Granted Patent
B2
US 12,534,530 · App. 17/725,240 · Granted Jan 27, 2026
Combination of a PD-1 antagonist and a VEGFR inhibitor for treating cancer
Inventors:
Jean-Francois Andre Martini (Carlsbad, CA); Jamal Christo Tarazi (San Diego, CA); Rodolfo Fleury Perini (Philadelphia, PA); David J. Mauro (North Wales, PA)
C07K16/2818A61K31/4439A61K39/39558A61K45/06C07K16/30C07K16/3015C07K16/3023C07K16/303C07K16/3038C07K16/3053C07K16/3061C07K16/3069C07K2317/24C07K2317/76
View Patent ↗
Loading inventors, assignments & file history…
Abstract
The present disclosure describes combination therapies comprising an antagonist of Programmed Death 1 receptor (PD-1) and a VEGFR inhibitor, and the use of the combination therapies for the treatment of cancer, and in particular for treating cancers that express PD-L1.
Claims (25)
1 . A method for treating a renal cell carcinoma (RCC) in an individual comprising administering to the individual a combination therapy which comprises pembrolizumab and axitinib,
wherein the individual has not been previously treated for RCC,
wherein axitinib is administered at a starting dose of 5 mg twice daily (BID), and
wherein if the individual tolerates axitinib with no drug-related grade >2 adverse events for two consecutive weeks, the dose of axitinib is then increased to a maximum dose of 10 mg BID.
2 . The method of claim 1 , wherein the individual is an adult human.
3 . The method of claim 1 , wherein the RCC comprises a solid tumor.
4 . The method of claim 1 , wherein the RCC is advanced renal cell carcinoma.
5 . The method of claim 1 , wherein pembrolizumab is administered at a dose selected from the group consisting of 1 mg/kg every three weeks (Q3W), 2 mg/kg Q3W, and 200 mg Q3W.
6 . The method of claim 5 , wherein pembrolizumab is administered at a dose of 2 mg/kg Q3W.
7 . The method of claim 5 , wherein pembrolizumab is administered at a dose of 200 mg Q3W.
8 . The method of claim 1 , wherein the dose of axitinib is increased to 7 mg BID.
9 . A method for treating a renal cell carcinoma (RCC) in an individual comprising administering to the individual a combination therapy which comprises pembrolizumab and axitinib,
wherein the individual has not been previously treated for RCC,
wherein axitinib is administered at a starting dose of 5 mg BID, and
wherein if the dose combination is not tolerated by the individual, the dose of axitinib is then reduced to a minimum dose of 3 mg BID.
10 . The method of claim 9 , wherein the individual is an adult human.
11 . The method of claim 9 , wherein the RCC comprises a solid tumor.
12 . The method of claim 9 , wherein the RCC is advanced renal cell carcinoma.
13 . The method of claim 9 , wherein pembrolizumab is administered at a dose selected from the group consisting of 1 mg/kg Q3W, 2 mg/kg Q3W, and 200 mg Q3W.
14 . The method of claim 13 , wherein pembrolizumab is administered at a dose of 2 mg/kg Q3W.
15 . The method of claim 13 , wherein pembrolizumab is administered at a dose of 200 mg Q3W.
16 . The method of claim 2 , wherein the individual has controlled hypertension.
17 . The method of claim 4 , wherein the advanced renal cell carcinoma in the individual is predominantly clear-cell subtype with primary tumor resected.
18 . The method of claim 10 , wherein the individual has controlled hypertension.
19 . The method of claim 12 , wherein the advanced renal cell carcinoma in the individual is predominantly clear-cell subtype with primary tumor resected.
Assignments (4)
CORRECTIVE ASSIGNMENT TO CORRECT THE APPLICATION NUMBER 17752240 TO 17725240 PREVIOUSLY RECORDED AT REEL: 063326 FRAME: 0670. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT.
Recorded Apr 20, 2023
From: MERCK SHARP & DOHME CORP.
To: MERCK SHARP & DOHME LLC
Reel/Frame 063409/0791 →
MERGER AND CHANGE OF NAME
Recorded Apr 14, 2023
From: MERCK SHARP & DOHME CORP.; MERCK SHARP & DOHME LLC
To: MERCK SHARP & DOHME LLC
Reel/Frame 063326/0670 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Aug 11, 2022
From: MARTINI, JEAN-FRANCOIS ANDRE; TARAZI, JAMAL CHRISTO
To: PFIZER INC.
Reel/Frame 060781/0005 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Aug 11, 2022
From: MAURO, DAVID J.; PERINI, RODOLFO FLEURY
To: MERCK SHARP & DOHME CORP.
Reel/Frame 060781/0054 →
Continuity (4)
Continuation
15115730
Provisional Application
61935809
· Feb 4, 2014
References Cited (213)
US 6534524B1
· Kania
· 2003
[cited by applicant]
US 6884890B2
· Kania
· 2005
[cited by applicant]
US 7141581B2
· Bender
· 2006
[cited by applicant]
US 7232910B2
· Ewanicki
· 2007
[cited by applicant]
US 7488802B2
· Collins
· 2009
[cited by applicant]
US 7521051B2
· Collins
· 2009
[cited by applicant]
US 8008449B2
· Korman
· 2011
[cited by applicant]
US 8168757B2
· Finnefrock
· 2012
[cited by applicant]
US 8354509B2
· Carven
· 2013
[cited by applicant]
US 8383796B2
· Korman
· 2013
[cited by applicant]
US 8791140B2
· Campeta
· 2014
[cited by applicant]
US 8900587B2
· Carven
· 2014
[cited by applicant]
US 8993731B2
· Tyson
· 2015
[cited by applicant]
US 9073994B2
· Honjo et al.
· 2015
[cited by applicant]
US 9220776B2
· Sharma
· 2015
[cited by applicant]
US 9457019B2
· Flynn et al.
· 2016
[cited by applicant]
US 9539245B2
· Peters
· 2017
[cited by applicant]
US 9683048B2
· Freeman et al.
· 2017
[cited by applicant]
US 9765147B2
· Wong et al.
· 2017
[cited by applicant]
US 9834605B2
· Carven
· 2017
[cited by applicant]
US 9993551B2
· Lebwohl et al.
· 2018
[cited by applicant]
US 20040224988A1
· Freddo
· 2004
[cited by applicant]
US 20060091067A1
· Fan
· 2006
[cited by applicant]
US 20060094763A1
· Ye
· 2006
[cited by applicant]
US 20070203196A1
· Ewanicki
· 2007
[cited by applicant]
US 20080274192A1
· Friesen
· 2008
[cited by applicant]
US 20140248347A1
· Morgado
· 2014
[cited by applicant]
US 20160303231A1
· Iannone et al.
· 2016
[cited by applicant]
US 20170008971A1
· Dennis et al.
· 2017
[cited by applicant]
US 20170088626A1
· Jure-Kunkel et al.
· 2017
[cited by applicant]
US 20170158776A1
· Feltquate et al.
· 2017
[cited by applicant]
US 20170209574A1
· Cao et al.
· 2017
[cited by applicant]
EP 3102605
· 2018
[cited by applicant]
EP 3498734
· 2021
[cited by applicant]
WO 2004004771
· 2004
[cited by applicant]
WO 2004056875
· 2004
[cited by applicant]
WO 2004072286
· 2004
[cited by applicant]
WO 2006048745
· 2006
[cited by applicant]
WO 2008100562
· 2008
[cited by applicant]
WO 2008156712
· 2008
[cited by applicant]
WO 2010027827
· 2010
[cited by applicant]
WO 2010077634
· 2010
[cited by applicant]
WO 2011066342
· 2011
[cited by applicant]
WO 2012135408
· 2012
[cited by applicant]
WO 2013019906
· 2013
[cited by applicant]
WO 2013164754
· 2013
[cited by applicant]
WO 2013181452
· 2013
[cited by applicant]
WO 2014163684
· 2014
[cited by applicant]
WO 2015069266
· 2015
[cited by applicant]
WO 2015119930
· 2015
[cited by applicant]
WO 2016059602
· 2016
[cited by applicant]
Ahmadzadeh et al., “Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired,”
[cited by applicant]
Amin et al., “Safety and Efficacy of Nivolumab in Combination with Sunitinib or Pazopanib in Advanced or Metastatic Renal Cell Carcinoma: the CheckMate 016 Study,”
[cited by applicant]
Anonymous, “Equivalent Surface Area Dosage Conversion Factors,” available from ncifrederick.cancer.gov/lasp/acuc/frederick/Media/Documents/ACUC42.pdf (2007).
