building on evidence to optimize treatment outcomes with ... 2019 satell… · building on evidence...

Building on evidence to optimize treatment outcomes with multikinaseinhibition in mCRCAxel Grothey, USA

PP-STI-ALL-0144-1PP-STI-ES-0079-1

July 2019

Adapted from NCCN and ESMO guidelines. BSC, best supportive care; EGFR, epidermal growth factor receptor; ESMO, European Society for Medical Oncology; mCRC, metastatic colorectal cancer; NCCN, National Comprehensive Cancer Network; VEGF, vascular endothelial growth factor. 1. Adapted from NCCN Clinical Practice Guidelines. Colon cancer. V2.2019; 2. Adapted from NCCN Clinical Practice Guidelines. Rectal cancer. V2.2019; 3. Adapted from Van Cutsem E, et al. Ann Oncol 2016;27:1386–1422.

mCRC guidelines recommend regorafenib as 3L in appropriate patients, regardless of RAS status1–3

2L1L 3L 4L

RASmutation

RASwild type

RASwild type

RASwild type

Chemo + anti-VEGF

Chemo + anti-VEGF

Chemo + anti-VEGF

Chemo + anti-VEGF

Chemo + anti-VEGF

Chemo + anti-EGFR

Chemo + anti-EGFR

Chemo + anti-VEGF

Chemo + anti-EGFR

REGORAFENIBor TAS-102

Other anticancer therapy, BSC, or clinical trial







Left-sided cancers only, per NCCN

*N=463 is the ITT population: response data based on 276 patients; data are missing for 186 patients (40.2%). ITT, intention-to-treat; PMS, post-marketing study; RCT, randomized controlled trial.1. Grothey A, et al. Lancet 2013;381:303–312; 2. Li J, et al. Lancet Oncol 2015;16:-619–629; 3. Eng C, et al. Lancet Oncol 2019;20:849–861; 4. Van Cutsem E, et al. Oncologist 2019;24:185–192; 5. Adenis A, et al. BMC Cancer 2016;16:412; 6. Yamaguchi K, et al. Oncologist 2019;doi: 10.1634/theoncologist.2018-0377 (Epub ahead of print); 7. Ducreux ESMO 2018. Abstract O-012 CORRELATE; 8. Kopeckova K, et al. ESMO 2018:Abstract 468P; 9. Schulz H, et al. J Clin Oncol 2018;36(4 suppl):748.

Broad global base of regorafenib clinical experience in mCRC: More than 7400 patients globally1–9

>7400 mCRC patients

CONSIGNN=2864

JAPANESE PMSN=1227

REBECCAN=654

RECORAN=463*

CORRELATEN=1037

CORECTN=555

CORRECTn=500

CONCURn=136

IMblaze370n=90

Phase 3 RCT evidence Real-world evidence

CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; mCRC, metastatic colorectal cancer; OS, overall survival.1. Grothey A, et al. Lancet 2013;381:303–312; 2. Li J, et al. Lancet Oncol 2015;16:619–629.

CORRECT and CONCUR: Significant improvements in OS with regorafenib vs placebo in mCRC patients with ECOG PS 0 or 1 and ≥2 prior lines of therapy1,2

6.4 months median OS with regorafenib

CORRECT1: 23% reduction in the risk of death (primary endpoint)

CONCUR2: 45% reduction in the risk of death (primary endpoint)

Median OS (95% CI): Regorafenib 6.4 months (3.6–11.8)Placebo 5.0 months (2.8–10.4)HR = 0.77, 95% Cl: 0.64–0.94; P = .0052

Median OS (95% CI): Regorafenib 8.8 months (7.3–9.8)Placebo 6.3 months (4.8–7.6) HR = 0.55, 95% Cl: 0.40–0.77; P = .00016

Ove

rall

Surv

ival

(%)

Months After RandomizationNumber at risk

RegorafenibPlacebo

2

452221

4

352150

6

18775

8

9332

10

339

12

73

Regorafenib 160 mgPlacebo

100

75

50

25

00 14

Ove

rall

Surv

ival

(%)

Months After Randomization2

13163

4

11345

6

8835

8

7223

10

5215

12

4211

Regorafenib PlaceboCensored patients

100

75

50

25

00

13668

18

..

..

Number at riskRegorafenib

Placebo

14

244

16

41


*For descriptive purposes only.CI, confidence interval; HR, hazard ratio; OS, overall survival. Eng C, et al. Lancet Oncol 2019;20:849–861.

IMblaze370 OS results confirm pivotalregorafenib trials, with an OS of 8.5 months

Median OS (95% CI): Regorafenib 8.5 months (6.41–10.71); 12-mo OS, 36.6%Median OS (95% CI): Atezolizumab + cobimetinib 8.9 months (7.00–10.61); 12-mo OS, 38.5%Median OS (95% CI): Atezolizumab 7.1 months (6.05–10.05); 12-mo OS, 27.2%HR vs rego (95% CI): Atezolizumab + cobimetinib 1.00 (0.73, 1.38) and atezolizumab 1.19 (0.83, 1.71)P value: Atezolizumab + cobimetinib = .99; atezolizumab = .34* and regorafenib = NA


Median PFS (95% CI): Regorafenib 1.9 months (1.6–3.9)Placebo 1.7 months (1.4–1.9)HR = 0.49, 95% CI: 0.42–0.58; P <.0001

CORRECT1: 51% reduction in the risk of progression or death

(secondary endpoint)

CONCUR2: 69% reduction in the risk of progression or death

(secondary endpoint)

Prog

ress

ion-

Free

Sur

viva

l (%

)


Placebo

2

23851

4

989

6

422

8

122

10

30

12

Regorafenib 160 mgPlacebo100

75

50

25

00

Months After Randomization

Prog

ress

ion-

Free

Sur

viva

l (%

)

2

746

4

462

6

271

8

141

10

100

12

90

Regorafenib PlaceboCensored patients

100

75

50

25

00

13668

18

..

