Table 2.
Selected studies of ICI monotherapy or combination therapy in gynecological cancers, with emphasis on biomarker-based subgroup responses. In most studies, not all patients were evaluated regarding biomarker status, notable in cases where the numbers do not add up to total number of patients. In several studies, subgroup analyses based on biomarker status reported outcomes should be interpreted cautiously, as they have not been powered enough.
| Trial | Phase | Intervention | Study Population and Biomarker Status (Number of Patients) | Outcomes | |||
|---|---|---|---|---|---|---|---|
| Endometrial Cancer—ICI Monotherapy | |||||||
| KEYNOTE—158 [37] | 2 | Pembro | A/R/M disease, ≥1 PST | MSI-H/dMMR (49) | ORR 57%, mPFS 25.7 mo | ||
| TMB-H (15) a | ORR 46% | ||||||
| Non-TMB-H (67) a | ORR 6% | ||||||
| GARNET [54] | 1 | Dostarlimab | A/R/M disease, ≥1 PST | MSI-H/dMMR (103) | ORR 46% (CR in 10.7%), DCR 59% | ||
| MSS/MMRp (156) | TMB-H a (141) | ORR 13% | ORR 45.5% | ||||
| Non TMB-H a (13) | DCR 35% | ORR 12.1% | |||||
| Endometrial Cancer—ICI Combined with Other Agents | |||||||
| KEYNOTE-775 [60] | 3 | Pembro + Lenvatinib vs. Chemo | A/R/M disease, ≥ 1 PST | All patients (827) | ORR 31.9% vs. 14.7%; mPFS 7.2 vs. 3.8 mo; mOS 18.3 vs. 11.4 mo | ||
| MSI-H/dMMR (130) | ORR 40% vs. 12.3%; mPFS 10.7 vs. 3.7 mo; mOS NR vs. 8.6 mo | ||||||
| MSS/MMRp (697) | ORR 30.3% vs. 15.1%; mPFS 6.6 vs. 3.8 mo; mOS 17.4 vs. 12.0 mo | ||||||
| KEYNOTE-158 [76] | 2 | Pembro | A/R/M disease, 78% pts received ≥1 PSTs | All patients (98) | ORR 12.2%, DCR 30.6% | ||
| PD-L1+ b (82) | ORR 14.6%, DCR 32.9% | ||||||
| PD-L1– b (15) | ORR 0%, DCR 20% | ||||||
| CHECKMATE-358 [78] | 1/2 | Nivo | A/R/M disease, ≥1 PST | All patients (24), of those 10 PD-L1+, 6 PD-L1−, 3 NA c | ORR 26.3%, DCR 68.4%, mPFS 5.1 mo | ||
| EMPOWER-Cervical 1 [79] | 3 | Cemiplimab vs. Chemo | Recurrent/metastatic ≥1 prior syst. Th. | All patients (608) | mOS 12 v 8.5 mo | ||
| PD-L1+ d (162) | mOS ~ 14.5 vs. 9 mo | ||||||
| PD-L1– d (92) | mOS ~ 8 vs. 6 mo | ||||||
| Uterine Cervical Cancer—ICI Combined with Other Agents | |||||||
| KEYNOTE-826 [82] | 3 | SoC + pembro vs. SoC (Platinum-based doublet + bev) |
A/R/M, no PST (first line) | All patients (619) | mPFS 10.4 vs. 8.2; HRPO 0.65 | ||
| PD-L1 CPS 1 (35, 11%) | HRPO 0.94 | ||||||
| PD-L1 CPS ≥ 1 (548, 88%) | mPFS 10.4 vs. 8.2 mo; HRPO 0.62 | ||||||
| PD-L1 CPS >10 (158, 51%) | mPFS 10.4 vs. 8.1 mo; HRPO 0.58 | ||||||
| Uterine Cervical Cancer—ICI Combined with Another ICI | |||||||
| CHECKMATE-358 [86] | 1/2 | Ipi + nivo | A/R/M, 0–2 PST | All patients(91) | ORR 46%, mPFS 8.5 mo, mOS 25.4 mo | ||
| RaPiDS [87] | 2 | Balstilimab+/−zalifrelimab | A/R/M, ≥1 PST | Combination group (143) | All (143) | ORR 22% | |
| PD-L1+ b (55%) | ORR 27% | ||||||
| PD-L1– b (25%) | ORR 11 % | ||||||
