Table 2.

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

Therapy	Posttranslational modifications	Condition or disease	Efficacy & safety	Clinical trial No. & phase	Clinical trial status & cohort sizes	Ref. No
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	\