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Table 2 NSCLC 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
Stage IV NSCLC Phase 1 Evaluation of treatment related toxicity of specified treatment regimen in ALK/EGFR mutated NSCLC patients for up to 36 months; secondary outcomes: OS, PFS, RR evaluated up to 36 months Arm 1 (EGFR mutant NSCLC): 4 doses of IPI 3 mg/kg + erlotinib 150 mg OD (or the tolerable dose); arm 2 (ALK positive NSCLC): 4 doses of IPI 3 mg/kg + crizotinib 250 mg BID (or tolerable dose); arm 3 (EGFR mutant NSCLC): erlotinib 150 mg OD (or tolerable dose) + NIVO 240 mg Q2W; arm D (ALK positive NSCLC): crizotinib 250 mg BID (or tolerable dose) + NIVO 240 mg Q2W 14 Active, not recruiting NA NCT01998126
Stage IIIb/IV NSCLC Phase 1 RCT Evaluate safety of specified treatment regimens; secondary outcomes: Evaluation of ORR and PFS rate (time frame: up to 24 weeks) Arm A: gemcitabine + cisplatin and NIVO; arm B: pemetrexed + cisplatin and NIVO; arm C: carboplatin + paclitaxel and NIVO; arm D: NIVO + maintenance with bevacizumab; arm E: erlotinib + NIVO; arm F: NIVO; arm G (squamous NSCLC): IPI + NIVO; arm H (non-squamous NSCLC): IPI + NIVO; arm I (squamous NSCLC): IPI + NIVO; arm J (non-squamous NSCLC): IPI + NIVO; arm K (squamous NSCLC): NIVO; arm L (non-squamous NSCLC): NIVO; arm M (NSCLC with asymptomatic and untreated brain metastases): NIVO; arm N (NSCLC with any histology): IPI + NIVO; arm O: IPI + NIVO; arm P: IPI + NIVO; arm Q: IPI + NIVO; arm R: IPI + NIVO; arm S: IPI + NIVO 412 Completed NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q12W (n = 38): grade 3–4 TRAE: 37%, ORR: 47% (95%CI: 31–64), median PFS: 8.1 months (95%CI: 5.6–13.6), 1 year OS rate: not calculated; NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W (n = 39): grade 3–4 TRAE: 33%, ORR: 39% (95%CI: 23–55), median PFS: 3.9 months (95%CI: 2.6–13.2), 1 year OS rate: 69% (95% CI: 52–81); NIVO 3 mg/kg Q2W (n = 52): grade 3–4 TRAE: 19%, ORR: 23% (95%CI: 13–37), median PFS: 3.6 months (95%CI: 2.3–6.6), 1 year OS rate: 73% (95% CI: 59–83); ORR for tumors having PD-L1 expression of ≥1% was reported as 57% and ORR for tumors having PD-L1 expression of ≥50% was reported as 92% with NIVO + IPI; ORR for tumors having PD-L1 expression of ≥1% was reported as 28% and ORR for tumors having PD-L1 expression of ≥50% was reported as 50% with NIVO monotherapy NCT01454102; CheckMate 012 [60]
Advanced NSCLC Phase 1b OR assessed at 24 weeks, number of study participants experiencing DLT and number of participants that report treatment associated toxicities Participants enrolled in dose escalation arm and all experimental arms receive MEDI4736 + tremelimumab combination therapy 747 Active, not recruiting, preliminary results available OR in tremelimumab 1 mg/kg combination therapy cohort: Overall: 23% (6 of 26 patients, 95%CI: 9 to 44); PD-L1 positive tumors: 22% (2 of 9 patients, 95%CI: 3 to 60); PD-L1 negative tumors: 29% (4 of 14 patients, 95%CI: 8 to 58); MTD exceeded for therapy with tremelimumab 3 mg/kg + MEDI4736 20 mg/kg with DLT of 30% (2 of 6 patients) NCT02000947 [62]
NSCLC with brain metastases Phase 1/Phase 2 Recommended phase 2 dose of NIVO + stereotactic radiosurgery/ NIVO + whole brain radiation therapy/ NIVO + IPI and stereotactic radiosurgery/ NIVO + IPI and whole brain radiation therapy; the observed MTD from phase 1 to become the starting dose for phase 2 Experimental arm 1: NIVO 3 mg/kg Q2W + stereotactic surgery; experimental arm 2: NIVO 3 mg/kg Q2W + whole brain radiation therapy 30 Gy in 10 fractions; experimental arm 3: NIVO MTD as decided in phase 1 + IPI 1 mg/kg Q6W and stereotactic radiosurgery; experimental arm 4: NIVO MTD as decided in phase 1 + IPI 1 mg/kg (Q6W) and whole brain radiation therapy (30 Gy in 10 fractions) 80 Not yet recruiting NA NCT02696993
Unresectable/metastatic NSCLC Phase 1/ Phase 2 RCT Part I: determine recommended phase 2 dose of PEMBRO; part II: OR rate for cohort G and H; secondary outcomes: PFS, OS and duration of response (assessed up to 2 years) Cohort H: IPI + PEMBRO (recommended phase 2 dose as per cohort D) 308 Recruiting, preliminary data available Not available for cohort H. NCT02039674; KEYNOTE 021 [61]
Advanced NSCLC Phase 2 Best ORR evaluated Q6W up to 48 weeks IPI 1 mg/kg Q6W + NIVO 3 mg/kg Q2W 35 Recruiting NA NCT02350764
Stage IV NSCLC Phase 2 OR rate; secondary outcomes: PFS, duration of response (time frame: 6 months) IPI + NIVO 590 Recruiting NA NCT02659059; CheckMate 568
