Table A4.
Select clinical data for pembrolizumab.
| Cancer | Study | Phase | Stage of Disease | Treatment Regimen | N | Median OS (Months) | Median PFS (Months) | ORR (%) | CRR (%) | Grade III/IV AEs (%) | Resultant FDA-Approved Indication |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Bladder cancer | Bellmunt et al. (2017) [151] KEYNOTE-045 | III | Metastatic urothelial carcinoma that recurred or progressed after platinum chemotherapy |
A. Pembrolizumab 200mg Q3wks. B. Investigator’s choice of paclitaxel, docetaxel, or vinflunine Q3wks. |
542 A. 270 B. 272 |
A. 10.3 B. 7.4 (HR = 0.73, p = 0.002) |
A. 2.1 B. 3.3 (HR = 0.98, p = 0.42) |
A. 21 B. 11 |
-- |
A. 15.0 B. 49.4 |
Locally advanced or metastatic urothelial carcinoma with progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy (May 2017) |
| Balar et al. (2017) [152] KEYNOTE-052, with update from O’Donnell et al. (2019) [153] | II | Advanced urothelial carcinoma ineligible for platin | Pembrolizumab 200mg Q3wks. | 370 CPS < 10. 251 CPS ≥ 10. 110 |
Combined: 11.3 CPS < 10: 9.7 CPS ≥ 10: 18.5 |
Combined: 2 months |
Combined: 28.4 CPS < 10: 20.0 CPS ≥ 10: 10.0 |
Combined: 9.0 | 21 | Expanded indication: locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing therapy and whose tumors express PD-L1 (CPS ≥ 10), or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status (June 2018) | |
| CSCC | Chung et al. (2019) [57] KEYNOTE-158 | II | Recurrent or metastatic advanced disease that has failed one or more lines of chemotherapy | Pembrolizumab 200mg Q3wks. | 98 CPS < 1. 16 CPS ≥ 1. 82 |
Combined: 9.4 CPS ≥ 1: 11 |
Combined: 2.1 CPS ≥ 1: 2.1 |
Combined: 12.2 CPS < 1:1.0 CPS ≥ 1:14.6 |
Combined: 3 | 12.2 | Second-line for recurrent or metastatic cervical cancer with CPS ≥ 1 (June 2018) |
| Endometrial Carcinoma | Makker et al. (2019) [94] KEYNOTE-146 | II | Metastatic endometrial cancer that had progressed following at least one prior systemic therapy | Pembrolizumab 200mg IV Q3wks + lenvatinib 20mg PO QD | 108, 94 of which were not MSI-H or dMMR | -- | -- | 38.3 | 10.6 | 52 | Approved in combination with lenvatinib for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR, or who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation (September 2019) |
| Esophageal cancer | Shah et al. (2019) [154] KEYNOTE-180 | II | Advanced, metastatic esophageal cancer that progressed after 2 or more lines of therapy | Pembrolizumab 200mg Q3wks. | 121 ESCC. 63 EAC. 58 |
ESCC: 6.8 EAC: 3.9 CPS < 10: 5.4 CPS ≥ 10: 6.4 (HR = 0.64) |
ESCC: 2.1 EAC: 1.9 CPS < 10: 2.0 CPS ≥ 10: 2.0 (HR = 0.66) |
ESCC: 14.3 EAC: 5.2 CPS < 10: 6.3 CPS ≥ 10: 13.8 |
ESCC: 0.0 EAC: 0.0 |
Combined: 11.60 | Recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS ≥ 10) (July 2019) |
| Kojima et al. (2019) [155] KEYNOTE-181 | III | Locally advanced or metastatic disease |
A. Pembrolizumab 200mg Q3wks. B. Investigator’s choice of paclitaxel, docetaxel, or irinotecan |
628 ESCC. 401 CPS ≥ 10. 222 |
ESCC: A. 8.2 B. 7.1 (HR = 0.78, p = 0.0095) CPS ≥ 10: A. 9.3 B. 6.7 (HR = 0.69, p = 0.0074) |
-- | -- | -- |
A. 18 B. 41 |
As above, with Shah et al. (2019) | |
