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16 januari 2018: Lees ook dit artikel 

https://kanker-actueel.nl/bepaalde-darmbacterien-kunnen-de-effectiviteit-van-immunotherapie-met-anti-pd-medicijnen-verhogen-bij-de-behandeling-van-melanomen.html

25 december 2017: Hier het originele volledige studierapport van onderstaande studie, waarin pembrolizumab (Keytruda) bij 11 verschillende primaire vormen van kanker met solide tumoren met MSI mutatie voor spectaculaire resultaten zorgt  (zie onder grafiek verslag daarvan d.d. 11 juni 2017, abstract staat onderaan artikel).

Deze studie is door Sciencemagazine uitgeroepen als een van de twee beste wetenschappelijke doorbraken van 2017.

Mismatch-repair deficiency predicts response of solid tumors to PD-1 blockade

pembrolizumab bij solide tumoren met MSI mutatie

Fig. 1

Patient survival and clinical response to Pembrolizumab across 12 different tumor types with mismatch repair deficiency. (A) Tumor types across 86 patients. (B) Waterfall plot of all radiographic responses across 12 different tumor types at 20 weeks. Tumor responses were measured at regular intervals and values show the best fractional change of the sum of longest diameters (SLD) from the baseline measurements of each measurable tumor. (C) Confirmed radiographic objective responses at 20 weeks in blue compared to the best radiographic responses in the same patients in red. The mean time to the best radiographic response was 28 weeks. (D) Swimmer plot showing survival for each patient with mismatch repair deficient tumors, indicating death, progression and time off therapy. (E) Kaplan-Meier estimates of progression-free survival and (F) overall patient survival.

11 juni 2017: Bron: Science en ASCO 2017

Immuuntherapie met pembrolizumab (Keytruda) geeft bij solide tumoren met de juiste mutatie / eiwitexpressie vanuit 12 verschillende primaire tumoren uitstekende resultaten met 53 procent gedeeltelijke remissies en 21 procent complete remissies. En progressievrije tijd en overall overleving is nog lang niet bereikt.
Keytruda foto 2(2)
Keytruda is al goedgekeurd voor melanomen en borstkanker maar blijkt nu dus ook effectief te zijn voor kanker vanuit andere primaire vormen van kanker. Waaronder alvleesklierkanker, prostaatkanker, darmkanker enz.

De primaire vorm doet er niet meer toe, als de tumorcellen een bepaalde expressie hebben, er sprake is van een bepaalde mutatie, dan is de kans heel groot dat pembrolizumab aanslaat. In het abstract staat er niet bij of de afwijking die gevraagd wordt ook de P1-ligand mutatie is. Bij andere anti-PD medicijnen, zoals atezolizumab of avelumab maakt het meestal niet zo heel veel uit of de mutatie P1-ligand wel verhoogd is of niet.

Uit het abstract van de studie:

We have expanded this study to now evaluate efficacy of PD-1 blockade in patients with advanced MMR-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients and complete responses were achieved in 21% of patients. Responses were durable with median progression-free and overall survival still not reached.

In een artikel in het Algemeen Dagblad over deze studie zegt dr. Jan Schellens van het Anthonie van Leeuwenhoek Ziekenhuis het volgende:

Immunotherapie

Jan Schellens, medisch oncoloog en geneesmiddelendeskundige van het Antoni van Leeuwenhoek in Amsterdam, legt uit hoe Keytruda precies werkt. ,,Het medicijn wordt gebruikt bij een type behandeling die wij immuuntherapie noemen. Het helpt het immuunsysteem om tumoren aan te vallen. Vanuit het afweersysteem worden T-cellen geproduceerd. Deze worden extra geactiveerd als ze in aanraking komen met de stof pembrolizumab, zodat ze kankercellen beter herkennen en kunnen ruimen.''

,,Het unieke aan deze toepassing is dat de patiënten geselecteerd kunnen worden voor behandeling met pembrolizumab aan de hand van een afwijkend eiwit in het kankerweefsel'', gaat hij verder. ,,Dat is nog nooit eerder zo gedaan. Waar we voorheen voornamelijk keken naar het soort kanker - dat kan zijn darmkanker, alvleesklierkanker, slokdarmkanker, borstkanker, maagkanker, etc. – kunnen we nu op een heel andere manier patiënten identificeren en behandelen.''>>>>>>>>Lees verder het hele artikel in het AD

Een andere studie met min of meer dezelfde insteek is deze: Phase 1 study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in Japanese patients with advanced solid tumors waarvan het studierapport volledig gratis is in te zien. Met interessante referentielijst. Zie onderaan artikel

De studie: Mismatch-repair deficiency predicts response of solid tumors to PD-1 blockade is tegen betaling verkrijgbaar.

Hier het abstract van deze studie:

the large proportion of mutant neoantigens in MMR-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers’ tissue of origin

Mismatch-repair deficiency predicts response of solid tumors to PD-1 blockade

+ See all authors and affiliations

Science  08 Jun 2017:
eaan6733
DOI: 10.1126/science.aan6733

Abstract

The genomes of cancers deficient in mismatch repair (MMR) contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with MMR deficiency were sensitive to immune checkpoint blockade with anti-PD-1 antibodies. We have expanded this study to now evaluate efficacy of PD-1 blockade in patients with advanced MMR-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients and complete responses were achieved in 21% of patients. Responses were durable with median progression-free and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in MMR-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers’ tissue of origin.

Pembrolizumab at both 2 and 10 mg/kg Q2W was well tolerated in Japanese patients with advanced solid tumors and showed encouraging anti-tumor activity against melanoma and NSCLC.

Invest New Drugs. 2016; 34: 347–354.
Published online 2016 Mar 22. doi:  10.1007/s10637-016-0347-6
PMCID: PMC4859860

Phase 1 study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in Japanese patients with advanced solid tumors

Toshio Shimizu,corresponding author Takashi Seto, Fumihiko Hirai, Mitsuhiro Takenoyama, Kaname Nosaki, Junji Tsurutani, Hiroyasu Kaneda, Tsutomu Iwasa, Hisato Kawakami, Kazuo Noguchi, Takashi Shimamoto, and Kazuhiko Nakagawa

Summary

Background This phase I study evaluated the safety and tolerability, pharmacokinetics and pharmacodynamics, immunogenicity, and antitumor activity of pembrolizumab in Japanese patients with advanced solid tumors. Methods Following an initial dose and a 28-day rest (cycle 1), pembrolizumab was administered as an intravenous infusion at escalating doses (2 or 10 mg/kg) every 2 weeks (Q2W) until disease progression or unacceptable toxicity. Adverse events (AEs) were assessed using CTCAE v4.0, and tumor response was assessed using both RECIST v1.1 and immune-related response criteria (irRC). Full pharmacokinetic sampling was performed during cycle 1. Results Three patients received pembrolizumab at 2.0 mg/kg and seven at 10 mg/kg. No dose-limiting toxicities were observed during cycle 1. Eighty percent of patients experienced drug-related AEs (mostly grade 1 or 2); the most common drug-related AEs were nausea, malaise, pyrexia, and aspartate aminotransferase/alanine transaminase (AST/ALT) elevations (n = 2 each). No drug-related grade 4 or 5 AEs occurred. Immune-related AEs comprised grade 3 ALT elevation (n = 1), grade 3 AST elevation (n = 1), grade 1 pneumonitis (n = 1), and grade 1 thyroid-stimulating hormone elevation (n = 1). The safety and pharmacokinetic profiles of Japanese patients were similar to those previously reported for Caucasian patients. A partial tumor response was observed in one patient with non-small-cell lung cancer (NSCLC) and in one patient with melanoma. Conclusions Pembrolizumab at both 2 and 10 mg/kg Q2W was well tolerated in Japanese patients with advanced solid tumors and showed encouraging anti-tumor activity against melanoma and NSCLC.

References

1. Disis ML. Immune regulation of cancer. J Clin Oncol. 2010;28:4531–4538. doi: 10.1200/JCO.2009.27.2146. [PMC free article] [PubMed] [Cross Ref]
2. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8:793–800. doi: 10.1038/nm0902-1039c. [PubMed] [Cross Ref]
3. Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nat Rev Immunol. 2002;2:116–126. doi: 10.1038/nri727. [PubMed] [Cross Ref]
4. Brown JA, Dorfman DM, Ma F-R, Sullivan EL, Munoz O, Wood CR, et al. Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J Immunol. 2003;170:1257–1266. doi: 10.4049/jimmunol.170.3.1257. [PubMed] [Cross Ref]
5. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev. 2010;236:219–242. doi: 10.1111/j.1600-065X.2010.00923.x. [PMC free article] [PubMed] [Cross Ref]
6. Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, et al. PD-1 is expressed by tumor-infiltrating immune cells and is associated with poor outcome for patients with renal cell carcinoma. Clin Cancer Res. 2007;13:1757–1761. doi: 10.1158/1078-0432.CCR-06-2599. [PubMed] [Cross Ref]
7. Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, et al. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res. 2007;13:2151–2157. doi: 10.1158/1078-0432.CCR-06-2746. [PubMed] [Cross Ref]
8. Gao Q, Wang X-Y, Qiu S-J, Yamato I, Sho M, Nakajima Y, et al. Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res. 2009;15:971–979. doi: 10.1158/1078-0432.CCR-08-1608. [PubMed] [Cross Ref]
9. Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, et al. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci U S A. 2007;104:3360–3365. doi: 10.1073/pnas.0611533104. [PMC free article] [PubMed] [Cross Ref]
10. Mu CY, Huang JA, Chen Y, Chen C, Zhang XG. High expression of PD-L1 in lung cancer may contribute to poor prognosis and tumor cells immune escape through suppressing tumor infiltrating dendritic cells maturation. Med Oncol. 2011;28:682–688. doi: 10.1007/s12032-010-9515-2. [PubMed] [Cross Ref]
11. Fourcade J, Kudela P, Sun Z, Shen H, Land SR, Lenzner D, et al. PD-1 is a regulator of NY-ESO-1-specific CD8+ T cell expansion in melanoma patients. J Immunol. 2009;182:5240–5249. doi: 10.4049/jimmunol.0803245. [PMC free article] [PubMed] [Cross Ref]
12. Gao Q, Wang XY, Qiu SJ, Yamato I, Sho M, Nakajima Y, et al. Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res. 2009;15:971–979. doi: 10.1158/1078-0432.CCR-08-1608. [PubMed] [Cross Ref]
13. Blank C, Mackensen A. Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an update on implications for chronic infections and tumor evasion. Cancer Immunol Immunother. 2007;56:739–745. doi: 10.1007/s00262-006-0272-1. [PubMed] [Cross Ref]
14. Tsushima F, Tanaka K, Otsuki N, Youngnak P, Iwai H, Omura K, et al. Predominant expression of B7-H1 and its immunoregulatory roles in oral squamous cell carcinoma. Oral Oncol. 2006;42:268–274. doi: 10.1016/j.oraloncology.2005.07.013. [PubMed] [Cross Ref]
15. Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A. 2002;99:12293–12297. doi: 10.1073/pnas.192461099. [PMC free article] [PubMed] [Cross Ref]
16. Sznol M, Powderly JD, Smith DC, Brahmer JR, Drake CG, McDermott DF, et al. Safety and antitumor activity of biweekly MDX-1106 (anti-PD-1, BMS-936558/ONO-4538) in patients with advanced refractory malignancies J Clin Oncol. 2010;28(Suppl):2506.
17. Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28:3167–3175. doi: 10.1200/JCO.2009.26.7609. [PMC free article] [PubMed] [Cross Ref]
18. Patnaik A, Kang SP, Rasco D, Papadopoulos KP, Elassaiss-Schaap J, Beeram M, et al. Phase I study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. Clin Cancer Res. 2015;21:4286–4293. doi: 10.1158/1078-0432.CCR-14-2607. [PubMed] [Cross Ref]
19. Ji Y, Li Y, Nebiyou Bekele B. Dose-finding in phase I clinical trials based on toxicity probability intervals. Clin Trials. 2007;4:235–244. doi: 10.1177/1740774507079442. [PubMed] [Cross Ref]
20. Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbé C, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15:7412–7420. doi: 10.1158/1078-0432.CCR-09-1624. [PubMed] [Cross Ref]
21. Chen TW, Razak AR, Bedard PL, Siu LL, Hansen AR. A systematic review of immune-related adverse event reporting in clinical trials of immune checkpoint inhibitors. Ann Oncol. 2015;26:1824–1829. doi: 10.1093/annonc/mdv182. [PubMed] [Cross Ref]
22. Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30:2691–2697. doi: 10.1200/JCO.2012.41.6750. [PubMed] [Cross Ref]
23. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372:2018–2028. doi: 10.1056/NEJMoa1501824. [PubMed] [Cross Ref]
24. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 Blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509–2520. doi: 10.1056/NEJMoa1500596. [PMC free article] [PubMed] [Cross Ref]
25. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124–128. doi: 10.1126/science.aaa1348. [PMC free article] [PubMed] [Cross Ref]
26. Ribas A, Robert C, Hodi FS, Wolchok JD, Joshua AM, Hwu WJ et al. (2015) Association of response to programmed death receptor 1 (PD-1) blockade with pembrolizumab (MK-3475) with an interferon-inflammatory immune gene signature [Meeting Abstract]. J Clin Oncol 33 (suppl; abstr 3001)
27. Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015;16:908–918. doi: 10.1016/S1470-2045(15)00083-2. [PubMed] [Cross Ref]
28. Robert C, Joshua AM, Weber JS, Ribas A, Hodi FS, Kefford RF et al. (2014) Pembrolizumab (Pembro; MK-3475) for advanced melanoma (MEL): randomized comparison of two dosing schedules. Ann Oncol 25 (suppl 4): doi: 10.1093/annonc/mdu438.42
29. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372:2521–2532. doi: 10.1056/NEJMoa1503093. [PubMed] [Cross Ref]
30. Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014;384:1109–1117. doi: 10.1016/S0140-6736(14)60958-2. [PubMed] [Cross Ref]
31. Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2015 [PubMed]

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