, phase I study

Terminated,

122 patients

\

SHR-1210 200 mg IV q2w + SHR6390 150 mg or 100 mg po daily with 3 weeks on and 1 week off

Ubiquitination

Advanced CRC, NSCLC or HCC

\

NCT03601598,

single group assignment, open label, phase I, II study

Unknown status,

41 patients

\

Atezolizumab 1,200 mg IV d1

+Carboplatin 5 mg/mL/min + Etoposide 100 mg/m² IV, days 1–3, q3w

Glycosylation

Untreated extensive-stage SCLC

\

NCT02748889,

randomized, parallel assignment, open label, phase I, II study

Terminated

\

Nivolumab + RXC004

Palmitoylation

Advanced Malignancies

\

NCT03447470,

nonrandomized, sequential assignment, open label, phase I study

Active, not recruiting

\

Nivolumab 480 mg q4w + RXC004 1.5 mg daily po

Palmitoylation

Advanced Colorectal Cancer

\

NCT04907539,

open label, multicenter, multiarm, phase II study

Recruiting

\

Pembrolizumab + ETC-1,922,159

Palmitoylation

Advanced solid tumors

\

NCT02521844

nonrandomized, open-label, sequential evaluation of safety and dose, phase I study

Active, not recruiting

\

Pembrolizumab + CGX1321

Palmitoylation

Advanced GI tumors

\

NCT02675946

multicenter, open-label, dose escalation and expansion, phase I study

Unknown status

\