Comprehensive overview of systemic treatment of kidney cancers: staging, diagnosis, risk stratification and treatment

1. Ahmed Zeeneldin
Associate professor of Medical Oncology , NCI
2013

2. ¡ AdenoCA:
§ Clear
§ Papillary
§ Chromophobe
§ Unclassified
§ Sarcomatoid
¡ TCC of renal pelvis
¡ Rare tumors
¡ Metastatic:
lung, ovary,
colon, breast

5. TNM staging
T1: limited to kidney <= 7cm
T1a: <=4cm
T1b: >4-7 cm
T2: limited to kidney > 7cm
T2a: 7-10 cm
T2b: >10 cm
T3: outside capsule but limited to Gerota’s fascia
T3a perinephric fat and limited to Gerota’s fascia, OR RV
T3b: infradiaph IVC
T3c: supradiaph IVC or IVC wall
T4: beyond Gerota’s fascia or into adrenal
N1: one + LN
M1: mets
T1 T2 T3 T4 M1
N0 I (95%) II (80%) III (65%) IV (25%) IV
N1 III III III IV IV

6. ¡ H&P:
§ PS >1
§ Time from Dx to start of systemic therapy <1y
¡ Lab:
§ CBC: HB <1N, ANC >1N& Plts>1N
§ KFT & urine
§ LFT
§ Others: calcium>10, LDH>1.5N, coagulation profile
¡ Imaging:
§ CT with contrast: CAP
§ MRI if we cannot use CT e contrast : CAP or to detect IVC invasion
§ Others if indicated: MRI/CT brain, Bone scan
§ PET alone : is not standard due to high false positive and negative
¡ Needle biopsy: diagnostic and guide surveillance

7. § Local Tx
▪ Surgery
▪ Thermal ablation, RFA
▪ RT: limited role
§ Systemic Tx:
▪ Chemotherapy not in clear cell type
▪ Cytokines
▪ Targeted therapy:
▪ VGEF pathway: TKIs, anti-VEGF mcAb
▪ mTORi
§ Surveillance
▪ Limited life expectancy
▪ Severe Comorbidities

8. Stage TNM Surgery RTx CTx Cytokine and
Targeted therapy
I T1: PN*/RN No No No adjuvant
<4 cm
<7om
II T2 RN No No No adjuvant
<10 cm
>10 cm
III T3 RN No No No adjuvant
N1
IV T4 RN/CRS/ No** Yes
M1 Metastatectomy Bone/brain met
* in T1 tumors (up to 7cm) Surveillance may be used in selected cases and thermal ablation if surgically unfit
**May be given in non-clear cell histology
PN: Partial nephrectomy, RN: radical nephrectomy, CRS: cytoreductive surgery

9. ¡ Surgery
§ Thermal ablation
§ Surveillance
¡ No role for adjuvant RTx or systemic Tx

10. T1a (<4cm) RN PN
No >5000 <2000
Death due to RCC 2% 4%
RR of death 1 0.54 (0.34-0.85)
Tan et al. JAMA. 2012;307(15):1629-35.
T1b-T3 (>4cm) RN PN
No 75 35
Overall mortality 11% 11%
RCC specific mortality 3% 3%
Recurrence 3% 6% (NS)
Simmons et al., Urology. 2009;73(5):1077-82

11. OS: HR 1.07 (0.89, 1.28)
Scherr et al. BMC CANCER; MAR 31, 2011; 11

12. DFS: HR 1.03 (0.87, 1.21)

13. ¡ Stage IV categories:
§ Locally advanced: T4
§ Distant: M1
¡ Options:
§ Surgery:
§ RTx: Bone or Brain mets
§ Systemic therapy:

14. T1-3 T4
¡ Types of surgery: M0 PN/RN CRS
§ 1ry : RN or CRS M1 multiple RN CRS
§ 2ry: Metastatectomy M1 single* RN + CRS+
metastatectmoy metastatectmoy
▪ Solitary mets: lungs, bone and brain
¡ Beneficial for patients treated with:
§ Cytokines: INF, IL
§ Targeted therapy
¡ More benefit in:
§ Lung only mets
§ Good prognostic features (0 score)
§ Good PS

15. ¡ Resectable Stage IV RCC
¡ RR of death decreased by
30%
¡ Independent of
§ patient performance status,
§ the site of metastases and
§ the presence of measurable
disease.
INF INF +
alone Surgery
MOS (P<0.002) 7.8 m 13.6 m
Flanigan et al, N Engl J Med.
2001;345(23):1655-9.