[cited by applicant]
Atkins et al., “Axitinib in Combination with Pembrolizumab in Patients with Advanced Renal Cell Carcinoma,” presented at the European Society of Medical Oncology (ESM), , pp. 266-295, Oct. 7-11, 2016, Copenhagen Denmark.
[cited by applicant]
Atkins et al., “Axitinib in Combination with Pembrolizumab in Patients (pts) with Advanced Renal Cell Carcinoma (aRCC): Preliminary Safety and Efficacy Results,”
[cited by applicant]
Atkins et al., “Axitinib in Combination with Pembrolizumab in Patients with Advanced Renal Cell Cancer: a Non-Randomised, Open-Label, Dose-Finding, and Dose-Expansion Phase 1b Trial,”
[cited by applicant]
Bai et al., “A Guide to Rational Dosing of Monoclonal Antibodies,”
[cited by applicant]
Bailey et al., “Immune Checkpoint Inhibitors as Novel Targets for Renal Cell Carcinoma Therapeutics,”
[cited by applicant]
Choueiri et al., “Trial in Progress: Phase 1b Dose-Finding Study of Axitinib Plus Pembrolizumab for First-Line Treatment of Advanced Renal Cell Carcinoma (RCC),”
[cited by applicant]
Clinical Trials: NCT02014636, “A Phase I/II Study to Assess the Safety and Efficacy of Pazopanib and MK 34 75 in Subjects With Advanced Renal Cell Carcinoma,” Clinical Trials.gov (Jan. 24, 2014), pp. 1-11. Retrieved on …
[cited by applicant]
Clinical Trials: NCT02133742, “A Phase 1 B, Open Label, Dose Finding Study to Evaluate Safety, Pharmacokinetics and Pharmacodynamics Of Axitinib (AG-013736) in Combination with MK-34 75 in Patients with Advanced Renal C…
[cited by applicant]
Clinical Trials: NCT02179918, “A Phase 1 Study of the 4-1B Agonist PF-05082566 in Combination with the PD-1 Inhibitor MK-3475 in Patients with Advanced Solid Tumors,” Clinical Trials.gov (Jul. 1, 2014), pp. 1-6. Retriev…
[cited by applicant]
Clinical Trial NCT02133742, “A Dose Finding Study to Evaluate Safety, Drug Interaction, Tumor Markers of Axitinib in Combination with MK-3475 in Adult Patients with Previously Untreated Advanced Renal Cell Cancer” (8 pa…
[cited by applicant]
Clinical Trial NTC02014636, “Safety and Efficacy Study of Pazopanib and MK 3475 in Advanced Renal Cell Carcinoma (RCC; KEYNOTE-018)” (6 pp) (Study record version available online at clinicaltrials.gov/ct2/history/NCT020…
[cited by applicant]
Clinical Trial NCT02039674, “A Study of Pembrolizumab (MK-3475) in Combination with Chemotherapy or Immunotherapy in Participants with Non-Small Cell Lung Cancer (MK-3475-021/KEYNOTE-021)” (5 pp) (Study record version a…
[cited by applicant]
Clinical Trial NCT02039674, “A Study of Pembrolizumab (MK-3475) in Combination with Chemotherapy or Immunotherapy in Participants with Non-Small Cell Lung Cancer (MK-3475-021/KEYNOTE-021),” (6 pp) (Study record version …
[cited by applicant]
Clinical Trial NCT01472081, “Nivolumab (BMS-936558; MDX-1106) in Combination with Sunitinib, Pazopanib, or Ipilimumab in Subjects with Metastatic Renal Cell Carcinoma (RCC) (CheckMate 016)” (5 pp) (Study record version …
[cited by applicant]
Clinical Trial NCT01984242, “A Study of Atezolizumab (an Engineered Anti-Programmed Death-Ligand 1 [PD-L1] Antibody) as Monotherapy or in Combination with Bevacizumab (Avastin®) Compared to Sunitinib (Sutent®) in Partic…
[cited by applicant]
Clinical Trial NCT02036502, “A study of Pembrolizumab (MK-3475) in Combination with Standard of Care Treatments in Participants with Multiple Myeloma (MK-3475-023/KEYNOTE-023)” (5 pp) (Study record version available onl…
[cited by applicant]
Clinical Trial NCT02331368, “Phase 2 Multi-Center Study of Anti-PD-1 during Lymphopenic State after HDT/ASCT for Multiple Myeloma” (4 pp) (Study record version available online at clinicaltrials.gov/ct2/history/NCT02331…