| Gastric or GEJ adenocarcinoma | Fuchs et al. (2018) [58] KEYNOTE-059 | II | Gastric/GEJ adenocarcinoma previously treated with 2 or more systemic therapies including fluoropyrimidine and platinum, and HER2/neu if indicated | Pembrolizumab 200mg Q3wks. | 259 | 5.6 | 2.0 |
Overall: 11.6 PD-L1+: 15.5 PD-L1-: 6.4 |
2.4 | 17.8 | Second-line therapy for patients with recurrent, locally advanced, or metastatic esophageal squamous cell carcinoma (September 2017) |
| HCC | Zhu et al. (2018) [62] KEYNOTE-224 | II | HCC with prior treatment with sorafenib | Pembrolizumab 200mg Q3wks. | 104 | 12.9 | 4.8 | 17 | 1 | 24 | Monotherapy for HCC that had been previously treated with sorafenib (November 2018) |
| HL | Chen et al. (2017) [63] KEYNOTE-087 | Recurrent or relapsed cHL | Pembrolizumab 200 mg Q3wks. in 3 cohorts: A. After ASCT and BV B. After salvage chemotherapy and BV C. After ASCT only |
210 A. 69 B. 81 C. 60 |
NR 24-month OS rate: A. 92.5 B. 90.6 C. 89.4 |
Overall: 13.7 A. 16.4 B. 11.1 C. 19.4 |
Overall: 71.9 A. 76.8 B. 66.7 C. 73.3 |
A. 26.1 B. 25.9 C. 31.7 |
11.9 | Refractory or relapsed cHL after three or more lines of prior therapy (March 2017) | |
| HNSCC | Seiwert et al. (2016) [59] KEYNOTE-012 | Ib | Recurrent or metastatic disease with PD-L1 positive status | Pembrolizumab 10mg/kg Q2wks. | 60 | 13 | 2 | 18 | 2 | 17 | Metastatic or recurrent HNSCC with disease progression on or after platinum therapy (August 2016) |
| Burtness et al. (2018) [61] KEYNOTE-048 | III | Locally incurable recurrent or metastatic disease and no prior systemic therapy |
A. Pembrolizumab 200mg Q3wks. B. Pembrolizumab 200mg Q3wks. + 6 cycles of platinum therapy C. Cetuximab + 6 cycles of platinum + FU |
882 A. 301 B. 281 C. 300 |
Overall: B. 11.5 C. 10.7 (HR = 0.83, p = 0.0199) CPS ≥ 20: B. 14.7 C. 11 (HR = 0.60, p = 0.0004) CPS ≥ 1: B. 13.6 C. 10.4 (HR = 0.65, p < 0.0001) |
NR Overall: HR = 1.29 CPS ≥ 20: HR = 0.76, p = 0.5 No further PFS analysis done |
Overall: B. 16.9 C. 36.0 CPS ≥ 20: B. 42.9 C. 38.2 CPS ≥ 1: B. 36.4 C. 35.7 |
-- |
A. 54.7 B. 85.1 C. 83.3 |
-- | |
| Rischin et al. 2019 [156] (KEYNOTE-048 final analysis) | III | Locally incurable recurrent or metastatic disease and no prior systemic therapy |
A. Pembrolizumab 200mg Q3wks. B. Pembrolizumab 200mg Q3wks. + 6 cycles of platinum therapy C. Cetuximab + 6 cycles of platinum + FU |
882 A. 301 B. 281 C. 300 |
CPS ≥ 20: A. 14.9 C. 10.7 (HR = 0.61 p = 0.0015) CPS ≥ 1: A. 12.3 C. 10.3 (HR = 0.65, p < 0.0001) Overall B. 13.0 C. 10.7 (HR = 0.77, p = 0.0067) |
CPS ≥ 20: A. 3.4 C. 5.0 (HR = 0.99) CPS ≥ 1: A. 3.2 C. 5.0 (HR = 1.15) Overall B. 4.9 C. 5.1 (HR = 0.92 p = 0.3394) |
CPS ≥ 20: A. 23 C. 36 CPS ≥ 1: A. 19 C. 35 Overall B. 36 C. 36 |
CPS ≥ 20: A. 8 C. 3 CPS ≥ 1: A. 5 C. 13 Overall B. 6 C. 3 |
A. 54.7 B. 85.1 C. 83.3 |
First line treatment of patients with metastatic or unresectable recurrent HNSCC, as monotherapy in patients whose tumors express PD-L1 or in combination with platinum and fluorouracil (June 2019) | |
| Cohen et al. (2019) [60] KEYNOTE-040 | III | Recurrent or metastatic disease |
A. Pembrolizumab 10mg/kg Q3wks. B. Investigator’s choice of MTX, docetaxel, cetuximab |
495 A. 247 B. 248 |
