More Infos, ESMO Press Release & Abstract

LBA5
Phase 3, Double-Blind, Placebo-Controlled Study of Vemurafenib Versus Vemurafenib + Cobimetinib in Previously Untreated BRAFV600 Mutation–Positive Patients With Unresectable Locally Advanced or Metastatic Melanoma (NCT01689519):

New data on combination treatments for melanoma

• Vemurafenib + cobimetinib achieves significant progression-free survival and response rates in melanoma
• Phase III trial data shows better outcomes with combination therapy than vemurafenib alone

Lugano/Madrid, 29 September 2014 -- Combination therapy with both BRAF inhibitor vemurafenib and MEK inhibitor cobimetinib achieves greater progression-free survival and response rates than vemurafenib plus placebo in BRAF-mutation positive melanoma, according to phase III data presented at the ESMO 2014 Congress in Madrid, Spain.

“Before the results of this study, we knew that cobimetinib plus vemurafenib could be safely delivered together with highly promising rates of tumour shrinkage; however until the performance of a scientifically rigorous randomised trial the potential magnitude of this benefit could not be measured,” says lead author Dr Grant McArthur, head of the Cancer Therapeutics Program at the Peter MacCallum Cancer Centre, Melbourne, Australia.

The ongoing CoBRIM study enrolled 495 treatment-naive patients with BRAFV600-mutation-positive unresectable locally advanced or metastatic melanoma. Patients were randomised to received a 28-day treatment cycle of vemurafenib (960 mg, twice daily), and either cobimetinib or placebo (60 mg daily from days 1-21), with a primary end-point of progression-free survival.

Patients in the combination arm of the study showed a significantly improved median progression-free survival of 9.9 months, compared to 6.2 months in the placebo arm, and a 49% reduction in the risk of progression. Researchers observed a response rate of 68% in the combination arm and 45% in the control arm, including a complete response in 10% of patients treated with combination therapy compared to 4% of patients treated with vemurafenib alone.

“This study is very important as it shows that using drugs together to turn off two individual proteins (BRAF and MEK), that interact and bind to each other in the cell, gives much improved results for patients. This is fundamental concept that could have far reaching consequences for how we treat many cancers,” says McArthur.

Combination therapy did lead to a greater number of grade 3 and above adverse events compared to vemurafenib alone, but treatment with cobimetinib plus vemurafenib also seemed to reduce the incidence of skin-related side-effects known to occur with vemurafenib.

In summary, McArthur says, “We anticipate that the combination of a BRAF and MEK inhibitor will become a new standard treatment for advanced BRAF-mutant melanoma. The data lay the foundation for the addition of treatments either in sequence or in further combination to obtain even better results.”

Improved response rate and survival with dabrafenib plus trametinib versus vemurafenib alone

Targeting BRAF V600E/K mutation-positive melanoma with a combination of dabrafenib plus trametinib achieves longer overall survival and progression-free survival as well as better response rates, compared to treatment with vemurafenib alone, according to data from an open-label phase III trial, also presented at ESMO 2014 in Madrid.

“We knew from previous studies of dabrafenib plus trametinib that the response rates were higher than those observed with dabrafenib monotherapy and that the progression-free survival was also significantly longer,” says lead author Dr Caroline Robert, head of Dermatology at the Institute Gustave Roussy, Paris, France.

The ongoing two-arm study has randomised 704 patients with advanced BRAF V600E/K mutation-positive melanoma either to a combination of dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily), or to vemurafenib (960 mg, twice daily) alone. The primary endpoint is overall survival, with secondary endpoints of progression-free survival, objective response rate, duration of response, and safety.

A pre-planned interim analysis shows a 31% improvement in overall survival among patients on combination therapy, and a 44% reduction in the risk of disease progression compared to vemurafenib monotherapy. Researchers found a median progression-free survival of 11.4 months for dabrafenib plus trametinib, and 7.3 months for vemurafenib.

Patients in both arms of the study had similar rates of severe adverse events, although treatment with combination therapy was associated with a much lower rate of cutaneous squamous cell carcinoma.

In July this year, the study was stopped, and patients originally randomised to the vemurafenib arm of the trial were allowed to cross over to the combination arm.

In summary, Robert says, “These results further corroborate the early preclinical data that more complete blockade of the MAP kinase pathway delays the emergence of resistance, translating into longer survival for the patients.”