[cited by applicant]
Clinical Trial NCT01472081, “Nivolumab (BMS-936558; MDX-1106) in Combination with Sunitinib, Pazopanib, or Ipilimumab in Subjects with Metastatic Renal Cell Carcinoma (RCC) (CheckMate 016)” (12 pp) (Study record version…
[cited by applicant]
Clinical Trial NCT02036502, “A study of Pembrolizumab (MK-3475) in Combination with Standard of Care Treatments in Participants with Multiple Myeloma (MK-3475-023/KEYNOTE-023)” (11 pp) (Study record version available on…
[cited by applicant]
Clinical Trial NCT02133742, “A Dose Finding Study to Evaluate Safety, Drug Interaction, Tumor Markers of Axitinib in Combination with MK-3475 in Adult Patients with Previously Untreated Advanced Renal Cell Cancer” (1 p)…
[cited by applicant]
Czarnecka et al., “The Activity of Tyrosine Kinase Inhibitors on Clear Cell Renal Cell Carcinoma Tumor Initiating Cells in Hypoxic Microenvironment,”
[cited by applicant]
Doloff et al., “VEGF Receptor Inhibitors Block the Ability of Metronomically Dosed Cyclophosphamide to Activate Innate Immunity-Induced Tumor Regression,”
[cited by applicant]
Domblides et al., “Emerging Antiangiogenics for Renal Cancer,”
[cited by applicant]
Dong et al., “Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion,”
[cited by applicant]
Dorff et al., “Novel Tyrosine Kinase Inhibitors for Renal Cell Carcinoma,”
[cited by applicant]
Drabkin, “Pazopanib and Anti-VEGF Therapy,”
[cited by applicant]
Duraiswamy et al., “Therapeutic PD-1 pathway blockade augments with other modalities of immunotherapy T-cell function to prevent immune decline in ovarian cancer,”
[cited by applicant]
Escudier et al., “Axitinib for the Management of Metastatic Renal Cell Carcinoma,”
[cited by applicant]
Escudier et al., “Optimal Management of Metastatic Renal Cell Carcinoma: Current Status,”
[cited by applicant]
European Search Report completed Mar. 12, 2019, issued in EP Application No. 18205542.
[cited by applicant]
Extended European Search Report completed Feb. 9, 2022, issued in EP Application No. 21187795.6.
[cited by applicant]
FDA-Approved Patient Labeling for INLYTA, reference ID:3078397 (Jan. 2012).
[cited by applicant]
Gao et al., “Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma,”
[cited by applicant]
Garon et al., “Abstract A20: MK-3475 Monotherapy for Previously Treated Non-Small Cell Lung Cancer (NSCLC): Preliminary Safety and Clinical Activity,” Proceedings of the AACR-IASLC Joint Conference on Molecular Origins …
[cited by applicant]
Ghebeh et al., “FOXP3+ Tregs and B7-H1+/PD-1+ T lymphocytes co-infiltrate the tumor tissues of high-risk breast cancer patients: Implication for immunotherapy,”
[cited by applicant]
Ghebeh et al., “The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: correlation with important high-risk prognostic factors,”
[cited by applicant]
Hamanishi et al., “Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer,”
[cited by applicant]
Hamid et al., “Safety and Tumor Responses with Lambrolizumab (Anti-PD-1) in Melanoma,”
[cited by applicant]
Heine et al., “The VEGF-Receptor Inhibitor Axitinib Impairs Dendritic Cell Phenotype and Function,”
[cited by applicant]
Hino et al., “Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma,”
[cited by applicant]
Hu-Lowe et al., “Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3,”
[cited by applicant]
Inman et al., “PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG- induced granulomata: associations with localized stage progression,”
[cited by applicant]
International Search Report, International Application No. PCT/US2015/014212, dated May 10, 2015 (12 pages).
