Table 2 Key clinical combination trials
Immune checkpoint blockade | Anticancer agents | Tumor types | Regimen | Result | Reference |
|---|---|---|---|---|---|
Atezolizumab | Carboplatin and etoposide | Extensive-stage NSCLC | Induction: carboplatin AUC 5 + etoposide 100 mg/m2 Day 1-3 + atezolizumab or placebo 1200 mg Q3W for 4 cycles; Maintenance: atezolizumab or placebo 1200 mg Q3W | The atezolizumab and chemotherapy combination resulted in significantly longer OS and PFS and became the first-line option for extensive-stage NSCLC. | Horn et al [133] |
Carboplatin and nab-paclitaxel | Stage IV squamous NSCLC | Induction: carboplatin AUC = 6 Day 1 + nab-paclitaxel 100 mg/m2 Day 1, 8 and 15 ± atezolizumab 1200 mg Day 1; Q3W for 4 or 6 cycles; Maintenance: atezolizumab 1200 mg Q3W in the triplet therapy group | The combination of atezolizumab and platinum-based chemotherapy significantly improved PFS in patients with squamous NSCLC; OS was similar between arms. | Jotte et al [134] | |
Carboplatin and nab-paclitaxel | Metastatic non-squamous NSCLC | Induction: carboplatin AUC = 6 Day 1 + nab-paclitaxel 100 mg/m2 Day 1, 8 and 15 ± atezolizumab 1200 mg Day1; Q3W for 4 or 6 cycles; Maintenance: atezolizumab 1200 mg Q3W in the triplet therapy group | The combination of atezolizumab and platinum-based chemotherapy significantly improved PFS and OS in patients with metastatic non-squamous NSCLC. | West et al [135] | |
Carboplatin, paclitaxel, bevacizumab | Metastatic non-squamous NSCLC | Induction: carboplatin AUC 6 + paclitaxel 200 mg/m2 + bevacizumab 15 mg/kg ± atezolizumab 1200 mg, Q3W for 4 or 6 cycles; Maintenance: bevacizumab 15 mg/kg ± atezolizumab 1200 mg, Q3W | The atezolizumab, bevacizumab, and chemotherapy combination significantly improved PFS and OS among patients with metastatic non-squamous NSCLC | Socinski et al [136] | |
Nab- paclitaxel | untreated metastatic TNBC | Nab- paclitaxel 100 mg/m2 Day 1, 8 and 15 of every 28-day cycle + atazolizumab or placebo 840 mg Q2W | Atezolizumab plus nab-paclitaxel prolonged PFS among patients with metastatic TNBC, especially those with PD-L1 positive tumors. | Schmid et al [132] | |
recurrent or metastatic TNBC | Nab- paclitaxel 125 mg/m2 day 1, 8 and 15 of every 28-day cycle + atazolizumab 800 mg Q2W | The combination therapy increased antitumor activity (ORR and PFS) and showed manageable toxicity. | Adams et al [137] | ||
Bevacizumab, sunitinib | Untreated metastatic RCC | Atezolizumab 1200 mg + bevacizumab 15 mg/kg Q3W vs. sunitinib monotherapy 50 mg QD for 4 weeks on, 2 weeks off | Atezolizumab plus bevacizumab prolonged PFS versus sunitinib in patients with metastatic RCC (median PFS: 11.2 vs. 8.4 months) and showed a favorable safety profile. | Rini et al [117] | |
Bevacizumab, sorafenib | Unresectable hepatocellular carcinoma | Atezolizumab 1200 mg + bevacizumab 15 mg/kg day 1 Q3W vs. sorafenib 400 mg twice per day Q3W | Atezolizumab plus bevacizumab resulted in better OS and PFS than sorafenib in patients with unresectable hepatocellular carcinoma | Finn et al [116] | |
