17/01/2017. Use of kinase inhibitors in oncology practice. Multikinase inhibitors. Sunitinib (Sutent )targets. Many more sunitinib kinase targets (42)

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1 Multikinase inhibitors Use of kinase inhibitors in oncology practice Prof Jacques De Grève, UZ Brussel Inhibit multiple intracellular and cell surface kinases Tyrosine or serine-threonine kinases Multitargeting can be useful but most often: leads to inhibition of targets that are not relevant for therapeutic efficacy will only add toxicity by targeting pathways relevant for normal cell biology VHL is driver of clear cell renal cell cancer pathogenesis Sunitinib (Sutent )targets Oxygenated condition Targets downstream inf constitutively activated pathway Linehan, W. M. & Srinivasan, R. (2013) Nat. Rev. Clin. Oncol Guadalupe Aparicio-Gallego et al. Mol Cancer Ther 2011;10: by American Association for Cancer Research Sunitinib (Sutent ) targets Many more sunitinib kinase targets (42) Guadalupe Aparicio-Gallego et al. Mol Cancer Ther 2011;10: by American Association for Cancer Research Gridling Mol Cancer Ther; 13(11); AACR 1

2 Quite toxic: any grade 95%; grade ¾ 50% Lab toxicities sunitinib Diarrhea (half of patients) Asthenia, fatigue 40% Nausea (and vomiting) 36% Loss of appetite 31% Hair depigmentation Dermatologic adverse events Cardiotoxicity Hypothyroidism Hypertension Hand-foot syndrome Sunitinib (Sutent ) Sunitinib efficacy in renal cell cancer Renal cell cancer (first-line) and GIST (second-line) Approved in 2006 (Motzer et al. 2009) 50 mg orally daily for 4 weeks, followed by 2 weeks off (4/2 schedule) Alternative continuous daily dosing 37.5 mg once daily (Renal EFFECT trial) ORR, median OS and adverse events not significantly different Trend towards an inferior median TTP and a statistically significant superiority in a composite endpoint of death, progression and disease related symptoms for the 4/2 schedule (Motzeret al. 2012) Alternative 2 weeks on, 1 week off schedule (2/1 schedule) seems similar efficacy and better tolerability Intermittent treatment with stop in remission and re-induction after progression efficacy in smaller trials currently being evaluated in a phase III trial Sunitinib vs IFNa Pazopanib (Votrient) Targets VEGFR-1, -2, -3, PDGFR-α and -β, c-kit and RET and BRAF Approved for renal cell carcinoma and soft tissue sarcoma Dosing: 800 mg per day Toxicity: hypertension, nausea/vomiting, diarrhea, anorexia, prolonged QT interval Overall significantly softer than sunitinib Cave hepatotoxicity Motzer RJ, J Clin Oncol Aug 1;27(22):

3 Pazopanib vs sunitinib Pazopanib vs sunitinib: Comparz trial Non-inferiority Progression-free Survival According to Independent Review OS pazopanib 28.4 months versus sunitinib 29.3 Pazopanib vs sunitinib Motzer RJ et al. N Engl J Med 2013;369: Comparz trial Pazopanib vs sunitinib: differential toxicity Pazopanib vs sunitinib: differential lab toxicity 3

4 Mean Change from Baseline in Fatigue Score and Mean Change from Baseline in Worst Foot Soreness. Pazopanib versus Sunitinib: patient preference Motzer RJ et al. N Engl J Med 2013;369: Pisces study, Escudier et al, J Clin Oncol May 10;32(14): Conclusions Renal cell cancer Phase II trials showed that sunitinib has also activity in nonclear cell cancer and is an option due to a lack of better alternatives Pazopanib and sunitinib have similar efficacy safety and quality-of-life profiles favour pazopanib Immune checkpoint inhibitors have shown very promising results in the second-line treatment of RCC, they are being tested in a number of phase III trials in the first-line setting Position of sunitinib and pazopanib in the first-line treatment of RCC in the era of the immune checkpoint inhibitors needs to be reassessed Comparative and combination trials ongoing Nivo vs everolimus second-line renal cell cancer Overall Survival Pazopanib in soft tissue sarcoma Significant unmet medical need Angiogenesis is a potential target both preclinical and clinically Phase II activity in leiomyosarcomas, synovial sarcomas, or other sarcomas but not in adipocytic sarcomas PALETTE, pivotal Phase III trial Improved progression-free survival in second-line No survival benefit Adipocytic sarcomas excluded Motzer RJ et al. N Engl J Med 2015;373: Approved 4

