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Table 1 Melanoma trials evaluating combination checkpoint inhibition with anti-CTLA-4 plus anti- PD-1/PD-L1 monoclonal antibodies

From: Current landscape and future of dual anti-CTLA4 and PD-1/PD-L1 blockade immunotherapy in cancer; lessons learned from clinical trials with melanoma and non-small cell lung cancer (NSCLC)

Cancer type Phase Primary outcome Dosing regimen Enrollment number Status Results Clinical trials identification number
Unresectable Stage III/stage IV malignant melanoma Phase 1 Assess the safety of specified doses of NIVO + IPI combination therapy for up to 5.5 years; secondary outcome: assessment of tumor response Cohort 1: induction with NIVO 0.3 mg/kg (Q3W for 21 weeks) + IPI 3 mg/kg (Q3W for 9 weeks), maintenance with NIVO 0.3 mg/kg + IPI 3 mg/kg (Q12W for a total of 84 weeks); cohort 2: induction with NIVO 1 mg/kg (Q3W for 21 weeks) + IPI 3 mg/kg (Q3W for 9 weeks), maintenance with NIVO 1 mg/kg + IPI 3 mg/kg (Q12W for 84 weeks); cohort 3: induction with NIVO 3 mg/kg (Q3W for 21 weeks) + IPI 3 mg/kg (Q3W for 9 weeks), maintenance with NIVO 3 mg/kg + IPI 3 mg/kg (Q12W for 84 weeks); cohort 4: induction with NIVO 10 mg/kg (Q3W for 21 weeks) + IPI 3 mg/kg (Q3W for 9 weeks), maintenance with NIVO 10 mg/kg + IPI 3 mg/kg (Q12W for a total of 84 weeks); cohort 5: induction with NIVO 10 mg/kg (Q3W for 21 weeks) + IPI 10 mg/kg (Q3W for 9 weeks), maintenance with NIVO 10 mg/kg + IPI 10 mg/kg (Q12W for 84 weeks); cohort 6: NIVO 1 mg/kg (Q2W for 96 weeks); cohort 7: NIVO 3 mg/kg (Q2W for 96 weeks); cohort 8: 4 doses of IPI 3 mg/kg + NIVO 1 mg/kg (Q3W for 12 weeks), then monotherapy with NIVO 3 mg/kg (Q2W for 96 weeks) 136 Completed, results available 53% patients had grade 3–4 AE; NIVO 0.3 mg/kg + IPI 3 mg/kg (n = 14): 1 year OS rate = 56%, median OS = 14.8 months; NIVO 1 mg/kg + IPI 3 mg/kg (n = 17): 1 year OS rate = 94%, median OS non recordable; NIVO 3 mg/kg + IPI 1 mg/kg (n = 16): 1 year OS rate = 89%, median OS non recordable; NIVO 3 mg/kg + IPI 3 mg/kg (n = 6): 1 year OS rate = 100%, median OS non recordable; concurrent NIVO + IPI (n = 53): 1 year OS rate = 82%, median OS = 39.7 months; sequenced regimen (NIVO + IPI followed by monotherapy with NIVO Q2W for 48 doses, n = 32): median OS = 13.0 months, insufficient follow-up of 1 year OS rate. Subgroup analysis: OR in PD-L1 positive tumors: concurrent therapy: 6 of 13 patients, sequential therapy: 4 of 8 patients; OR in PD-L1 negative tumors: concurrent therapy: 9 of 22 patients; sequential therapy: 1 of 13 patients NCT01024231 [54]
Advanced melanoma Phase 1 Incidence of serious AE and treatment emergent AE; secondary outcomes: PFS, OS, ORR and duration of response (assessed up to week 49) Arm 1: NIVO Q2W + TAK 580 QW; arm 2: plozalizumab 2 mg QW for weeks 1, 3, 5 and 9, then plozalizumab Q4W + NIVO Q2W; arm 3: IPI (once in week 3, 6, 9 and 12) + NIVO (administered in weeks 3, 6, 9, 12 and 15, Q2W thereafter) and vedolizumab (once in weeks 1, 3, 5 and 13) 156 Recruiting NA NCT02723006
