Nieuwe behandelingen in de oncologie:

immunotherapie en TKI’s, veiligheid en interacties Een keerzijde van nieuwe immuuntherapieen?

Rob Jansen Internist-oncoloog MUMC+

Disclosures

Advisory boards of Amgen, Roche No conflicts of interest

New therapies means new kind of side effect:

Adverse events Targeted therapy

“Immunotherapie”

Immunotherapie “in engere zin”: ipilimumab, nivolumab, pembrolizumab,……….

“Targeted therapie”/TKI’s Intussen zeer vele middelen!!

“Targeted” therapie(1)

• Afatinib (NSCLC) • Aflibercept (CRC) • Axitinib (nier) • Bevacizumab (CRC, nier, mamma) • Cetuximab (HH, evt. CRC)) • Cobemetinib (melanoom met Braf-mutatie) • Dabrafenib (melanoom met Braf-mutatie) • Erlotinib (NSCLC, pancreascarcinoom) • Everolimus (mammacarcinoom, niercarcinoom) • Gefinitib (NSCLC)

“Targeted” therapie(2)

• Imatinib (GIST) • Lapatinib (mamma) • Panitumumab (CRC) • Pazopanib (niercarcinoom) • Pertuzumab (mamma) • Regorafenib (GIST, CRC) • Sorafenib (nier, HCC) • Sunitinib (nier, GIST) • Trastuzumab (mamma) • Vandetanib (schildklier)

“Targeted” therapie(3)

• Vismodegib • ……….. • HEMATOLOGIE- …….. • LONGZIEKTEN- ……..

Indeling “targeted” therapie

• TKI’s (-ibjes)(bijv. sunitinib) • EGF-receptor remmers(-abjes) (bijv. panitumumab) • Braf-remmers (-ibjes)(bijv. vemurafenib) • HER2-neu remmers(-abjes)(bijv. trastuzumab) • MEK-remmers(-ibjes)(bijv. cobemetinib) • Angiogeneseremmers (bevacizumab) • PARP-remmers • ……

Bijwerkingen enkele middelen

• Ipilimumab • Nivolumab • Sunitinib • Vemurafenib • Panitumumab • Bevacizumab

“Immunotherapie” ( in engere zin)

• Momenteel in de praktijk te gebruiken: • Ipilimumab (CTLA-4 remmer): melanoom • Nivolumab (anti-PD 1): melanoom, NSCLC • Pembrolizumab: vooralsnog niet in Nederland

“goedgekeurd”

De rest (nog) niet!

11

Bijwerkingen

• Checkpoint inhibitors: Immunologische bijwerkingen:

PD-1 CTLA-4 Dermatologische toxiciteit

+ ++

Mucositis + +/- Diarree/colitis + ++ Levertestafwijkingen + + Hypofysitis (hoofdpijn, vermoeidheid)

+ +

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Bijwerkingen: Ipilimumab (CTLA-4)

J Clin Oncol 2012; 30:2691-7.

Bijwerkingen ipilimumab en nivolumab

• Bij ipilimumab rond 20 % ernstige bijwerkingen (diarree 11%)

• Bij nivolumab vergelijkbare bijwerkingen, maar minder vaak en minder ernstig (graad III-IV diarree maar bij 1%)

Hodi FS et al. N Engl J Med 2010;363:711-723.

Kaplan–Meier Curves for Overall Survival and Progression-free Survival in the Intention-to-Treat Population.

Larkin J et al. N Engl J Med 2015;373:23-34.

Progression-free Survival.

Ipilimumab of nivolumab??

• Voordeel ipilimumab: maar 4 toedieningen, lange termijn resultaten bekend, wschl. soms curatie

• Nadeel ipilimumab: ernstigere toxiciteit • Voordeel nivolumab: is effectiever, minder toxiciteit • Nadeel nivolumab: iedere 2 weken, hoe lang??, nog

geen lange termijnresultaten bekend

Bijwerkingen sunitinib

• Hand-voet syndroom • Diarree • Misselijkheid • Huiduitslag • Hoge bloeddruk • …….

