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

Cancer typePhasePrimary outcomeDosing regimenEnrollment numberStatusResultsClinical trials identification number
Unresectable Stage III/stage IV malignant melanomaPhase 1Assess the safety of specified doses of NIVO + IPI combination therapy for up to 5.5 years; secondary outcome: assessment of tumor responseCohort 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)136Completed, results available53% 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 patientsNCT01024231 [54]
Advanced melanomaPhase 1Incidence 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)156RecruitingNANCT02723006
Stage III unresectable or stage IV melanomaPhase 1bTo determine MTD of specified treatment regimen (time frame: 12 months); secondary outcome: ORRNIVO + IPI and ACY 24136RecruitingNANCT02935790
BRAF mutant metastatic/unresectable melanomaPhase 1 RCTIncidence 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 IPIArm 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)40RecruitingNANCT01940809
Stage IIIC/IV skin melanomaPhase 1/Phase 2Assess the safety of adjuvant NIVO + low-dose IPILow fixed dose NIVO in combination with low fixed dose IPI6RecruitingNANCT02941744
Uveal melanoma with liver metastasesPhase 1/Phase 2Evaluate 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 years18Not yet recruitingNANCT02913417
Metastatic melanomaPhase 1/ Phase 2 RCTEvaluation of grade 3–4 toxicity (treatment associated) event-free survival for up to 6 monthsActive 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 Q2W65RecruitingNANCT02857569 (NIVIPIT)
Recurrent/advanced melanomaPhase 1/Phase 2 RCTPathological 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 Q3W66RecruitingNANCT02736123
Advanced melanoma/renal cell carcinomaPhase 1/ Phase 2 RCTPFS, 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 2Arm 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 Q3W343Completed(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 irAEsOR: 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 metastasesPhase 2OS rate assessed at 2 yearsPre-determined doses of IPI + NIVO combination therapy, then monotherapy with NIVO, duration of each treatment cycle to be 6 weeks18Not yet recruitingNANCT02939300
Resected stage IIIB/IIIC/IV melanomaPhase 2Evaluation of adverse effects with specified treatment regimen; secondary outcomes: time to relapse and immunological responseCycle 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 weeks25Not yet recruitingNANCT02970981
Stage III/resected stage IV melanomaPhase 2Recurrence free survival and OS; evaluate toxicity of adjuvant low-dose IPI and NIVO for up to 7 monthsAdjuvant therapy with NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W, for a total of 6 months duration25RecruitingNANCT02656706; BrUOG 324
Uveal melanomaPhase 2OS at 12 months4 doses of IPI + NIVO Q3W, then NIVO monotherapy Q2W48RecruitingNANCT02626962; GEM1402
Uveal melanomaPhase 2ORR at 12 weeksInduction 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 toxicity52RecruitingNANCT01585194
Advanced melanomaPhase 2RR, evaluated up to 16 weeks; secondary outcomes: PFS assessed up to 24 months and safetyIPI + PEMBRO (all study participants to have received initial PD-1/PD-L1 antibody therapy prior to enrollment as per selection criteria)70RecruitingNANCT02743819
Advanced mucosal/acral lentiginous melanomaPhase 2OR rate for mucosal melanoma (assessed up to 2 years); secondary outcomes: OR rate for acral lentiginous melanoma, PFS, OSInduction 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 CR72Not yet recruitingNANCT02978443
MelanomaPhase 2Evaluation of clinical benefit rate up to 6 monthsInduction: IPI + NIVO; maintenance phase: NIVO only110RecruitingNANCT02320058; CheckMate 204
Advanced melanoma/bladder cancerPhase 2Evaluation of RR up to 12 weeksTreatment regimen for melanoma patients: 4 doses of NIVO 1 mg/kg + IPI 3 mg/kg Q2W120RecruitingNANCT02553642
Stage III/IV melanoma with progression/relapse on PD-1 inhibitor therapyPhase 2 RCTPathological CR with neoadjuvant IPI + NIVO combination therapy and neoadjuvant NIVO monotherapy, assessed at day 57Group 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 A40RecruitingNANCT02519322
Stage III/IV melanoma with progression/relapse on PD-1 inhibitor therapyPhase 2 RCTOR 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 Q3W70RecruitingNANCT02731729
Melanoma with brain metastasesPhase 2 RCTIntracranial response rate assessed for up to 3 years; secondary outcomes: ORR, PFS, OS, extracranial responseCohort 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 Q2W76RecruitingNANCT02374242
Stage III melanomaPhase 2 RCTPathological 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 690RecruitingNANCT02977052
Advanced/metastatic melanomaPhase 2 RCTDetermining 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 progressionCohort 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 years177Results available- Grade 3–5 TRAEsCohort 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 melanomaPhase 2 RCTPercent 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 Q2W179Completed, results availableParticipants 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]
MelanomaPhase 2 RCTEvaluation of the best ORR at 18 weeks; secondary outcomes: OS and PFSExperimental arm: induction with cobimetinib + vemurafenib for 6 weeks followed by NIVO + IPI; Control arm: NIVO + IPI only200Not yet recruitingNANCT02968303
BRAF mutant metastatic melanomaPhase 2 RCTOS 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 disease230RecruitingNANCT02631447; SECOMBIT study
Malignant melanomaPhase 2 RCTEvaluation 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 progression312RecruitingNANCT02523313
Treatment naïve unresectable/metastatic advanced melanomaPhase 3To 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 NIVO102RecruitingNANCT02905266
Stage III unresectable or stage IV melanomaPhase 3TRAE for up to 24 months; secondary outcomes: PFS (investigator assessed), OS, ORRNIVO monotherapy or NIVO + IPI combination therapy615RecruitingNANCT02599402; CheckMate 401
Stage III/IV melanomaPhase 3 RCTOS rate at the end of 2 years follow-up; secondary outcomes: PFS and RRArm 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 courses300RecruitingNANCT02224781
Treatment naïve unresectable/metastatic advanced melanomaPhase 3 RCTTo determine the incidence of TRAE; Secondary outcomes: ORR, PFS, OSArm 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/kg340RecruitingNANCT02714218
Treatment naïve unresectable/metastatic advanced melanomaPhase 3 RCTOS (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)915Completed, results availableOR: 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]

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