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1 februari 2020: lees ook dit artikel:
31 januari 2020: Bron: Journal of Clinical Oncology
Bij patienten met solide tumoren waaronder gevorderde nierkanker, gevorderde baarmoederkanker, gevorderde melanomen waarbij geen operatie kan worden uitgevoerd of andere behandelingen hebben gefaald en er verder geen opties meer zijn blijkt de combinatie van Lenvatinib (een zogeheten VEGFR remmer - vascular endothelial growth factor receptors) en immuuntherapie met een anti-PD medicijn, in dit geval pembrolizumab, toch nog een veelbelovende behandelingsoptie.
In deze grafiek zijn de deelnemende patienten per vorm van kanker vermeld, hun status en of ze wel of niet PD-L1 expressie hadden ja of nee.:
Uit het abstract overgenomen de resultaten op 2-jaars meting van een complete of gedeeltelijke remissie van 50 procent of meer:
- nierkanker - RCC: 63% (19/30; 95% CI, 43.9% to 80.1%);
- buikvlieskanker: 52% (12/23; 95% CI, 30.6% to 73.2%);
- melanomen: 48% (10/21; 95% CI, 25.7% to 70.2%);
- Hoofd-halstumoren - SCCHN: 36% (8/22; 95% CI, 17.2% to 59.3%);
- Nier-kleincellige longkanker - NSCLC: 33% (7/21; 95% CI, 14.6% to 57.0%);
- urinewegenkanker: 25% (5/20; 95% CI, 8.7% to 49.1%).
De meest voorkomende behandelingsgerelateerde bijwerkingen waren vermoeidheid (58%), diarree (52%), hypertensie - te hoge bloeddruk (47%) en hypothyreoïdie = tekort aan schildklierhormonen (42%).
Het volledige studierapport: Phase IB/II Trial of Lenvatinib Plus Pembrolizumab in Patients With Advanced Renal Cell Carcinoma, Endometrial Cancer, and Other Selected Advanced Solid Tumors is gratis in te zien.
Hier het abstract en daaronder de referentielijst:
The combination of lenvatinib plus pembrolizumab had promising efficacy among patients with selected solid tumors, with a manageable safety profile
Phase IB/II Trial of Lenvatinib Plus Pembrolizumab in Patients With Advanced Renal Cell Carcinoma, Endometrial Cancer, and Other Selected Advanced Solid Tumors
Creative Commons Attribution Non-Commercial No Derivatives 4.0 License: https://creativecommons.org/licenses/by-nc-nd/4.0/
ABSTRACT
Modulation of vascular endothelial growth factor–mediated immune suppression via angiogenesis inhibition may augment the activity of immune checkpoint inhibitors. We report results from the dose-finding and initial phase II expansion of a phase Ib/II study of lenvatinib plus pembrolizumab in patients with selected advanced solid tumors.
Eligible patients had metastatic renal cell carcinoma (RCC), endometrial cancer, squamous cell carcinoma of the head and neck (SCCHN), melanoma, non–small-cell lung cancer (NSCLC), or urothelial cancer. The primary objective of phase Ib was to determine the maximum tolerated dose (MTD) for lenvatinib plus pembrolizumab (200 mg intravenously every 3 weeks). In the preplanned phase II cohort expansion, the primary objective was objective response rate at week 24 (ORRweek 24) at the recommended phase II dose.
Overall, 137 patients were enrolled during phase Ib (n = 13) and the initial phase II expansion (n = 124). Two dose-limiting toxicities (DLTs; grade 3 arthralgia and grade 3 fatigue) were reported in the initial dose level (lenvatinib 24 mg/d plus pembrolizumab). No DLTs were observed in the subsequent dose–de-escalation cohort, establishing the MTD and recommended phase II dose at lenvatinib 20 mg/d plus pembrolizumab. ORRweek24 was as follows: RCC, 63% (19/30; 95% CI, 43.9% to 80.1%); endometrial cancer, 52% (12/23; 95% CI, 30.6% to 73.2%); melanoma, 48% (10/21; 95% CI, 25.7% to 70.2%); SCCHN, 36% (8/22; 95% CI, 17.2% to 59.3%); NSCLC, 33% (7/21; 95% CI, 14.6% to 57.0%); and urothelial cancer 25% (5/20; 95% CI, 8.7% to 49.1%). The most common treatment-related adverse events were fatigue (58%), diarrhea (52%), hypertension (47%), and hypothyroidism (42%).