2012 Sept. Start sunitinib ( for metastatic renal cell carcinoma), 50 mg OD, 4/2 schedule

Before start: RR 150/80 mmHg creatinine 123 µmol/L (Cockroft-Gault 41 mL/min) no proteinuria

After 1 day:

Painful, red hand palms, RR 180/104 mmHg R/ Urea*, tavegil, added amlodipine After few days: RR normalized, no hand foot syndrome

complaints

* Urea is a keratolytic that dissolves the intercellular matrix, which results in loosening the horny layer of skin and the shedding of scally skin, thereby softening

hyperkeratotic areas, effectively reducing epidermal thickness and proliferation.

After 26 days:

Fatigue grade 3, Karnofsky index 60% Mucositis grade 3 Intertrigo inframammary & groins Alopecia grade 1 RR142/82, Creatinine 130 µmol/L (prerenal)

Treatment: • Admission for 11 days • Sunitinib stopped • Local therapy started • Morphinomimetics • Rehydration

2011 Febr. Karnofsky index 80%, progressive disease Start sunitinib 25 mg OD, 4/2 schedule No toxicity

rn 1939

Decoloration of hair (sunitinib 17%) • 5-6 weeks after initiation • Hair grows progressively discolered • Repigmentation occurs after stopping • Pigmented bands (salt & pepper) of hair: correlate with on and off periods of treatment

Huidtoxiciteit

Robert et al. Lancet Oncol 2005; 6: 491-500 Courtesy of Cleveland Clinic Taussing Cancer Center

Vemurafenib

1. Bollag G, et al. Nature 2010;467:596–9. 2. Tsai J, et al. Proc Natl Acad Sci USA 2008;105:3041–6. 3. Yang H, et al. Cancer Res

2010;70:5518–27. 4. Søndergaard JN, et al. J Transl Med 2010;8:39.

Binds to and selectively inhibits oncogenic BRAFV6001

Has a novel mode of action Is a potent and selective inhibitor of oncogenic BRAFV6001

vemurafenib

Oncogenic BRAF signaling arrested with vemurafenib

blocks constitutively

active pathway3

Mutated BRAF

Arrested cell proliferation3 and

promoted cell death4

MEK

vemurafenib1

ERK

ERK = extracellular signal-related kinase; MEK = MAP (mitogen-activated protein) kinase kinase.

RTK = receptor tyrosine kinase; GTP = guanosine triphosphate; ERK = extracellular signal-related kinase;

MEK = MAP (mitogen-activated protein).

BRAF

Activated RAS

MEK

ERK

P

Oncogenic BRAF signaling2

Normal RAS–RAF pathway signaling1

Growth factors

RTK

Mutated BRAF

Excessive cell proliferation and

survival

MEK

ERK

P

P P

RAS–GTP

Normal cell proliferation and

survival

• Constitutive activation is independent of extracellular factors

• Not responsive to normal regulatory signals

• Normal activation of RAS by extracellular factors

1. Garnett MJ, et al. Cancer Cell 2004;6:313–9. 2. Wan PTC, et al. Cell 2004;116:855–67.

Mutated BRAF is frequently identified in cancer

0

10

20

30

40

50

60

70

80

90

100

Melanoma Thyroidcancer

Ovariancancer

Colorectalcancer

All solidtumors

Onc

ogen

ic B

RA

F (%

)

Garnett MJ, et al. Cancer Cell 2004;6:313–9. Davies H, et al. Nature 2002;417:949–54. Libra M, et al. Cell Cycle 2005;4:1382–4. Forbes SA, et al. Nucleic Acids Res

2010;38:D652–7. Tsao H, et al. J Invest Dermatol 2004;122:337–41. Wong KK, et al. Am J Pathol 2010;177:1611–7. Ricarte-Filho JC, et al. Cancer Res 2009;69:4885–93

Bijwerkingen vemurafenib

• Uitslag, droge huid, jeuk • Plaveicelcarcinoom of basaalcelcarcinoom • (Zeer) gevoelig voor zonlicht ( Factor 50!) • Diarree • Minder eetlust, gewichtsverlies • Moeheid • Gewrichtsklachten • Leverfunctiestoornissen • …….