Stage III unresectable or stage IV melanoma Phase 1b To determine MTD of specified treatment regimen (time frame: 12 months); secondary outcome: ORR NIVO + IPI and ACY 241 36 Recruiting NA NCT02935790
BRAF mutant metastatic/unresectable melanoma Phase 1 RCT Incidence of AE (≥ grade 3 NCI CTCAE v4.0) evaluated up to 3 weeks after induction therapy with IPI; secondary outcomes: disease control rate and RR evaluated till 4 weeks after completion of therapy; proportion of patients with ≥ grade 3 AE after progression of disease on IPI Arm A1: trametinib QID + dabrafenib BID for the first 25 days, then 4 courses of IPI Q3W; arm A2: 25 days of trametinib QID + dabrafenib BID, then 4 courses of IPI + NIVO Q3W, maintenance with NIVO Q2W (42 courses); arm B1: 25 days of trametinib QID, then 4 courses of IPI Q3W; arm B2: 25 days of trametinib QID, then 4 courses of IPI + NIVO Q3W, maintenance with NIVO Q2W (42 courses); arm C1: dabrafenib BID for 25 days, then 4 courses of IPI Q3W; arm C2: 25 days of dabrafenib BID, then 4 courses of IPI + NIVO Q3W, maintenance with NIVO Q2W (42 courses); arm D1: 4 courses of IPI Q3W; arm D2: 4 courses of IPI + NIVO Q3W, maintenance with NIVO Q2W (42 courses) 40 Recruiting NA NCT01940809
Stage IIIC/IV skin melanoma Phase 1/Phase 2 Assess the safety of adjuvant NIVO + low-dose IPI Low fixed dose NIVO in combination with low fixed dose IPI 6 Recruiting NA NCT02941744
Uveal melanoma with liver metastases Phase 1/Phase 2 Evaluate tolerance and safety profile for treatment regimen (time frame: 3 years); secondary outcomes: PFS and RR (as per RECIST criteria) Yttrium 90 followed by 4 doses of NIVO 1 mg/kg + IPI 3 mg/kg Q3W; maintenance with NIVO 3 mg/kg monotherapy Q2W for a maximum of 3 years 18 Not yet recruiting NA NCT02913417
Metastatic melanoma Phase 1/ Phase 2 RCT Evaluation of grade 3–4 toxicity (treatment associated) event-free survival for up to 6 months Active comparator: 4 doses of NIVO 1 mg/kg IV + IPI 3 mg/kg IV Q3W, then monotherapy with NIVO 3 mg/kg Q2W; experimental arm: 4 doses of NIVO 1 mg/kg IV + IPI 0.3 mg/kg IT Q3W, followed by monotherapy with NIVO 3 mg/kg Q2W 65 Recruiting NA NCT02857569 (NIVIPIT)
Recurrent/advanced melanoma Phase 1/Phase 2 RCT Pathological complete RR; secondary outcome: ORR, PFS (time frame: 5 years) Arm A: 3 doses of NIVO 3 mg/kg Q2W, then surgery at weeks 6 to 8; maintenance with NIVO 3 mg/kg Q3W after surgery; Arm B: 2 doses of IPI 3 mg/kg + NIVO 1 mg/kg Q3W and then surgery; maintenance with 2 doses of NIVO 1 mg/kg + IPI 3 mg/kg Q3W, continued as NIVO 3 mg/kg at Q3W 66 Recruiting NA NCT02736123