Lenvatinib plus pembrolizumab demonstrated a manageable safety profile and promising antitumor activity in patients with selected solid tumor types.
Conception and design: All authors
Provision of study materials or patients: Matthew H. Taylor, Robert J. Motzer, Chung-Han Lee, Vicky Makker, Drew Rasco
Collection and assembly of data: Matthew H. Taylor, Robert J. Motzer, Chung-Han Lee, Vicky Makker, Drew Rasco
Data analysis and interpretation: All authors
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).
Consulting or Advisory Role: Bristol-Myers Squibb, Eisai, Array BioPharma, Loxo, Bayer, ArQule, Blueprint Medicines, Novartis, Sanofi/Genzyme
Speakers' Bureau: Bristol-Myers Squibb, Eisai
Consulting or Advisory Role: Exelixis, Eisai, Amgen, Bristol-Myers Squibb
Research Funding: Pfizer (Inst), Eisai (Inst), Bristol-Myers Squibb (Inst), Calithera Biosciences (Inst), Exelixis (Inst)
Travel, Accommodations, Expenses: Eisai
Travel, Accommodations, Expenses: Calithera Biosciences
Honoraria: Eisai, Merck
Consulting or Advisory Role: Eisai, Merck, Karyopham, Takeda, ArQule
Research Funding: Lilly, AstraZeneca, Eisai, Merck, Takeda, Bristol-Myers Squibb
Travel, Accommodations, Expenses: Eisai, Merck, Karyopharm Therapeutics
Other Relationship: IBM
Consulting or Advisory Role: Boehringer Ingelheim, Lilly
Research Funding: Celgene (Inst), Millennium (Inst), Rexahn Pharmaceuticals (Inst), Five Prime Therapeutics (Inst), Pharmacyclics (Inst), Asana Biosciences (Inst), Eisai (Inst), Aeglea Biotherapeutics (Inst), Merck (Inst), Ascentage Pharma (Inst), Macrogenics (Inst), Apexian Pharmaceuticals (Inst), Birdie (Inst), AbbVie (Inst), Constellation Pharmaceuticals (Inst), Syndax (Inst), Astex Pharmaceuticals (Inst), Compugen (Inst), Coordination Therapeutics (Inst), GlaxoSmithKline (Inst), Incyte (Inst)
Travel, Accommodations, Expenses: Asana Biosciences
Employment: Eisai
Employment: Eisai
Employment: Eisai
Employment: Eisai, RRD International (I)
Consulting or Advisory Role: Pfizer, Novartis, Eisai, Exelixis, Merck, Genentech, Incyte, Lilly
Research Funding: Pfizer (Inst), Bristol-Myers Squibb (Inst), Eisai (Inst), Novartis (Inst), Genentech (Inst)
No other potential conflicts of interest were reported.
ACKNOWLEDGMENT
We thank the patients, their families, the investigators, and the teams who participated in this trial. We also thank Emmett Schmidt, MD, PhD (Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ); Marcia Brose, MD, PhD (Department of Otorhinolaryngology – Head and Neck Surgery, Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA); Peter Kubiak, PhD (Eisai Inc., Woodcliff Lake, NJ); and Lea Dutta, Pharm.D (Eisai Inc., Woodcliff Lake, NJ) for their contributions. This study was funded by Eisai Inc., Woodcliff Lake, NJ, and was also supported by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ. Patients treated at Memorial Sloan Kettering Cancer Center were supported in part by a Memorial Sloan Kettering Cancer Center Support Grant/Core Grant (P30 CA008748). Medical writing and editorial support was provided by Oxford PharmaGenesis Inc., Newtown, PA, and was funded by Eisai Inc., Woodcliff Lake, NJ, and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ.