[cited by applicant]
Joshi, J. “ASCO GU 2018: Safety and Efficacy of Axitinib in Combination with Pembrolizumab in Patients with Advanced Renal Cell Cancer” available at urotodav.com (downloaded Oct. 19, 2018).
[cited by applicant]
Kaufman et al., “The Society for Immunotherapy of Cancer Consensus Statement on Tumour Immunotherapy for the Treatment of Cutaneous Melanoma,”
[cited by applicant]
Lieu et al., “Beyond VEGF: Inhibition of the Fibroblast Growth Factor Pathway and Anti-Angiogenesis,”
[cited by applicant]
Lipson et al., “Durable Cancer Regression Off-Treatment and Effective Reinduction Therapy with an Anti-PD-1 Antibody,”
[cited by applicant]
Logan et al., “Systemic Therapy for Metastatic Renal Cell Carcinoma: A Review and Update,”
[cited by applicant]
Ma et al., “Modulation of the Antitumor Activity of Metronomic Cyclophosphamide by the Angiogenesis Inhibitor Axitinib,”
[cited by applicant]
McDermott et al., “PD-1 as a Potential Target in Cancer Therapy,”
[cited by applicant]
McDermott et al., “A Phase I/II study to assess the safety and efficacy of pazopanib (paz) and pembrolizumab (pembro) in patients (pts) with advanced renal cell carcinoma (aRCC),”
[cited by applicant]
Minner et al., “Epidermal Growth Factor Receptor Protein Expression and Genomic Alterations in Renal Cell Carcinoma,”
[cited by applicant]
Nakanishi et al., “Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers,”
[cited by applicant]
Nomi et al., “Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer,”
[cited by applicant]
Ohigashi et al., “Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer,”
[cited by applicant]
Pal et al., “Novel Therapies for Metastatic Renal Cell Carcinoma: Efforts to Expand beyond the VEGF/mTOR Signaling Paradigm,”
[cited by applicant]
Pardoll, “The Blockade of Immune Checkpoints in Cancer Immunotherapy,”
[cited by applicant]
Patel et al., “Clinical Cancer Advances 2013: Annual Report on Progress Against Cancer from the American Society of Clinical Oncology,”
[cited by applicant]
Patnaik et al., “Phase I Study of MK-3475 (Anti-PD-1 Monoclonal Antibody) in Patients with Advanced Solid Tumors,”
[cited by applicant]
Procopio et al., “Combination Therapies for Patients with Metastatic Renal Cell Carcinoma,”
[cited by applicant]
Rini et al., “Phase 1 Dose-Escalation Trial of Tremelimumab Plus Sunitinib in Patients with Metastatic Renal Cell Carcinoma,”
[cited by applicant]
Rini et al., “Comparative Effectiveness of Axitinib Versus Sorafenib in Advanced Renal Cell Carcinoma AXIS): A Randomised Phase 3 Trial,”
[cited by applicant]
Rini et al., “Five-Year Survival in Patients with Cytokine-Refractory Metastatic Renal Cell Carcinoma Treated with Axitinib,”
[cited by applicant]
Robert et al., “Drug of the Year: Programmed Death-1 Receptor/Programmed Death-1 Ligand-1 Receptor Monoclonal Antibodies,”
[cited by applicant]
Robert et al., “LBA-Pembrolizumab (Pembro:MK-3475) for Advanced Melanoma (MEL): Randomized Comparison of Two Dosing Schedules,”
[cited by applicant]
Rothermundt et al., “Successful treatment with an anti-PD-1 antibody for progressing brain metastases in renal cell cancer,”
[cited by applicant]
Search Report dated Sep. 11, 2018 in ROC (Taiwan) Patent Application No. 104103603.
[cited by applicant]
Seliger et al., “Antitumour and Immune-Adjuvant Activities of Protein-Tyrosine Kinase Inhibitors,”
[cited by applicant]
Sequence Listing from PCT/US2008/007463 filed Jun. 13, 2008.
[cited by applicant]
Sequence Listing from PCT/US2012/031063 (WO 2012/135408) filed Mar. 29, 2012.