Advanced melanoma/renal cell carcinoma Phase 1/ Phase 2 RCT PFS, the number of study participants with AE (evaluation for up to 2 years), those discontinuing of study due to AE (evaluation for up to 2 years) and the patients that experienced DLT (assessed up to 6 weeks); secondary outcomes: OS, duration of response and ORR for phase 1b and 2 Arm 1: PEMBRO monotherapy; arm 2: two 6-weeks cycles of PEMBRO + IPI Q3W; arm 3: pegIFN-2b QW for each cycle (cycle duration: 6 weeks) + PEMBRO Q3W 343 Completed (October 17, 2016 cut-off date): 153 participants received a minimum of 1 dose of PEMBRO + IPI; 72% (110 of 153 patients) received all 4 doses of PMEBRO + IPI; 42% (64 of 153 patients) were on PEMBRO monotherapy; - TRAEs: 45% (69 of 153 patients) developed grade 3–4 TRAEs, 51% (78 of 153 patients) developed grade 1–2 TRAEs; irAEs: seen in 60% (92 of 153) participants, 27% (42 of 153 patients) documented to have grade 3–4 irAEs OR: 61% (93 of 153 patients, 95%CI: 53–69) - CR: 15% (23 of 153 patients) - PR: 46% (70 of 153 patients) - SD: 18% (28 of 153 patients) - PD: 19% (29 of 153 patients) - PFS at 12 months: 69% (95%CI: 60–75) NCT02089685; KEYNOTE-029 [58]
Melanoma with leptomeningeal metastases Phase 2 OS rate assessed at 2 years Pre-determined doses of IPI + NIVO combination therapy, then monotherapy with NIVO, duration of each treatment cycle to be 6 weeks 18 Not yet recruiting NA NCT02939300
Resected stage IIIB/IIIC/IV melanoma Phase 2 Evaluation of adverse effects with specified treatment regimen; secondary outcomes: time to relapse and immunological response Cycle 1: 4 doses of IPI 1 mg/kg + NIVO 3 mg/kg Q3W for 12 weeks; cycles 2, 3, 4 and 5: monotherapy with NIVO 480 mg Q4W for 48 weeks 25 Not yet recruiting NA NCT02970981
Stage III/resected stage IV melanoma Phase 2 Recurrence free survival and OS; evaluate toxicity of adjuvant low-dose IPI and NIVO for up to 7 months Adjuvant therapy with NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W, for a total of 6 months duration 25 Recruiting NA NCT02656706; BrUOG 324
Uveal melanoma Phase 2 OS at 12 months 4 doses of IPI + NIVO Q3W, then NIVO monotherapy Q2W 48 Recruiting NA NCT02626962; GEM1402
Uveal melanoma Phase 2 ORR at 12 weeks Induction phase: 4 doses of IPI 3 mg/kg + NIVO 1 mg/kg at week 1, 4, 7 and 10, continued through week 12; maintenance phase: monotherapy with NIVO 3 mg/kg Q2W for study participants with unmanageable toxicity or no progression after 12 weeks of induction therapy, to be continued till progression or unacceptable toxicity 52 Recruiting NA NCT01585194
Advanced melanoma Phase 2 RR, evaluated up to 16 weeks; secondary outcomes: PFS assessed up to 24 months and safety IPI + PEMBRO (all study participants to have received initial PD-1/PD-L1 antibody therapy prior to enrollment as per selection criteria) 70 Recruiting NA NCT02743819
Advanced mucosal/acral lentiginous melanoma Phase 2 OR rate for mucosal melanoma (assessed up to 2 years); secondary outcomes: OR rate for acral lentiginous melanoma, PFS, OS Induction phase: 4 doses of IPI 3 mg/kg + NIVO 1 mg/kg Q3W; maintenance phase: monotherapy with NIVO 3 mg/kg Q2W for 48 doses; NIVO monotherapy to be continued for another 12 weeks in study participants demonstrating CR 72 Not yet recruiting NA NCT02978443
Melanoma Phase 2 Evaluation of clinical benefit rate up to 6 months Induction: IPI + NIVO; maintenance phase: NIVO only 110 Recruiting NA NCT02320058; CheckMate 204
