Selected trials involving combination with immunotherapy
| Agents tested | Study details | Main outcomes | Adverse events | Target | Author, year |
|---|---|---|---|---|---|
| Chemotherapy combinations with immunotherapy | |||||
| Dacarbazine (D) vs. ipilumamab + dacarbazine (I+D) | Phase 3 randomised 480 pts metastatic melanoma | Median OS I+D 11.2 months vs. D 9.1 months (HR=0.72 P=0.001); I+D 3 y survival 20.8% vs. D 12.2% | G3/4 AE I+D 56%, D 40%; G3 irAE I+D 41%, D 6% | CTLA4 | Robert, 2011 |
| Carboplatin + paclitaxel (CP) vs. CP + ipilimumab concurrent (CPIcon) vs. CP+ipilumumab phased (CPIph) | Phase 2 randomised 204 pts metastatic NSCLC | Phased ipilimumab irPFS 5.7 m vs. CP 4.6 m (HR=0.72, P=0.05); ORR CPIph 32%, CPIcon 21%, CP 14% | G3/4 irAE CP 6%, CPIcon 20%, CPIph 15% | CTLA4 | Lynch, 2012 |
| Carboplatin + paclitaxel (CP) vs. CP + ipilimumab concurrent (CPIcon) vs. CP+ipilumumab phased (CPIph) | Phase 2 randomised 130 pts extensive small cell lung cancer | Phased ipilimumab irPFS 6.4 m vs. CP 5.3 m (HR = 0.64, P=0.03) irORR CPIph 71%, CPIcon 49%, CP 53% | G3/4 irAE CP 9%, CPIcon 21%, CPIph 17% | CTLA4 | Reck, 2012 |
| Nivolumab + cisplatin/gemcitabine or cisplatin/pemetrexed or carboplatin/paclitaxel | Phase 1, 56 pts metastatic 1st line NSCLC | ORR 43%, 1 y OS 59%-87% | G3/4 AE 47% | PD-1 | Antonia, 2014 |
| Pembrolizumab + carboplatin/paclitaxel (CP) or carboplatin/ pemetrexed (CPem) | Phase 1, 44 pts metastatic NSCLC | Pembro + CP ORR 30% Pembro + CPem ORR 58% | G3/4 AE Pembro +CP 15%; Pembro + CPem 38% | PD-1 | Papadimitrakopoulou, 2015 |
| Atezolizumab + nab-paclitaxel | Phase 1, 32 pts metastatic TNBC | ORR 70.8%, SD 20.8% | G3/4 AE 56% (41% neutropenia) | PD-L1 | Adams, 2015 |
| Targeted therapy combinations with immunotherapy | |||||
| Ipilimumab + vemurafenib | Phase 1, 10 pts BRAF mutant metastatic melanoma | 7/10 G2-3 hepatotoxcity | CTLA4 BRAF | Ribas, 2013 | |
| Durvalumab (Dur) + trametinib (T) + dabrafenib (Da) durvalumab + trametinib | Phase 1, 41 pts metastatic melanoma BRAF Mut Dur+T+Da BRAF WT Dur+T | ORR Dur+T+Da 16/21 (76%), Dur+T 6/20 (30%) | G3/4 AE Dur+T+Da 17 40%, Dur+T 17 40% | PD-L1 BRAF/MEK | Ribas, 2015 |
| Tremelimumab + sunitinib | Phase 1, 21 pts metastatic RCC | PR 9/21 pts 43% | 9/29 DLT 31% (3 acute renal failure) | CTLA4 VEGF | Rini, 2011 |
| Nivolumab (N) + sunitinib (S) or pazopanib (P) | Phase 1, 37 pts metastatic RCC | ORR N+S 17/33 (52%) N+P 9/20 (45%) | G3/4 AE N+S 24/33 (73%), N+P 12/20 (60%) | PD-1 VEGF | Amin, 2014 |
| Ipilimumab + bevacizumab | Phase 1, 46 pts metastatic melanoma | ORR 17%, clinical benefit rate 64% | G3/4 AE 13/46 | CTLA4 VEGF | Hodi, 2014 |
| Vaccine therapy combinations | |||||
| GVAX + CRS-207 vs. GVAX | Phase 2 randomized 90 pts metastatic pancreatic carcinoma | Median OS GVAX+CRS 6.1 months vs. 3.9 months m GVAX (HR=0.59; P=0.02) | Gvax+CRS 4/61 G3 transaminitis; 5/61 G3/4 lymphopenia | Vaccine | Le, 2015 |
| T-VEC+ipilimumab | Phase 1, 19 pts metastatic melanoma | ORR 41% | G3/4 AE 32% | CTLA4 | Puzanov, 2014 |
| T-VEC+pembrolizumab | Phase 1, 21 pts | Not reported | G3/4 AE 29% | PD-1 | Long, 2015 |
| Immunotherapy combinations | |||||
| Nivolumab (N) + ipilimumab (I) vs. nivolumab (N) vs. ipilimumab (I) | Phase 3 randomized 945 pts metasatic melanoma | Median PFS N+I 11.5 months, N 6.9 months, I 2.9 months (HR N+I vs. I 0.57; 99.5% CI, 0.43 to 0.76; P<0.001; ORR N+I 57.6%, N 43.7%, I 19% | G3/4 AE N+I 55%, N 16.3%, 27% I | CTLA4 PD-1 | Larkin, 2015 |
| Pembrolizumab (P) + ipilimumab (I) | Phase 1, 17 pts metastatic NSCLC | ORR 54% | G3/4 AE 2/17 (6%) pts | CTLA4 PD-1 | Patnaik, 2015 |
| Pembrolizumab (P) + ipilimumab (I) | Phase 1, RCC, melanoma | ORR 6/17 pts (35%) | G3 AE 6/19 (31%) pts | CTLA4 PD1 | Atkins, 2015 |
| Durvalumab (Du) + tremelimumab (T) | Phase 1, 61 pts metastatic NSCLC | ORR 26%, SD 35% | G3/4 AE 31% | CTLA4 PD-L1 | Antonia, 2015 |
| Ipilimumab + epacadostat | Phase 1, 40 pts melanoma | ORR 30%, SD 30% DCR 30% pts with previous immunotherapy | G3 AE 23% | CTLA4 IDO1 | Gibney, 2015 |
| Ipilimumab + indoximid | Phase 1, 9 pts melanoma | Not reported | No DLT, 1/7pts colitis | CTLA4 IDO1 | Zakharia, 2015 |
| Pembrolizumab + epacadostat | Phase 1, 54 pts advanced solid tumors | ORR 10/19 (53%) | G3/4 irAE 8% | PD-1 IDO1 | Gangadhar 2015 |
patients (pts); non small cell lung carcinoma (NSCLC); small cell lung cancer (SCLC); objective response rate (ORR); partial response (PR); stable disease (SD); disease control rate (DCR); adverse events (AE); immune related adverse events (irAE); dose limiting toxicity (DLT); progression free survival (PFS); overall survival (OS); immune related objective response rate (irORR); programmed cell death 1 (PD-1); programmed cell death 1 ligand (PD-L1); cytotoxic T lymphocyte antigen 4 (CTLA4); indoleamine 2,3-dioxygenase 1 (IDO1); vascular endothelial growth factor receptor (VEGFR).