Renal Cell Carcinoma - Amazon S3Summaries/RenalCellCancerFinal.pdf · Renal Cell Carcinoma Updated...
Transcript of Renal Cell Carcinoma - Amazon S3Summaries/RenalCellCancerFinal.pdf · Renal Cell Carcinoma Updated...
Renal Cell Carcinoma Updated February 2016 by Dr. Safiya Karim (PGY5 Medical Oncology Resident, University of Toronto) Reviewed by Dr. Nimira Alimohamed (Staff Medical Oncologist, University of Calgary) and Dr.Bjarnason (Staff Medical Oncologist, University of Toronto) DISCLAIMER: The following are study notes compiled by the above PGY5 medical oncology residents and reviewed by a staff medical oncologist. They reflect what we feel is relevant knowledge for graduating medical oncology residents preparing for their final examination. The information has not been surveyed or ratified by the Royal College. A) PUBLIC HEALTH
EPIDEMIOLOGY Incidence: 9th most common cancer worldwide, 11th most common in Canada, incidence 12.9/
100,000 in Canada in 2015, highest incidence in developing countries, most common in 6th 8th decade of life, M > F
Mortality: 5 year overall survival 71% (all stages)
RISK FACTORS Environmental/Chemical/Infections:
o Established: Smoking, phenacetin containing analgesics, hypertension, obesity o Possible: Diabetes Mellitus, trichloroethylene, renal cystic disease, renal transplant,
endstage renal disease patients on dialysis, physical activity
Genetic: o Clear cell Loss of mutation of Von Hippo Lindau gene (VHL), mutations in PBRM1,
BAP1, SETD2, as well as mutations in additional histone modifiers (KDM5a, ARID1a, and UTX)
o Papillary cell – mutations in MET prooncogene, mutations in fumarase hydratase (FH)(causing syndrome of hereditary leiomyomatosis and renal cell carcinoma)
o Chromophobe RCC – loss of chromosomes 1,26,10,13, 17 and 21, mutations in PTEN, BirtHoggDube syndrome (caused by germline mutation in folliculin gene – FLCN)
o Renal medullary – associated with hemoglobinopathies, most commonly sickle cell trait, loss of expression of the chromatin regulatory gene SNF5/INI1.
PREVENTION & SCREENING Prevention: Nil Screening: Only for highrisk individuals – i.e. VHL syndrome, tuberous sclerosis, strong family
history, previous kidney irradiation, young patients with endstage renal disease on dialysis x >35 years. Screen with yearly U/S Abdo/ CT Abdo/ MRI
B) PRESENTATION & DIAGNOSIS
SYMPTOMS & SIGNS Common Symptoms: Flank pain, abdominal pain, hematuria, asymptomatic Common Signs: abdominal/ flank mass, paraneoplastic syndromes – anemia, hypertension,
hepatic dysfunction, feverand night sweats, hypercalcemia, cachexia, thrombocytosis Not so common:AA amyloidosis, polycythemia, polymyalgia rheumatica
INVESTIGATIONS Laboratory: (e.g. important bloodwork, tumour markers): CBC, lytes, urea, creatinine, calcium Diagnostic Imagingand staging: renal ultrasound, CT Abdo, MRI (if CT nondiagnostic), CT
Chest, CTHead, Bone scan (if bone pain or elevated ALP) Diagnostic Procedures: percutaneous biopsy, partial/ full nephrectomy
PATHOLOGY & MOLECULAR BIOLOGY Common Histology:
o Clear cell RCC o Papillary cell RCC o Chromophobe RCC o Rare: collecting duct, renal medullary, urothelial o Other types – see 2013 Classification (Srigley, JR et al. Am J Surg Pathol 2013)
Common Metastatic Sites: lung, bone, brain, liver, adrenals Relevant Molecular Biology: Lots of stuff here. Unclear what you are expected to know. Not
generally agreed on biomarkers to guide the choice of therapy
STAGING TNM:
American Joint Committee on Cancer. Kidney. In: Edge SB, Byrd DR, Compton CC, et al., eds. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 201047989
5 yr overall survival by stage: I – 8095% II – 80% III – 60% IV – 1030% (improved with recent targeted therapies) Heng Criteria Prognostic factors (in metastatic disease): Poor prognostic factors: Karnovsky performance status (PS) <80% Hemoglobin less than lower limit of normal Time from diagnosis to treatment <1 year Corrected calcium above the upper limit of normal Platelets greater than the upper limit of normal Neutrophils greater than the upper limit of normal Favourable risk (0 factors) – mOS not reached, 2 yr OS =75% Intermediate risk (12 factors) – mOS 27 months, 2 yr OS = 53% Poor risk (36 factors) – mOS 8.8 months, 2 yr OS = 7% C) TREATMENT LOCALIZED / LOCALLY ADVANCED/ ADJUVANT
Bottom Line General Approach: surgical resection via total or partial nephrectomy, if not a candidate for surgery and small renal mass (often just observed. This is a separate topic), radiofrequency ablation/ cryotherapy can be considered. Observation can also be considered. No role for adjuvant therapy post resection. Multiple negative IL2, interferon trials and now a negative Sutent vs Sorafenib vs observation trial.
Surveillance: labs and imaging q 6months initially then less frequently for up to 6 years. Canadian and US guidelines available (see references) Prognosis:
o Stage 1 – 5 yr OS 90% o Stage 2 – 5 yr OS 7590% o Stage 3 – 5970%
Important Phase III Clinical Trials:
Adjuvant therapy trials:
Adjuvant Phase III study of interferon alfaNL as adjuvant treatment for resectable renal cell carcino
ma: an Eastern Cooperative Oncology Group/Intergroup trial. Messing et al. J Clin Oncol. 2003; 21(7): 121422
Regimen InterferonalfaNL x 12 cycles vs. observation Mechanism of Action of Experimental Drug
Pleotrophic protein that has antiviral, immunomodulatory and antiproliferative activities
Primary Endpoint OS Secondary endpoint: recurrence free survival
Inclusion/Exclusion Criteria
pT3pT4a and/or node positive disease post nephectomy and lymphandectomy
Size (N) 283 Results Median OS: 7.4 years vs. 10.4 years p=0.09
Median DFS: 2.2 years vs 3 years p=0.33 Toxicity Severe (grade 4) toxicities including neutropenia, myalgia,
fatigue, depression, and other neurologic toxicities occurred in 11.4% of those randomly assigned to interferon treatment
Conclusion No benefit to adjuvant interferon on overall survival or on recurrence free survival
Adjuvant ASSURE Trial
Lancet oncology 2006 DOI: http://dx.doi.org/10.1016/S01406736(16)005596 Haas et al. Lancet Oncology. 2016 March 9. Epub ahead of print.
Regimen Sunitinib vs. Sorafenib vs Placebo Mechanism of Action of Experimental Drug
Inhibition of vascular endothelial growth factor receptor, platelet derived growth factor, ckit and other kinases
Shown to be effective in metastatic disease Primary Endpoint DFS Inclusion/Exclusion Criteria
Completely resected high risk local/ locally advanced disease (pT1b high grade to pT4 any grade N any)
Size (N) 1322 patients Results Median DFS: 5.6 vs. 5.6 vs. 5.7
Quality of Life: not reported Toxicity Higher rates of grade 3/4 hypertension, hand/foot, rash, fatigue with
sunitinib and sorafenib Conclusion No benefit to adjuvant sunitinib or sorafenib in locally advanced high
risk renal cell carcinoma Other Comments
METASTATIC
Bottom Line General Approach: o First line: Sunitinib or Pazopanib for good/ intermediate risk patients. Temsirolimus is on
option in poor risk patients o Second line: New evidence shows benefit of both Nivolumab (PD1 antibody) vs
Everolimus in the secondline setting, and Cabozantinib vs Everolimus. Funding decisions are pending. Current standard is everolimus or axitinib.
o Third line and beyond: Everolimus if not previously used o Cytoreductive nephrectomy: Previous SWOG and EORTC studies showed improvements in
overall survival in selected patients with cytoreductive nephrectomy. Current Phase III studies in the era of targeted therapy are ongoing. Need to carefully select patients.
Prognosis: median OS 824+ months based on risk factors (see Heng criteria above) Important Phase III Clinical Trials:
1st line trials:
1st line Sunitinib vs Interferon Alpha in Metastatic Renal Cell Carcinoma
Motzer et al. N Eng J Med. 2007; 356; 2. 11524
Regimen Sunitinib 50mg daily x 4 weeks (then 2 weeks off) vs. interferon alpha 9MU SC 3x/week
Mechanism of Action of Experimental Drug
Tyrosine kinase inhibitor – including VEGF receptor and platelet derived growth factor receptor
Primary Endpoint PFS Inclusion/Exclusion Criteria
Treatment naïve metastatic renal cell carcinoma No brain metastases No evidence of uncontrolled hypertension ECOG 0/1
Size (N) 750 patients Results PFS: 11 months (Sunitinib) vs. 5 months (Int.alpha) HR 0.42, p<0.001
Response Rate: 31% vs 6%, p>0.001 Overall Survival: Data not yet mature Quality of Life: Much better with sunitinib vs. interferon alpha based
on FACTG and FKSI questionnaires.
Toxicity Higher grade 3/4 fatigue in interferon group Higher rates of grade 3 diarrhea, vomiting, hypertension, and
handfoot syndrome on sunitinib Higher rates of leucopenia, neutropenia, thrombocytopenia in sunitinib
group Conclusion Significant improvement in PFS and QoL with Sunitinib vs.
InterferonAlpha for treatment naïve metastatic renal celll carcinoma
Phase III Trial of Bevacizumab Plus Interferon Alfa Versus Interferon Alfa Monotherapy in
Patients With Metastatic Renal Cell Carcinoma: Final Results of CALGB 90206 Rini et al. J Clin Oncol 2010; 28: 213743
Regimen Bevacizumab 10mg/kg q 2weeks and Interferon2a 9MU SC 3x/ week
vs.placebo plus Interferon2a 9MU SC 3x/week Mechanism of Action of Experimental Drug
Humanized monocolonal antibody towards VEGF Shown in phase 2 studies to be beneficial in metastatic RCC
Primary Endpoint OS Secondary endpoints: PFS, ORR and safety
Inclusion/Exclusion Criteria
Metastatic renal cell ca with predominant clear cell component (>=50%)
Undergone partial or full nephrectomy No prior systemic treatment No brain metastasis, adequate hepatic and renal function KPS >=70%
Size (N) 649 Results OS: 23.3 months vs. 21.3 months, HR=0.91, p=0.3360
PFS: 10.2 months vs. 5.4 months, HR 0.63, p=0.001 OS adjusted for independent factors predictive of survival – HR 0.78,
p=0.02 ORR: 70% vs. 39%
Toxicity Higher rates of grade 3 + fatigue, asthenia, proteinuria, hypertension with bevacizumab + interferon
4 cases of GI perforation (1%) and 4 cases of arterial thrombotic events (1%) with bevacizumab + interferon
Conclusion Bevacizumab + interferon did not show a statistically significant benefit in OS compared to placebo + interferon
PFS was improved with bevicizumab + interferon compared to placebo + interferon
Other Comments Several confounding factors may have led to no statistically significant OS benefit – extensive use of TKI treatment post progression, cross over of 13 patients from placebo to bevacizumab arm upon progression
Bevacizumab is not approved for the treatment of RCC in Canada
Bevacizumab plus interferon Alfa2a for treatment of metastatic renal cell carcinoma: a randomized, doubleblind phase III trial Escudier et al. Lancet 2007; 370: 210311
Regimen Bevacizumab 10mg/kg q 2weeks and Interferon2a 9MU SC 3x/ week vs. placebo and interferon2a 9MU SC 3x/week
Mechanism of Action of Experimental Drug
Humanized monocolonal antibody towards VEGF Shown in phase 2 studies to be beneficial in metastatic RCC
Primary Endpoint OS Secondary endpoints: PFS, ORR and safety
Inclusion/Exclusion Criteria Metastatic renal cell ca with a clear cell component No prior systemic treatment No brain metastasis, adequate hepatic and renal function KPS >=70% BP <160/90
Size (N) 732
Results OS: 18.3 months vs. 17.4 months, HR=0.86, p=0.069 Median OS was better in patients who received subsequent TKI
treatment
Toxicity Higher rates of grade 3 + hypertension, anorexia, fatigue and proteinuria in bevacizumab arm
Conclusion Bevacizumab + interferon did not show a statistically significant benefit in OS compared to Interferon alone
Other Comments In a retrospective analysis, PFS, ORR and OS was statistically improved in patients who developed grade >=2 hypertension
Randomized Phase III Trial of Temsirolimus and Bevacizumab Versus Interferon Alfa and Bevacizumab in Metastatic Renal Cell Carcinoma: INTORACT Trial
Rini et al. J Clin Oncol. 2014; 32: 75259
Regimen Temsirolimus 25mg IV weekly plus bevacizumab 10mg/kg IV q2weeks vs. Interferon 9MU SC 3x/week + bevacizumab 10mg/kg IV q2weeks
Mechanism of Action of Experimental Drug
Temsirolimus is a highly specific inhibitor of mTOR, the signaling pathway of which is altered in RCC with clear cell histology, of advanced stage, or with poor prognostic features.
Has shown activity in phase 2 studies in pretreated patients with advanced RCC
Bevacizumab is an inhibitor of VEGR, which is highly expressed The combination of temsirolimus and bevacizumab has the potential to further
improve efficacy and possibly overcome or delay resistance to bevacizumab by concomitantly blocking alternative signaling pathways
Primary Endpoint PFS Secondary endpoints: OS, ORR and safety
Inclusion/Exclusion Criteria
Advanced renal cell ca with a clear cell component No prior systemic treatment No brain metastasis Adequate hepatic and renal function KPS >=70% No history of thrombotic events in past 6 weeks No inadequately controlled BP >=150/100
Size (N) 732
Results Median PFS: 9.1 months vs. 9.3 months, HR 1.1, p=0.8 ORR: 27.0% vs 27.4% Median OS: 25.8 vs. 25.5, HR =1.0, p=0.6 QOL – No statistically significant difference
Toxicity More grade >=3 hypercholesteremia, mucosal inflammation, stomatitis, hyperglycemia with temsiromlimus/ bevicizumab
More grade >= 3 neutropenia and myalgia with interferon/ bevicizumab arm
Conclusion No differences were observed for PFS, OS, or ORR between the combination regimens of temsirolimus/bevacizumab and IFN/bevacizumab when administered as firstline treatment in patients with advanced RCC.
Axitinib versus sorafenib as firstline therapy in patients with metastatic renalcell carcinoma: a randomised openlabel phase 3 trial
Hutson et al. Lancet. 2014; 14, 128794
Regimen Axitinib 5mg mg twice daily vs sorafenib 400 mg twice daily
Mechanism of Action of Experimental Drug
Axitinib is a potent and selective secondgeneration VEGFR inhibitor
Primary Endpoint PFS (noninferiority) Secondary endpoints: OS, ORR, response duration, patient reported
outcomes, safety
Inclusion/Exclusion Criteria
Metastatic RCC with a clear cell component ECOG 0 or 1 No previous systemic treatment No brain mets or CNS involvement Adequate organ function No uncontrolled hypertension, no MI/CVA/TIA within the past 12 months
Size (N) 288
Results Median PFS – 10.1 months vs 6.5 months, HR=0.77, 95% CI 0.561.05 p=0.038
Median PFS for ECOG 0 (prespecified analysis)– 13.7 vs 6.6 months, HR=0.64, p=0.022
Median PFS for patients with previous nephrectomy (posthoc analysis) –10.3 vs. 6.4 months, HR=0.67, p=0.009
ORR: 32% vs 15%, p=0.0006 Median duration of response: 14.7 vs. 14.3 months Patient reported outcomes: No significant difference between treatment
arms
Toxicity More diarrhoea, hypertension, weight decrease, decreased appetite, dysphonia, hypothyroidism and upper abdominal pain with axitinib
More palmarplantar erythrodysaesthesia, rash, alopecia and erythema with sorafenib
Conclusion Although median progressionfree survival was numerically longer with axitinib than with sorafenib, the difference was not significant
Median PFS was statistically significant in ECOG 0 patients
Other Comments Trial had an ambitious prediction of improved PFS of 4.3 months over sorafenib which is why it did not meet it’s primary endpoint and did not get FDA approval in the first line even tough Axitinib was clearly better.
Pazopanib versus Sunitinib in Metastatic RenalCell Carcinoma
Motzer et al. N Eng J Med. 2014; 369: 722731 * Final overall survival data published as correspondance in N Eng J Med. 2014; 370: 17691770
Regimen Pazopanib 800 mg once daily vs Sunitinib 50 mg daily x 4 weeks (then 2 weeks off)
Mechanism of Action of Experimental Drug
Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptors (VEGFR)1/2/3, plateletderived growth factor receptors (PDGFR)a/b and stem cell factor receptor cKit
Comparison of efficacy across trials suggested similar progressionfree survival benefits with pazopanib and sunitinib.7 Comparison of safety suggested that pazopanib was associated with a lower incidence of fatigue, the hand–foot syndrome, stomatitis, and myelosuppression and with a higher incidence of liverfunction abnormalities than was sunitinib
Primary Endpoint PFS (noninferiority) Secondary endpoints: OS, ORR, QoL medical resource utilization
Inclusion/Exclusion Criteria
Advanced and/or metastatic RCC with a clear cell component No previous systemic treatment KPS >=70% No brain mets, no poorly controlled hypertension Adequate organ function
Size (N) 1110 Results Median PFS – 8.4 vs 9.5 months, HR=1.05 (Similar amongst all
subgroups) ORR: 31% vs 25%, p=0.03 Median OS: 28.3 months vs. 29.1 months, HR=0.92, p=0.24 Median duration of treatment: 8.0 months vs. 7.6 months QoL – Fatigue and treatment related side effects were better with
pazopanib compared to sunitinib Toxicity More hand–foot syndrome, mucosal inflammation, stomatitis,
hypothyroidism, dysgeusia, dyspepsia, epistaxis, and fatigue with sunitinib
More changes in hair color, weight loss, and alopecia with pazopanib Conclusion This phase 3, randomized study showed noninferiority of
progressionfree survival with pazopanib versus sunitinib. The similar rates of overall survival in the two groups and the higher objective response rates observed with pazopanib versus sunitinib are consistent with noninferiority in overall efficacy
Other Comments These data may not apply in countries that do not use the Sutent 4/2 schedule as is true for most centers in Canada. Because of this the uptake of Pazopanib in Canada has been much lower than in most other countries.
2nd line trials:
Cabozitinib vs Everolimus in Advanced Renal Cell Carcinoma Choueiri et al. N Engl J Med 2015; 373:181423
Regimen Cabozitinib 60mg OD vs Everolimus 10mg OD Mechanism of Action of Experimental Drug
Cabozitinib is an oral smallmolecule tyrosine kinase inhibitor that targets VEGFR as well as MET and AXL, each of which has been implicated in the pathogenesis of metastatic RCC or in the resistance to antiangiogenic drugs.
Primary Endpoint PFS Secondary endpoints: OS, ORR
Inclusion/Exclusion Criteria
18 years plus Advanced or metastatic RCC with a clear cell component and
measurable disease Previous treatment with at least 1 VEGFRtargeting TKI with radiologic
progression during treatment or within 6 months after the most recent dose
KPS at least 70% No previous therapy with an mTOR inhibitor or with cabozitinib
Size (N) 658 Results PFS: 7.4 months with cabozitinib vs 3.8 months with everolimus, HR
0.58, p<0.001 ORR: 21% with cabozitinib vs 5% with everolimus, p<0.001 OS: trend towards better OS with cabozitinib at interim analysis with
HR of 0.67, p=0.005 (p<0.0019 required for significance at the interim analysis). OS analysis updated Feb 2016 in a press release state that OS data now show a statistically significant survival benefit for cabozitinib
PFS and ORR were higher in patients on cabozitinib who only had sunitinib as previous therapy (posthoc analysis)
Toxicity Grade 3/4 toxicity occurred in 68% of patients on cabozitinib vs. 58% of patients on everolimus
Cabozitinib grade 3/4 toxicities included hypertension, diarrhea and fatigue
Everolimus grade 3/4 toxicities included anemia, fatigue and hyperglycemia
Conclusion Cabozitinib was associated with a higher PFS in patients with advanced RCC who had progressed on previous VEGF targeted therapy
Nivolumab vs. Everolimus in Advanced RenalCell Carcinoma
Motzer et al. N Engl J Med 2015;373:180313
Regimen Nivolumab 3mg/kg IV q2weeks vs Everolimus 10mg OD Mechanism of Action of Experimental Drug
Nivolumab is a fully human IgG4 PD1 inhibitor that selectively blocks the interaction between PD1 (expressed on activated tcells) and PDL1 and 2 which are expressed on tumor cells. It has been hypothesized that blocking this interaction leads to restored antitumor immunity
Primary Endpoint OS Secondary endpoints: ORR and safety
Inclusion/Exclusion Criteria
Advanced or metastatic RCC with a clear cell component and measurable disease
Received 1 or 2 previous regimens of antiangiogenic therapy No more than 3 previous total regimens of systemic therapy KPS of at least 70% Exclusion – no CNS metastases, no previous treatment with an mTOR
inhibitor, no condition requiring glucocorticoids >10mg or prednisone per day
Size (N) 821 Results OS: 25.0 months for nivolumab vs 19.6 months for everolimus, HR
0.73, p=0.002 OS benefit was seen regardless of PDL1 expression ORR: 25% with nivolumab vs 5% with everolimus, Odds ratio 5.98,
p<0.001 PFS: nivolumab 4.6 months vs. everolimus 4.4 months, HR 0.88,
p=0.11 Quality of Life: Improved in the nivolumab arm and significantly
different from the everolimus arm Toxicity Grade 3/4 adverse events: 19% with nivolumab and 37% with
everolimus Most common grade 3/4 toxicity with nivolumab was fatigue and with
everolimus was anemia Conclusion Nivolumab was associated with longer overall survival and fewer
grade 3/4 adverse events compared to everolims in patients with previously treated advanced renal cell carcinoma
2nd line
Sorafenib for Treatment of Renal Cell Carcinoma (TARGET): Final Efficacy and Safety Results of the Phase III Treatment Approaches in Renal Cancer Global Evaluation Trial
Escudier et al. N Engl J Med 2007;356:12534. and J Clin Oncol. 2009; 27:33123318.
Regimen Sorafenib 400mg bid vs placebo Mechanism of Action of Experimental Drug
Orally active multikinase inhibitor that blocks VEGFR2, VEGFR3, and PDGF receptor (PDGFR), as well as RAF1, Flt3, and cKIT
Primary Endpoint OS Secondary endpoints: PFS, RR and patient reported outcomes
Inclusion/Exclusion Criteria
Unresectable or metastatic RCC who had undergone 1 prior systemic treatment with IL2 and/or interferon
Size (N) 903 Results PFS: preplanned analysis in 2005 showed superior PFS for Sorafenib
5.5 months vs. 2,8 months, HR 0.44, p>0.001 Overall Survival: 17.8 months vs. 15.2 months, HR 0.88, p=0.146
(crossover was however allowed) OS (with crossover patients sensored) – 17.8 months vs. 14.3
months, HR 0.78, p=0.287 Correlation with VEGF levels – both high and low levels of VEGF
responded to Sorafenib Toxicity Higher rates of grade 3 /4 hypertension, handfoot syndrome,
rash/desquamation, diarrhea and fatigue in sorafenib groups Conclusion Sorafenib is effective as 2nd line treatment for advanced/ metastatic
renal cell carcinoma after 1st line immunotherapy (INT or IL2). Since these immunotherapies are never given 1st line Sorafenib is not used 2nd line in Canada.
2nd line
Randomized Phase III Trial of Temsirolimus Versus Sorafenib As SecondLine Therapy After Sunitinib in Patients With Metastatic Renal Cell Carcinoma
Hutson et al. J Clin Oncol. 2014; 32: 760767
Regimen Temsirolimus 25mg IV weekly vs. Sorafenib 400 mg bid Mechanism of Action of Experimental Drug
Temsirolimus is a highly specific inhibitor of mTOR, the signaling pathway of which is altered in RCC with clear cell histology, of advanced stage, or with poor prognostic features.
Has shown activity in phase 2 studies in pretreated patients with advanced RCC
Primary Endpoint PFS Secondary endpoints: OS, ORR and safety
Inclusion/Exclusion Criteria
Any histology mRCC Progressive disease after sunitinib ECOG 0 or 1 No brain metastases Adequate hepatic, renal and cardiac function
Size (N) 512 Results Median PFS: 4.3 vs. 3.9 months HR=0.87, p=0.89
ORR: 8% in both arms Median OS: 12.3 vs. 16.6 months, HR =1.31, p=0.01
Toxicity More grade >=3 anemia and hyperglycemia with temsirolimus More grade >=3 palmarplantar erythrodysesthesia with sorafenib
Conclusion No differences were observed for PFS or ORR between temsirolimus vs. sorafenib in the 2nd line setting
OS was significantly improved with sorafenib compared to temsirolimus in the 2nd line setting
Other Comments A TKI to TKI sequence may be better than a TKI to mTOR sequence?
Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a
randomised phase 3 trial Rini et al. Lancet. 2011; 378, 193139
Regimen Axitinib 5mg mg twice daily vs sorafenib 400 mg twice daily Mechanism of Action of Experimental Drug
Axitinib is a potent, selective, secondgeneration inhibitor of VEGFR 1, 2, and 3 that blocks VEGFRs at subnanomolar drug concentrations. Relative potency of axitinib is 50–450 times greater than that of the firstgeneration VEGFR inhibitors. Additionally, firstgeneration inhibitors block other targets, such as plateletderived growth factor receptors (PDGFR), bRAF, KIT, and FLT3, which are not substantially inhibited by axitinib.These offtarget activities might contribute to the adverse effects of the firstgeneration inhibitors, suggesting that more specific inhibitors of VEGFR such as axitinib might have an enhanced therapeutic window.
Primary Endpoint PFS (noninferiority) Secondary endpoints: OS, ORR, duration of response, time to deterioration
Inclusion/Exclusion Criteria
Advanced/ metastatic RCC with a clear cell component ECOG 0 or 1 Progressive disease after 1 line of previous systemic treatment No brain mets or CNS involvement Adequate organ function No present use or anticipated need for cytochrome P450 (CYP)3A4inhibiting,
CYP3A4inducing, or CYP1A2inducing drugs; No known HIV or acquired immunodeficiency syndromerelated disease No uncontrolled hypertension, no MI/CVA/TIA within the past 12 months No DVE/ PE within the past 6 months
Size (N) 723 Results Median PFS – 6.7 months vs 4.7 months, HR=0.665, p<0.001
Median PFS for patients who had previously received cytokines– 12.1 vs 6.5 months, HR=0.464, p<0.001
Median PFS for patients previously treated with sunitinib – 4.8 vs 3.4 months, HR=0.741, p=0.01
ORR: 19% vs 9%, p=0.0001 Median duration of response: 11 vs. 10.6 months Time to deterioration: 17% risk reduction with axitinib
Toxicity Most common grade 3+ adverse events with axitinib: hypertension, diarrhea and fatigue
Most common grade 3+ adverse events with sorafenib: palmarplantar erythrodysaesthesia, hypophosphataemia, lipase elevation, and hypertension
Conclusion Axitinib led to a statistically significant and clinically meaningful increase in the primary efficacy endpoint of PFS compared with sorafenib
Time to deterioration was also improved with axitinib The tolerability of axitinib was similar to that of sorafenib and other VEGFR
inhibitors, with some exceptions
Other Comments This study was not a blinded trial, although all efficacy endpoints were adjudicated by masked independent radiology review
Patients on axitinib were able to increase their dosages while patients on sorafenib were not – this may have led to increase efficacy of axitinib
2nd line and beyond:
Efficacy of everolimus in advanced renal cell carcinoma: a doubleblind, randomized, placebocontrolled phase III trial
Motzer et al. Lancet. 2008; 372: 44956
Regimen Everolimus 10 mg once daily vs placebo Mechanism of Action of Experimental Drug
Everolimus is an inhibitor of the mammalian target of rapamycin (mTOR), a component of an intracellular signalling pathway that regulates cellular metabolism, growth, proliferation, and angiogenesis. Everolimus, a derivative of rapamycin, binds to an intracellular protein, FKBP12, forming a complex that inhibits the mTOR serinethreonine kinase
Primary Endpoint PFS Secondary endpoints: OS, ORR, safety, QoL, disease related symptoms
Inclusion/Exclusion Criteria
mRCC with a clear cell component Progressed on or within 6 months of being on sunitinib or sorafenib No previous exposure to mTOR inhibitor KPS >=70% No untreated brain metastases Adequate hepatic, renal and bone marrow function
Size (N) 410 Results Median PFS: 4.0 vs. 1.9 months HR=0.30, p <0.001
ORR: 1% vs 0% Median OS: Not reached vs. 8.8 months, HR 0.83, p=0.23 QoL – No significant difference between treatment arms
Toxicity More grade 3/4 stomatitis, infections, noninfectious pnuemonitis, lymphopenia, hyperglycemia, hypophosphotemia, hypercholesterolemia in everolimus group
Conclusion Everolimus was associated with a reduction in the risk of progression or death compared with placebo in patients with metastatic renal cell carcinoma whose disease had progressed after treatment with VEGFtargeted therapies
Increased risk of toxicity with everolimus vs. placebo Other Comments OS likely not significant due to cross over
In this study leading to the approval for Everolimus 2nd line, 269 pts received Everolimus. However, most were heavily pretreated and received Everolimus 2nd line (89 pts), 3rd line (141 pts), 4th line (104 pts) and 5th line (82 pts)
A randomized, doubleblind phase III study of pazopanib in patients with advanced and/or
metastatic renal cell carcinoma: Final overall survival results and safety update Sternberg et al. European Journal of Cancer. 2013; 49: 12871296
Regimen Pazopanib 800 mg once daily vs placebo Mechanism of Action of Experimental Drug
Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptors (VEGFR)1/2/3, plateletderived growth factor receptors (PDGFR)a/b and stem cell factor receptor cKit
Primary Endpoint PFS Secondary endpoints: OS, ORR, QoL duration of response
Inclusion/Exclusion Criteria
Advanced and/or metastatic RCC Clear cell or predominately clear cell Treatment naïve or patients who had progressed on 1 line of previous
cytokine therapy ECOG 0 or 1 No brain metastases or leptomeningeal disease Adequate hepatic, renal and bone marrow function
Size (N) 435 (233 treatment naïve, 202 pretreated) Results Median PFS – entire population: 9.2 vs 4.2 months HR=0.46, p
<0.001 Median PFS – treatment naïve: 11.1 vs. 2.8 months, HR=0.4, p<0.001 Median PFS – cytokine pretreated: 7.4 vs. 4.2 months, HR=0.54,
p<0.001 ORR: 30% vs 3% Median OS: 22.9 months vs. 20.5 months, HR=0.91, p=0.224 QoL – No significant difference between treatment arms
Toxicity Higher rates of grade 3/4 adverse events with pazopanib – 33% vs 7% Most common grade 3/4 adverse events with pazopanib were
hypertension and diarrhea 3% arterial thrombotic events on pazopanib 13% all grades of hemorrhagic events on pazopanib
Conclusion Pazopanib demonstrated a statistically significant and clinically meaningful improvement in PFS compared with placebo in treatmentnaive and cytokinepretreated patients with advanced RCC.