Advanced melanoma/bladder cancer Phase 2 Evaluation of RR up to 12 weeks Treatment regimen for melanoma patients: 4 doses of NIVO 1 mg/kg + IPI 3 mg/kg Q2W 120 Recruiting NA NCT02553642
Stage III/IV melanoma with progression/relapse on PD-1 inhibitor therapy Phase 2 RCT Pathological CR with neoadjuvant IPI + NIVO combination therapy and neoadjuvant NIVO monotherapy, assessed at day 57 Group A: Neoadjuvant therapy with NIVO 3 mg/kg on weeks 1, 3, 5 and 7, then surgical excision, later adjuvant phase with NIVO 3 mg/kg Q2W for 6 months; group B: neoadjuvant therapy with IPI 3 mg/kg and NIVO 1 mg/kg on weeks 1, 4 and 7, then surgical excision and later adjuvant therapy same as group A 40 Recruiting NA NCT02519322
Stage III/IV melanoma with progression/relapse on PD-1 inhibitor therapy Phase 2 RCT OR as per RECIST v1.1 (time frame: 18 weeks) Experimental arm 1: 4 doses of NIVO 1 mg/kg + IPI 3 mg/kg Q3W; experimental arm 2: 4 doses of IPI 3 mg/kg monotherapy Q3W 70 Recruiting NA NCT02731729
Melanoma with brain metastases Phase 2 RCT Intracranial response rate assessed for up to 3 years; secondary outcomes: ORR, PFS, OS, extracranial response Cohort 1: monotherapy with NIVO 3 mg/kg Q2W; cohort 2: monotherapy with NIVO 3 mg/kg Q2W; cohort 3: 4 doses of NIVO 1 mg/kg + IPI 3 mg/kg Q3W, followed by NIVO 3 mg/kg Q2W 76 Recruiting NA NCT02374242
Stage III melanoma Phase 2 RCT Pathological response rate at 6 weeks; RR (assessed up to 6 weeks); incidence of treatment related AE (time frame: 12 weeks) Arm A: 2 cycles of NIVO 1 mg/kg + IPI 3 mg/kg before surgery at week 6; arm B: 2 cycles of NIVO 3 mg/kg + IPI 1 mg/kg before surgery at week 6; arm C: 2 cycles of NIVO 3 mg/kg + IPI 3 mg/kg before surgery at week 6 90 Recruiting NA NCT02977052
Advanced/metastatic melanoma Phase 2 RCT Determining the percent candidates that develop grade 3–5 AE attributable to induction therapy (time frame: 25 weeks); secondary outcomes: investigator assessed duration of response, RR and rate of progression Cohort A: NIVO preceding IPI: induction with 6 doses of NIVO 3 mg/kg IV Q2W, to be continued in maintenance phase for up to 2 years; 4 doses of IPI 3 mg/kg Q3W in induction phase only; Cohort B: IPI preceding NIVO: 4 doses of IPI 3 mg/kg Q3W in induction phase only; 6 doses of NIVO 3 mg/kg IV Q2W during induction, continued in maintenance phase for up to 2 years 177 Results available - Grade 3–5 TRAEs Cohort A: 34 of 68 patients (95%CI: 37.6–62.4); Cohort B: 30 of 70 patients (95%CI: 31.1–55.3) - Response at 25 weeks: Cohort A: 41% (28 patients, 95%CI: 29.4–53.8); Cohort B: 20% (14 patients, 95%CI: 11.4–31.3) - 12 months OS: Cohort A: 76% (95%CI: 64–85) Cohort B: 54% (95%CI: 42–65) NCT01783938; CheckMate 064 [57]