[cited by applicant]
Sharpe et al., “The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection,”
[cited by applicant]
Shimauchi et al., “Augmented expression of programmed death-1 in both neoplastic and non-neoplastic CD4+ T-cells in adult T-cell leukemia/lymphoma,”
[cited by applicant]
Sliwkowski et al., “Antibody Therapeutics in Cancer,”
[cited by applicant]
Solowiej et al., “Characterizing the effects of the juxtamembrane domain on vascular endothelial growth factor receptor-2 enzymatic activity, autophosphorylation, and inhibition by axitinib,”
[cited by applicant]
Stehle et al., “Reduced Immunosuppressive Properties of Axitinib in Comparison with Other Tyrosine Kinase Inhibitors,”
[cited by applicant]
Submission of the applicant dated May 10, 2017, during examination of EP 15703439.8.
[cited by applicant]
Tang et al., “Programmed Death 1 Pathway Inhibition in Metastatic Renal Cell Cancer and Prostate Cancer,”
[cited by applicant]
Thompson et al., “Significance of B7-H1 overexpression in kidney cancer,” Clinical Genitourinary Cancer, 5(3):206-211 (2006).
[cited by applicant]
Thompson et al., “PD-1 is expressed by tumor-infiltrating immune cells and is associated with poor outcome for patients with renal cell carcinoma,” Clinical Cancer Research, 13(6):1757-1761 (2007).
[cited by applicant]
Thorn et al., “PharmGKB Summary: Pazopanib Pathway, Pharmacokinetics,”
[cited by applicant]
Topalian et al., “Safety, Activity, and Immune Correlates of Anti-PD-1 Antibody in Cancer,”
[cited by applicant]
Tykodi, “Progress and Potential of Immune Checkpoint Blockage for Treating Advanced Renal Cell Carcinoma,”
[cited by applicant]
Van Geel et al., “Concise Drug Review: Pazopanib and Axitinib,”
[cited by applicant]
Wei et al., “Combinatorial PD-1 blockade and CD137 activation has therapeutic efficacy in murine cancer models and synergizes with cisplatin,”
[cited by applicant]
[cited by applicant]
Yang et al., “PD-L1: PD-1 interaction contributes to the functional suppression of T-cell responses to human uveal melanoma cells in vitro,”
[cited by applicant]
Yasuda et al., “Simultaneous Blockade of Programmed Death 1 and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Induces Synergistic Anti-Tumour Effect in vivo,”
[cited by applicant]
Yousaf et al., “Axitinib in advanced renal-cell carcinoma,”
[cited by applicant]
Amin et al., “High-Dose Interleukin-2: Is It Still Indicated for Melanoma and RCC in an Era of Targeted Therapies?,”
[cited by applicant]
Anonymous, “Clinical Development Success Rates 2006-2015,” Biotechnology Innovation Organization, Biomedtracker, 28 pp. (2016).
[cited by applicant]
[cited by applicant]
CAS Lambrolizumab, Registry No. 1374853-91-4 (entered STN May 31, 2012).
[cited by applicant]
Clinical Trial NCT01295827, “Study of MK-3475 in Participants with Progressive Locally Advanced or Metastatic Carcinoma, Melanoma, or Non-Small Cell Lung Carcinoma (P07990/MK-3475-001),” latest version submitted Nov. 22…
[cited by applicant]
Clinical Trial NCT01472081, “Nivolumab (BMS-936558; MDX-1106) in Combination with Sunitinib, Pazopanib, or Ipilimumab in Subjects with Metastatic Renal Cell Carcinoma (RCC) (CheckMate016),” last submitted Nov. 30, 2021;…
[cited by applicant]
Clinical Trial NCT01704287, “Study of MK-3475 Versus Chemotherapy in Participants with Advanced Melanoma,” latest version submitted Apr. 29, 2020.
[cited by applicant]
Clinical Trial NCT02036502, “Study of Pembrolizumab (MK-3475) in Combination with Lenalidomide and Dexamethasone in Participants with Multiple Myeloma (MK-3475-023/KEYNOTE-023)” as of Jan. 15, 2015.