| PD-L1 NA (20) | ORR 21% | ||||||
| Ovarian Cancer—ICI Monotherapy | |||||||
| NINJA [113] | 3 | Nivo vs. single -agent chemo (GEM or PLD) | Relapsed, platinum resistant | All (316) | mPFS 2 vs. 3.8 mo; mOS 10.1 vs. 12.1 (favours chemo) | ||
| PD-L1+ (123) d | |||||||
| PD-L1− (189) d | |||||||
| Ovarian Cancer—ICI Combined with Other Agents | |||||||
| JAVELIN Ovarian 200 [114] | 3 | Ave (188) vs. Ave + PLD (188) vs. PLD (190) | Relapsed, platinum -resistant or refractory (no PST for platinum resistant disease) | All (566) | PD-L1+ e (288) | ORR 4% vs. 13% vs. 4%; DCR 33% vs. 49% vs. 57% |
|
| PD-L1– e (220) | |||||||
| TIL+ f (228) | |||||||
| TIL– f (227) | |||||||
| JAVELIN Ovarian 100 [115] | 3 | PDC + maintenance Ave vs. PDC + Ave + maintenance Ave vs. PDC | First line—ACT or NACT | All (998) | PD-L1+ e (477) | mPFS 16.8 vs. 18.1 vs. NE Mo; HRP 1.43 vs. 1.14 vs. 1 (results favour PDC) | HRP 1.23 vs. 0.98 vs. 1 |
| PD-L1– e (326) | HRP 1.02 vs. 1.36 vs. 1 | ||||||
| gBRCA mut. (93) | HRP 1.98 vs. 2.51 vs. 1 | ||||||
| gBRCA wt (854) | HRP 1.32 vs. 1.14 vs. 1 | ||||||
| Kunde et.al. [117] | 2 | Pembro + metronomical CPA + bev | Relapsed, platinum—sensitive (25%) and platinum—resistant (75%) | 40 patients | BRCA g mut 35% | ORR 47.5%, DCR 95%, mPFS 10 mo | / |
| BRCA g wt 57.5% | / | ||||||
| PD-L1+ h 47.5% | ORR 52.6% | ||||||
| PD-L1– h 42.5% | ORR 35.3% | ||||||
| IMagyno-050 [118] | 3 | PDC + bev vs. PDC + bev + atezolizumab | First line—ACT or NACT | All patients (1301) | mPFS 18.4 vs. 19.5 (HRP 0.92) | ||
| PD-L1 < 1% IC i (517) | |||||||
| PD-L1 ≥ 1% IC i (784) | |||||||
| PD-L1 ≥ 5% IC i (260) | |||||||
| PD-L1 >= 1% TC i (73) | |||||||
| LEAP-005 [119] | 2 | Lenvatinib + pembro | Relapsed, 3 PST, (80% platinum resistant/refractory) | All patients (31) | ORR 32%, DCR 74%, mPFS 4.4 mo | ||
| TOPACIO/KEYNOTE-162 [120] | 1/2 | Niraparib + pembro | Relapsed, platinum sensitive and resistant disease, 1–5 PST; median number of PSTs was 3 | All patients (60) | ORR 18%, DCR 65% | ||
| tBRCAj | Mut(11, 18%) | ORR 18% | |||||
| Wt(49, 79%) | ORR 18% | ||||||
| PD-L1 k | +(35, 56%) | ORR 21% | |||||
| −(21, 34% | ORR 10% | ||||||
| HRDb | +(22, 35%) | ORR 14% | |||||
| −(33, 53% | ORR 19% | ||||||
| MEDIOLA [121,137] | 2 | Olaparib + durva | Relapsed, platinum sensitive, ≥ 1 PST | gBRCA mut (32) (doublet) | ORR 71.9%, mPFS 11.1 mo | ||
| sBRCA mut. (32) (doublet) | ORR 31 %, mPFS 5.5 mo | ||||||
| Olaparib + durva + bev | sBRCA mut. (31) (triplet) | ORR 77%, mPFS 14.7 mo | |||||
| Ovarian Cancer—ICI Combined with Another ICI | |||||||
| NRG-GY003 [123] | 2 | Nivo vs. Nivo + ipi |
Relapsed, 1–3 PST, platinum resistant or platinum sensitive, PFI < 12 mo | All (100) | mPFS 2 vs. 3.9 mo; mOS 22 vs. 28 mo | ||
| Nivo or Nivo + Ipi (pooled data) |
Any PD-L1 in TC l | +(5) | ORR 36%, mPFS 2.5 mo | ||||