Previously untreated unresectable/metastatic melanoma Phase 2 RCT Percent study participants (BRAF wild-type) with OR (time frame: 6 months or more) Experimental regimen 1: 4 doses of NIVO 1 mg/kg + IPI 3 mg/kg Q3W followed by monotherapy with NIVO 3 mg/kg Q2W; experimental regimen 2: placebo + 4 doses of IPI 3 mg/kg Q3W followed by placebo Q2W 179 Completed, results available Participants with BRAF wild-type tumors: OR and CR with placebo: 11% (4 of 37 patients, 95%CI: 3 to 25) and 0%, respectively; OR and CR with combination therapy: 61% (44 of 72 patients, 95%CI: 49 to 72) and 22% (16 patients), respectively; HR = 0.40 (95%CI: 0.23 to 0.68, p < 0.001) for death or progression of disease when comparing IPI + NIVO combination therapy versus IPI + placebo. Participants with BRAF mutant tumors: OR and CR with placebo: 10% (1 of 10 patients, 95%CI: 0 to 45) and 0%, respectively; OR and CR with combination therapy: 52% (12 of 23 patients, 95%CI: 31 to 73) and 22% (5 patients), respectively; HR = 0.38 (95%CI: 0.15 to 1.00); Subgroup analysis: OR rate with combination therapy: PD-L1 positive tumors: 58, 95%CI: 37 to 78, PD-L1 negative tumors: 55, 95%CI: 41 to 69); OR with IPI monotherapy: PD-L1 positive tumors: 18% (95%CI: 2 to 52), PD-L1 negative tumors: 4% (95%CI: 0 to 19) NCT01927419; CheckMate 069 [53]
Melanoma Phase 2 RCT Evaluation of the best ORR at 18 weeks; secondary outcomes: OS and PFS Experimental arm: induction with cobimetinib + vemurafenib for 6 weeks followed by NIVO + IPI; Control arm: NIVO + IPI only 200 Not yet recruiting NA NCT02968303
BRAF mutant metastatic melanoma Phase 2 RCT OS evaluated up to 24 months; secondary outcomes: PFS (time frame: 2 years), 3 year PFS rate, duration of response (evaluated for 24 months) Arm A: binimetinib 45 mg BID + encorafenib 450 mg OD till progression, then 4 doses of NIVO 1 mg/kg + IPI 3 mg/kg Q3W and later NIVO 3 mg/kg Q2W; arm B: 4 doses of IPI 3 mg/kg + NIVO 1 mg/kg Q3W, later NIVO 3 mg/kg Q2W till disease progression, binimetinib 45 mg BID + encorafenib 450 mg OD till progression; arm C: binimetinib 45 mg BID + encorafenib 450 mg OD for 8 weeks, then 4 doses of NIVO 1 mg/kg + IPI 3 mg/kg Q3W and later NIVO 3 mg/kg Q2W till progression. Thereafter, treatment continued with binimetinib 45 mg BID + encorafenib 450 mg OD till progression of disease 230 Recruiting NA NCT02631447; SECOMBIT study
Malignant melanoma Phase 2 RCT Evaluation of efficacy with adjuvant therapy with NIVO + IPI or NIVO monotherapy (time frame: 24 months) Active comparator: Placebo + NIVO: IPI substituted with placebo for weeks 1, 4, 7 and 10; NIVO substituted with placebo for weeks 4 and 10; Experimental regimen: 4 doses of IPI 3 mg/kg + NIVO 1 mg/kg Q3W, placebo to replace NIVO on weeks 3, 5, 9 and 11, monotherapy with NIVO 3 mg/kg Q2W to be continued during maintenance phase for 1 year after induction or disease progression 312 Recruiting NA NCT02523313
Treatment naïve unresectable/metastatic advanced melanoma Phase 3 To determine the incidence of TRAE; Secondary outcomes: ORR and PFS (time frame: 20 weeks) Arm 1: concomitant NIVO + IPI followed by monotherapy with NIVO; arm 2: sequential administration of NIVO and IPI, followed by monotherapy with NIVO 102 Recruiting NA NCT02905266
Stage III unresectable or stage IV melanoma Phase 3 TRAE for up to 24 months; secondary outcomes: PFS (investigator assessed), OS, ORR NIVO monotherapy or NIVO + IPI combination therapy 615 Recruiting NA NCT02599402; CheckMate 401
