腎臓がんに対する分子標的薬

腎臓がんに対する分子標的薬～最新の話題～

15/02/27 Department of Medical Oncology, Nippon Medical School Musashikosugi Hospital

本日のお話

• Current therapy for advanced renal cancer

•  1st line treatment

•  2nd line treatment

• How to overcome for resistant disease

•  New agents

•  Dose Titration


腎臓がんに対する分子標的薬

• Anti-VEGF •  tyrosine kinase (TK) inhibitors

- Sunitinib - Sorafenib - Pazopanib - Axitinib

• monoclonal antibody - Bevacizuzumab

• mTOR inhibitor - Temsirolimus - Everolimus


Biological pathways and the resulting therapeutic targets in renal cell carcinoma


Lancet 2009; 373:1119

Algorithm for Clear Cell RCC Therapy Setting Phase III Alternative

1st line Good or

intermediate risk

Sunitinib Pazopanib Bevacizumab+IFN

HD IL-2

Poor risk Temsirolimus Sunitinib

2nd line Prior cytokine Sorafenib

Pazopanib Sunitinib or Bevacizumab

Prior VEGFR inhibitor

Everolimus Axitinib Clinical trials

Prior mTOR inhibitor Clinical trials

3rd line Clinical trials


ASCO 2014

Which is the best first-line treatment?


Pazopanib 800 mg QD continuous dosing Dose reductions to 600 mg or 400 mg

Sunitinib 50 mg QD 4 wks on/2 wks off Dose reductions to 37.5 mg or 25 mg

Key Eligibility Criteria §  Advanced/metastatic RCC §  Clear-cell histology §  No previous systemic therapy §  Measurable disease (RECIST 1.0) §  KPS ≥ 70 §  Adequate organ function

Stratification factors §  KPS 70/80 vs 90/100 §  Previous nephrectomy §  Baseline LDH > 1.5 vs ≤ 1.5 x ULN

COMPARZ: Phase III Noninferiority Trial of Pazopanib vs Sunitinib in First-line mRCC

Randomized 1:1

Motzer RJ, et al. N Engl J Med 2013;369:722-31.

Primary Endpoint: PFS (Independent Review)

N Median PFS, Mos (95% CI)

Pazopanib 557 8.4 (8.3-10.9) Sunitinib 553 9.5 (8.3-11.1)

HR: 1.047 (95% CI: 0.898-1.220)

Pts at Risk, n 557 553

361 351

245 249

136 147

105 111

61 69

46 48

19 18

13 10

1 3

Pazopanib Sunitinib

1.0

0.8

0.6

0.4

0.2

0 Prop

ortio

n of

Pts

Pro

gres

sion

Fre

e

0 4 8 12 16 20 24 28 32 36 40 Mos

Interim Analysis of OS N Median OS, Mos

(95% CI) Pazopanib 557 28.4 (26.2-35.6) Sunitinib 553 29.3 (25.3-32.5)

HR: 0.908 (95% CI: 0.762-1.082; P = .275)

Motzer RJ, et al. ESMO 2012. Abstract 2325.

Pazopanib Sunitinib

1.0

0.8

0.6

0.4

0.2

0

Estim

ated

Sur

viva

l Fun

ctio

n

0 0 4 8 12 16 20 24 28 32 36 40 Mos

44 Pts at Risk, n

557 553

521 501

458 431

384 354

327 313

274 269

223 225

142 148

82 69

3 3

28 28

Most Common Adverse Events (Treatment Emergent)

Adverse Event,* % Pazopanib (n = 554) Sunitinib (n = 548) All Grades Grade 3/4 All Grades Grade 3/4

Any event† > 99 59/15 > 99 57/17 Diarrhea 63 9/0 57 7/< 1 Fatigue 55 10/< 1 63 17/< 1 Hypertension 46 15/< 1 41 15/< 1 Nausea 45 2/0 46 2/0 Decreased appetite 37 1/0 37 3/0 ALT increased 31 10/2 18 2/< 1 Hair color changes 30 0/0 10 < 1/0 Hand–foot syndrome 29 6/0 50 11/< 1 Taste alteration 26 < 1/0 36 0/0 Thrombocytopenia 10 2/< 1 34 12/4

Motzer RJ, et al. N Engl J Med 2013;369:722-31.