| −(26) | ORR 23%, mPFS 4 mo | ||||||
| PD-L1 ≥ 1% in IC l | +(20) | ORR 31%, mPFS 4 mo | |||||
| −(11) | ORR 19%, mPFS 2.3 mo | ||||||
| Vulvar Cancer | |||||||
| KEYNOTE-028 [25] | 1 b | Pembro | Advanced, PD-L1 positive h | All (18) | ORR 6%, mPS 3.1 mo, mOS 3.8 mo | ||
| CHECKMATE-358 [78] | 1/2 | Nivo | Advanced | All (5), of those 4 PD-L1+ m, 1 pt NA | ORR 20%, DCR 80% | ||
a—TMB-H was defined as ≥ 10 mut/Mb as per FoundationOne CDx assay; b—tumors with PD-L1 CPS ≥ 1 and <1 by IHC were regarded as PD-L1 positive or negative, respectively; c—Tumor cell PD-L1 expression was defined as the percentage of tumor cells exhibiting plasma membrane staining at any intensity; d—tumors with PD-L1 TPS ≥ 1 and <1 by IHC were regarded as PD-L1 positive or negative, respectively; e—A sample was considered PD-L1- positive if either at least 1% of assessed tumor cells expressed membranous PD-L1, at least 5% of immune cells within the tumor area expressed PD-L1, or both; f—Tumor infiltrating lymphocytes (CD8+) are associated with prognosis. A sample was considered TIL positive if at least 1% of cells within the tumor area expressed CD8; g—in this study mutation status included germline and somatic mutations; h—PD-L1 positivity was defined by the presence of the interface pattern staining or a modified; proportion score ≥1%; i—in this study PD-L1 status was segregated in more groups, depending on the IHC staining on immune cells (IC) or tumor cells (TC). Results in PD-L1 ≥ 1% TC were encouraging, but the group had small number of patients who largely overlap with PD-L1 ≥ 1% IC population; j—BRCA mutation status was assessed using the Myriad genetics assay; k—HRD status was assessed using the Myriad genetics assay; l—in this study PD-L1 status was determined separately on tumor or immune cells by IHC staining; In contrast to other studies, this also included a category where any staining of tumor cells was regarded as PD-L1 positive; m—PD-L1 + was defined as PD-L1 ≥ 1% TC or PD-L1 CPS > 1. PLD: pegylated liposomal doxorubicin; PST: past systemic therapy; HRD: homologous recombination deficiency; vs.: versus; ACT: adjuvant chemotherapy; NACT: neoadjuvant chemotherapy; PDC: platinum-based doublet chemotherapy; Maint.: maintenance; NE: not estimable; 5%PFS: lower bound of 95% CI for PFS (as mPFS is not estimable in all subgroups); Mo: months; HRP: HR (hazard ratio) for PFS; HRPO: HR (hazard ratio) for PFS or OS; CPA: cyclophosphamideMut.: mutated; Nivo: nivolumab; Ipi: ipilimumab; TC: tumor cells; IC: immune cells; NA: not assessed; Chemo: chemotherapy; Ave: avelumab; Bev: bevacizumab; A/R/M: advanced/recurrent/metastatic; SoC: standard of care; GEM: gemcitabine; gBRCA: germline BRCA status (mutated (mur) /wild-type (wt)); tBRCA: tumor/somatic BRCA status (mutated (mur) /wild-type (wt)).