| 1. | Fontanini G, Vignati S, Boldrini L, et al: Vascular endothelial growth factor is associated with neovascularization and influences progression of non-small cell lung carcinoma. Clin Cancer Res 3:861-865, 1997 Medline, Google Scholar |
| 2. | Sato K, Tsuchiya N, Sasaki R, et al: Increased serum levels of vascular endothelial growth factor in patients with renal cell carcinoma. Jpn J Cancer Res 90:874-879, 1999 Crossref, Medline, Google Scholar |
| 3. | Ott PA, Hodi FS, Buchbinder EI: Inhibition of immune checkpoints and vascular endothelial growth factor as combination therapy for metastatic melanoma: An overview of rationale, preclinical evidence, and initial clinical data. Front Oncol 5:202, 2015 Crossref, Medline, Google Scholar |
| 4. | Kato Y, Tabata K, Hori Y, et al: Effects of lenvatinib on tumor-associated macrophages enhance antitumor activity of PD-1 signal inhibitors. Mol Cancer Ther 14, 2015 (12, suppl 2; abstr A92) Google Scholar |
| 5. | Kato Y: Upregulation of memory T cell population and enhancement of Th1 response by lenvatinib potentiate antitumor activity of PD-1 signaling blockade. Cancer Res 77, 2017 (13, suppl; abstr 4614) Google Scholar |
| 6. | Matsui J, Yamamoto Y, Funahashi Y, et al: E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition. Int J Cancer 122:664-671, 2008 Crossref, Medline, Google Scholar |
| 7. | Matsui J, Funahashi Y, Uenaka T, et al: Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase. Clin Cancer Res 14:5459-5465, 2008 Crossref, Google Scholar |
| 8. | Tohyama O, Matsui J, Kodama K, et al: Antitumor activity of lenvatinib (e7080): An angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer models. J Thyroid Res 2014:638747, 2014 Crossref, Medline, Google Scholar |
| 9. | Lieu C, Heymach J, Overman M, et al: Beyond VEGF: Inhibition of the fibroblast growth factor pathway and antiangiogenesis. Clin Cancer Res 17:6130-6139, 2011 Crossref, Medline, Google Scholar |
| 10. | Bergers G, Hanahan D: Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8:592-603, 2008 Crossref, Medline, Google Scholar |
| 11. | Capozzi M, De Divitiis C, Ottaiano A, et al: Lenvatinib, a molecule with versatile application: From preclinical evidence to future development in anti-cancer treatment. Cancer Manag Res 11:3847-3860, 2019 Crossref, Google Scholar |
| 12. | Kato Y, Bao X, Macgrath S, et al: Lenvatinib mesilate (LEN) enhanced antitumor activity of a PD-1 blockade agent by potentiating Th1 immune response. Ann Oncol 27, 2016 (suppl 6; abstr 2PD) Google Scholar |
| 13. | Medina PJ, Adams VR: PD-1 pathway inhibitors: Immuno-oncology agents for restoring antitumor immune responses. Pharmacotherapy 36:317-334, 2016 Crossref, Google Scholar |
| 14. | Wolchok JD, Hoos A, O’Day S, et al: Guidelines for the evaluation of immune therapy activity in solid tumors: Immune-related response criteria. Clin Cancer Res 15:7412-7420, 2009 Crossref, Medline, Google Scholar |
| 15. | Robert C, Schachter J, Long GV, et al: Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 372:2521-2532, 2015 Crossref, Medline, Google Scholar |
| 16. | Motzer RJ, Hutson TE, Glen H, et al: Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: A randomised, phase 2, open-label, multicentre trial. Lancet Oncol 16:1473-1482, 2015 Crossref, Medline, Google Scholar |
| 17. | Schlumberger M, Tahara M, Wirth LJ, et al: Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 372:621-630, 2015 Crossref, Medline, Google Scholar |
| 18. | Schlumberger M, Jarzab B, Cabanillas ME, et al: A phase II trial of the multitargeted tyrosine kinase inhibitor lenvatinib (E7080) in advanced medullary thyroid cancer. Clin Cancer Res 22:44-53, 2016 Crossref, Google Scholar |