CPS ≥ 1: A. 8.7 B. 7.1 |
A. 2.1 B. 2.3 (HR = 0.95, p = 0.030) |
A. 14.6 B. 10.1 |
-- |
A. 13 B. 36 |
Expanded indication: combination with platinum and fluorouracil (FU) as first-line treatment of metastatic or unresectable, recurrent HNSCC, and as single agent for patients whose tumors express PD-L1 and CPS ≥ 1 (June 2019) | |
| MCC | Nghiem et al. (2019) [69] KEYNOTE-017 | II | Recurrent locally advanced Merkel Cell Carcinoma or metastatic MCC with no prior therapy | Pembrolizumab 2mg/kg Q3wks. | 50 | NR | 16.8 | 56 | -- | 28 | Treatment of adult and pediatric patients with recurrent locally advanced or metastatic MCC (December 2018) |
| Melanoma | Robert et al. (2014) [65] KEYNOTE-001 | I | Unresectable or metastatic disease with progression following ipilimumab and, if BRAF V600 mutation positive, BRAF inhibitor |
A. Pembrolizumab 2mg/kg Q3wks. B. Pembrolizumab 10mg/kg Q3wks. |
173 A. 89 B. 84 |
12-month survival rate: A. 58 B. 63 (HR = 1.09) |
A. 5.1 B. 3.2 (HR = 0.84) |
Combined: 26 A. 26 B. 26 (p = 0.96) |
A. 1 B. 1 |
Combined: 12 A. 15 B. 8 |
Unresectable or metastatic melanoma with disease progression following ipilimumab and, if BRAF V600 mutation positive, BRAF inhibitor (September 2014) |
| Ribas et al. (2015) [66] KEYNOTE-002 | II | Advanced melanoma following ipilimumab and, if BRAF V600 positive, BRAF inhibitor | A. Pembrolizumab 2mg/kg Q3wks.B. Pembrolizumab 10mg/kg Q3wks.B. Investigator’s choice of paclitaxel + carboplatin, paclitaxel, carboplatin, dacarbazine, or temozolomide | 540 A. 180 B. 181 C. 179 |
-- |
A. 2.9 B. 2.9 C. 2.7 (HR = 0.57, p < 0.0001 A vs. C; HR = 0.50, p < 0.0001 B vs. C) |
A. 38 B. 46 C. 8 |
A. 2 B. 3 C. 0 |
A. 11 B. 14 C. 26 |
-- | |
| Robert et al. (2015) [67] KEYNOTE-006 | III | Stage III or IV melanoma with no more than 1 prior treatment |
A. Pembrolizumab 10mg/kg Q2wks. B. Pembrolizumab 10mg/kg Q3wks.C. Ipilimumab 3mg/kg Q3wks. |
834 A. 279 B. 277 C. 278 |
NR for all groups 12-month OS rate: A. 74.1 B. 68.1 C. 58.2 (HR = 0.63, p < 0.0005 A vs. C; HR = 0.69, p = 0.0036 B vs. C) |
A. 5.5 B. 4.1 C. 2.8 (HR = 0.58, p < 0.001 A vs. C; HR = 0.58, p < 0.001 B vs. C) |
A. 33.7 B. 32.9 C. 11.9 (p < 0.001 A vs. C; p < 0.001 B vs. C) |
A. 5.0 B. 6.1 C. 1.4 |
A. 13.3 B. 10.1 C. 19.9 |
Expanded indication: first-line treatment of unresectable or metastatic melanoma (December 2015) | |
| Eggermont et al. (2018) [68] KEYNOTE-054 | III | Completely resected stage III disease |
A. Pembrolizumab 200mg Q3wks. B. Placebo |
1019 A. 514 B. 505 |
-- |
Median recurrence-free survival A. NR B. 20.4 (HR = 0.57, p < 0.001) |
Recurrence rate: A. 26 B. 43 |
-- |
A. 14.7 B. 3.4 |
Expanded indication: adjuvant treatment of melanoma following complete resection (February 2019) | |
| MSI-H or dMMR | Le et al. (2018) [157] KEYNOTE-164 | II | Metastatic CRC with >2 prior treatments including FU, oxaliplatin, and irinotecan +/- anti-VEGF/EGFR mAb | Pembrolizumab 200mg Q3wks. | 61 | NR | 4.1 | 32 | 3.1 | 11 | Adult and pediatric patients with MSI-H or dMMR solid tumors that have progressed with no other treatment alternatives or colorectal cancer that has progressed after fluoropyrimidine, oxaliplatin, and irinotecan (May 2017) |