BRIM-3 – Selected adverse events (% of patients)

Discontinuations due to AE: 6% Vemurafenib; 4% Dacarbazine

Vemurafenib, n= 336 Dacarbazine, n= 282 Adverse events All Grade 3 Grade≥ 4 All Grade 3 Grade ≥4

Arthralgia 49 3 - 3 <1 - Rash 36 8 - 1 - - Fatigue 33 2 - 31 2 - Photosensitivity 30 3 - 4 - - ↑LFTs 18 7 <1 5 1 - Cutaneous SCC 12 12 - <1 <1 - Keratoacanthoma 8 6 - - - - Skin papilloma 18 <1 - - - - Nausea 30 1 - 41 2 - Neutropenia <1 - <1 11 5 3

Chapman, et al. NEJM 2011;364:2507-2516

38% required dose reduction vemurafenib because of toxic effects ≥ CTC-grade 2 16% required dose reduction dacarbazine because of toxic effects ≥ CTC-grade 3

Vemurafenib - Conclusion

• Vemurafenib associated with 63% decrease in hazard of death (p<0.0001)

• 74% decrease in hazard of tumor progression (p<0.0001) • Benefit seen in all subgroups, including M1c and ↑ LDH • Manageable safety profile with few drug related discontinuations • First single drug for melanoma to improve response rate, PFS, and OS

compared to standard chemotherapy • Vemurafenib is a promising new therapy for patients with metastatic

BRAFV600E-mutated melanoma and a foundation upon which to build combination therapies

Bijwerkingen panitumumab

• Huidreacties • Hypomagnesiemie, hypokaliemie • Diarree • Misselijkheid • Dyspnoe ( zelden) • Droge ogen • Moeheid • …..

Acneiform Eruption Associated With EGFR Inhibitors

Bijwerkingen VEGF-remming, m.n. bevacizumab

• Hypertensie • Proteinurie • Perforatie (plotselinge heftige buikpijn!) • Bloedingen/trombose

Toxicity/Hypertension

Anti-VEGF induced hypertension • Mostly starts within 1st week (sometimes minutes)

• Rapid increase in BP

• Decrease in BP during drug holiday is possible

• Frequent temporary or permanent withdrawal of therapy

• More frequent when preexisting hypertension

• Risk of hypertensive crises

• Associated with reversible leukoencephalopathy (RLP)

– Headache, altered mental status, seizures, loss of vision – White matter disturbances – Reversible syndrome until certain stage

Incidence anti-VEGF proteinuria

Zhu et al. Am J Kidney Dis 2007; 49: 186-193; Yang et al. NEJM 2003; 349: 427-434; Escudier et al. Lancet 2007; 370: 2103-2111

Incidence proteinuria Bevacizumab 15-63%, nephrotic syndrome 1-1.8%

Probably dose-dependancy:

• RR low dose (2.5-7.5 g/kg): 1.4 (→ 21-41%)

RR high dose (10-15 g/kg): 1.6 (→ 22-63%) Colorectal cancer: 23-38% Renal cell carc: -64%, grade 3-4 6.0-6.5%

Sunitinib / sorafenib Not reported in trials <10 pts described

Axitinib 18-36%, grade 3/4 0-5%

Toxicity/Proteinuria

Conclusies

• Nieuwe specifieke bijwerkingen • Meestal per groep verschillend • Bijwerkingen vereisen specifieke therapie (en evt.

andere specialisten) • Bijwerkingen van m.n. ipilimumab (en in veel mindere

mate nivolumab) kunnen levensbedreigend zijn