SWITCH Phase III Study: Sorafenib → Sunitinib vs Sunitinib → Sorafenib in mRCC

•  Primary endpoint: total PFS (from randomization to confirmed progression or death during second-line therapy, or first line for pts who did not receive second-line treatment)

•  Pts enrolled in Germany, Austria, and The Netherlands •  Efficacy assessed every 12 wks (per RECIST 1.0) and at end of treatment

Michel M, et al. ASCO GU 2014. Abstract 393.

Pts with mRCC, unsuitable for

cytokines, no prior systemic therapy, ECOG PS 0-1, ≥ 1

lesion

Sorafenib 400 mg BID

Sunitinib 50 mg QD

Progression or

intolerable toxicity Sorafenib

400 mg BID

Sunitinib 50 mg QD

Stratified by MSKCC prognostic group (favorable or intermediate)

SWITCH Study of Sorafenib → Sunitinib vs Sunitinib → Sorafenib in mRCC: PFS


Median PFS So → Su (n = 182): 12.5 mos (95% CI: 11.5-15.0) Su → So (n = 183): 14.9 mos (95% CI: 10.5-17.2) HR: 1.01; P = .54

100

80

60

40

20

0 0 5 10 15 20 25 30 35 40 45 50

Mos From Randomization

Prob

abili

ty o

f PFS

(%)

Pts at Risk, n So → Su → So

182 183

127 116

83 85

66 62

45 43

30 26

17 19

14 16

7 10

6 9

Intent-to-treat population

SWITCH Study of Sorafenib → Sunitinib vs Sunitinib → Sorafenib in mRCC: OS


100

80

60

40

20

0 0 5 10 15 20 25 30 35 40 45 50

Mos From Randomization

Prob

abili

ty o

f OS

(%)

Pts at Risk, n So → Su → So

182 183

148 147

123 119

105 95

79 80

58 59

36 37

25 29

17 18

9 12

Median OS So→ Su (n = 182): 31.5 mos (95% CI: 23.3-36.9) Su → So (n = 183): 30.2 mos (95% CI: 23.6-50.1) HR: 1.00; P = .49

55

6 7

Sorafenib → Sunitinib vs Sunitinib → Sorafenib in mRCC: Conclusions

• Sorafenib and sunitinib both benefited patients with mRCC in both treatment sequences

• Primary endpoint not met: PFS of sorafenib → sunitinib not superior to sunitinib → sorafenib (HR: 1.01)

• OS comparable in both arms (HR: 1.00) • Adverse events for both agents generally less frequent in

second-line vs first-line treatment


RECORD-3: Phase II Sequential Study of Sunitinib and Everolimus

•  Primary endpoints: first PFS noninferiority of everolimus •  Secondary endpoints: second PFS, ORR, duration of response, patient-

reported outcomes, OS

Everolimus 10 mg/day

Sunitinib 50 mg/day

(schedule 4/2)

Sunitinib 50 mg/day

(schedule 4/2)

Everolimus 10 mg/day

Eligibility §  Patients with

advanced RCC (N = 390)

Stratification §  KPS ≥70% §  No previous

systemic therapy for advanced or mRCC

RANDOM I ZA T I ON

ClinicalTrials.gov. NCT01784978.

Discontinuation (due to progressive disease/toxicity)

RECORD-3: PFS


Which is the best second treatment?


NCCN. Clinical practice guidelines in oncology: kidney cancer. v.1.2013.