..


Placebo

14

50

16

10

Months After Randomization

Median PFS (95% CI): Regorafenib 3.2 months (2.0–3.7))Placebo 1.7 months (1.6–1.8)HR = 0.31, 95% CI: 0.22–0.44; P <.0001

CI, confidence interval; HR, hazard ratio; mCRC, metastatic colorectal cancer; PFS, progression-free survival.1. Grothey A, et al. Lancet 2013;381:303–312; 2. Li J, et al. Lancet Oncol 2015;16:619–629.

Regorafenib significantly improves PFS in 3L mCRC patients with good performance status: at first scan, patients may have an opportunity for PFS of up to a year

1.9 months median PFS with regorafenib

3.2 months median PFS with regorafenib

Presenter

Presentation Notes

CI, confidence interval; HR, hazard ratio; PFS, progression-free survival; RCT, randomized controlled trial.Eng C, et al. Lancet Oncol 2019;20:849–861.

The significant effect of regorafenib on PFS was confirmed in the IMblaze 370 phase 3 RCT

Median PFS (95% CI): Regorafenib 2.0 months (1.87–3.61);Median PFS (95% CI): Atezolizumab + cobimetinib 1.9 months (1.87–1.97);Median PFS (95% CI): Atezolizumab 1.9 months (1.91–2.10);HR vs rego (95% CI): Atezolizumab + cobimetinib 1.25 (0.94–1.65) and atezolizumab 1.39 (1.00–1.94)

2.0 months PFS with regorafenib

*19% (98/505) represents the percentage of patients with long-term PFS >4 months, regardless of censoring or deaths in CORRECT; †Long-term PFS in CONSIGN by investigator assessment. Intervals for radiologic assessments were not predetermined as they were in CORRECT and CONCUR; ‡IMblaze370 data were calculated based on patients alive at 6 and 9 months over the number of patients at start of regorafenib therapy.CI, confidence interval; HR, hazard ratio; PFS, progression-free survival.1. Grothey A, Van Cutsem E, et al. Lancet 2013;381:303–312; 2. Van Cutsem E, et al. Oncologist 2019;24:185–192; 3. Bendell J, et al. WCGI 2018:Abstract LBA-004; 4. Eng C, et al. Lancet Oncol 2019;20:849–861.

Regorafenib consistently demonstrates long-term PFS in a subset of treated patients1–3

14% PFS rate at 6 months


IMblaze3703,4‡CONSIGN2†

23%

15%

8%

PFS rate at 6 months



CORRECT1*


CI, confidence interval; mo, month; NE, not estimable; OS, overall survival; PFS, progression-free survival.1. Grothey A, et al. Ann Oncol 2016;27(Suppl 6):Abstract 516P3; 2. Kim TW, et al. WCGI 2017:Abstract P-295; 3. Garcia-Carbonero R, et al. Ann Oncol 2016;27(Suppl 6):Abstract 506P.

CORRECT: A subset of patients with extended PFS trend toward improved OS when treated with regorafenib in 3L mCRC

CORRECT1 CONCUR2 CONSIGN3

Long PFS (n=98)

Short PFS (n=407)

Long PFS(n=46)

Short PFS(n=90)

Long PFS (n=674)

Short PFS (n=2198)

Median PFS, mo 6.7 1.8 - - 6.2 2.0

6-mo PFS, % 54 - - - 54 -

9-mo PFS, % 21 - - - 27 -

12-mo PFS, % - - - - 14 -

Median OS, mo 11.8 5.1 16.4 5.8 - -

6-mo OS, % 93 42 100 48 - -

9-mo OS, % 79 26 85 29 - -

12-mo OS, % 43 17 63 23 - -

CORRECT: OS by PFS subgroup1

100

75

50

25

00 50 100 150 200 250 300 350 400 450

Time after randomization (days)

OS

(%)

PFS and OS in patients with long PFS (>4 months) vs short PFS (≤4 months)

MEDIAN OS (months)━ Long PFS (>4 months): 11.8

95% CI: 11.5–NE━ Short PFS (≤4 months): 5.1

95% CI: 4.6–5.7⃝ Censored

CI, confidence interval; HR, hazard ratio; mCRC, metastatic colorectal cancer; PFS, progression-free survival.Ricotta R, et al. ESMO Open 2017;1:e000111.

RadioCORRECT: 3L mCRC patients on regorafenib and radiologic lung cavitations at 8 weeks showed longer PFS

Months after randomization

Prog

ress

ion-

free

sur

viva

l (%

)

100

75

50

25

0

0 1 2 3 4 5 6

HR = 0.58 (95% CI: 0.36–0.93); P = .02No Week 8 cavitation (median PFS: 1.9 months [95% CI: 1.8–3.4]) Week 8 cavitation (median PFS: 3.5 months [95% CI: 2.8–5.7])

Number at riskNo

Yes5236

5035

2325

2023

1115

1113

611

Patients in RadioCORRECT with lung metastases, N = 88

RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease.Images courtesy of Dr. Salvatore Siena and Dr. Axel Grothey.

Cavitation of lung metastasis after treatmentwith regorafenib

DCR = CR + PR + SD (per RECIST v1.1).BSC, best supportive care; CR, complete response; DCR, disease control rate; PR, partial response; RCT, randomized controlled trial; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease. 1. Grothey A, et al. Lancet 2013;381:303–312; 2. Li J, et al. Lancet Oncol 2015;16:619–29; 3. Eng C, et al. Lancet Oncol 2019;20:849–861.

Regorafenib significantly improved DCR in threephase 3 RCTs

41%

15%

Regorafenib +BSC

Placebo + BSC

DCR of regorafenib vs placebo in CORRECT1

51%

7%

Regorafenib +BSC

Placebo + BSC

DCR of regorafenib vs placebo in CONCUR2

34%26%

21%

Regorafenib Atezolizumab +Cobimetinib

Atezolizumb

DCR with regorafenib in IMblaze3703

*Regorafenib vs placebo for CORRECT and CONCUR; vs. atezolizumab and atezolizumab plus cobimetinib for IMblaze370. **Relative to other studies with RWE, the REBECCA and REOCRA studies had a higher proportion of ECOG PS 2 patients, at 11% and 19%, respectively. †N = 463 is the ITT population: response data based on 276 patients; data missing for 186 patients (40.2%); ‡n=54 for dose escalation arm; OS of 9.8 months observed in dose escalation arm, vs 6.0 in the standard dose arm (n=62); p=0.12. ¶Regorafenib vs placebo for randomized placebo-controlled trials. PMS, post-marketing study.1. Grothey A, et al. Lancet 2013;381:303–312; 2. Li J, et al. Lancet Oncol 2015;16:619-629; 3. Eng C, et al. Lancet Oncol 2019;20:849–861; 4. Schulz H, et al. J Clin Oncol 2018;36(4 suppl):748; 5. Adenis A, et al. BMC Cancer 2016;16:412; 6. Yamaguchi K et al. Oncologist 2019; Jan 3: doi: 10.1634/theoncologist.2018-0377; 7. Ducreux M, et al. WCGI 2018. Abstract O-012; 8. Kopeckova K, et al. ESMO 2018. Abstract 468P; 9. Bekaii-Saab T, et al. Lancet Oncol 2019 [epub ahead of print] DOI:https://doi.org/10.1016/S1470-2045(19)30272-4.

Regorafenib has established efficacy in 3L mCRC, supported by a large body of RCT and real-world evidence

4

5

6

7

8

9

10

11

OS

(mon

ths)

Phase 3 RCT evidence Real-world evidence

CORRECT*n=5001

6.42013

CORECTN=5558

9.32018

ReDOSN=1169‡

9.82018

RECORA**†

N=4634

5.92013

CONCUR*n=1362

8.82015

IMblaze370*n=903

8.52018

REBECCA*N=6545

5.62016

Japanese PMSN=12276

6.92017

CORRELATEN=10377

7.62018

Medium OS of 5.6 to 9.8 months for regorafenib-treated mCRC patients globally

1. Bevacizumab + FOLFOX2. Cetuximab + FOLFIRI3. Regorafenib4. Aflibercept + FOLFIRI5. Trifluridine/tipiracil

Polling question: Which of the below are chemotherapy-free regimens in mCRC?

FOLFIRI, folinic acid, fluorouracil and irinotecan; FOLFOX, folinic acid, fluorouracil and oxaliplatin; mCRC, metastatic colorectal cancer.

4%

2%

87%

0%

7%

FOLFIRI, folinic acid, fluorouracil and irinotecan; FOLFOX, folinic acid, fluorouracil and oxaliplatin; mCRC, metastatic colorectal cancer.

Polling question: Which of the below are chemotherapy-free regimens in mCRC?

1. Bevacizumab + FOLFOX

2. Cetuximab + FOLFIRI

3. Regorafenib

4. Aflibercept + FOLFIRI

5. Trifluridine/tipiracil

What have we learned from these studies about how to improve outcomes for patients in 3L mCRC?

MOA matters

Patient selection matters

Duration of therapy matters

AE management experience matters

• Inhibits CSF-1R, a receptor involved in macrophage recruitment and differentiation into tumor-associated macrophages6,7,25

• Reduces macrophage infiltration in preclinical CRC models26,27

• Inhibits several tyrosine kinase receptors (e.g. VEGFR1, VEGFR2, VEGFR3, PDGFRβ, FGFR1, and TIE-2) involved in angiogenesis, lymphatic vessel formation, and vessel stabilization within the tumor microenvironment24,25

• Blocks autophosphorylation of VEGFR2 in human umbilical vein endothelial cells and VEGFR3 in human lymphatic endothelial cells in vitro23,25

• Decreases tumor vascularization in various preclinical tumor models23,24,26,28–31

• Suppresses the proliferation of CRC cells in vitro23

• Potently inhibits growth of patient-derived CRC tumorxenografts23,32

• Inhibits VEGFR2 and VEGFR3 involved in endothelial cell growth and migration23,25

• Blocks PDGFR, which is involved in cancer-associated, fibroblast-induced metastasis of CRC24,29