| 19. | Garon EB, Rizvi NA, Hui R, et al: Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372:2018-2028, 2015 Crossref, Medline, Google Scholar |
| 20. | Herbst RS, Baas P, Kim DW, et al: Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): A randomised controlled trial. Lancet 387:1540-1550, 2016 Crossref, Medline, Google Scholar |
| 21. | Patnaik A, Kang SP, Rasco D, et al: Phase I study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. Clin Cancer Res 21:4286-4293, 2015 Crossref, Medline, Google Scholar |
| 22. | Reck M, Rodríguez-Abreu D, Robinson AG, et al: Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 375:1823-1833, 2016 Crossref, Medline, Google Scholar |
| 23. | Bellmunt J, de Wit R, Vaughn DJ, et al: Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 376:1015-1026, 2017 Crossref, Medline, Google Scholar |
| 24. | Kudo M, Finn RS, Qin S, et al: Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: A randomised phase 3 non-inferiority trial. Lancet 391:1163-1173, 2018 Crossref, Medline, Google Scholar |
| 25. | McDermott DF, Lee J-L, Szczylik C, et al: Pembrolizumab monotherapy as first-line therapy in advanced clear cell renal cell carcinoma (accRCC): Results from cohort A of KEYNOTE-427. J Clin Oncol 36, 2018 (15, suppl; abstr 4500) Google Scholar |
| 26. | Rini BI, Plimack ER, Stus V, et al: Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 380:1116-1127, 2019 Crossref, Google Scholar |
| 27. | Motzer RJ, Penkov K, Haanen J, et al: Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 380:1103-1115, 2019 Crossref, Google Scholar |
| 28. | Kato Y, Tabata K, Kimura T, et al: Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway. PLoS One 14:e0212513, 2019 Crossref, Google Scholar |
| 29. | Rini BI, Powles T, Atkins MB, et al: Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): A multicentre, open-label, phase 3, randomised controlled trial. Lancet 393:2404-2415, 2019 Crossref, Google Scholar |
| 30. | Vergote I, Teneriello M, Powell MA, et al: A phase II trial of lenvatinib in patients with advanced or recurrent endometrial cancer: Angiopoietin-2 as a predictive marker for clinical outcomes. J Clin Oncol 31:5520, 2013 (15, suppl; abstr 5520) Google Scholar |
| 31. | Ott PA, Bang YJ, Berton-Rigaud D, et al: Safety and antitumor activity of pembrolizumab in advanced programmed death ligand 1-positive endometrial cancer: Results from the KEYNOTE-028 study. J Clin Oncol 35:2535-2541, 2017 Link, Google Scholar |
| 32. | Kloor M, von Knebel Doeberitz M: The immune biology of microsatellite-unstable cancer. Trends Cancer 2:121-133, 2016 Crossref, Google Scholar |
| 33. | Schachter J, Ribas A, Long GV, et al: Pembrolizumab versus ipilimumab for advanced melanoma: Final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet 390:1853-1862, 2017 Crossref, Medline, Google Scholar |
| 34. | O’Day S, Gonzalez R, Kim K, et al: A phase II study of the multitargeted kinase inhibitor lenvatinib in patients with advanced BRAF wild-type melanoma. J Clin Oncol 31 2013 (15, suppl; abstr 9026) Google Scholar |
| 35. | Seiwert TY, Burtness B, Mehra R, et al: Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): An open-label, multicentre, phase 1b trial. Lancet Oncol 17:956-965, 2016 Crossref, Medline, Google Scholar |
| 36. | Larkins E, Blumenthal GM, Yuan W, et al: FDA approval summary: Pembrolizumab for the treatment of recurrent or metastatic head and neck squamous cell carcinoma with disease progression on or after platinum-containing chemotherapy. Oncologist 22:873-878, 2017 Crossref, Google Scholar |
| 37. | Medical Dictionary for Drug Regulatory Affairs. www.meddra.org Google Scholar |
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