[cited by applicant]
Clinical Trial NCT02133742, “A dose finding study to evaluate safety, drug interaction, tumor markers of axitinib in combination with MK-3475 in adult patients with previously untreated advanced renal cell cancer,” (fir…
[cited by applicant]
Clinical Trial NCT02133742, “A Dose Finding Study to Evaluate Safety, Drug Interaction, Tumor Markers of Axitinib in Combination with MK-3475 in Adult Patients with Previously Untreated Advanced Renal Cell Cancer,” late…
[cited by applicant]
Clinical Trial NCT02133742, “A Dose Finding Study to Evaluate Safety, Drug Interaction, Tumor Markers of Axitinib in Combination with MK-3475 in Adult Patients with Previously Untreated Advanced Renal Cell Cancer,” last…
[cited by applicant]
Clinical Trial NCT02014636, “A phase I/II study to assess the safety and efficacy of pazopanib and MK 3475 in subjects with advanced renal cell carcinoma,” last submitted Feb. 28, 2020; available at ClinicalTrials.gov/c…
[cited by applicant]
Clinical Trial NCT02014636, “Safety and Efficacy Study of Pazopanib and MK 3475 in Advanced Renal Cell Carcinoma (RCC; KEYNOTE-018),” last update posted Mar. 3, 2020; available at ClinicalTrials.gov/ct2/show/NCT02014636.
[cited by applicant]
Clinical Trial NCT02133742, “A dose finding study to evaluate safety, drug interaction, tumor markers of Axitinib in combination with MK-3475 in adult patients with previously untreated advanced renal cell cancer,” last…
[cited by applicant]
Dolgin, “Cancer's True Breakthroughs,”
[cited by applicant]
European Patent Office Decision of the Opposition Division Revoking the European Patent 3102605, dated Jul. 29, 2021.
[cited by applicant]
Friedman et al. (eds),
[cited by applicant]
Garon et al., “Antitumor Activity of Pembrolizumab (PEMBRO; MK-3475) and Correlation with Programmed Death Ligand 1 (PD-L1) Expression in a Pooled Analysis of Patients (PTS) with Advanced Non-Small Cell Lung Carcinoma (…
[cited by applicant]
Gross-Goupil et al., “Axitinib: A Review of its Safety and Efficacy in the Treatment of Adults with Advanced Renal Cell Carcinoma,”
[cited by applicant]
Hutson et al., “Axitinib Versus Sorafenib as First-Line Therapy in Patients with Metastatic Renal-Cell Carcinoma: A Randomised Open-Label Phase 3 Trial,”
[cited by applicant]
Kindler et al., “Axitinib Plus Gemcitabine Versus Placebo Plus Gemcitabine in Patients with Advanced Pancreatic Adenocarcinoma: a Double-Blind Randomised Phase 3 Study,”
[cited by applicant]
Mahan, “Clinical Trial Phases,”
[cited by applicant]
Mullard, “Learning from the 2012-2013 Class of Breakthrough Therapies,”
[cited by applicant]
O'Sullivan et al., “The VEGF Inhibitor Axitinib has Limited Effectiveness as a Therapy for Adrenocortical Cancer,”
[cited by applicant]
Patel et al., “Clinical Cancer Advances 2013: Annual Report on Progress Against Cancer from the American Society of Clinical Oncology,”
[cited by applicant]
Prescribing Information for KEYTRUDA, reference ID: 3621876 (2014).
[cited by applicant]
Prescribing Information for KEYTRUDA, Reference ID: 4543239, revised Jan. 2020.
[cited by applicant]
Press Release Fierce Biotech, “Top 10 experimental cancer drugs—2013” (May 2013).
[cited by applicant]
Press Release, Reuters, “Update 1-Pfizer Pancreatic Cancer Drug Fails, Trial Halted” (Jan. 31, 2009).
[cited by applicant]
Press Release, Merck, “Merck announces breakthrough therapy designation for lambrolizumab an investigational antibody therapy for advanced melanoma” (Apr. 2013).
[cited by applicant]
Press Release, Merck, “PD-1 inhibitor becomes ‘Breakthrough Therapy’,”
[cited by applicant]
Press Release, The ASCO Post Staff, “Breakthrough therapy designation for lambrolizumab for the treatment of advanced melanoma” (May 2013).
[cited by applicant]
Press Release, Clinical Trials Arena, “Merck Withdraws Keytruda for Lung Cancer Amid FDA Crackdown” (Mar. 3, 2021).