• Inhibits metastasis in various colon cancer models26,29

References 1. Al-Sohaily S, et al. J Gastroenterol Hep. 2012;27:1423–1431. 2. Markowitz SD & Bertagnolli MM. N Engl J Med. 2009;361:2449–2460. 3. Müller MF, et al. VirchowsArch. 2016;469:125–134. 4. Kim H, et al. Oncology Lett. 2017;14:553–560. 5. Zhang J-H, et al. Asian Pac J Cancer Prev. 2014;15:8651–8656. 6. Huang L, et al. Rom J Morphol Embryol. 2014;55(2 Suppl):501–506. 7. Cannarile MA, et al. J ImmunoTherapy Cancer. 2017;5:53. 8. Lee YC, et al. Expert Opin Investig Drugs. 2015;24:1307–1320. 9. Schimanski CC, et al. Int J Colorectal Dis. 2010;25:181–186. 10. Takahashi M. Cytokine Growth Factor Rev. 2001;12:361–373. 11. Graham DM, et al. Curr Colorectal Cancer Rep. 2016;12:141–150. 12. Zhao Y & Adjei A. Oncologist. 2015;20:660–673. 13. Jang JH. Oncogene. 2005;24:945–948. 14. Le Rolle A-F, et al. Oncotarget. 2015;6: 28929–28937. 15. Samuels Y, et al. Science. 2004;304:554. 16. Moriarity A, et al. Ther Adv Med Oncol. 2016;8:276–293. 17. Hu W, et al. Clin Transl Oncol. 2016;18:251–258. 18. Sun W. J Hepatol Oncol. 2012;5:63. 19. Balan BJ, et al. Centr Eur J Immunol. 2009;34:254–260. 20. Martins SF, et al. Cancer Genomics Proteomics. 2013;10:55–68. 21. Beauchemin N. Cancer Microenvironment. 2011;4:181–185. 22. Tacconi C, et al. Gastroenterology. 2015;148:1438–1451. 23. Schmieder R, et al. Int J Cancer. 2014;135:1487–1496. 24. Wilhelm SM, et al. Int J Cancer. 2011;129:245–255. 25. Zopf D, et al. Cancer Med. 2016;5:3176–3185. 26. Abou-Elkacem L, et al. Mol Cancer Ther.2013;12:1322–1331. 27. Hoff S, et al. Ann Oncol. 2017;28(suppl_5):v403‒v427. 28. Daudigeos-Dubus E, et al. PLoS One. 2015;10:e0142612. 29. Takigawa H, et al. Cancer Sci. 2016;107:607‒608. 30. Jost G, et al. Invest Radiol. 2013;48:715–721. 31. Cyran CC, et al. PLoS One. 2013;8:e76009. 32. Schütte M, et al. Nat Commun. 2017;8:14262.

Type of abnormality1–3

Increased expression

Activating mutation

Deactivating mutation

Decreased expression

Tumor angiogenesisTumor immunity Oncogenesis Metastasis

MOA matters: Regorafenib’s broad multikinase inhibition may provide putative mechanisms for its robust antitumor efficacy in CRC

mCRC, metastatic colorectal cancer. 1. Wilhelm SM, et al. Int J Cancer 2011;129:245–255; 2. Zopf D, et al. Cancer Med 2016;5:3176–3185; 3. Abou-Elkacem L, et al. Mol Cancer Ther 2013;12:1322–1331; 4. Matsushime H, et al. Cell 1991;65:701–713; 5. Schmieder R, et al. Int J Cancer 2014;135:1487–1496; 6. Takigawa H, et al. Cancer Sci 2016;107:601–608.

Regorafenib offers chemotherapy-free treatment in a single agent, targeting mCRC tumors in four ways

Disrupts tumor immunity by inhibiting CSF-1R, a receptor

important for macrophage proliferation2–4

Inhibits key angiogenic receptors VEGFR1–3, TIE-2, PDGFR-α/β,

and FGFR1 and 2 via kinase inhibition1–3

Potently blocks multiple protein kinases, including KIT, RAF, and

RET, which are important in oncogenesis1,2

Inhibits VEGFR2 and 3, which are important mediators in endothelial cell proliferation

and migration. Blocks PDGFR, believed to play a role in cancer-associated fibroblast-

induced metastasis1,5,6

Presenter

Presentation Notes

Abbreviations: CSF-1R, colony-stimulating factor 1 receptor; FGFR, fibroblast growth factor receptor; PDGFR, platelet-derived growth factor receptor; VEGFR, vascular endothelial growth factor receptor.

BSC, best supportive care; DCR, disease control rate; ECOG PS, Eastern Cooperative Oncology Group performance status; OS, overall survival; RCT, randomized controlled trial; MT, mutant; WT, wild-type.1. Grothey A, et al. Lancet 2013;381:303–312; 2. Li G, et al. Lancet Oncol 2015;16:619–29; 3. Røed Skårderud M, et al. Cancer Treat Rev 2018;62:61–73.

Patient selection matters: Regorafenib appears to provide greater benefit in less-heavily pre-treated patients1–3

0 5 10

Median OS (months)DCR

CORRECT1,3

Phase 3 RCTPatients (N=760)

Regorafenib + BSC (n=505)

Placebo + BSC (n=255)

6.4

5.0

41.0%

15.0%

• ECOG PS 0 or 1

• 52% of regorafenib patientshad ≤3 prior therapies

• 53% of placebo patients

CONCUR2,3

Phase 3 RCTPatients (N=204)

Regorafenib + BSC (n=136)

Placebo + BSC (n=68)

8.8

6.3

51.0%

7.0%

• ECOG PS 0 or 1


• 60% of placebo patients

Note: cross-trial comparisons cannot be performed

• This study was designed to evaluate the primary endpoint of OS in 3 study arms: atezolizumab + cobimetinib, atezolizumab monotherapy, and regorafenib

• Regorafenib was the comparator arm• The combination regimen of atezolizumab + cobimetinib failed to meet its primary endpoint of superior OS relative to

regorafenib. The OS difference between the combination arm and the regorafenib arm was not statistically significant (p=0.9871)1

*After ~5% cap for MSI-H patients, only MSS patients; once 50% cap for RAS WT, only RAS MT. †Number of previous systemic therapies (on or after diagnosis of metastatic disease.BSC, best supportive care; DCR, disease control rate; ECOG PS, Eastern Cooperative Oncology Group performance status; OS, overall survival; RCT, randomized controlled trial; MT, mutant; WT, wild-type.1. Eng C, et al. Lancet Oncol 2019;20:849–861.