| KEYNOTE-016, 018, 028, 158 [70] | MSI-H/dMMR CRC, gastric, bladder, breast, biliary, endometrial, esophageal cancer | Pembrolizumab at varying doses | 149 CRC = 90 Other types = 59 |
-- | -- |
Combined: 39.6 CRC: 36 Other: 46 |
7.4 | -- | -- | ||
| NPC | Hsu et al. (2017) [158] KEYNOTE-028 | Ib | Unresectable or metastatic disease, failure on standard therapy, PD-L1 expression in 1% or more of tumor cells | Pembrolizumab 10 mg/kg Q2wks | 27 | 16.5 (95% CI: 10.1-NR) | 3.7 (95% CI: 2.1–13.4) | 25.9 (95% CI: 11.1–46.3) | 0 | 29.6 | -- |
| NSCLC | Garon et al. (2015) [64] KEYNOTE-001 | I | Advanced disease |
A. Pembrolizumab 2mg/kg Q3wks. B. Pembrolizumab 10mg/kg Q3wks. C. Pembrolizumab 10mg/kg Q2wks. |
495 Prior treatment = 394 No prior treatment = 101 |
Combined: 12.0 Prior treatment: 9.3 No prior treatment: 16.2 |
Combined: 3.7 Prior treatment: 3.0 No prior treatment: 6.0 |
Combined: 19.4 Prior treatment: 18.0 No prior treatment: 24.8 |
-- | Combined: 9.5 | Metastatic NSCLC with PD-L1 expression and disease progression on or after platinum therapy; those with EGFR or ALK tumor mutations should have disease progression on FDA-approved therapy for these mutations prior to pembrolizumab (October 2015) |
| Reck et al. (2016) [159] KEYNOTE-024 interim analysis | III | Previously untreated NSCLC with TPS≥50% and no EGFR or ALK mutations |
A. Pembrolizumab 200mg Q3wks B. Investigator’s choice platinum therapy |
305 A = 154 B = 151 |
MOS not reached, overall survival greater in group A with HR = 0.6, p = 0.005) |
A. 10.3 B. 6.0 (HR = 0.5, p < 0.001) |
A. 44.8 B. 27.8 |
-- |
A. 26.6 B. 53.3 |
First line therapy metastatic NSCLC with TPS>50% and no EGFR, ALK mutations (October 2016) | |
| Herbst et al. (2016) [160] KEYNOTE-010 | II/III | Previously treated metastatic NSCLC with TPS>1% | A. Pembrolizumab 2mg/kg Q3wks.B. Pembrolizumab 10mg/kg Q3wks.C. Docetaxel 75mg/m2 Q3wks. | 1034 A = 345 B = 346 C = 343 |
A. 10.4 B. 12.7 C. 8.5 (HR = 0.71, p ≤ 0.001 A vs. C; HR = 0.61, p ≤ 0.001 B vs. C) |
A. 3.9 B. 4.0 C. 4.0 (HR = 0.88, p = 0.068 A vs. C; HR = 0.79, p = 0.005 B vs. C) |
A. 18 B. 19 C. 9 |
-- |
A. 13 B. 16 C. 35 |
Expanded indication: second-line therapy for metastatic NSCLC with TPS >1% following disease progression on or after platinum chemotherapy (October 2016) | |
| Gandhi et al. (2018) [161] KEYNOTE-189 | III | Previously untreated metastatic NsqNSCLC without ALK or EGFR mutations | A. Pemetrexed and platinum-based therapy + pembrolizumab Q3wks.B. Placebo Q2wks. x 4 cycles, then pembrolizumab/placebo for up to 35 cycles + pemetrexed | 616 A = 405 B = 202 |
A. NR B. 11.3 (HR = 0.49, p ≤ 0.0001) |
A. 8.8 B. 4.8 (HR = 0.52, p ≤ 0.0001) |
A. 47.6 B. 18.9 |
A. 0.5 B. 0.5 |
A. 67.2 B. 65.8 |
Expanded indication: first-line therapy in combination with platinum-based chemotherapy and pemetrexed for metastatic NsqNSCLC without EGFR or ALK genomic aberrations (May 2018) | |
| Paz-Ares et al. (2018) [162] KEYNOTE-407 | III | Untreated metastatic squamous disease | A. Pembrolizumab 200mg + carboplatin + paclitaxel/nab-paclitaxel for first 4 cyclesB. saline placebo + carboplatin and paclitaxel or nab-paclitaxel for first 4 cycles | 559 A = 278 B = 281 |
