Background
Drug | Brand name | Indication |
---|---|---|
CTLA-4 blockers | ||
Ipilimumab | Yervoy | As monotherapy for metastatic melanoma and surgically resectable ‘high-risk’ melanoma (adjuvant setting) |
PD-1 blockers | ||
Nivolumab | Opdivo | Metastatic melanoma, metastatic non-small-cell lung cancer (NSCLC), renal cell carcinoma (RCC), classical Hodgkin’s lymphoma, head and neck squamous cell carcinoma (HNSCC), metastatic urothelial carcinoma, hepatocellular carcinoma (HCC), colorectal cancer with MSI-H and MMR aberrations |
Pembrolizumab | Keytruda | Metastatic melanoma, surgically resectable ‘high-risk melanoma (adjuvant setting), metastatic NSCLC, classical Hodgkin’s lymphoma, primary mediastinal B-cell lymphoma (PMBCL), HNSCC, gastric cancer, solid tumors with MSI-H and MMR aberrations, metastatic urothelial carcinoma, Merkel cell carcinoma, renal cell carcinoma, cervical cancer, hepatocellular carcinoma, |
Cemiplimab | Libtayo | Metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who are not candidates for curative surgery or curative radiation |
PD-L1 blockers | ||
Atezolizumab | Tecentriq | Metastatic urothelial carcinoma, metastatic NSCLC (monotherapy and in combination with chemotherapy), metastatic SCLC (in combination with chemotherapy) and metastatic triple negative breast cancer (in combination with paclitaxel) |
Avelumab | Bevencio | Merkel cell carcinoma, metastatic urothelial carcinoma |
Durvalumab | Imfinzi | Metastatic urothelial carcinoma, unresectable stage III NSCLC |
Combination of CTLA-4 and PD-1 blockers | ||
Ipilimumab plus nivolumab | Yervoy plus Opdivo | Metastatic melanoma, metastatic renal cell carcinoma, colorectal cancer with MSI-H and MMR aberrations |
CTLA-4
Receptor | CTLA-4 | PD-1 |
Synonyms | CD152 | PDCD1, CD279 |
Gene location | Chromosome 2q33 | Chromosome 2q37.3 |
Protein details | Amino acids #223 Type 1 transmembrane glycoprotein belonging to Ig super family Dimer Domains: a single peptide, an extracellular ligand-binding domain, a transmembrane domain, and a short cytoplasmic tail | Amino acids #288 Type I transmembrane protein belonging to Ig super family Monomer Domains: extracellular N-terminal IgV-like domain, a transmembrane domain, and a cytoplasmic tail |
Signaling motif | Cytoplasmic tail | ITSM |
Cells expressing receptor | Effector T-cells & TRegs | Effector T-cells, TRegs, NK cells & macrophages |
Ligands | CD80 (B7-1), CD86 (B7-2) | PD-L1 (B7-H1), PD-L2 (B7-DC) |
Cells expressing ligands | APCs | APCs, hematopoetic & nonhematopoetic cells & tumor cells |
PD-1
Rationale for combination
Clinical evidence
Melanoma
Patients | Trial, ID | Follow-up | Outcomes | Reference |
---|---|---|---|---|
Advanced melanoma | Phase 1 NCT01024231 | ≥24 weeks | ORR, 53% Grade 3-4 AEs, 53% | Wolchok et al 2013 |
Previously untreated advanced melanoma | Phase 1 NCT01927419 | ≥11 months | In patients with BRAF-WT tumors ORR 61% Median PFS, not reached HR for disease progression or death, 0.40 Grade 3-4 AEs, 54% | Postow et al 2015 |
Previously untreated advanced melanoma | Phase 3 NCT01844505 | > 12 months | Median PFS, 11.5 months HR for death or disease progression, 0.42 Investigator assessed ORR, 57% Grade 3-4 AEs, 55% | Larkin et al 2015 |
Previously untreated advanced melanoma | Phase 3 NCT01844505 | ≥ 36 months | Median OS, not reached 3-year OS rate, 58% HR for death, 0.55 Grade 3-4 AEs, 59% | Wolchok et al 2017 |
Previously untreated advanced melanoma | Phase 3 NCT01844505 | ≥ 48 months | Median OS, not reached 4-year OS rate, 54% ORR, 58% HR for death, 0.54 HR for progression-free survival, 0.42 Grade 3-4 AEs, 59% | Hodi et al 2018 |