Vemurafenib and cobimetinib | BRAFV600- mutated metastatic melanoma | Run-in period (28 days): vemurafenib 960 mg/d BID for 21 days, then 720 mg/d BID for 7 days + cobimetinib 60 mg QD, 1-21 days; Combination period: atezolizumab 800 mg Q2W + vemurafenib 720 mg/d BID and cobimetinib 60 mg QD 1–21 days in 28 days cycle | The triple combination therapy demonstrated promising PFS. The run-in period of vemurafenib and cobimetinib might result in better tolerance and the antitumor response of atezolizumab. | Sullivan et al [138] | |
BRAFV600- mutated Unresectable locally advanced or metastatic melanoma | Run-In Period (28 days): vemurafenib 960 mg/d BID + cobimetinib 60 mg QD on Days 1 to 21 followed by vemurafenib 720 mg/d BID on Days 22 to 28; Combination Period (Cycle 1 onwards): atezolizumab or placebo 840 mg Day 1 and 15 + cobimetinib 60 mg QD on Days 1 to 21 + vemurafenib 720 mg/d BID on Days 1 to 28 of each 28-day cycle. | The triple combination therapy demonstrated promising PFS vs. dual vemurafenib and cobimetinib (median PFS: 15.1 vs. 10.6 months). Severe treatment-related adverse events were comparable between the two groups (33.5% vs. 28.8%). | McArthur et al [139] | ||
Avelumab | Axitinib or sunitinib | Advanced RCC | Avelumab 10 mg/kg Q2W + axitinib 5 mg BID vs. sunitinib monotherapy 50 mg QD for 4 weeks on, 2 weeks off | Avelumab plus axitinib prolonged PFS versus sunitinib in patients with advanced RCC (median PFS: 13.8 vs. 8.4 months). Grade ≥ 3 treatment-related adverse events were comparable between the two groups. | Motzer et al [10] |
Camrelizumab | Decitabine | Relapsed or refractory classic Hodgkin Lymphoma | Camrelizumab 200 mg monotherapy Q3W or decitabine 10 mg/d, days 1 to 5 plus camrelizumab 200 mg, day 8 Q3W | The addition of decitabine to camrelizumab significantly improved the tumor response in patients who were clinically naïve to the PD-1 blockade. | Nie et al [140] |
Gemcitabine and cisplatin | Recurrent or metastatic nasopharyngeal carcinoma | Camrelizumab 200 mg (day 1), gemcitabine 1 g/m2 (days 1 and 8), and cisplatin 80 mg/m2 (day 1) every 3 weeks followed by camrelizumab 200 mg maintenance once every 3 weeks | The combination of camrelizumab plus gemcitabine and cisplatin has a manageable toxicity profile and promising preliminary antitumor activity in treatment-naive patients. | Fang et al [141] | |
Durvalumab | Platinum and etoposide | Extensive-stage SCLC | Etoposide 80–100 mg/m2 on days 1 to 3 + carboplatin AUC=5/6 or 75–80 mg/m2 + durvalumab 1500 mg, Q3W for 4 cycles + maintenance durvalumab 1500 mg Q4W vs. platinum and etoposide for 6 cycles | Durvalumab plus platinum-etoposide significantly improved OS in patients with ES-SCLC vs. chemotherapy alone (median OS: 13.0 vs. 10.3 months). The safety of the two regimens was similar. | Paz-Ares et al [142] |
Ipilimumab | Carboplatin and etoposide | Extensive-stage SCLC | Carboplatin AUC=6 + etoposide 120 mg/m2 day 1 and 100 mg day 2 and 3, Q3W up to 6 cycles + ipilimumab 10 mg/kg day 1 of chemotherapy cycles 3-6 and then once every 12-weeks from week 30 | The combination therapy showed a beneficial effect in extensive-stage SCLC; however, the toxicity was also significant. Sequential immunotherapy after chemotherapy might be a more feasible approach. | Arriola et al [143] |