Patient selection matters: Regorafenib appears to provide greater benefit in less-heavily pre-treated patients1

0 5 10

Median OS (months)DCR

IMblaze3701*Phase 3 RCTPatients (N=363)

Atezolizumab + cobimetinib (n=183)

Regorafenib (n=90)

Atezolizumab (n=90)

8.9

8.5

7.1

26.2%

34.4%

21.1%

• ECOG PS 0 or 1


• 71% of atezolizumab patients• 73% of cobimetinib patients

CI, confidence interval; OR, objective response; OS, overall survival; PD, progressive disease; SD, stable disease. 1. Grothey A, Van Cutsem E, et al. Lancet 2013;381:303–312 [Supplementary Material]; 2. Kidd MT, et al. ASCO GI 2015. Abstract 678.

Subsequent therapies may be used after regorafenib in the treatment sequence1,2

Systemic anticancer treatment during CORRECT trial follow up

Regorafenib,n (%)

(n=505)

Placebo,n (%)

(n=255)

Patients with ≥1 medication 131 (26) 76 (30)

Any antineoplastic or immunomodulating agent 130 (26) 74 (29)

Examples include:

Pyrimidine analogs 94 (19) 52 (20)

Monoclonal antibodies 39 (8) 22 (9)

Platinum compounds 35 (7) 14 (6)

Best response n (%)

PD 11 (33)

Not evaluable 2 (6)

OR or SD 20 (61)

Reintroduction of treatment previously discontinued without definitive PD 8 (24)

Rechallenge with treatment previously discontinued due to PD 4 (12)

New treatment with no prior exposure 8 (24)

Median OSpost-regorafenibdiscontinuation

Probability of OS

6 months 12 months

6.5 months (95% CI: 4.9–9.4) 52% 27%

26% of patients in CORRECT received cytotoxic chemotherapy after regorafenib1

Mayo, MDA, and USC experience demonstrates efficacy of chemotherapy after regorafenib2

mCRC, metastatic colorectal cancer; RWE, real-world evidence.1. Mayer RJ, et al. N Engl J Med 2015;372:1909–1919; 2. Falcone A, et al. WCGI 2018:Presentation O-013.

Subsequent therapies may be used after regorafenib in the mCRCsequence: RECOURSE and PRECONNECT demonstrate efficacy of chemotherapy after regorafenib1,2

Tipiracil/trifluridineRECOURSEPhase 3 study

17.0%91/534 patients received tipiracil/trifluridine AFTER

regorafenib

35.7%164/462 patients received tipiracil/trifluridine AFTER

regorafenib

Tipiracil/trifluridinePRECONNECT

RWE study

†Not reported as drug-related AEsAE, adverse event; ALT, alanine transaminase; AST, aspartate transaminase; HFSR, hand–foot skin reaction; mCRC, metastatic colorectal cancer; NR, not reported.1. Grothey A, Van Cutsem E, et al. Lancet 2013;381:303–312; 2. Li J, et al. Lancet Oncol 2015;16:619–629; 3. Eng C, et al. Lancet Oncol 2019;20:849–861; 4. Røed Skårderud M, et al. Cancer Treat Rev 2018;62:61–73.

AE management experience matters: Phase 3 RCT evidence supports an improvement in regorafenib tolerability over time1–4

Most common drug-related AEs, %

Randomized controlled phase 3 trialsCORRECT1,4 CONCUR2,4

Regorafenib (n=500)

Regorafenib (n=136)

All grades Grade 3/4 All grades Grade 3/4HFSR 47 17 73 16

Fatigue 47 9 17 3

Hypertension 28 7 23 11Diarrhea 34 7 18 1Rash/desquamation/skin toxicity 26 6 - -Anorexia 30 3 8 1Mucositis, oral 27 3 - -Hyperbilirubinemia 9 2 36 6ALT increased 5† 2† 24 7AST increased 7† 2† 24 6Thrombocytopenia 13 3 10 3Fever 10 1 NR NRNausea 14 <1 NR NRVoice changes 29 <1 - -Weight loss 14 0 NR NR

Most common drug-related AEs, %IMblaze3703

Regorafenib (comparator arm) (n=80)All grades Grade 3/4

HFSR 53 11

Fatigue 46 9

Hypertension 31 13Diarrhea 38 6Rash/desquamation/skin toxicity 24 3Anorexia - -Mucositis, oral - -Hyperbilirubinemia 4 2ALT increased 1 -AST increased - -Thrombocytopenia - -Fever 25 -Nausea 14 -Voice changes - -Weight loss 21 -This study was designed to evaluate the primary endpoint of OS in 3 study arms: atezolizumab + cobimetinib, atezolizumabmonotherapy, and regorafenib. Regorafenib was the comparator arm. The combination regimen of atezolizumab + cobimetinibfailed to meet its primary endpoint of superior OS relative to regorafenib. The OS difference between the combination arm and the regorafenib arm was not statistically significant (p=0.9871)1


*In CONSIGN, hyperbilirubinemia, AST, ALT, and thrombocytopenia were reported as treatment-emergent laboratory toxicities; ‡Reported as “liver dysfunction”.AE, adverse event; ALT, alanine transaminase; AST, aspartate transaminase; HFSR, hand–foot skin reaction; mCRC, metastatic colorectal cancer; NR, not reported. 1. Adenis A, et al. BMC Cancer 2016;16:412; 2. Van Cutsem E, et al. Oncologist 2019;24:185–192; 3. Yamaguchi K, et al. Oncologist 2019;doi: 10.1634/theoncologist.2018-0377 (Epub ahead of print); 4. Ducreux M, et al. WCGI 2018. Abstract O-012; 5. Kopeckova K, et al. Target Oncol 2017;12:89–95.

AE management experience matters: Real-world evidence supports an improvement in regorafenib tolerability over time1–5

Most common drug-related AEs, %

Open-label real-world studiesREBECCA1 CONSIGN2 Japanese PM3 CORRELATE4 CORECT5

Regorafenib (N=654)

Regorafenib (N=2864)

Regorafenib (N=1227)

Regorafenib(N=1037)

Regorafenib(N=555)

All grades Grade 3/4 All grades Grade 3/4 All grades Grade 3/4 All grades Grade ≥3 All grades Grade ≥3HFSR 29 9 42 14 58 19 26 7 - -

Fatigue 41 15 46 13 15 2 41 9 2.0 -

Hypertension 11 5 30 15 29 16 14 6 - 0.7Diarrhea 19 4 25 5 - - 19 3 - 0.7Rash/desquamation/skin toxicity 4 1 10 3 - - - - - 0.7Anorexia 15 3 24 2 - - 13 2 - 0.7Mucositis, oral 11 1 25 2 - - 15 2 - -Hyperbilirubinemia 1 0 15* 4* - - - - - -ALT increased - - - -

31‡ 11‡- - - -

AST increased - - 7* 2* - - - -Thrombocytopenia 3 <1 15 5 - - - -Fever - - 7 <1 12 1 3 <1 - -Nausea - - 11 1 - - - - - -Voice changes - - 12 <1 10 0 - - - -Weight loss 5 <1 13 1 - - - - - -


• The incidence and severity of HFSR, hypertension, liver abnormalities, fatigue, diarrhea, and oral mucositis did not increase over time1

AE, adverse event; HFSR, hand–foot skin reaction.1. Grothey A, et al. Oncologist 2014;19:669–680; 2. Grothey A, et al. ASCO 2013. Abstract 3637.

Regorafenib AEs frequently occur early in treatment and are noncumulative1,2

Median time to first occurrence and worst grade of select common AEs in regorafenib-treated patients2

15.0

15.0

31.5

22.0

20.0

15.0

14.0

23.5

15.0

15.0

0 5 10 15 20 25 30 35

Rash

Hypertension

Diarrhea

HFSR

Fatigue

First occurrenceWorst grade

Median days (regorafenib arm)

End of cycle 1

AE, adverse event.1. Grothey A, Van Cutsem E, et al. Lancet 2013;381:303–312; 2. Grothey A, et al. ASCO 2013. Abstract 467; 3. Grothey A, et al. ASCO 2013. Abstract 3637; 4. Li J, et al. Lancet Oncol 2015;16:619–629.

AE management experience matters: Regorafenib AEs can be managed with dose modifications, with a low rate of treatment discontinuation due to AEs1–4

Patients with an AE, %

CORRECT1 CONCUR4

Regorafenib (n=500)

Placebo (n=253)

Regorafenib (n=136)

Placebo (n=68)

Leading to dose modification 67 23 71 16

Leading to dose reduction 38 3 40 0

Leading to dose interruption 61 22 63 16

Leading to treatment discontinuation 17 12 14 6

HFSR, hand foot skin reaction.1. Bekaii-Saab T, et al. Lancet Oncol 2019 [epub ahead of print] DOI:https://doi.org/10.1016/S1470-2045(19)30272-4; 2. NCT02835924; 3. Kudo T, et al. ASCO GI 2018. Abstract 821.

Can tolerability with regorafenib be improved with flexible first cycle dose-optimization strategies?

ReDOS1

(PI: A. Grothey/T. Bekaii-Saab;an ACCRU Network study)

REGOCC3

(PI: T. Kudo)

3× phase 2 first cycledose-optimized

REARRANGE2

(PI: G. Argiles/J. Tabernero)

Dose escalation and preemptive clobetasol

(HFSR)

Dose escalation and alternative dose

interval

Dose escalation and dose de-escalation

1. Start at 160 mg and reduce the dose as needed2. Start at 120 mg with intention to escalate to 160 mg3. Start at 80 mg with intention to escalate to 160 mg4. Start at 120 mg and reduce the dose as needed5. Other

mCRC, metastatic colorectal cancer.

Polling question: What is your current approach to regorafenib dosing in patients with mCRC?

20%

15%

57%

5%

3%


Polling question: What is your current approach to regorafenib dosing in patients with mCRC?

1. Start at 160 mg and reduce the dose as needed

2. Start at 120 mg with intention to escalate to 160 mg



5. Other

mCRC, metastatic colorectal cancer; w, week1. Bekaii-Saab T, et al. Lancet Oncol 2019 [epub ahead of print] DOI:https://doi.org/10.1016/S1470-2045(19)30272-4; 2. NCT02835924; 3. Kudo T, et al. ASCO GI 2018. Abstract 821.

Duration of therapy matters: Regorafenib flexible first cycle dosing strategies have been explored in phase 2 trials to enhance tolerability and prolong treatment duration

RE-ARRANGE2

PI: G. Argiles/J. Tabernero(NCT02835924)

Patients with previously treated mCRC (N=299)

Week Dose1 160 mg2 160 mg3 160 mg4 off

Week Dose1 160 mg2 off3 160 mg4 off



Regorafenib 160 mg 3w on/1w off from Cycle 2

ReDOS1

PI: A. Grothey/T. Bekaii-Saab(NCT02368886)2

Patients with previously treated mCRC (N=123)

REGOCC3

PI: T. Kudo(UMIN000018968)

Patients with unresectable mCRC who have progressed after standard chemotherapy (N=60)

Optional

Regorafenib 120 mg 3w on/1w off from Cycle 2

RR


Clobetasol is a steroid cream used to treat skin conditions and may help prevent HFSR in patients receiving regorafenib. HFSR, hand–foot skin reaction; mCRC, metastatic colorectal cancer; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetic; QoL, quality of life; R, randomization; TTP, time to progression.Bekaii-Saab T, et al. Lancet Oncol 2019 [epub ahead of print] DOI:https://doi.org/10.1016/S1470-2045(19)30272-4.

