Table 2.
Summary of reported clinical efficacy of PD-1/PD-L1 inhibitors
| Agent | Clinical trials identifier | Phase of clinical trial | Sample size (no. Pt) | Patient population | Biomarker | Regimen | Tumor responses (ORR) | Median PFS (months) | OS (months; median unless otherwise specified) | Reference: author (year) |
|---|---|---|---|---|---|---|---|---|---|---|
| Nivolumab | NCT01642004 (CheckMate 017) | Phase III | 272 all: 135 nivolumab, 137 docetaxel | Advanced squamous NSCLC with disease progression during or after first-line chemotherapy | PD-L1-positive tumor cells | Nivolumab 3 mg/kg IV every 2 weeks | 20 % | 3.5 | 9.2 | Brahmer J (2015) [125] |
| Docetaxel 75 mg/m2 IV every 3 weeks | 9 % | 2.8 | 6 | |||||||
| NCT01673867 (CheckMate 057) | Phase III | 582 all: 292 nivolumab, 290 Docetaxel | Advanced non-squamous NSCLC after platinum-based doublet chemotherapy | PD-L1-positive tumor cells | Nivolumab 3 mg/kg IV every 2 weeks | 19 % | 2.3 | 12.2 | Borghaei H (2015) [126] | |
| Docetaxel 75 mg/m2 IV every 3 weeks | 12 % | 4.2 | 9.4 | |||||||
| NCT01668784 (CheckMate 025) | Phase III | 821 all: 406 nivolumab, 397 Everolimus | Advanced clear-cell renal-cell carcinoma with one or two regimens of anti-angiogenic therapy | PD-L1-positive tumor cells | Nivolumab 3 mg/kg IV every 2 weeks | 25 % | 4.6 | 25 | Motzer RJ (2015) [127] | |
| Everolimus 10 mg orally daily | 5 % | 4.4 | 19.6 | |||||||
| NCT01721746 (CheckMate 037) | Phase III | 631 all: 272 nivolumab,133 investigators choice of chemo | Unresectable or metastatic melanoma after ipilimumab or ipilimumab and BRAF inhibitor if BRAF positive | PD-L1-positive tumor cells | Nivolumab 3 mg/kg IV every 2 weeks | 32 % | 4.7 | NA | Weber JS (2015) [128] | |
| Chemo: either dacarbazine 1000 mg/m2 IV every 3 weeks or carboplatin AUC = 6 plus paclitaxel 185 mg/m2 IV every 3 weeks | 11 % | 4.2 | NA | |||||||
| NCT01927419 (CheckMate 069) | Phase III | 142 all: 95 nivolumab + ipilimumab, 47 ipilimumab | Unresectable or metastatic melanoma treatment naïve with measurable disease | Tissue available for PD-L1 biomarker analysis | Nivolumab 1 mg/kg IV every 3 weeks × 4 doses plus ipilimumab 3 mg/kg IV every 3 weeks × 4 doses, then maintenance nivolumab 3 mg/kg IV every 2 weeks | BRAF wild type: 61 %; BRAF mutation: 52 % | BRAF wild type: NR; BRAF mutation: 8.5 | NA | Postow MA (2015) [4] | |
| Same dose schedule with nivolumab placebo in both the combination and maintenance phase | BRAF wild type: 11 %; BRAF mutation: 22 % | BRAF wild type: 4.4; BRAF mutation: 2.7 | NA | |||||||
| NCT01721772 (CheckMate 066) | Phase III | 418 all: 210 nivolumab, 208 dacarbazine | Untreated metastatic melanoma without BRAF mutation | Tissue available for PD-L1 biomarker analysis | Nivolumab 3 mg/kg IV every 2 weeks plus placebo every 3 weeks | 40 % | 5.1 | 1-year OS: 72.9 % | Robert C (2015) [129] | |
| Dacarbazine 1000 mg/m2 IV every 3 weeks plus placebo every 2 weeks | 13.9 % | 2.2 | 1-year OS: 42.1 % | |||||||
| NCT01844505 (CheckMate 067) | Phase III | 945 all: 316 nivolumab, 314 combination, 315 ipilimumab | Untreated, unresectable stage III or IV melanoma | Tissue available for PD-L1 biomarker analysis | Nivolumab 3 mg/kg IV every 2 weeks (plus ipilimumab placebo) | 43.7 % | 6.9 | NA | Larkin J (2015) [130] | |
| Nivolumab 1 mg/kg IV every 3 weeks plus ipilimumab 3 mg/kg IV every 3 weeks × 4 doses; then maintenance nivolumab 3 mg/kg IV every 2 weeks | 58 % | 11.5 | ||||||||