Platinum and etoposide | Extensive-stage SCLC | Induction: etoposide 100 mg/m2 on days 1 to 3 + carboplatin AUC=5 or cisplatin 75 mg/m2 day 1 Q3W for 4 cycles + 4 cycles of ipilimumab or placebo 10 mg/kg Q3W from cycle 3 of chemotherapy; Maintenance: ipilimumab or placebo 10 mg/kg Q12W | The combination of ipilimumab and chemotherapy did not prolong the OS of patients with extensive-stage SCLC. | Reck et al [144] | |
Paclitaxel and carboplatin | extensive-disease SCLC | Induction (Q3W for a maximum of 18 weeks): carboplatin AUC=6 + paclitaxel 175 mg/m2 vs. concurrent ipilimumab (4 cycles of ipilimumab 10 mg/kg + paclitaxel + carboplatin followed by 2 cycles of placebo + paclitaxel + carboplatin) vs. phased ipilimumab (4 cycles of placebo + paclitaxel + carboplatin followed by 2 cycles of ipilimumab + paclitaxel + carboplatin); Maintenance: ipilimumab for phased- and concurrent-ipilimumab arms) or placebo (control arm) Q12W | Phased ipilimumab, but not concurrent ipilimumab, significantly prolonged immune-related PFS vs. chemotherapy alone. A numerical, but not significant, improvement of OS was also observed. | Reck et al [145] | |
Advanced squamous NSCLC | Induction: carboplatin AUC = 6 + paclitaxel 175 mg/m2 Q3W for 6 cycles + 4 doses of ipilimumab or placebo 10 mg/kg started at cycle 3 of chemotherapy; Maintenance: ipilimumab or placebo once every 12 weeks | The combination of ipilimumab, paclitaxel, and carboplatin did not prolong the OS of patients with advanced squamous NSCLC vs. chemotherapy alone. | Govindan et al [146] | ||
Nivolumab | Cisplatin and gemcitabine or pemetrexed; paclitaxel and carboplatin | Advanced NSCLC | Nivolumab 10 mg/kg plus gemcitabine-cisplatin (squamous) or pemetrexed-cisplatin (nonsquamous) or nivolumab 5 or 10 mg/kg plus paclitaxel-carboplatin (all histologies) Q3W for 4 cycles, followed by nivolumab monotherapy every 3 weeks | The combination regimen, especially the paclitaxel-carboplatin plus nivolumab 5 mg/kg, showed encouraging activity (2-year OS rate: 62%). However, the treatment-related adverse events led to greater treatment discontinuation in combination therapies. | Rizvi et al [147] |
Erlotinib | Advanced EGFR-mutant NSCLC | Nivolumab 3 mg/kg every 2 weeks and erlotinib 150 mg/d | The concomitant nivolumab and erlotinib was tolerable and resulted in durable responses in patients with EGFR-mutant, TKI-treated NSCLC. | Gettinger et al [148] | |
Cizotinib | ALK-positive NSCLC. | Nivolumab 240 mg every 2 weeks and crizotinib 250 mg twice daily | Such a concomitant regimen of nivolumab and crizotinib resulted in severe, even fatal, hepatic toxicities. | Spigel et al [149] | |
Oxaliplatin and S-1 or capecitabine | advanced gastric/gastroesophageal junction cancer | Nivolumab 360 mg day 1+ oxaliplatin 130 mg/m2 day 1 + S-1 40 mg/m2 or capecitabine 1000 mg/m2 twice daily for 14 days followed by 7 days off, Q3W | Nivolumab combined with chemotherapy was well tolerated and demonstrated a higher objective response rate and longer PFS. | Boku et al [150] | |
Sunitinib or pazopanib | Advanced or metastatic RCC | Sunitinib (50 mg/day, 4 weeks on/2 weeks off) or pazopanib (800 mg/day) + nivolumab starting dose was 2 mg/kg every 3 weeks, with planned escalation to 5 mg/kg every 3 weeks | The combination therapy resulted in a high incidence of high-grade toxicities (grade 3/4 treatment-related adverse events: 70% – 82%). | Amin et al [151] | |