Current Management of Advanced RCC

First-line Therapy Second-line Therapy

Favorable risk

Sunitinib or pazopanib

Everolimus or axitinib

(or TKI, temsirolimus, bevacizumab)

Intermediate risk

Sunitinib or pazopanib

Everolimus or axitinib

(or TKI, temsirolimus, bevacizumab) Poor risk Temsirolimus Unknown

((sunitinib, clinical trial, supportive care)

Drug Control Study Design ORR, % PFS, Mos OS, Mos

VEG

F In

hibi

tors

Sorafenib[1,2] Placebo

Randomized 1:1; patients previously

treated with IL-2 or IFN-α

10 vs 2 (P < .001)

5.5 vs 2.8 (HR: 0.44; P < .01)

17.8 vs 15.2 (HR: 0.88; P = .146) (17.8 vs 14.3‡;

HR: 0.78; P = .029)

Axitinib[3] Sorafenib


treated with sunitinib,

bevacizumab with IFN-α, temsirolimus,

or cytokines

19 vs 9 (P = .0001)

6.7 vs 4.7 (HR: 0.665; P < .0001)

20.1 vs 19.2 (HR: 0.969; P = .374)

mTO

Ri

Everolimus[4] Placebo


treated with VEGFR TKI

2.0 vs 0

4.9 vs 1.9*

(HR: 0.33; P < .001)*

5.5 vs 1.9†

(HR: 0.32; P < .001)†

14.8 vs 14.4 (HR: 0.87; P = .162)

1. Escudier B, et al. N Engl J Med. 2007;356:125-134. 2. Escudier B, et al. J Clin Oncol. 2009;27:3312-3318. 3. Rini BI, et al. Lancet. 2011;378:1931-1939. 4. Motzer R, et al. Cancer. 2010;116:4256-4265.

Pivotal Phase III Data in Second Line

AXIS Trial: Axitinib Superior to Sorafenib in Second-line mRCC Therapy

Rini BI, et al. Lancet. 2011;378:1931-1939.

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1

0 0 2 4 6 8 10 12 14 16 18 20

Pro

babi

lity

of P

FS Axitinib

Sorafenib

Median PFS, Mos (95% CI) 6.7 (6.3-8.6) 4.7 (4.6-5.6)

Stratified HR: 0.665 (95% CI: 0.544-0.812; P < .0001)

Pts at Risk, n Axitinib

Sorafenib 256 224

361 362

202 157

145 100

96 51

64 28

38 12

20 6

10 3

1 1

0 0

Months

Patients with mRCC and PD on first-line sunitinib

(N = 512) Stratification factors: § Duration of sunitinib therapy (≤ or > 6 mos) § MSKCC risk group § Histology (clear cell or non–clear cell) § Nephrectomy status

RANDOMIZE

Temsirolimus 25 mg IV weekly*

(n = 259)

1:1

Sorafenib 400 mg oral BID*

(n = 253)

Treat until PD, unacceptable toxicity, or discontinuation for any other reason

Primary endpoint:

PFS (per IRC)

ClinicalTrials.gov. NCT00474786.

*Dose reductions were allowed: temsirolimus (to 20 mg, then 15 mg), sorafenib (to 400 mg/day, then every other day).

INTORSECT Study Design

J Clin Oncol 2014;32:760-767

Hutson T, et al. ESMO 2012. Abstract LBA22.

Temsirolimus Sorafenib

Pro

babi

lity

of P

FS

252 72 22 11 6 0 259 96 28 9 5 0

Sorafenib Temsirolimus

Mos 0 5 10 15 20 25

PFS (IRC Assessment)

Stratified HR: 0.87 (95% CI: 0.71-1.07; log rank P = .1933)

Median PFS, Mos (95% CI)

4.28 (4.01-5.43) 3.91 (2.80-4.21)

Pts at Risk, n

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

J Clin Oncol 2014;32:760-767

Pro

babi

lity

of O

S

253 158 74 34 13 0 259 132 54 22 8 0

Sorafenib Temsirolimus

0 10 20 30 40 50

Temsirolimus Sorafenib

Pts at Risk, n Mos

Stratified HR: 1.31 (95% CI: 1.05-1.63; log rank P = .014)

12.27 (10.13-14.80) 16.64 (13.55-18.72)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Median OS, Mos (95% CI)

Hutson T, et al. ESMO 2012. Abstract LBA22.

Overall Survival

J Clin Oncol 2014;32:760-767

OS by Duration of Previous Sunitinib (ITT Population)

Previous Sunitinib Use Temsirolimus (n = 259)

Sorafenib (n = 253) HR (95% CI) P

Value* < 90 days, n (%) Median OS, mos (95% CI)

38 (15) 8.0 (5.3-14.7)

29 (12) 10.3 (5.7-13.8)

1.11 (0.64-1.93)

.708

90-270 days, n (%) Median OS, mos (95% CI)

99 (38) 11.6 (10.1-16.1)

97 (38) 16.8 (11.1-19.8)

1.32 (0.95-1.84)

.096

> 270 days, n (%) Median OS, mos (95% CI)

121 (47) 14.4 (10.9-17.6)

126 (50) 17.6 (15.3-22.9)

1.40 (1.02-1.92)

.036

*Unstratified log rank test.

Longer time on first-line TKI predicts for greater benefit from second-line TKI

Hutson T, et al. ESMO 2012. Abstract LBA22. J Clin Oncol 2014;32:760-767

Second-line Post-TKI Results

Agent PFS, Mos OS, Mos Comments

Everolimus 4.9 (5.4 in second line only) 14.8 Second and third line

Temsirolimus 4.3 12.3 Shorter OS than sorafenib

Axitinib 4.8 15.2 Substantially higher in non-sunitinib subgroups

Sorafenib 3.4 (AXIS) 3.9 (INTORSECT)

16.5 (AXIS) 16.6 (INTORSECT)

Consistent low PFS but high OS results

Placebo 1.9 14.4 80% crossover to

everolimus (5.0 mos PFS)

Motzer RJ, et al. Cancer. 2010;116:4256-4265. Rini et al, Lancet Oncology. 2011;378:1931-1936. Hutson T, et al. ESMO 2012. Abstract LBA22.

How to Overcome for Resistant Disease in Advanced RCC？

Sorafenib treatment

Baseline Follow-up 1 Follow-up 2

Tumor volume (cm3) 295 341 285

Tumor necrosis (%) 2.09 53.07 51.03

Abou-Alfa G, et al. EORTC-NCI-AACR 2004, Geneva, Switzerland

RECIST vs. Progressive Disease

Placebo

0

20

40

60

80

100

120

140

160

180

200

0 20 40 60 80

Tum

or B

urde

n C

ompa

red

to B

asel

ine

(%)

Low Dose

0

20

40

60

80

100

120

140

160

180

200

0 20 40 60 80

Weeks of Treatment

High Dose

0

20

40

60

80

100

120

140

160

180

200

0 20 40 60 80

Change in tumor burden in mRCC patients

Adapted from Elaraj et al. J Immunotx 27(4), 2004

Easy to call PD

Easy to say NOT PD ???? PD

Patterns of Tumor Progression vs. Selection of Subsequent Therapy

Chan

ge in

Tum

or

Mea

sure

men

ts (

%)

Chan

ge in

Tum

or

Mea

sure

men

ts (

%)

Chan

ge in

Tum

or

Mea

sure

men

ts (

%)

Primary Refractory Early Progression Late Progression

Rini BI and Flaherty K, Urol Oncol 2008

New agent Synergic combination Single agent

Cabozantinib •  Inhibitor of MET and VEGF receptor • Striking response seen in bone of patients with prostate

cancer • Agent is being explored in multiple other cancers,

including RCC • Currently FDA approved for use in patients with

progressive, metastatic medullary thyroid cancer

Cabozantnib in RCC

Tumor Response<br />Best Response in Patients With ≥1 Post-Baseline Scan (n = 21)*

Response Example: RCC with Sarcomatoid Differentiation

<br />Example of Partial Bone Scan Resolution in a Symptomatic Patient With Predominantly Osteolytic Bone Metastases

Cabozantinib (CaboSun)

Cabozantinib

Novel Immunotherapy

Nivolumab in mRCC

Nivolumab Phase 3 Trial

Novel Immunotherapy: Combinations

Second-line Trials to Watch • Phase III Nivolumab (anti-PD1) vs everolimus • Phase III cabozantinib (XL184) vs everolimus • Phase III dovitinib vs sorafenib (completed, third line) • Phase III everolimus with or without bevacizumab

(CALGB, closed)

Combination with approved drugs in randomized trials

•  4 important comparative (II/III) studies:

– BeST study phase II (6 arm trial of Combination Targeted Therapy With Bevacizumab, Sorafenib and Temsirolimus)

– TORAVA study phase II –  IFN-Bev vs TEMS-Bev phase III –  IFN-Bev vs EVER-Bev phase II

Pts with mRCC, no prior systemic therapy, > 75% clear cell, prior nephrectomy

RANDOMIZE

Arm A Bevacizumab 10mg/kg IV q2wks (n = 89)

Primary endpoint: PFS

ASCO GU 2013 (suppl 6; abstr 345)

BEST trial (E2804)

Arm B Bevacizumab 10mg/kg IV q2wks Temsirolimus 25mg IV wkly (n = 91)

Arm C Bevacizumab 5mg/kg IV q2wks Sorafenib 200mg PO bid d1-15, 8-12 (n = 90)

Arm D Sorafenib 200mg PO bid d1-28 Temsirolimus 25mg IV wkly (n = 91)

BEST trial (E2804): PFS


BEST trial (E2804): OS


Temsirolimus and Avastin (TORAVA) study (Phase II)

•  Objectives –  primary: PFS –  secondary: safety, ORR (independently assessed), OS –  tertiary: circulating endothelial cells, functional imaging

Avastin + temsirolimus (n=80)

Sunitinib (n=40)

Metastatic RCC patients (n=160)

Avastin + IFN-α2a (n=40)

2:1:1 PD

PD

PD

Review of Other Ongoing and Planned Trials (Phase II/III)

Temsirolimus + bevacizumab

IFN-α + Bevacizumab

Patients with mRCC

Randomized phase III trial of temsirolimus + bevacizumab vs IFN-α + bevacizumab in mRCC

Everolimus + bevacizumab

IFN-α + Bevacizumab

Patients with mRCC

Randomized phase II trial of everolimus + bevacizumab vs IFN-α + bevacizumab in mRCC

R A N D O M I S E

R A N D O M I S E

Hypertension as Marker of Efficacy in Pts With Metastatic RCC After Sunitinib Treatment

Rini BI, et al. J Natl Cancer Inst. 2011;103:763-773.

With HTN (n = 442) Median OS: 30.9 mos (95% CI: 27.9-33.7) Without HTN (n = 92) Median OS: 7.2 mos (95% CI: 5.6-10.7)

Mos

Pro

babi

lity

of O

S 1.0

0.8

0.6

0.4

0.2

0 0 5 10 15 35 45 50 30 40 20 25

442 418 377 308 257 224 190 106 29 92 55 38 21 15 7 5 3 1

Pts at Risk, n

P < .0001

With HTN Without HTN

With HTN Without HTN Month N S, % 95% CI N S, % 95% CI

10 377 86.3 (82.7-89.2) 38 43.5 (33.0-53.5) 20 257 66.3 (61.5-70.6) 15 21.4 (13.1-31.0) 30 190 51.9 (46.9-56.7) 5 8.2 (3.2-16.1)

Axitinib With or Without Dose Titration for First-line Metastatic Renal Cell

Carcinoma: Unblinded Results From a Randomized Phase II Study

BI Rini,1 V Grünwald,2 MN Fishman,3 B Melichar,4 T Ueda,5 AH Bair,6 Y Chen,6 P Bycott,6 D Pavlov,7 S Kim,6 E Jonasch8

1Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; 2Hannover Medical School, Hannover, Germany; 3H. Lee Moffitt Cancer Center, Tampa, FL; 4Palacky University Hospital, Olomouc, Czech Republic; 5Chiba Cancer Center, Urology, Chiba, Japan; 6Pfizer Oncology, San Diego, CA; 7Pfizer Inc, New York, NY; 8The University of Texas M. D. Anderson Cancer Center, Houston, TX

Rini BI, et al. ASCO GU 2013. Abstract LBA349.

