Interferon
Immunomodulator.
Response rates of 10 – 15 %. Durable complete response very rare (< 2 %)
Was initially the treatment of choice prior to TKI therapies.
Interleukin-2
Response rates of 15 – 20 %, with higher complete response rates (5 – 10 %)
Considerable toxicity – vascular leak syndrome, respiratory compromise, multiorgan damage and an early mortality rate of 2 – 5 %.
Tyrosine kinase inhibitors
Molecular basis for TKIs:
- One of the functions of VHL as a tumour suppressor gene is cause breakdown of hypoxia inducible factors (HIFs)
- Normally, HIF levels are controlled by local oxygen conditions
- Mutations in VHL prevent breakdown and lead to accumulation of HIFs
- HIF accumulation -> upregulation of pro-angiogenic growth factors like VEGF, PDGF (platelet derived growth factor) etc -> angiogenesis and growth and progression of ccRCC
Side effects of TKIs
- GI – diarrhoea
- Hand-foot syndrome, rash
- Cardiac toxicity – reduction in EF, as well as others like arrhythmia, cardiomyopathy. Use in caution with cardiac history.
- Fatigue
- Hypothyroidism
- Neutropenia, thrombocytopenia.
Sunitinib
- VEGFR kinase inhibitor – potent inhibitor of VEGFR2, PDGFR, c-kit amongst others
- Oral, 50 mg / day
- Motzer 2007 – demonstrated improved PFS and overall response cf. interferon, and subsequent analysis confirmed OS benefit
Pazopanib
- VEGFR kinase inhibitor – still inhibits VEGFR2, PDGFR but more selective for these
- A good alternative to sunitinib with similar efficacy, and perhaps less toxicity, although some more liver derangement
- Listed in Aust as initial treatment or in patients unable to tolerate sunitinib.
- Contraindicated in liver failure.
Axitinib
- Highly selective inhibitor of VEGFR1, VEGFR2, VEGFR3.
- Initial evidence showed it was useful in second line setting after progression on sunitinib.
- Currently being explored in combinations with PD-1/PD-L1 inhibitors with promising data.
- Listed in Aust for use after failure of one prior systemic therapy.
Cabozantinib
- Inhibitor of VEGFR, Met and axl – Met and axl are thought to be overexpressed perhaps in ccRCC with resistance to VEGF inhibition.
- Initially studied as a second line therapy, but subsequent data (CABOSUN) showed improved PFS and overall response cf. sunitinib as first line treatment in intermediate or poor risk RCC.
- Subsequent listed in Aust for first line treatment of intermediate or poor risk met ccRCC, or after failure of another TKI.
Bevacizumab
- Not actually a TKI but humanised monoclonal antibody against VEGF-A. Initially showed promise in combination with interferon, but since superseded and no longer used in Aust.
mTOR inhibitors
Mammalian target of Rapamycin is a key intracellular protein involved in several signalling cascades – it is involved in regulating translation and stability of HIF-a
Temsirolimus
- Given IV. Approved in Australia for initial treatment with poor prognosis, but not PBS listed.
- Initially studied for all types of RCC with poor prognosis versus interferon and was comparable.
Everolimus
- Oral mTOR inhibitor. Has shown improvement in OS vs placebo after failure of TKI.
- Listed in Aust for same – after failure of TKI.
- Main side effects – mucositis, neutropenia/thrombocytopenia, diarrhoea, fatigue, hyperglycaemia and hyperlipidaemia, pulmonary toxicity
Immunotherapy
Recent data has shown immunotherapy is able to achieve better responses than TKI therapy as a first line treatment, usually in combination therapies or combined with TKIs.
The host immune response to tumours is complex and regulated at multiple levels.
Host antitumor responses are downregulated by activation of T cell receptors like CTLA-4 and those mediating programmed cell death (PD-1).
Checkpoint inhibitors “take off the brakes” and allow restoration of tumour specific T cell activity.
Ipilumumab – monoclonal antibody inhibiting CTLA-4
Nivolumab – anti PD-1 antibody
Side effects of immunotherapy
- Rash 30 %
- Hypothyroidism 20 %
- Colitis
- Hepatitis
- Encephalitis
- Nephritis
- Pneumonitis
- Hypoadrenalism
- Diabetes
- “Unusual immune mediated side effects”
Recent trials
- Checkmate 214 – ipi/nivo had better OS, PFS, and health related QoL cf. sunitinib in intermediate and poor risk patients
- Therefore ipi/nivo combination immunotherapy considered standard of care and is PBS listed for intermediate and poor risk metastatic ccRCC.
- 15 % grade 3-5 toxicity ; 1.5 % treatment related death
- 75 % OS at 18 months for ipi/nivo vs 60 %; HR for death 0.63 for ipi/nivo vs sunitinib
KEYNOTE 426 – axitinib/pembrolizumab > sunitinib
Checkmate 9ER – nivolumab/cabozantinib > sunitinib
CLEAR – lenvantinib/pembrolizumab > sunitinib
JAVELIN – avelumab/axitinib > sunitinib
In summary – all of the above combinations are “standard of care” for first line treatment of metastatic ccRCC – but only ipi/nivo is covered by PBS in Australia, and so this is the treatment I am familiar with. It has only been studied and approved in intermediate or poor risk.
Complete response rate somewhere around 10 %
Non clear cell RCC
No phase III trials have been done for non ccRCC.
EAU guidelines:
- Offer cabozantinib or pembrolizumab to metastatic papillary RCC
- Offer sunitinib to other non papillary non ccRCC
- ?Nothing PBS approved in Aust
- -> clinical trial / MDT