Commenting on the results from these two studies, Dr Reinhard Dummer, from the University of Zurich Hospital, ESMO Faculty Coordinator for melanoma, says: “While monotherapy with a BRAF inhibitor is currently considered as a standard of care for patients with BRAF mutated advanced melanoma, the data from these two trials, along with trial data presented earlier this year, provide convincing evidence that combination therapy with either dabrafenib and trametinib, or vemurafenib and cobimetinib will be the standard systemic therapy for this patient population.”

“The combination provides more efficacy concerning response rate and progression-free survival and overall survival documented for the trametinib and dabrafenib combination with a similar to lower load of adverse reactions,” Dummer says.

“Of special relevance is the lower risk for new cutaneous malignancies which might be a surrogate for other secondary malignancies associated with the use of monotherapy BRAF inhibitors.”

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Notes to Editors

4LBA_PR: COMBI-v: A randomised, open-label, Phase III study comparing the combination of dabrafenib (D) and trametinib (T) with vemurafenib (V) as first-line therapy in patients (pts) with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma

5LBA_PR: Phase 3, Double-Blind, Placebo-Controlled Study of Vemurafenib Versus Vemurafenib + Cobimetinib in Previously Untreated BRAFV600 Mutation–Positive Patients With Unresectable Locally Advanced or Metastatic Melanoma (NCT01689519)

Disclaimer

Information contained in this press release was provided by the abstracts authors and reflects the content of the studies. It does not necessarily express ESMO's point of view.

Session info

5LBA_PR                              Monday, September 29, 2014 – 16:00 PM – 17:25 PM  - Hall Madrid

4LBA_PR                              Monday, September 29, 2014 – 16:00 PM – 17:25 PM  - Hall Madrid

 

 

Abstract: 5LBA_PR

Phase 3, Double-Blind, Placebo-Controlled Study of Vemurafenib Versus Vemurafenib + Cobimetinib in Previously Untreated BRAFV600 Mutation–Positive Patients With Unresectable Locally Advanced or Metastatic Melanoma (NCT01689519)

G.A. McArthur1, P.A. Ascierto2, J. Larkin3, A. Ribas4, G. Liszkay5, M. Maio6, M. Mandalà7, L.V. Demidov8, D. Stroyakovsky9, L. Thomas10, L. De La Cruz Merino11, V. Atkinson12, C. Dutriaux13, C. Garbe14, I. Chang15, S.P. Hack16, B. Dréno17

1Cancer Therapeutics, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia, 2Melanoma, Cancer Immunotherapy and Innovative Therapies, Istituto Nazionale Tumori Fondazione “G. Pascale”, Napoli, ITALY, 3Department of Medicine, Royal Marsden Hospital, London, UK, 4Department of Medicine, UCLA, Los Angeles, CA, USA, 5Oncodermatology, National Institute of Oncology, Budapest, HUNGARY, 6Oncology, University Hospital of Siena, Siena, ITALY, 7Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, ITALY, 8Tumor Biotherapy, NN Blokhin Russian Cancer Research Center, Moscow, RUSSIAN FEDERATION, 9Chemotherapy, Moscow City Oncology Hospital # 62, Istra, RUSSIAN FEDERATION, 10Dermato-oncology, Centre Hospitalier Lyon Sud, Rhone, FRANCE, 11Clinical Oncology, Hospital Universitario Virgen Macarena, Sevilla, SPAIN, 12Division of Cancer Services, Princess Alexandra Hospital, Woolloongabba, AUSTRALIA, 13Dermato-oncology, Hôpital Saint André, Bordeaux, FRANCE, 14Dermatology, University of Tubingen, Tubingen, GERMANY, 15Product Development, Roche, South San Francisco, CA, USA, 16Product Development (oncology), Roche/Genentech, South San Francisco, CA, USA, 17Department of Dermato Cancerology, CHU Nantes - Nantes Hospital University, Nantes, FRANCE

Background: Combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib.

Methods: Between January 2013 and January 2014, 495 patients (pts) were randomly assigned to receive vemurafenib + cobimetinib or vemurafenib + placebo. In a 28-day treatment cycle, vemurafenib was administered at 960 mg twice daily from Days 1-28 and cobimetinib or placebo was administered at 60 mg daily from Days 1-21. Eligibility included treatment-naive BRAFV600 mutation–positive pts with unresectable locally advanced or metastatic melanoma and adequate performance status and organ function. Primary end point was investigator-assessed progression-free survival (PFS).