Stage III/IV melanoma Phase 3 RCT OS rate at the end of 2 years follow-up; secondary outcomes: PFS and RR Arm A: induction with 2 courses of NIVO + IPI Q6W, maintenance with NIVO monotherapy Q6W for a total of 12 courses, patients cross over to arm C if disease progresses; arm D: induction with 2 courses of NIVO + IPI Q6W, maintenance with NIVO monotherapy Q6W for a total of 12 courses 300 Recruiting NA NCT02224781
Treatment naïve unresectable/metastatic advanced melanoma Phase 3 RCT To determine the incidence of TRAE; Secondary outcomes: ORR, PFS, OS Arm 1: IPI 1 mg/kg + NIVO 3 mg/kg; arm 2: IPI 1 mg/kg + NIVO 6 mg/kg; arm 3: IPI 3 mg/kg + NIVO 1 mg/kg 340 Recruiting NA NCT02714218
Treatment naïve unresectable/metastatic advanced melanoma Phase 3 RCT OS (time frame: 44.1 months), PFS (time frame: up to 5 years) Arm A: NIVO 3 mg/kg Q2W + placebo substituting IPI on weeks 1 and 4, followed by placebo substituting NIVO on week 4 for cycle 1 and 2; Arm B: 4 doses of NIVO 1 mg/kg + IPI 3 mg/kg Q3W followed by NIVO 3 mg/kg Q2W (placebo substituting NIVO on 3rd and 5th weeks for cycle 1 and 2; Arm C: 4 doses of IPI 3 mg/kg Q3W + placebo (replacing NIVO on 3rd and 5th weeks for cycles 1 and 2) 915 Completed, results available OR: NIVO+IPI 58%, NIVO mono 44%, IPI mono 19%; CR: NIVO+IPI 19%, NIVO mono 16%, IPI mono 5%; Median PFS: NIVO monotherapy: 6.9 months (95%CI: 4.3 to 9.5), IPI monotherapy: 2.9 months (95%CI: 2.8 to 3.4) and IPI + NIVO: 11.5 months (95%CI: 8.9 to 16.7); median PFS for participants with PD-L1 positive malignancy: 14.0 months in NIVO arm and combination therapy arm; median PFS for participants with PD-L1 negative malignancy: 5.3 months (95%CI: 2.8 to 7.1) for NIVO monotherapy and 11.2 months (95%CI: 8.0 - not reached) for IPI + NIVO; OS at 2 years: NIVO+ IPI 64%, NIVO monotherapy 59% and IPI monotherapy 45%; OS at 3 years: NIVO+ IPI 58%, NIVO monotherapy 52% and IPI monotherapy 34%; median OS NIVO+ IPI-not reached (95%CI 38.2 months - not reached), NIVO monotherapy-37.6 months (95%CI: 29.1 - not reached) and IPI monotherapy-19.9 months (95%CI: 16.9–24.9); Grade 3–4 TRAEs: NIVO+IPI 59%, NIVO mono 21%, IPI mono 28% NCT01844505; CheckMate 067 [56]
  1. Abbreviations: MTD maximum tolerable dose, DLT dose limiting toxicity, RCT randomized controlled trial, NA not available, CI confidence interval, ORR overall response rate, OS overall survival, PFS progression free survival, RR response rate, OR objective response, CR complete response, PR partial response, SD stable disease, PD progressive disease, TRAE Treatment-related adverse events, irAE immune related adverse events, OD once daily dosing, BID twice daily, QID four times a day, NIVO, nivolumab, IPI ipilimumab, PEMBRO pembrolizumab, RECIST response evaluation criteria in solid tumors, NCI CTCAE National Cancer Institute common terminology criteria for adverse events, Q(x)W, every (x) weeks; D(x), day(x); TRAE treatment related adverse events, AE adverse events