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Use of kinaseinhibitors in oncology

practice

Prof Jacques De Grève, UZ Brussel

Multikinase inhibitors

• 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

Linehan, W. M. & Srinivasan, R. (2013)

Nat. Rev. Clin. Oncol. 2013.183

Oxygenated condition

Targets downstream inf constitutively activated pathwayGuadalupe Aparicio-Gallego et al. Mol Cancer Ther 2011 ;10:2215-2223

©2011 by American Association for Cancer Research

Sunitinib (Sutent®)targets

Guadalupe Aparicio-Gallego et al. Mol Cancer Ther 2011 ;10:2215-2223

©2011 by American Association for Cancer Research

Sunitinib (Sutent®) targets

Many more sunitinib kinase targets (42)

Gridling Mol Cancer Ther; 13(11); 2751–62. ©2014 AACR

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Quite toxic: any grade 95%; grade ¾ 50%

• 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

Lab toxicities sunitinib

Sunitinib (Sutent®)

• 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 efficacy in renal cell cancer

Sunitinib vs IFNa

Motzer RJ, J Clin Oncol. 2009 Aug 1;27(22):3584-90

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

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Pazopanib vs sunitinib Pazopanib vs sunitinib: Comparz trial

Non-inferiority

Progression-free Survival According to Independent Review

Motzer RJ et al. N Engl J Med 2013;369:722-731

OS pazopanib 28.4 months versus sunitinib 29.3

Comparz trial

Pazopanib vs sunitinib

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.

Motzer RJ et al. N Engl J Med 2013;369:722-731

Pazopanib versus Sunitinib: patient preference

Pisces study, Escudier et al, J Clin Oncol. 2014 May 10;32(14):1412-8.

Conclusions

Pazopanib and sunitinib have similar efficacy

safety and quality-of-life profiles favour pazopanib

Renal cell cancer

• Phase II trials showed that sunitinib has also activity in non-clear cell cancer and is an option due to a lack of better alternatives

• 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

Motzer RJ et al. N Engl J Med 2015;373:1803-1813.

Nivo vs everolimus second-line renal cell cancer Overall Survival

Approved

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

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Pazopanib in soft tissue sarcoma: Palette trial

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 (Glivec®)

Savage DG, Antman KH. Imatinib mesylate–a new oral ta rgeted therapy. N Engl J Med. 2002;346:683-693 .

• 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)

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 long-term remission will be available (definitive cures)

GIST is the most frequent sarcomaGIST 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

• 50% 5y OS with optimal surgery

• Median survival < 1y when inoperable

• Chemotherapy & radiotherapy inefficient: < 5% ORR

GIST mutated targets

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

Imatinib in GIST

Before imatinib After imatinib

Imatinib discontinuation in GIST

Le Cesne Lancet Oncol 2010; 11: 942–49

Second-line sunitinib

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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

• Anti-angiogenic activity responsible for therapeutic efficacy in CRC

Regorafenib

• Doses = 160 mg (4 x 40 mg tablets)/d • 21/28 days

• With large glass of water after light meal

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

• Dysphonia

• Diarrhea

• Rarely GI perforation

Regorafenib efficacy in colorectal cancer

Grothey A et al Lancet. 2013 Jan 26;381(9863):303-12.

Correct trial

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

Sorafenib (Nexavar®)

• Thyroid cancer (metastatic DTC, resistant to RAIodine)

• Hepatocellular cancer

• Renal cell cancer

In thyroid cancer (DTC)

• 2 important targets:

• Angiogenesis (VEGFR 2 and 3, PDGFR)

• Oncogenic mutations (BRAF and RET)

Graphic adapted from Keefe SM, et al. Clin Cancer Res 2010;16:778-783.

• Growth • HIF1a• Survival • Inhibition of apoptosis• Proliferation • Migration

PTC

RET/PTCC-MET

FTC

Ras

B-Raf

MEK

ERK

PI3K

AKT

mTOR

S6K

Ras

PTEN

Targets for sorafenib in DTC

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DECISION - results

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.Sorafenib in thyroid cancer

Brose MS et al Lancet. 2014 Jul 26;384(9940):319-28

Hepatocellular carcinoma

Overall Survival, the Time to Symptomatic Progressi on, and the Time to Radiologic Progression

Llovet JM et al. N Engl J Med 2008;359:378-390

3 mth median OS gain