Advanced melanoma patients with at least one brain metastasis | Phase 2 NCT02320058 | ≥ 6 months | Rate of intracranial clinical benefit, 57%; Rate of extracranial clinical benefit, 56% 9-month PFS (global) rate, 57%; 9-month OS rate, 83 12-month OS rate, 82% Grade 3-4 AEs, 55% | Tawbi et al 2018 |
Advanced melanoma | Phase 2 NCT01783938 | ≥ 15 months | ORR, 56% Median OS, not reached 1-year OS rate, 76% Grade 3-5 AEs, 50% | Weber et al 2018 |
Previously untreated advanced clear cell renal cell carcinoma | Phase 3 NCT02231749 | > 17 months | ORR, 42% Median OS, not reached HR for death, 0.63 Median PFS, 11.6 months HR for disease progression, 0.82 | Motzer et al 2018 |
Previously treated, MMR/MSI-H positive advanced colorectal cancer | Phase 2 NCT02060188 | > 9 months | ORR, 55% Median PFS, not reached 12-month PFS rate, 71% Median OS, not reached 12-month OS rate, 85% Grade 3-4 AEs, 32% | Overman et al 2018 |
Pembrolizumab plus ipilimumab combination
Nivolumab plus ipilimumab for surgically resectable ‘high-risk’ melanoma
Renal cell carcinoma
Colorectal cancer
Lung cancer
Durvalumab plus tremelimumab for non-small cell lung cancer (NSCLC)
Patients | Trial, ID | Follow-up | Outcomes | Reference |
---|---|---|---|---|
Advanced NSCLC | Phase 1b NCT02000947 | 24 weeks | ORR, 23% Grade 3-4 AEs, 35% | Antonia et al 2016 |
Treatment relapsed advanced SCLC | Phase 1/2 NCT01928394 | ≥ 12 weeks | ORR, 23% Median OS, 7.7 months 1-year OS rate, 43% Median PFS, 2.6 months 1-year PFS rate, 19% Grade 3-4 AEs, 30% | Antonia et al 2016 |
Untreated advanced NSCLC | Phase 1 NCT01454102 | > 9 months | ORR, 47% Median PFS, 8.1 months 24-week PFS rate, 68% Grade 3-4 AEs, 37% | Hellman et al 2017 |
Untreated advanced NSCLC | Phase 2 NCT02659059 | ≥ 6 months | In patients with TMB≥10 mutations/megabase ORR, 44% Median PFS, 7.1 months 6-month PFS rate, 55% Grade 3-4 AEs, 29% (all patients) | Ready et al 2019 |
Untreated advanced NSCLC | Phase 3 NCT02477826 | > 11 months | In patients with TMB≥10 mutations/megabase ORR, 45% Median PFS, 7.2 months 12-month PFS rate, 43% HR for disease progression or death, 0.58 Grade 3-4 AEs, 31% | Hellman et al 2018 |
Nivolumab plus ipilimumab for NSCLC
Nivolumab plus ipilimumab for small cell lung cancer (SCLC)
Mesothelioma
Cancer type | Patients | Trial, ID | Follow-up | Outcomes | Reference |
---|---|---|---|---|---|
Malignant pleural mesothelioma | Previously treated | Phase 2 NCT03048474 | > 12 months | ORR, 38% Median PFS, 6.2 months 6-month PFS rate, 50% Median OS, not reached 12-month OS rate, 64% Grade 3-4 AEs, 38% | Disselhorst et al 2019 |
Malignant pleural mesothelioma | Previously treated | Phase 2 NCT02716272 | > 16 months | ORR, 28% Median PFS, 5.6 months 12-month PFS rate, 23% Median OS rate, 15.9 months 12-month OS rate, 58% Grade 3-4 AEs, 26% | Scherpereel et al 2019 |
Unresectable Sarcoma | Previously treated | Phase 2 NCT02500797 | > 12 months | Confirmed response, 16% Median PFS, 4.1 months Median OS, 14.3 months Grade 3-4 AEs, 14% | D’Angelo et al 2018 |
Esophagogastric cancer | Previously treated | Phase 1/2 NCT01928394 | Investigator assessed ORR, 24% Median PFS, 1.4 months 12-month PFS rate, 17% Median OS, 6.9 months 18-month OS rate, 28% Grade 3-4 AEs, 35% | Janjigian et al 2018 | |
Prostate cancer | Previously treated, AR-V7 positive | Phase 2 NCT02601014 | ≥ 1.9 months | ORR, 25% Median PFS,3.7 months Median OS, 8.2 months Grade 3-4 AEs, 46% | Boudadi et al 2018 |