Advanced NSCLC Phase 2 RCT PFS rate, ORR and duration of response (assessed up to 24 weeks) Comparator arm: monotherapy with NIVO; arm 2: BMS-986016 + NIVO; arm 3: dasatinib + NIVO; arm 4: IPI + NIVO 504 Recruiting NA NCT02750514
Locally advanced/metastatic NSCLC Phase 2 RCT CR rate (assessed up to 2 years); secondary outcomes: ORR and disease control rate (assessed up to 2 years) Arm 1: gefitinib + MEDI4736; arm 2: AZD9291 + MEDI4736; arm 3: docetaxel + selumetinib and MEDI4736; arm 4: tremelimumab + MEDI4736 49 Completed Not yet available NCT02179671
Recurrent Stage IV squamous cell lung carcinoma Phase 2/ Phase 3 RCT ORR, OS (assessed for 3 years), IA-PFS (evaluated for 18 months), IA-PFS and OS in study participants receiving experimental regimen versus standard of care; secondary outcomes: duration of response, RR, PFS and OS for experimental regimen, frequency of toxicity events (assessed for 3 years) S1400I arm I: IPI + NIVO; S1400I arm II: NIVO monotherapy 10,000 Recruiting NA NCT02154490; lung-MAP trial [79]
Stage IV/recurrent NSCLC Phase 3 Percent study participants with high grade toxicity; secondary outcomes: PFS, ORR, duration of response (assessed for 40 months) NIVO + IPI 1500 Recruiting NA NCT02869789
NSCLC Phase 3 RCT Major pathological response rate (determined at surgery); secondary outcomes: complete pathological response rate (determined at surgery), OS and event free survival assessed for up to 130 months Experimental arm: IPI + NIVO 326 Not yet recruiting NA NCT02998528
Stage IV squamous cell carcinoma Phase 3 RCT OS (time frame: 3 years), IA-PFS (time frame: 18 months) Active comparator: NIVO on D1, repeated every 14 days; experimental arm: NIVO + IPI D1 of every 3rd course, course to be repeated every 14 days 350 Recruiting NA NCT02785952
Chemotherapy naïve/recurrent stage IV NSCLC Phase 3 RCT OS, assessed up to 48 months; PFS, assessed up to 40 months; Secondary outcome: OR rate, assessed up to 48 months Arm A: NIVO monotherapy; arm B: IPI + NIVO combination therapy; arm C: platinum doublet chemo (carboplatin/ cisplatin + gemcitabine for squamous histology and carboplatin/ cisplatin + pemetrexed for non-squamous histology) + NIVO 2220 Recruiting NA NCT02477826; CheckMate 227
Stage IV/recurrent NSCLC Phase 3 RCT PFS for T790 M negative, EGFR positive NSCLC, evaluated for 33 months; secondary outcomes: PFS rate, ORR and duration of response evaluated for 33 months; OS assessed for 5 years Arm 1: IPI + NIVO; arm 2: platinum doublet therapy (cisplatin/ carboplatin + pemetrexed) + NIVO 465 Recruiting NA NCT02864251; CheckMate 722
Advanced/metastatic NSCLC Phase 3 RCT OS with MEDI4736 + tremelimumab combination versus standard of care treatment (evaluated for 4 years) Arm 1: MEDI4736 + tremelimumab 800 Recruiting NA NCT02542293; NEPTUNE study
Locally advanced/metastatic NSCLC Phase 3 RCT PFS and OS assessed up to 3 years; secondary outcomes: ORR (evaluated for 3 years), proportion of study participants alive at end of 1 year of randomization and duration of response (evaluated for 3 years) Sub-study-A experimental arm: participants with PD-L1 positive malignancy to receive MEDI4736; sub-study B experimental arm 1: participants with PD-L1 negative malignancy to receive MEDI4736 + tremelimumab; sub-study experimental arm 2: participants with PD-L1 negative malignancy to receive MEDI4736 only; sub-study B experimental arm 3: participants with PD-L1 negative malignancy to receive tremelimumab only 730 Active, not recruiting NA NCT02352948; ARCTIC study
Advanced/metastatic NSCLC Phase 3 RCT OS and PFS with MEDI4736 + tremelimumab combination versus standard of care treatment (evaluated for up to 3 years) Arm 1: MEDI4736 monotherapy; arm 2: MEDI4736 + tremelimumab 1092 Active, not recruiting NA NCT02453282; MYSTIC study
  1. Abbreviations: NSCLC non-small cell lung cancer, EGFR epithelial growth factor receptor, ALK anaplastic lymphoma kinase, MTD maximum tolerable dose, DLT dose limiting toxicity, RCT randomized controlled trial, NA not available, OR objective response, CR complete response, CI confidence interval, TRAE treatment-related adverse events, NIVO nivolumab, IPI ipilimumab, PEMBRO pembrolizumab, MEDI4736, durvalumab, ORR overall response rate, OS overall survival, PFS progression free survival, RR response rate, OD once daily dosing, BID twice daily, Q(x)W, every (x) weeks; D(x), day(x)