[cited by applicant]
Press Release, European Pharmaceutical Review, “Pfizer and Merck to Collaborate on Innovative Anti-Cancer Combination Studies” (Feb. 5, 2014).
[cited by applicant]
Press Release, Pfizer, “Pfizer and Merck to Collaborate on Innovative Anti-Cancer Combination Studies” (Feb. 5, 2014).
[cited by applicant]
Rini et al., “Axitinib for First-Line Metastatic Renal Cell Carcinoma (mRCC): Overall Efficacy and Pharmacokinetic (PK) Analyses from a Randomized Phase II Study,”
[cited by applicant]
Rini et al., “Axitinib with or without Dose Titration for First-Line Metastatic Renal Cell Carcinoma (mRCC): Unblinded Results from a Randomized Phase II Study,”
[cited by applicant]
Rini et al., “Axitinib with or without Dose Titration for First-Line Metastatic Renal Cell Carcinoma: a Randomized Double Blind Phase 2 Trial,”
[cited by applicant]
Rizvi et al., “Safety and Clinical Activity of MK-3475 as Initial Therapy in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC),”
[cited by applicant]
Summary of Product Characteristics of Axitinib, Pfizer, May 22, 2017.
[cited by applicant]
Summary of Product Characteristics of Pembrolizumab, Merck, Mar. 24, 2020.
[cited by applicant]
Amin et al., “Nivolumab (anti-PD-1; BMS-936558, ONO-4538) in combination with sunitinib or pazopanib in patients (pts) with metastatic renal cell carcinoma (mRCC),”
[cited by applicant]
Harshman et al., “PD-1 Blockade in Renal Cell Carcinoma: To Equilibrium and Beyond,”
[cited by applicant]
Powles et al., “Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial,”
[cited by applicant]
Rini et al., “Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal- Cell Carcinoma,”
[cited by applicant]
Chowdhury et al., “A phase I/II study to assess the safety and efficacy of pazopanib (PAZ) and pembrolizumab (PEM) in patients (pts) with advanced renal cell carcinoma (aRCC),”
[cited by applicant]
Furlow, “Pazopanib Is Not Safe for Patients With RCC”
[cited by applicant]
Furlow, “Pembrolizumab Plus Pazopanib Is Not Safe for Patients With RCC,”
[cited by applicant]
Highlights of Prescribing Information for FDA-Approved Drug Nexavar (sorafenib) tablets, reference ID:4585765 (Jan. 2005), 30 pages.
[cited by applicant]
Highlights of Prescribing Information for FDA-Approved Drug Sutent (sunitinib malate) capsules, reference ID:36758965 (Jan. 2006), 31 pages.
[cited by applicant]
Highlights of Prescribing Information for FDA-Approved Drug Votrient (pazopanib) tablets, reference ID:3122369 (Jan. 2009), 32 pages.
[cited by applicant]
Hutson et al., “Axitinib Versus Sorafenib as First-Line Metastatic Renal Cell Carcinoma: Overall Survival From a Randomized Phase III Trial,”
[cited by applicant]
Lee et al., “Combination VEGFR/Immune Checkpoint Inhibitor Therapy: A Promising New Treatment for Renal Cell Carcinoma,”
[cited by applicant]
Clinical Trials.gov: “NCT02014636 A phase I/II study to assess the safety and efficacy of pazopanib and MK 3475 in subjects with advanced renal cell carcinoma”. The document was first posted online in Dec. 2013. Retriev…
[cited by third party]
Hamid et al., “Safety and Tumor Responses with Lambrolizumab (Anti-PD-1) in Melanoma”, N. Engl. J. Med., vol. 369(2): pp. 134-144. Published on Jun. 2, 2013.
[cited by third party]
Approval label of Axitinib by the FDA from Jan. 2012.
[cited by third party]
Van Geel et al., “Concise drug review: Pazopanib and Axitinib”. The Oncologist, vol. 17: pp. 1081-1089. Published Jun. 25, 2012.
[cited by third party]
Stehle et al., “Reduced immunosuppressive properties of axitinib in comparison with other tyrosine kinase inhibitors”, J Biol Chem, vol. 288(23): pp. 16334-16347. Published Jun. 7, 2013.
[cited by third party]