16. OS BENEFIT WAS MORE
WITH PS>80%
VEGFTx alone CSR+VEGFTx
MOS p<0.01 9m 20m

17. ¡ Indications
§ Metastatic (M1)
§ Irresectable (T4)
§ Recurrent
¡ Risk stratification

18. ¡ Memorial Sloan Kettering cancer center (MSKCC):
§ for Advanced stages treated with immunotherapy
▪ INF treated
¡ International mRCC Database Consortium (IMRDC)
prognostic model or Heng’s model:
§ For patients treated with anti-VEGF therapy
▪ sunitinib, sorafenib, or bevacizumab plus interferon

19. INF ERA ANTI-VEGF ERA
MSKCC MODEL IMRDC (HENG) MODEL
1. Clinical 1. Clinical
1. Interval from original 1. Interval from original
diagnosis to the start of diagnosis to the start of
cytokine therapy < 1 year anti-VEGF therapy < 1year
2. KPS < 80 (ECOG >1) 2. KPS < 80 (ECOG >1)
2. Lab: 2. Lab:
1. Calcium (corrected S) > 10 1. Calcium (corrected S) > 10
mg/dl (2.5 mmol/liter) mg/dl (2.5 mmol/liter)
2. HB <1 LLN 2. HB <1 LLN
------ 3. ANC >1x ULN
--- 4. Plts > 1x ULN
3. LDH >1.5 ULN --------------------------

21. ¡ Chemotherapy not in clear cell type
¡ Cytokines
¡ Targeted therapy:

22. ¡ Agents:
§ IL-2 (not other ILs same results as combinations with LAK)
§ INF a (not INFγ)
¡ Mechanism of action
§ Poorly understood
§ Induction of antitumor immunity through direct killing of tumor
cells by activated T cells (LAK) and natural killer (NK) cells
§ INFa also may have antiangiogenic effects
¡ May be used in
§ Goof PS 0-1
§ Good organ function
§ Clear RCC + alveolar features
§ Better after nephrectomy

23. Drug Route Dose Duration
IL-2 IV 15min 600,000 -720,000 q2w X2à q3m X3*
(Proleukin) IU/kg q 8h, D1-5
IV or SC 0.1 dose ? X2 q2w à X3 q3m*
INFa SC 9 MU 3times q w Continuous
(roferon a)
IL2 + INFa SC Both: 5MU/sqm ?Continuous
Drug Toxicity RR% CR% RD m PFS m OS m
IL-2 +++++ 20 10 19m ~17m
++ 13 Lower ~15m
INFa ++ 15 3 <12m 5m ~13m
(+4m)
IL2 + INFa ++ 10 15m 13m

24. IL2 INFA
¡ Hypotension ¡ Less than IL-2
¡ Cardiac arrhythmia
¡ Metabolic acidosis ¡ Fatigue
¡ Fevers/chills ¡ Fever, chills
¡ Nausea/vomiting ¡ myalgia
¡ Dyspnea ¡ Flu-like
¡ Peripheral edema
¡ Oliguria, rising creatinine ¡ Nausea
¡ Transminase elevations ¡ rash
¡ Neurotoxicity
¡ Skin rash, pruritus
INFa is recommended to be the control arm in future
studies

26. ¡ VEGF pathway
§ VEGF Receptor-TKI
§ Anti-VEGF mcAb
¡ mTOR inhibitors

30. TKI Route Dose Duration Toxicity
Sunitinb (sutent) PO 50mg qd x 4w Continuous
and 2w off
Pazopanib (Votrient) PO 800 mg qd Continuous Liver
Axitinb (Inlyta) PO 5mg BID Continuous
Tivozanib (AV 951 ) PO 1.5 mg qd 3w Continuous
and 1w off
Sorafinib (Nexavar) PO 400mg BID Continuous
mcAb Route Dose Duration Toxicity
Bevacizumab (avastin) + IV 10 mg/kg q2w Continuous
INF

32. PFS: 11 VS 5 M (P <0.001) OS : 26 M VS 22 M (P0.051)
¡ 90% had nephrectomy Motzer et al, N Engl J Med 2007;356:115-124.
¡ 90% were low or intermediate risk

33. No improvement in PFS in poor risk patinets

34. ¡ Mainly retrospective data
¡ Effectiveness following cytokine therapy
¡ effective after soreafenib and vice versa

35. - Most patients were low or intermediate risk
- OS still immature
- PFS all p <0.001
all patinets: 9m vs 4m
Tx naieve: 11m vs 3m
prior cytokine: 7m vs 4m
Cora et al, JCO 2010;28:1061-1068.

