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Table 2 Summary of reported clinical efficacy of PD-1/PD-L1 inhibitors

From: Current status and perspectives in translational biomarker research for PD-1/PD-L1 immune checkpoint blockade therapy

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)

  1. 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