ReDOS: Regorafenib dose-optimization study comparing first cycle dose-optimization with standard dose in patients with refractory mCRC – A randomized phase 2 trial

Patients with

previously treated mCRC

(N = 123)

RPrimary endpoint: proportion of patients who complete 2 cycles and initiated the third cycleSecondary endpoints: PFS, OS, TTP, cumulative dose, dose intensity, grade 3/4 HFSR or fatigue, QOLOther: PK

Arm A1:Preemptive clobetasol

Arm A2:Reactive clobetasol

Arm B1:Preemptive clobetasol

Arm B2:Reactive clobetasol

1:1:1:1

Arm A: Lower starting regorafenib dose

Arm B: Standard regorafenib dose

Weeks after C1 Dose

1 160 mg

2 160 mg

3 160 mg

4 off

Weeks of C1Escalation phase Dose

1 Starting dose 80 mg

2 ↓ 120 mg

3 End dose of C1 160 mg

4 off

Weeks after C1 Dose

1 160 mg

2 160 mg

3 160 mg

4 off

The primary endpoint is a composite endpoint integrating efficacy (patients needed to have at least stable disease at the planned disease evaluation) and safety (patients need to tolerate the drug with no unacceptable toxicity issues).*One-sided P-value. PD, progressive disease. Bekaii-Saab T, et al. Lancet Oncol 2019 [epub ahead of print] DOI:https://doi.org/10.1016/S1470-2045(19)30272-4.

ReDOS: 43% of patients on the first cycle dose-optimization arm started Cycle 3 of therapy, vs 26% of patients on standard dose

0

5

10

15

20

25

30

35

40

45

50

43

26

Perc

enta

ge o

f pat

ient

s

Escalating dose Standard dose

P = 0.043*

37% PD

47% PD

CI, confidence interval; HR, hazard ratio; OS, overall survival.Bekaii-Saab T, et al. Lancet Oncol 2019 [epub ahead of print] DOI:https://doi.org/10.1016/S1470-2045(19)30272-4.

ReDOS OS confirms survival seen in other trialswith regorafenib

Events/totalMedian

(95% CI), months

HR (95% CI)

━ Escalating dose 40/54 9.8 (7.5–11.9) 0.72 (0.47–1.10)

━ Standard dose 46/62 6.0 (4.9–10.2) Reference

Log-rank P=0.12 + Censor

OS

CI, confidence interval; HR, hazard ratio; PFS, progression-free survival.Bekaii-Saab T, et al. Lancet Oncol 2019 [epub ahead of print] DOI:https://doi.org/10.1016/S1470-2045(19)30272-4.

ReDOS PFS confirms results shown in other trialswith regorafenib

Events/totalMedian

(95% CI), months

HR (95% CI)

━ Escalating dose 48/54 2.8 (2.0–5.0) 0.84 (0.57–1.24)

━ Standard dose 58/62 2.0 (1.8–2.8) Reference

Log-rank P=0.12 + Censor

PFS

AE, adverse event; HFSR, hand–foot skin reaction.Bekaii-Saab T, et al. Lancet Oncol 2019 [epub ahead of print] DOI:https://doi.org/10.1016/S1470-2045(19)30272-4.

ReDOS: AEs occurring in ≥4% of patients

n (%)Escalating dose (n=54) Standard dose (n=62)

Grade 3 Grade 4 Grade 3 Grade 4Fatigue 7 (13.0) 0 11 (18) 0HFSR 8 (15) 0 10 (16) 0Abdominal pain 9 (17) 0 4 (6) 0Hypertension 4 (7) 0 9 (15) 0Hyponatremia 2 (4) 1 (2) 4 (6) 1 (2)Bilirubin increased 2 (4) 0 5 (8) 0Alkaline phosphatase increased 3 (6) 0 1 (2) 1 (2)Aspartate aminotransferase increased 1 (2) 0 4 (6) 0Dehydration 0 0 5 (8) 0Dyspnea 1 (2) 1 (2) 4 (6) 0Lymphocyte count decreased 4 (7) 0 0 0Maculopapular rash 0 0 3 (5) 0Colonic obstruction 3 (6) 0 0 0

AE, adverse event; HFSR, hand–foot skin reaction.Jatoi F, et al. ASCO 2019. Abstract 11586.

ReDOS: Pre-emptive clobetasol increased the number of patients without HFSR development (a priori secondary analysis)

Pre-emptiveclobetasol(n=61/116)

Reactiveclobetasol(n=55/116)

P-value

Cycle 1: HFSR incidence, % 46 52 0.52

Cycle 2: HFSR incidence, % 56 80 0.02

Cycles 1 and 2: Patients without HFSR, % 33 15 0.02

Pre-emptiveclobetasol(n=61/116)

Reactiveclobetasol(n=55/116)

P-value

Cycle 2: Grade 1 AEs, % 40 45 0.07

Cycle 2: Grade 1 AEs, % 11 25 0.07

Cycle 2: Grade 1 AEs, % 4 10 0.07

HFSR incidence

AE incidence

AE, adverse event; QoL, quality of life.Bekaii-Saab T, et al. Lancet Oncol 2019 [epub ahead of print] DOI:https://doi.org/10.1016/S1470-2045(19)30272-4.

