Download 5 MULTIKINASE INHIBITORS Use in oncology

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Multikinase inhibitors
• Inhibit multiple intracellular and cell surface kinases
Use of kinase
inhibitors in oncology
practice
Prof Jacques De Grève, UZ Brussel
• 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
Sunitinib (Sutent®)targets
VHL is driver of clear cell renal cell cancer pathogenesis
Oxygenated condition
Targets downstream inf constitutively activated pathway
Guadalupe Aparicio-Gallego et al. Mol Cancer Ther 2011;10:2215-2223
Linehan, W. M. & Srinivasan, R. (2013)
Nat. Rev. Clin. Oncol. 2013.183
©2011 by American Association for Cancer Research
Sunitinib (Sutent®) targets
Many more sunitinib kinase targets (42)
Guadalupe Aparicio-Gallego et al. Mol Cancer Ther 2011;10:2215-2223
©2011 by American Association for Cancer Research
Gridling Mol Cancer Ther; 13(11); 2751–62. ©2014 AACR
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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 (Motzer et 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. 2009 Aug 1;27(22):3584-90
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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;369:722-731
Comparz trial
Pazopanib vs sunitinib: differential toxicity
Pazopanib vs sunitinib: differential lab toxicity
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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;369:722-731
Pisces study, Escudier et al, J Clin Oncol. 2014 May 10;32(14):1412-8.
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;373:1803-1813.
Approved
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Pazopanib in soft tissue sarcoma: Palette trial
Imatinib (Glivec®)
• Second-line CML (bcr-abl)
• or first-line in frail patients
• Ph+ ALL
• MDS/MPD
• Hypereosinophilic syndrome (HES) and
chronic eosinophilic leukemia (CEL)
• Dermatofibrosarcoma protuberans (DFSP)
• Gastrointestinal stromal tumors (GIST)
Cranmer LD, Ther Clin Risk Manag. 2016 Jun 9;12:941-55
van der Graaf WT, et al Lancet. 2012 May 19;379(9829):1879-86
Imatinib
• Dose 400 mg/d
• with large glass of water and food
• possible escalations
• Well tolerated
• Toxicity (> 30% of patients)
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Hematologic
Nausea and vomiting
Edema (face, feet, hands)
Muscle cramps and bone pain
Diarrhea
Skin rash and stomatitis
Fever
Bleeding diathesis
Savage DG, Antman KH. Imatinib mesylate–a new oral targeted therapy.
N Engl J Med. 2002;346:683-693.
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):973-83
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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
Imatinib discontinuation in GIST
After imatinib
Second-line sunitinib
Le Cesne Lancet Oncol 2010; 11: 942–49
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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
• RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha,
PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A,
RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl
Regorafenib
• Doses = 160 mg (4 x 40 mg tablets)/d
• 21/28 days
• 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
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Other toxicities
Regorafenib efficacy in colorectal cancer
• Dysphonia
• Diarrhea
• Rarely GI perforation
Correct trial
Grothey A et al Lancet. 2013 Jan 26;381(9863):303-12.
Sorafenib (Nexavar®)
Sorafenib (Nexavar®)
• BRAF, VEGFR 2 and 3, PDGFR, and RET
• Thyroid cancer (metastatic DTC, resistant to RAIodine)
• Common or significant toxicities
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hand–foot syndrome (75%), rash/desquamation (50%)
fatigue
dyspepsia diarrhea (70%)
alopecia (70%)
hypertension, thromboembolic and cardiovascular events
• Hepatocellular cancer
• Renal cell cancer
• cutaneous squamous cell carcinomas in up to 5%
• keratoacanthomas and other premalignant actinic
lesions
In thyroid cancer (DTC)
Targets for sorafenib in DTC
FTC
PTC
• 2 important targets:
RET/PTC
C-MET
• Angiogenesis (VEGFR 2 and 3, PDGFR)
Ras
Ras
• Oncogenic mutations (BRAF and RET)
PI3K PTEN
B-Raf
AKT
MEK
mTOR
ERK
S6K
• Growth
• Survival
• Proliferation
• HIF1a
• Inhibition of apoptosis
• Migration
Graphic adapted from Keefe SM, et al. Clin Cancer Res 2010;16:778-783.
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DECISION - results
Brose MS et al
Lancet. 2014 Jul 26;384(9940):319-28.
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. 2014 Jul 26;384(9940):319-28
Overall Survival, the Time to Symptomatic Progression, and the Time to Radiologic
Progression
Hepatocellular carcinoma
3 mth median OS gain
Llovet JM et al. N Engl J Med 2008;359:378-390
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