5 Pazopanib in soft tissue sarcoma: Palette trial Imatinib (Glivec ) Second-line CML (bcr-abl) or first-line in frail patients Ph+ ALL MDS/MPD Hypereosinophilicsyndrome (HES) and chronic eosinophilic leukemia (CEL) Dermatofibrosarcoma protuberans(dfsp) Gastrointestinal stromal tumors (GIST) Cranmer LD, Ther Clin Risk Manag Jun 9;12: van der GraafWT, et al Lancet May 19;379(9829): Savage DG, Antman KH. Imatinib mesylate a new oral targeted therapy. N Engl J Med. 2002;346: Imatinib Dose 400 mg/d with large glass of water and food possible escalations Well tolerated Toxicity (> 30% of patients) Hematologic Nausea and vomiting Edema (face, feet, hands) Muscle cramps and bone pain Diarrhea Skin rash and stomatitis Fever Bleeding diathesis Imatinib in CML: long-term effects 8-year survival > 80% Gastrointestinal events, fluid retention, muscle cramps, fatigue, and hepatotoxicity most common and most clinically relevant adverse events Interruption for reasons of toxicity and resumption after PD does not influence survival In may 2017 results of treatment interruption after longterm remission will be available (definitive cures) GIST is the most frequent sarcoma Gastrointestinal stromal tumor Cells of Cajal Joensuu H, et al. Gastrointestinal stromal tumor. Lancet. 2013;382(9896):

6 GIST before 2000 GIST mutated targets 50% 5y OS with optimal surgery Median survival < 1y when inoperable Chemotherapy & radiotherapy inefficient: < 5% ORR Imatinib in GIST Imatinib in GIST Dose 400 mg with possible escalations increased starting dose (exon 9 mutations) 50% PR + SD 80% clinical benefit mos between 5 and 10 years Before imatinib After imatinib Imatinib discontinuation in GIST Second-line sunitinib Le Cesne Lancet Oncol 2010; 11:

7 REGORAFENIB (Stivarga ) Regorafenib (Stivarga ) Gastrointestinal stromal tumors (GIST) Third line Colorectal cancer Advanced or metastatic Second-line after Folfiri or Folfox +/- anti-egfr (cetuximab, if KRASwt) or anti-vegf (bevacizumab) Regorafenib Inhibits multiple kinases Also active metabolites M-2 and M-5 Regorafenib Doses = 160 mg (4 x 40 mg tablets)/d 21/28 days RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl With large glass of water after light meal Anti-angiogenic activity responsible for therapeutic efficacy in CRC Special warning Possible liver toxicity Even fatal (0.3%) Liver tests baseline Q2 wks. Monthly If toxicity > interrupt and resume lower dose Other toxicities Bleeding Respiratory, GI GU 15%; 0,6% fatal Skin in 75% Rash, Hand-foot syndrome (50%) Grade 3 in 20% Erythema multiforme (0.2%) Stevens Johnson Syndrome (0.2%) Hypertension 40% Fatigue can be very important 7

8 Other toxicities Regorafenib efficacy in colorectal cancer Dysphonia Diarrhea Rarely GI perforation Correct trial Grothey A et al Lancet Jan 26;381(9863): Sorafenib (Nexavar ) Sorafenib (Nexavar ) BRAF, VEGFR 2 and 3, PDGFR, and RET Common or significant toxicities hand foot syndrome (75%), rash/desquamation (50%) fatigue dyspepsia diarrhea (70%) alopecia (70%) hypertension, thromboembolic and cardiovascular events cutaneous squamous cell carcinomas in up to 5% keratoacanthomas and other premalignant actinic lesions Thyroid cancer (metastatic DTC, resistant to RAIodine) Hepatocellular cancer Renal cell cancer In thyroid cancer (DTC) Targets for sorafenib in DTC 2 important targets: Angiogenesis (VEGFR 2 and 3, PDGFR) Oncogenic mutations (BRAF and RET) PTC RET/PTC C-MET Ras B-Raf MEK FTC Ras PI3K PTEN AKT ERK mtor S6K Growth HIF1a Survival Inhibition of apoptosis Proliferation Migration Graphic adapted from Keefe SM, et al. Clin Cancer Res 2010;16:

9 DECISION - results Brose MS et al Lancet Jul 26;384(9940): Sorafenib in thyroid cancer 10.8 vs 5.8 months AEs, most Grade 1 or 2, occurred in 98.6% of patients receiving sorafenib and in 87.6% of patients receiving placebo Brose MS et al Lancet Jul 26;384(9940): Hepatocellular carcinoma Overall Survival, the Time to Symptomatic Progression, and the Time to Radiologic Progression 3 mthmedian OS gain Llovet JM et al. N Engl J Med 2008;359: