GD Demetri
This presentation is the property of its rightful owner.
Sponsored Links
1 / 19

Wilhelm SM et al. Int J Cancer 2011; 129 : 245-255. PowerPoint PPT Presentation


  • 36 Views
  • Uploaded on
  • Presentation posted in: General

Download Presentation

Wilhelm SM et al. Int J Cancer 2011; 129 : 245-255.

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript


Wilhelm sm et al int j cancer 2011 129 245 255

GD Demetri, P Reichardt, Y-K Kang, J-Y Blay, H Joensuu, RG Maki,P Rutkowski, P Hohenberger, H Gelderblom, MG Leahy, M von Mehren,P Schöffski, ME Blackstein, A Le Cesne, G Badalamenti, J-M Xu, T Nishida,D Laurent, I Kuss, and PG Casali, on behalf of GRID Investigators

Ludwig Center at Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA;HELIOS Klinikum,BadSaarow, Germany; Asan Medical Center, Seoul, South Korea; Centre Léon Bérard, Lyon, France; Helsinki University Central Hospital, Helsinki, Finland;Mount Sinai School of Medicine,New York, NY, USA; Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland; Mannheim University Medical Center, Mannheim, Germany; Leiden University Medical Center, Leiden, Netherlands;Christie NHS Foundation Trust, Manchester, UK; Fox Chase Cancer Center, Philadelphia,PA, USA; UniversitaireZiekenhuisGasthuisberg, Leuven, Belgium; Mount Sinai Hospital, Toronto, Canada; InstitutGustaveRoussy, Villejuif, France; University of Palermo, Italy; Affiliated Hospital of Academy Military Medical Sciences, Beijing, China; Department of Surgery, Osaka Police Hospital, Osaka, Japan;Bayer HealthCare Pharmaceuticals, Berlin, Germany; IstitutoNazionaledeiTumori, Milan, Italy

Randomized Phase III Trial of Regorafenibin Patients (pts) with Metastatic and/or Unresectable Gastrointestinal Stromal Tumor (GIST)Progressing Despite Prior Treatment with at least Imatinib (IM) and Sunitinib (SU): The GRID Trial


Wilhelm sm et al int j cancer 2011 129 245 255

Background: Advances and Limitations in Current Therapeutic Options for Patients with Metastatic GIST

  • GIST is the most common subtype of sarcoma and the most common mesenchymal malignancy of the GI tract

  • Tyrosine kinase inhibitors (TKIs) are the mainstay of therapy for patients with metastatic GIST, targeting the root cause of the disease: uncontrolled signaling from KIT or PDGFRA kinases

  • Imatinib and sunitinib are currently the only two drugs approved for the treatment of advanced GIST

  • Although imatinib and sunitinib have revolutionized the management of GIST, drug resistance remains a challenge

    • TKI-refractory GIST is a life-threatening unmet medical need


Wilhelm sm et al int j cancer 2011 129 245 255

Regorafenib (BAY 73-4506) is a Structurally Distinct Oral Inhibitor of Multiple Kinases Relevant to GIST and Other Cancers

Regorafenib

Biochemical activity

Percent control

0%

0.1%

0.1-1%

1-5%

5-10%

10-35%

Wilhelm SM et al. Int J Cancer 2011; 129: 245-255.


Wilhelm sm et al int j cancer 2011 129 245 255

Clinical Experience of Regorafenib in Patients With Solid Tumors and Advanced GIST: Rationale for Phase III Trial

  • Phase I dose escalation study in unselected solid tumor patients 1

    • Established recommended phase II dose and schedule as160 mg orally once daily for 3 weeks on and 1 week off (4-week cycle)

    • Acceptable safety profile and preliminary evidence of efficacy

  • Phase II study in patients with metastatic GISTafter failure of at least imatinib and sunitinib2

    • Disease control in 79% of patients

    • Median progression-free survival: 10 months

    • Median overall survival: not reached after 8.3 monthsof follow up

Mross K et al. Clin Cancer Res 2012; 18: 2658-2667.

George S et al. J ClinOncol2012; May 21 (epub ahead of print).


G ist r egorafenib i n progressive d isease grid study design

GIST – RegorafenibIn Progressive Disease (GRID): Study Design

Regorafenib + best supportive care (BSC)

160 mg once daily 3 weeks on, 1 week off (n=133)

  • Multicenter, randomized, double-blind,placebo-controlled phase III study

    • Global trial: 17 countries across Europe,North America, and Asia-Pacific

    • Stratification: treatment line (2 vs >2 prior lines),geographical location (Asia vs “Rest of World”)

RANDOM I ZAT I ON

Metastatic/ unresectable GIST pts progressing despite at least prior imatiniband sunitinib

(n=236 screened;

n=199 randomized)

Disease progression

per independent blinded central review

2 : 1

OF F

TREATMENT

Placebo + BSC 3 weeks on, 1 week off (n=66)

Unblinding

Crossover offered for placebo arm or continued regorafenib for treatment arm

Regorafenib(unblinded)until next progression


Grid study endpoints

GRID Study: Endpoints

  • Primary Endpoint: Progression-Free Survival (PFS)

    • 90% power to detect 100% increase in PFS,hazard ratio [HR]=0.5, with 1-sided overall α=0.01

