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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)