Axitinib With or Without Dose Titration for First-line Metastatic RCC

Assessments Tumor assessments performed according to RECIST version 1.0 at screening, Wks 8, 16, and 24 of therapy, and every 12 wks thereafter Safety assessed throughout the study period with adverse events graded according to CTCAE v3.0


* For at least 2 consecutive wks. †Titrated stepwise to 7 mg BID and then to a maximum of 10 mg BID if criteria for randomization to dose titration were met.

1:1

Lead-in period (Cycle 1)

Axitinib 5 mg BID

(4 wks)

Arm C Axitinib ≤ 5 mg BID (no dose titration)

Arm B Axitinib 5 mg BID

+ Placebo dose

titration† (blinded therapy)

Arm A Axitinib 5 mg BID

+ Active (axitinib) dose

titration† (blinded therapy)

Randomization Criteria*

BP ≤ 150/90 mm Hg and ≤ 2 concurrent anti-HTN

medications and no grade 3 or 4

axitinib-related toxicities and no dose reduction R

ando

miz

e A

ssig

n

Yes

No

Axitinib With or Without Dose Titration: Study Objectives

• Primary objective •  To compare the ORR in patients randomized to axitinib plus axitinib

titration vs axitinib plus placebo titration

• Secondary objectives •  PFS, OS, safety, duration of response, axitinib plasma

pharmacokinetics, BP measurements, biomarker and pharmacogenetic analyses


Clinical Efficacy of Axitinib in First-line Metastatic RCC

Total* (N = 213)

Active Titration (n = 56)

Placebo Titration (n = 56)

Nonrandomized (n = 91)

ORR, % (95% CI)

48 (42-55)

54 (40-67)

34 (22-48)

59 (49-70)

P value† .019

Median PFS, mos (95% CI)

14.6 (11.5-17.5)

14.5 (9.2-24.5)

15.7 (8.3-19.4)

16.6 (11.2-22.5)

HR (95% CI)‡ 0.85 (0.54-1.35)

P value§ .244

*Includes 10 patients who withdrew during lead-in period. †P value is from a 1-sided Cochran-Mantel-Haenszel test stratified by ECOG PS from randomization system. ‡Assuming proportional hazards, HR < 1 indicates a reduction in favor of active titration; HR > 1 indicates a reduction in favor of placebo titration. §P value is from a 1-sided log-rank test stratified by ECOG PS from randomization system.


Axitinib With or Without Dose Titration: Adverse Events

Treatment-Emergent, All-Causality AEs in > 30% of Treated Patients, %

Total* (N = 213)

Active Titration (n = 56)

Placebo Titration (n = 56)

Nonrandomized (n = 91)

All Grades

Grade ≥ 3

All Grades

Grade ≥ 3

All Grades

Grade ≥ 3

All Grades

Grade ≥ 3

Hypertension 65 30 61 18 43 9 82 50

Diarrhea 60 8 61 13 63 4 63 9

Fatigue 49 7 45 5 46 4 54 8

Dysphonia 40 1 32 2 36 0 48 0

Decreased appetite 36 3 38 5 30 0 39 4

Hypothyroidism 35 0 32 0 23 0 45 0

Nausea 34 2 38 5 34 0 34 1

Hand–foot syndrome 32 4 32 4 18 2 44 6

Proteinuria 30 1 20 4 20 0 43 0

*Includes 10 patients who withdrew during lead-in period.


Axitinib With or Without Dose Titration: Conclusions • Axitinib dose titration significantly improved ORR

compared with placebo • Median PFS was not altered in randomized dose

escalation group compared with control •  The nonrandomized group did best of all highest response

rate and PFS •  High proportion of Asian patients in this group, suggestive of host

genomic features that predispose to benefit from VEGF pathway targeting agents


腎臓がんに対する分子標的薬

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