36. Pazopanib Sunitinb
No 557 553
PFS 8.4m 9.5m NS
OS 28.4m 29.3m ns
RR 31% 25% 0.03

37. No improvement in PFS
Cross over of INF patients and dose escalation of sorafenib

38. improvement in PFS (6m vs 3m)
Cross over of placebo patientsà OS (19 vs 16 m, NS)
Can also be used after sunitinb or avastin

39. improvement in PFS (7m vs 5m)
Cytokine pretreated: PFS 12m vs 7m
Sunitinb pretreated: PFS 5vs 3m

40. ¡ PFS: ++ (5à8.5 m) OS not mature
CALGB trial Brian et al, Clin Oncol 2008; 26:5422-5428

41. ¡ PFS: ++ (5à10 m, S) OS (21 vs 23m , NS)
AVERON trial Brian et al, Clin Oncol 2008; 26:5422-5428

42. ¡ Subgroup analysis: not poor MSKCC risk
AVERON trial Brian et al, Clin Oncol 2008; 26:5422-5428

43. ¡ TKIs may be used after Avastin
¡ Sorafenib after sunitinb: 10%RR
¡ Axitinib after sorafenib: 23% RR

44. TKI Vs. RR% CR% SD% PFS m OS m
Sunitinb (sutent) INF 31 vs.6 0 48 vs49 11 vs. 5m 26 vs. 22*
Pazopanib (Votrient) Placebo 30 vs 3 9 vs 4 m 23 vs 22 m
Axitinb (Inlyta) sorafenib 18 vs 9 27 vs 20 7 vs. 5m ??
Tivozanib (AV 951 ) sorafenib 33 vs 23 12 vs 10 m ??
Sorafinib (Nexavar) Placebo 5.5 vs. 2.5 m 18 vs 15m
mcAb Vs. RR% CR% SD% PFS m OS m
Bevacizumab (avastin) + INF 31 vs. 13 10 vs 5.5 23 vs 21 m
INF

45. ¡ Hypertension: 25%
¡ Renal impairment RR1.36
¡ Arterial thromboembolism: 1.4%
¡ Thyroid dysfunction
¡ Cutaneous toxicity : hand foot syndrome
¡ Glucose metabolism: hypoglyemia
¡ Hepatotoxicity
¡ Muscle wasting

46. ¡ In 25% of patients receiving Sunitinib or
sorafenib
¡ Severe in 25% of the 25% i.e. 6%
¡ May predict good response to TKI
HT NO HT
RR 55% (x5) 10%
PFS 13m (X5) 3m
OS 31m (x5) 7m

47. Drug Route Dose Duration Toxicity
Temsorilimus (Torisel) IV 15mg q w Continuous
Everolimus (Afinitor) PO 10 mg qd Continuous
Drug Vs. RR% CR% SD% PFS m OS m
Temsorilimus (Torrisel) INF 6m vs 3m 11 vs 7ms
Everolimus (Affinitor) placebo 1vs 0 63 vs 32 5m vs 2 m 15 vs 14.s m

48. OS

49. PFS

50. PFS: 5VS 2 M (P <0.001) OS: 14.8 VS 14.4 M (P = 0.18)
Independent prognostic factors for shorter OS Cross over
low performance status, high corrected calcium,
low hemoglobin, and prior sunitinib (P < .01).

51. ¡ Common: asthenia, rash, anemia, nausea,
and anorexia
¡ Hypersensitivity
¡ pneumonitis

52. Regimen Setting Therapy Options
MSKCC risk: Sunitinib High-dose IL-2
Good (0) or pazopanib
1st line intermediate (1-2) bevacizumab + IFN-α
MSKCC risk:
Temsirolimus Sunitinib
Poor (>2)
Cytokine- Sorafenib Temsirolimus
refractory Sunitinib bevacizumab
pazopanib
2nd line Sequential TKIs (Sorafenib,
Sunitinib
TKI Refractory Everolimus pazopanib) or
Bevacizumab
Temsirolimus
mTOR inhibitors TKI Bevacizumab

53. ¡ Bevacizumab (+erlotinib) x 8 w
§ PFS = 11m
§ OS = 25 m
§ Most was SD
¡ Sunitinb 2-3 cycles
§ PR: 6%
§ Tumor necrosis was common
§ PFS: 8m
¡ Sorafenib 33 days
§ Shrinkage by 10%

54. ¡ Temsorilimus: No 1
¡ TKIs: sorafenib and sunitinb
¡ Erlotinib
¡ Chemotherapy: Dox-Gem with sarcomatoid
varaints
¡ Collecting duct: Gem-cis/carbo

56. Stage TNM Surgery RTx CTx Cytokine and
Targeted therapy
I T1 PN*/RN No No No adjuvant
II T2 RN No No No adjuvant
III T3 RN No No No adjuvant
N1
IV T4 RN/CRS/ No** Yes-à
M1 Metastatectomy Bone/brain met risk stratification

57. Workup
Stage I-III Stage IV
(T1-3 & N-0r N+, M0) (T4 or M1)
Surgery Surgery Systemic therapy
(PN, RN) (RN, CRN, met’my (Cytokines, VGEF targeted, mTORi)
Good risk
Intermediate risk
IL-2 Poor risk
Sunitinib
Sunitinib temsorilimus
Pazopanib
Pazopanib ?everolimus
INF-bevaciz
INF-bevaciz