Pazopanib did not show a statistically significant effect on OS in the final ITT analysis
Other Comments OS likely not significant due to cross over and post progression therapy (66% of patients in the placebo arm)
Other Important Published Data: 1. Dabestani, S., Marconi, L., Hoffman, F. et al. Local treatments for metastases of renal cell carcinoma: a systematic review. Lancet Oncology 2014; 15: e54961. Partial or complete removal of the metastatic lesions was associated with improved overall survival,
especially in patients with adequate performance and functional statuses All included studies were retrospective analyses and there was a high degree of bias in this review
D) REFERENCES 1. Capitano, U. and Montosi, F. Renal Cancer. Lancet. 2015. Epub ahead of print. 2. Renal Cell Cancer Treatment (PDQ®): Health Professional Version. PDQ Cancer Information Summaries. Bethesda (MD): National Cancer Institute (US); 20022015 Dec 3. 3. Heng et al. Prognostic Factors for Overall Survival in Patients With Metastatic Renal Cell Carcinoma Treated With Vascular Endothelial Growth Factor–Targeted Agents: Results From a Large, Multicenter Study. J Clin Oncol. 2009; 27: 579499. 4. Kassouf, W et al. Followup guidelines after radical or partial nephrectomy for localized and locally advanced renal cell carcinoma. Can Urol Assoc J. 2009 Feb; 3(1): 73–76. 5. Li, H., Samawi, H. and Heng, D. The use of prognostic factors in metastatic renal cell carcinoma. Urologic oncology: seminars and original investigations. 2015; 33: 509516 6. Srigley, JR et al. The International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia. Am J Surg Pathol 2013; 37(10): 146989. 7. Followup for clinically localized renal neoplasms: AUA guideline. Available at https://www.auanet.org/education/guidelines/renalcancerfollowup.cfm New data in the 2nd line setting that will impact the Canadian landscape: Two new 2nd line studies, published in the NEJM in September 2015 will impact the Canadian landscape for 2nd line therapy. Both drugs are expected to obtain Health Canada approval and be funded in the 2nd and perhaps also in the 3rd line setting. Will displace Everolimus alone to 3rd and 4th line. In the first study, 658 patients were randomized to receive cabozantinib vs. Everolimus. Median PFS was 7.4 months with cabozantinib and 3.8 months with everolimus. The rate of progression or death was 42% lower with cabozantinib than with everolimus (hazard ratio, 0.58; 95% confidence interval CI 0.45 to 0.75; P<0.001). The objective response rate was 21% with cabozantinib and 5% with everolimus (P<0.001). A planned interim analysis showed that overall survival was longer with cabozantinib than with everolimus (hazard ratio for death, 0.67; 95% CI, 0.51 to 0.89; P = 0.005) but did not cross the significance boundary for the interim analysis. These OS data have now been updated in a press release Feb 1 2016, confirming that the OS data now show a significantly improved survival for cabozantinib. In the second study, 821 pts were randomized to Nivolumab vs. Everolimus. The median overall survival was 25.0 months (95% CI, 21.8 to not estimable) with Nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus. The hazard ratio for death with Nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P = 0.002), which met the prespecified criterion for superiority (P≤0.0148). The objective response rate was greater with Nivolumab than with everolimus (25% vs. 5%; odds ratio, 5.98 (95% CI, 3.68 to 9.72); P<0.001). The main interest of immunotherapy is the potential for durable responses and even a cure in a subset of patients. The aggregate data on immunotherapy to date suggest that only 1015% of RCC patients could be potentially cured. Therefore, targeted therapies will continue to be the most important therapy for the majority of RCC patient. In another phaseII study that may have impact in the 2nd line setting, 153 patients were randomly allocated to receive either the combination of lenvatinib plus everolimus (n=51), singleagent lenvatinib (n=52), or singleagent everolimus (n=50). Lenvatinib plus everolimus significantly prolonged PFS compared with everolimus alone (median 14.6 months (95% CI 5.9–20.1) vs 5.5 months (3.5–7.1); hazard ratio 0.40, 95% CI 0.24–0.68; p=0.0005), but not compared with lenvatinib alone. Singleagent lenvatinib significantly
prolonged progressionfree survival compared with everolimus alone (HR 0.61, 95% CI 0.38–0.98; p=0.048). Combination lenvatinib/everolimus demonstrated an improved response rate compared with everolimus (43.1% vs. 6.0%; P<0.0001). The difference in median overall survival between patients assigned lenvatinib plus everolimus and those allocated singleagent everolimus was significantly increased (25.5 months (95% CI 16.4–NE) vs 15.4 months (11.8–19.6); HR 0.51, 95% CI 0.30–0.88; p=0.024).