| Ipilimumab 3 mg/kg IV every 3 weeks (plus nivolumab placebo) | 19 % | 2.9 | ||||||||
| NCT01721759 (CheckMate 063) | Phase II single arm trial | 117 | Advanced NSCLC | PD-L1-positive tumor cells | Nivolumab 3 mg/kg every 2 weeks until progression or unacceptable toxic effects | 14.5 % | 1.9 | 8.2 | Rizvi NA (2015) [131] | |
| NCT00730639 | Phase I with expansion cohorts | 107 | Advanced melanoma | Unselected | Nivolumab at 1, 3, or 10 mg/kg every 2 weeks for up to 96 weeks | 31 % | 3.7 | 16.8 | Topalian SL (2014) [67] | |
| Phase I with expansion cohorts | 34 | Previously treated advanced RCC | Unselected | Nivolumab at 1, 3, or 10 mg/kg every 2 weeks for up to 96 weeks | 29 % | 7.3 | 22.4 | McDermott DF (2015) [132] | ||
| Phase II with expansion cohorts | 129 | Heavily pretreated advanced NSCLC | Unselected | Nivolumab at 1, 3, or 10 mg/kg every 2 weeks for up to 96 weeks | 17 % | 2.6 | 9.9 | Gettinger SN (2015) [133] | ||
| Pembrolizumab | NCT01866319 (KEYNOTE-006) | Phase III | 834 all: 279 pembrolizumab, 277 pembrolizumab, 278 ipilimumab | Unresectable stage III or IV melanoma | PD-L1-positive tumor cells | Pembrolizumab 3 mg/kg IV every 2 weeks | 33.7 % | 5.5 | NA | Robert C (2015) [134] |
| Pembrolizumab 3 mg/kg IV every 3 weeks | 32.9 % | 4.1 | ||||||||
| Ipilimumab 3 mg/kg IV every 3 weeks | 11.9 % | 2.8 | ||||||||
| NCT01704287 (KEYNOTE-002) | Phase II | 540 all: 180 pembrolizumab, 181 pembrolizumab, 179 chemotherapy | Ipilimumab-refractory melanoma | Will be reported with the final overall survival analysis | Arm A 2 mg/kg (n = 180) | 21 % | 5.4 | NA | Ribas A (2015) [135] | |
| Arm B 10 mg/kg (n = 181) | 25 % | 5.8 | ||||||||
| Chemotherapy | 4 % | 3.6 | ||||||||
| NCT012958297 (KEYNOTE-001) | Phase I | 495 | Advanced NSCLC | PD-L1-positive tumor cells | Pembrolizumab 2 or 10 mg/kg IV every 3 weeks or 10 mg/kg every 2 weeks over a 30-min period | 19.4 % | 3.7 | 12 | Garon EB (2015) [5] | |
| Phase I | 655 | Melanoma | Unselected | Pembrolizumab 2 mg/kg every 3 weeks (Q3W), 10 mg/kg Q3W, or 10 mg/kg Q2W until unacceptable toxicity, disease progression, or investigator decision | 33 % | 12-month PFS 35 % | 23 | Adil Daud (2015) [136]; Ribas A (2016) [137] | ||
| Phase I with expansion cohort | 173 | Advanced melanoma after at least 2 ipilimumab doses | Unselected | Pembrolizumab 2 mg/kg IV every 3 week or 10 mg/kg IV every 3 weeks | 26 % | 2 | NA | Robert C (2014) [138] | ||
| NCT01848834 (KEYNOTE-012) | Phase IB | 32 | Metastatic triple-negative breast cancer | PDL-1-positive tumor cells | Pembrolizumab 10 mg/kg IV every 2 weeks | 19 % | 6-month PFS 23.3 % | NA | Nanda R (2014) [139] | |
| NCT1905657 (KEYNOTE-010) | Phase II/III | 1034 all: 339 pembrolizumab, 343 pembrolizumab, 309 docetaxel | Previously treated PD-L1-positive advanced NSCLC | PDL-1-positive tumor cells | Pembrolizumab 2 mg/kg, IV every 3 weeks | 18 % | 3.9 months | 14.9 | Herbst RS [2015] [140] | |
| Pembrolizumab 10 mg/kg, IV every 3 weeks | 18.5 % | 4.0 month | 17.3 | |||||||
| Docetaxel, 75 mg/m2 every 3 weeks | 9.3 % | 4.0 month | 8.2 | |||||||
| NCT01953692 (KEYNOTE-013) | Phase IB | 15 | Hodgkin lymphoma | Unselected | Pembrolizumab 10 mg/kg IV every 2 weeks up to 2 years | 53 % | NA | NA | Moskowitz C (2014) [141] | |
| Atezolizumab (MPDL3280A) | NCT01846416 | Phase II | 205 | NSCLC | PD-L1-positive tumor cells | Atezolizumab 1200 mg IV every 3 weeks | The highest ORR was seen in pts with PD-L1 TC3 or IC3 tumors | NA | NA | Spigel DR (2015) [142] |