A. 15.9 B. 11.3 (HR = 0.64, p = 0.0017) |
A. 6.4 B. 4.8 (HR = 0.56, p ≤ 0.0001) |
A. 58 B. 35 |
-- |
A. 69.8 B. 68.2 |
Expanded indication: first-line therapy in combination with carboplatin and paclitaxel/nab-paclitaxel for metastatic sqNSCLC (October 2018) | |
| Reck et al. (2019) [163] KEYNOTE-024 | III | Metastatic disease with TPS > 50% without ALK or EGFR mutations |
A. Pembrolizumab 200mg Q3wks. B. Investigator’s choice of platinum-based chemo (platinum-based therapy + paclitaxel/pemetrexed/gemcitabine) |
305 A = 154 B = 151 |
A. 30 B. 14.2 (HR = 0.60, p = 0.005) |
A. 10.3 B. 6.0 (HR = 0.50, p ≤ 0.001) |
A. 44.8 B. 27.8 |
A. 4 B. 1 |
A. 26.6 B. 53.3 |
Expanded indication: first-line treatment for stage III/IV NSCLC that is not amenable to surgical resection or definitive chemoradiation with TPS ≥1% and without EGFR or ALK mutations (April 2019) | |
| PMBCL | Armand et al. (2018) [71] KEYNOTE-170 | II | Refractory or relapsed disease after or who were ineligible for ASCT w/ ≥2 lines of therapy | Pembrolizumab 200mg Q3wks. | 53 | NR | 5.5 | 45 | 11 | 26 | Approved as monotherapy in refractory or relapsed PMBCL after or who were ineligible for ASCT w/ ≥2 lines of therapy (June 2018) |
| RCC | Rini et al. (2019) [73] KEYNOTE-426 | I | Preciously untreated advanced disease | A. 200mg Pembrolizumab Q3wks. + axitinib 5mg BIDB. Sunitinib 50mg daily for first 4 weeks of each 6-week cycle | 861 A = 432 B = 423 |
NR (HR = 0.53, p < 0.0001) |
A. 15.1 B. 11.1 (HR = 0.69, p < 0.001) |
A. 59.3 B. 35.7 (p < 0.001) |
-- |
A. 75.8 B. 70.6 |
First-line therapy in combination with axitinib for patients with advanced RCC (April 2019) |
| SCLC | Ott et al. (2017) [164] KEYNOTE-028 | I | SCLC or other lung neuroendocrine tumor with PD-L1≥1% that has previously failed platinum therapy plus etoposide | Pembrolizumab 10mg/kg Q2wks. | 24 | 9.7 | 1.9 | 33.3 | 4.2 | 33 | -- |
| Chung et al. (2019) [165] KEYNOTE-158 | II | Unresectable or metastatic disease that has failed 2 prior lines of therapy | Pembrolizumab 200mg Q3wks. | 98 | 9.4 | 2.1 | 12.20 | 3 | 12.20 | Second-line therapy for SCLC or other lung neuroendocrine tumor that has failed previous platinum-based therapy and one other prior line of therapy (June 2019) |
ALK = anaplastic lymphoma kinase, ASCT = autologous stem cell transplant, BV = brentuximab vedotin, cHL = classical Hodgkin lymphoma, CI = confidence interval, CPS = combined positive score (CPS), CSCC = cervical squamous cell carcinoma, EAC = esophageal adenocarcinoma, EGFR = epidermal growth factor receptor, ESCC = esophageal squamous cell carcinoma, FU = fluorouracil, GEJ = gastroesophageal junction, HL = Hodgkin lymphoma, HNSCC = head and neck squamous cell carcinoma, HR = hazard ratio, MCC = Merkel cell carcinoma, MTX = methotrexate, NPC = nasopharyngeal carcinoma, NR = not reached, NSCLC = non-small cell lung cancer, NsqNSCLC = non-squamous non-small cell lung cancer, PMBCL = primary mediastinal B-cell lymphoma, RCC = renal cell carcinoma, SCLC = small cell lung cancer, sqNSCLC = squamous non-small cell lung cancer, TPS = tissue polypeptide-specific antigen.