ReDOS: A slight improvement in QOL was observed with first cycle dose-optimization compared to the standard dosing

• No deterioration in QoL in the dose-optimization arm

• A decrease in QoL at the time point one would expect maximal grade AEs(at Week 2)

Regorafenib standard dosing schedule1‡ NCCN guidelines2 ReDOS3* dose escalation schedule†

Percentage patients starting treatment at cycle 33*

(primary endpoint)P =.04343%

26%

Escalatingdose

Standarddose

37% PD47% PD

Median OS (months)3

Escalating dose

Standard dose

9.8

6.0 (secondary endpoint P=.0943)

0 5 10

ReDOS dose-optimization study3* results

38

HR (95% CI):0.72 (0.47–1.10)P=.012

*The study supporting the dose-escalation schedule has not been reviewed by the FDA. The study was a randomized, phase 2, US-based trial, through the ACCRU (Academic and Community Cancer Research United) research network, that looked at the proportion of patients who completed 2 cycles of regorafenib and initiated a third cycle (N=116). The efficacy of the alternative dosing schedule cannot be compared to the efficacy of other trials; †The escalating dose regimen was 80 mg orally, once daily on Days 1 through 7; 120 mg orally, once daily on Days 8 through 14; 160 mg orally, once daily on Days 15 through 21; followed by 7 days off therapy. Cycle 2 started at the last level dosed during Cycle 1; ‡The standard dosing regimen was regorafenib 160 mg orally, once daily, for 21 days followed by 7 days off therapy.CI, confidence interval; HR, hazard ratio; OS, overall survival; PD, progressive disease; NCCN, National Comprehensive Cancer Network.1. Stivarga [prescribing information]. Whippany, NJ, USA: Bayer Pharma; 2017; 2. NCCN Guidelines: Colon Cancer v2.2019; 3. Bekaii-Saab T, et al. Lancet Oncol 2019 [epub ahead of print] DOI:https://doi.org/10.1016/S1470-2045(19)30272-4.

Duration of therapy matters: The NCCN guidelines now recommend the ReDOS first cycle dose-optimization strategy as a dosing option2,3

This dosing regimen is not recommended in the Stivarga Summary of Product Characteristics.

3L, third-line; AE, adverse event; DCR, disease control rate; mCRC, metastatic colorectal cancer; OS, overall survival; PD, progressive disease; PFS, progression-free survival; R, randomization; TTF, time to treatment failure.ClinicalTrials.gov ID: NCT02835924. Argiles G et al. WCGI 2019

RE-ARRANGE: Comparison of different regorafenib first cycle dose optimizations in 3L mCRC – A randomized phase 2 trial

R

Primary endpoint:Percentage of patients with grade 3/4 treatment-related AEs in each arm(time frame: 30 months)

Secondary endpoints:Percentage of total administrated dose over the planned dose, dose intensity during the whole treatment, dose intensity during the first2 cycles, DCR, PFS, TTF, OS

1:1:1

ON ON ON OFF ON ON ON OFF

ON ON ON OFF ON ON ON OFF

ON OFF ON OFF ON ON ON OFF

Arm A: Control arm (labelled regimen)160 mg/day 3w on/1w off

Arm B: Experimental arm 1120 mg/day 3w on/1w off in cycle 1160 mg/day 3w on/1w off in cycle 2

Arm C: Experimental arm 2160 mg/day 1w on/1w off in cycle 1160 mg/day 3w on/1w off in cycle 2

PD

Patients with mCRC PD or intolerant to

standard treatments (N=299)

“Results of REARRANGE trial: A randomized phase 2 study comparing different dosing approaches for regorafenib (REG) during the first cycle of

treatment in patients (pts) with metastatic colorectal cancer (mCRC)”Argiles G, et al.

• Saturday 6 July• 10:25• Auditorium A

WCGI 2019 abstract presentation

• Most dose escalations occurred during the first 8 weeks of treatment– 39/47 in the 120 mg start group– 56/61 in the 80 mg start group

AE, adverse event; OS, overall survivalDucreux M et al. WCGI 2019. Abstract PD-029.

First cycle dosing strategies toward improving regorafenibtolerability in real-world practice: Observations from CORRELATE

n (%)

N=1037

160 mg 120 mg 80 mg

Patients who started at this initial daily dose 591 (57) 315 (30) 127 (12)

Patients who had any dose escalation NA 47/315 (19) 61/127 (48)

Patients who dose escalated directly to 160 mg NA 47/47 (100) 4/61 (7)

Patients who dose escalated to 120 mg NA NA 45/61 (74)

Patients who dose escalated to 120 mg and then to 160 mg NA NA 12/61 (20)

Dose escalations in CORRELATE

• Regorafenib first cycle dose-optimization strategies – Improve tolerability and may prolong treatment duration in 3L mCRC– Offer clinicians options that can be tailored to specific patient conditions

• ReDOS• RE-ARRANGE

– Have been adopted by treatment guidelines• NCCN guidelines now recommend ReDOS as a first cycle dose-optimization strategy

3L, third-line; mCRC, metastatic colorectal cancer; NCCN, National Comprehensive Cancer Network.

Regorafenib first cycle dose-optimization strategies offer options to improve tolerability and duration of therapy

1. Start at 160 mg and reduce the dose as needed2. Start at 120 mg with intention to escalate to 160 mg3. Start at 80 mg with intention to escalate to 160 mg4. Start at 120 mg and reduce the dose as needed5. Other


Polling question: Which regorafenib dosing approach do you plan to use going forward in patients with mCRC?

11%

5%

80%

2%

2%


Polling question: Which regorafenib dosing approach do you plan to use going forward in patients with mCRC?





5. Other

• Regorafenib is a proven standard of care in 3L mCRC, supported by a large body of evidence in >7400 patients

• The mechanism of action of regorafenib offers a break from chemotherapy for patients on chemotherapy-based regimens

• Regorafenib appears to provide greater benefit in good performance status, less heavily pre-treated patients, and allows for subsequent treatment with chemotherapy-based regimens

• Regorafenib first cycle dose-optimization strategies:– Improve tolerability and may prolong treatment duration in 3L mCRC– Offer clinicians options that can address specific patient conditions– NCCN guidelines now recommend ReDOS as a first cycle dose-optimization strategy

3L, third-line; AE, adverse event; mCRC, metastatic colorectal cancer; NCCN, National Comprehensive Cancer Network.

Summary

building on evidence to optimize treatment outcomes with ... 2019 satell… · building on evidence...

Documents