Pembrolizumab | Carboplatin and pemetrexed | Non-squamous NSCLC | Carboplatin AUC 5 and pemetrexed 500 mg/m2 Q3W for 4 cycles optional pemetrexed 500 mg/m2 ± pembrolizumab 200 mg Q3W for 2 years | The triplet therapy could be an effective and tolerable first-line treatment option for patients with advanced non-squamous NSCLC | Langer et al [152] |
Pemetrexed and platinum | Non-squamous NSCLC | Pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 or carboplatin AUC=5 plus pembrolizumab or placebo 200 mg for 4 cycles, followed by pemetrexed + pembrolizumab or placebo for 35 cycles | The triplet therapy resulted in significantly longer survival (1-year OS rates: 69.2% vs. 49.4%, median PFS: 8.8 vs. 4.9 months). | Gandhi et al [7] | |
Carboplatin and paclitaxel | Squamous NSCLC | Pembrolizumab or placebo 200 mg Q3W for up to 35 cycles + carboplatin AUC6 Q3W and either paclitaxel 200 mg/m2 Q3W or (nab)-paclitaxel at 100 mg/m2 QW for the first four cycles | The combination therapy resulted in a longer median OS (15.9 vs. 11.3 months) and PFS (6.4 vs. 4.8 months). This regimen became the first-line treatment. | Paz-Ares et al [8] | |
Cyclophosphamide | Sarcoma | Cyclophosphamide 50 mg BID (1 week on and 1 week off), and pembrolizumab 200 mg Q3W | Limited antitumor efficacy might be caused by an immunosuppressive TME. | Toulmonde et al [153] | |
Paclitaxel, carboplatin, doxorubicin or epirubicin, and cyclophosphamide | TNBC | Pembrolizumab or placebo 200 mg Q3W + paclitaxel 80 mg/m2 QW + carboplatin (QW or Q3W) for 4 cycles, followed by (doxorubicin 60 mg/m2 or epirubicin 90 mg/m2) + cyclophosphamide 600 mg/m2 Q3W + pembrolizumab or placebo 200 mg Q3W for 4 cycles before surgery; followed by 9 cycles of pembrolizumab or placebo 200 mg Q3W post-surgery | The neoadjuvant pembrolizumab - chemotherapy treatment resulted in a significantly higher pathological complete response (64.8% vs. 51.2%). | Schmid et al [154] | |
5-fluorouracil and cisplatin or carboplatin | HNSCC | Pembrolizumab 200 mg Q3W up for 35 cycles, carboplatin AUC=5 or cisplatin 100 mg/m2 + 5-fluorouracil 1000 mg/m2 per day for 4 consecutive days, Q3W for 6 cycles | The triple-therapy was recommended as an appropriate first-line treatment for recurrent or metastatic head and neck squamous cancer. | Barbara et al [155] | |
Axitinib | RCC | Axitinib 5 mg BID and pembrolizumab 200 mg Q3W | The treatment combination led to significantly longer survival (1-year OS rates: 89.9% vs. 78.3%, median PFS: 15.1 vs. 11.1 months) as well as a higher objective response rate (59.3% vs. 35.7%). | Atkins et al [156] Rini et al [157] | |
Dabrafenib and trametinib | BRAFV600-mutated melanoma | Concomitant dabrafenib 150 mg/day in divided dose (BID) + trametinib 2 mg QD + pembrolizumab 2 mg/kg Q3W up to 2 years | The triple-therapy was feasible for patients with BRAFV600-mutated melanoma, especially those with poor prognostic factors. However, it also significantly increased the grade ≥ 3 treatment-related adverse events. | Ribas et al [110] Ascierto et al [111] | |
Toripalimab | Axitinib | Metastatic mucosal melanoma | Toripalimab 1 or 3 mg/kg Q2W + axitinib 5 mg BID | The combination of toripalimab plus axitinib was tolerable and showed promising antitumor activity (ORR 48.3%). | Sheng et al [158] |