| NCT01903993 (POPLAR) | Phase II | 287 | Previously treated NSCLC patients (pts) were stratified by PD-L1 IC status | PD-L1-positive tumor cells | Atezolizumab 1200 mg IV every 3 weeks | 57 % | 2.7 | 12.6 | Spira AI (2015) [143]; Fehrenbacher L (2016) | |
| Docetaxel 75 mg/m2 IV every 3 weeks | 24 % | 3.0 | 9.7 | |||||||
| NCT01375842 | Phase I | 35 | Metastatic melanoma | PD-L1-positive tumor cells | Atezolizumab IV every 3 weeks for up to 1 year | 26 % | 24-week PFS 35 % | NA | Omid Hamid (2013) [144] | |
| Phase I | 277 | Multiple cancer types | PD-L1-positive tumor cells | Atezolizumab intravenously every 3 weeks doses >1 ml/kg | 18 % | 2.6 | NA | Herbst RS (2014) [145] | ||
| NCT01633970 | Phase Ib | 37 | Untreated NSCLC | PD-L1-positive tumor cells | Atezolizumab 15 mg/kg IV every 3 weeks with standard chemo dosing for 4–6 cycles followed by MPDL3280A maintenance therapy until progression | 67 % | NA | NA | Stephen V (2015) [146] | |
| Phase Ib | 14 | Arm A: refractory metastatic colorectal cancer; arm B: oxaliplatin-naive mCRC | Not mentioned | Arm A: MPDL3280A 20 mg/kg every 3 weeks and bevacizumab (bev) 15 mg/kg every 3 weeks | 8 % (1/13) in arm A | NA | NA | Bendell, J.C. (2015) [147] | ||
| Arm B: MPDL3280A 14 mg/kg every 2 weeks, bev 10 mg/kg every 2 weeks and mFOLFOX6 at standard doses | 36 % (9/25) in Arm B | NA | NA | |||||||
| Phase Ib | 12 | Metastatic renal cell carcinoma | Not selected | Atezolizumab 15 mg/kg given alone on cycle 1 day 1 and concurrently with 20 mg/kg every 2 weeks thereafter | 40 % | NA | NA | Sznol M (2015) [148] | ||
| Durvalumab (MEDI4736) | NCT01693562 | Phase I/II | 198 | NSCLC | Tissue available for PD-L1 biomarker analysis | Durvalumab 10 mg/kg IV every 2 weeks until unacceptable toxicity, disease progression, or for up to 12 months | 14 % (23 % in PD-L1+ tumors) | NA | NA | Rizvi NA (2015) [149] |
| Phase I | 13 | NSCLC | Tissue available for PD-L1 biomarker analysis | Durvalumab 7 doses (1–25) across 6 cohorts (0.1–10 mg/kg every 2 weeks; 15 mg/kg every 3 weeks) | NA | NA | NA | Brahmer JR (2014) [150] | ||
| Multi-arm expansion study | 62 | A squamous cell carcinoma of the head and neck expansion cohort | Tissue available for PD-L1 biomarker analysis | Durvalumab IV every 2 weeks at 10 mg/kg for 12 months | 12 % (25 % in PD-L1+ pts) | NA | NA | Segal NH (2015) [151] | ||
| Phase I | 26 | Advanced solid tumors | Durvalumab IV every 2 (q2w) or 3 weeks (q3w) in a 3 + 3 dose escalation with a 28-day (q2w) or 42-day (q3w) DLT window | NA | NA | NA | Lutzky J (2014) [152] | |||
| NCT02088112 | Phase I | 10 | NSCLC | Unselect | Durvalumab cohort A received 3 mg/kg (starting dose) every 2 weeks plus gefitinib 250 mg QD | NA | NA | NA | Creelan BC (2015) [153] | |
| NCT02000947 | Phase Ib | 118 (102 eligible) | NSCLC | Tissue available for PD-L1 biomarker analysis | Durvalumab 10–20 mg/kg every 2 or 4 weeks plus tremelimumab 1 mg/kg (N = 56) | 23 % (6/26): 22 % (2/9) in PD-L1+ versus 29 % (4/14) in PD-L1- | NA | NA | Antonia SJ (2015) [154]; Updated in Antonia SJ (2016) [155] | |
| Durvalumab 10–20 mg/kg every 2 weeks plus tremelimumab 3 mg/kg (N = 34) | 20 % (5/25) | |||||||||
| Durvalumab 15 mg/kg every 4 weeks plus tremelimumab 10 mg/kg (N = 9) | 0 % (0/9) |
Abbreviations: DLT dose-limiting toxicity, q2w every 2 weeks, q3w every 3 weeks, q4w every 4 weeks, QD once daily, BRAF B-raf and v-raf murine sarcoma viral oncogene homologue B1, NA not available