  • Secondary Endpoints:

    • Overall survival

    • Time to progression

    • Overall response rate

    • Disease control rate

    • Duration of response

  • Exploratory Endpoints:

    • Correlative science to assess impact of GIST genotype with outcomes

    • Assay circulating DNA to screen more comprehensivelyfor GIST kinase mutations (“liquid biopsy”)

    • Health-related quality of life


Grid study patient eligibility

GRID Study: Patient Eligibility


Grid study baseline patient demographics

GRID Study: Baseline Patient Demographics


Grid study prior gist therapies at entry

GRID Study: Prior GIST Therapies at Entry


Grid study results

GRID Study: Results

  • Patient accrual initiated January 2011 and completed July 2011

  • Data cut-off for final efficacy analysis: January 2012

  • Analysis of primary endpoint (PFS) demonstrated a highly statistically significant difference between regorafenib and placebo

  • Treatment was unblinded after reaching the prespecified number of events and final efficacy analysis

  • Data reviewed by steering committee and independent data and safety monitoring board


Grid study progression free survival primary endpoint per blinded central review

GRID Study: Progression-Free Survival (primary endpoint per blinded central review)

Regorafenib significantly improved PFS vs placebo (p<0.0001);primary endpoint met


Prespecified subgroup analysis pfs per central review

Prespecified Subgroup Analysis: PFS per central review


Grid study overall survival following 85 cross over of patients on placebo arm

GRID Study: Overall Survival (following 85% cross-over of patients on placebo arm)

Because of the crossover design, lack of statistical significance between regorafenib and placebo was not unexpected


Progression free survival following crossover per investigator assessment

Progression-Free Survival Following Crossover (per Investigator Assessment)

Days from first progression for open label

Days from first randomization for double blind

Substantial PFS benefit in patients initially randomized to placebo and subsequently crossed over to open-label regorafenib

PFS benefit in placebo arm after crossover to regorafenib is comparable to PFS benefit in patients initially randomized to regorafenib


Disease control and overall response rates

Disease Control and Overall Response Rates

Responses based on modified RECIST v1.1

Regorafenib improved rates of disease control vs placebo


Drug related treatment emergent adverse events in 10 of patients during double blind treatment

Drug-Related Treatment-Emergent Adverse Eventsin ≥10% of Patients During Double-Blind Treatment

Treatment-Emergent Adverse Events Leading to Permanent Discontinuation of Study Treatment

RegorafenibPlacebo

8 (6.1%)5 (7.6%)


Baseline gist genotype per site reports exploratory analysis of outcomes

Baseline GIST Genotype per Site Reports:Exploratory Analysis of Outcomes


Conclusions

Conclusions

  • Regorafenib significantly increases PFS compared with placeboin patients with metastatic or unresectable GIST progressingdespite prior therapy with at least imatinib and sunitinib

    • PFS: median 4.8 vs 0.9 months, HR 0.27, p<0.0001

  • No new or unexpected safety findings with regorafenib

    • Most common grade ≥3 adverse events related to regorafenib were hand-foot skin reaction, hypertension, and diarrhea

  • Regorafenib has the potential to fulfill an unmet need for advanced GIST patients progressing after imatinib and sunitinib

    • Potential new standard of care for this patient population


Thanks to the patients families and colleagues at all of the investigating centers

Thanks to the patients, families, and colleagues at all of the investigating centers

Lead investigators at centers which accrued patients to this trial:

AUSTRIA: HellmutSamonigg, Thomas Brodowicz, Wolfgang Eisterer

BELGIUM: Patrick Schöffski

CANADA: Martin Blackstein, Karen Mulder, JawaidYounus

CHINA: Jin Li, Shukui Qin, De Sen Wan, JianmingXu

FINLAND: HeikkiJoensuu

FRANCE: Jean-Yves Blay, Binh Bui Nguyen, Antoine Adenis, Axel Le Cesne

GERMANY: Peter Reichardt, Jens Chemnitz, Sebastian Bauer, Peter Hohenberger, Viktor Grünwald, Frank Mayer, JochenSchütte

ISRAEL: OferMerimsky

ITALY: Paolo Casali, Guido Biasco, Massimo Aglietta, Giuseppe Badalamenti

JAPAN: Toshihiko Doi, Tatsuo Kanda, Toshirou Nishida, Yasuhide Yamada, Yoshito Komatsu,Akira Sawaki

NETHERLANDS: A J Gelderblom, Winette Van der Graaf

POLAND: PiotrRutkowski

SINGAPORE: Richard Quek

SOUTH KOREA: Yoon-Koo Kang, Hyuk Chan Kwon, Seock-Ah Im, Joon Oh Park, Sun Young Kim

SPAIN: Claudia M Valverde Morales, Xavier Garcia Del Muro

UK: Ian Judson, Michael Leahy, Anne Thomas

USA: George Demetri, Mary Louise Keohan, Michael Heinrich, Margaret von Mehren, Robin Jones, Bruce Brockstein, Pamela Kaiser, Keith Skubitz, Michael Gordon

The GRID trial was sponsored by Bayer HealthCare AG, Leverkusen, Germany


  • Login