Results: Median PFS was 9.9 months with the combination compared with 6.2 months in the control arm (hazard ratio [HR] = 0.51; 95% confidence interval [CI], 0.39-0.68; P <0.0001). The rate of complete and partial response was 68% in the combination arm and 45% in the control arm (P <0.0001), including complete response in 10% of pts treated with the combination and 4% of pts in the control group. Subgroup analyses of PFS based on key demographic and tumor characteristics were consistent with PFS in the intent-to-treat population. PFS assessed by independent review was comparable with investigator-assessed PFS. Interim overall survival (OS) data showed an HR of 0.65 (95% CI, 0.42-1.00) but did not cross the prespecified stopping boundary. Vemurafenib + cobimetinib combination, compared with vemurafenib alone, was associated with a higher incidence of grade ≥ 3 adverse events ([AEs] 65% vs 59%); however, there was no difference in the rate of AEs leading to study drug discontinuationand there was a decrease in the occurrence of secondary cutaneous neoplasms with the combination.

Conclusions: Cobimetinib in combination with vemurafenib significantly improved PFS among pts with BRAFV600-mutant metastatic melanoma.

Disclosure: G.A. McArthur: Provided research support for Novartis, Pfizer, Millenium, and Celgene; P.A. Ascierto: Received honoraria for serving on advisory boards for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Glaxo SmithKline, and Novartis; received honoraria and research funds as a consultant for Bristol Myers Squibb, Roche-Genentech, and Ventana;  J. Larkin: Serves as non-remunerated consultant to Pfizer, Novartis, GlaxoSmithKline, Bristol-Myers Squibb, Merck Sharp & Dohme, and Roche; A. Ribas: Holds stock in Kite Pharma and serves as consultant, with honoraria, to Amgen, Compugen, Flexus, GlaxoSmithKline, Genentech, Novartis, Merck, and Pierre Fabre; G. Liszkay: Received honoraria for serving on advisory boards for Roche; M. Maio: Serves on advisory boards and as speaker with honoraria for, and has received research grants and fees/patient from, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, GlaxoSmithKline, and MedImmune; M. Mandalà: Serves on advisory boards and as speaker, with honoraria, for GlaxoSmithKline, Roche, and Bristol-Myers Squibb; L.V. Demidov: Received GMTF for advisory boards for MSD; consultant for MSD and Roche; investigator for Roche, GSK, Pfizer, and BMS; speaker for MSD, Roche, and BMS
L. Thomas: Principal investigator for clinical trials sponsored by Roche; institution received honoraria
L. De La Cruz Merino: Participated in advisory boards by Roche; V. Atkinson: Advisory boards for Roche and Bristol-Myers Squibb; speaker for GlaxoSmithKline dabrafenib launch meeting 2014; C. Dutriaux: Investigator for Roche; C. Garbe: Serves on advisory boards and as speaker, with honoraria, for Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Roche, and Philogen, and received research grants from Bristol-Myers Squibb, GlaxoSmithKline, and Roche; I. Chang: Roche employee with salary and stock options; S.P. Hack: Employee of Genentech with salary and stock options; B. Dréno: Served on advisory board, as consultant, and as speaker for Roche for which honoraria was received; served as investigator for Roche for which a grant was received. All other authors have declared no conflicts of interest.

Keywords: metastatic melanoma, cobimetinib, vemurafenib, MEK inhibitor.

 

Abstract: 4LBA_PR

COMBI-v: A randomised, open-label, Phase III study comparing the combination of dabrafenib (D) and trametinib (T) with vemurafenib (V) as first-line therapy in patients (pts) with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma

C. Robert¹, B. Karaszewska², J. Schachter³, P. Rutkowski⁴, A. Mackiewicz⁵, D. Stroiakovski⁶, M. Lichinitser⁷, R. Dummer⁸, F. Grange⁹, L. Mortier¹⁰, V. Chiarion-Sileni¹¹, K. Drucis¹², I. Krajsova¹³, A. Hauschild¹⁴, P. Sun¹⁵, S. D. Rubin¹⁵, J. Legos¹⁵, W. A. Crist¹⁵, S.M. Little¹⁵, D. Schadendorf¹⁶

¹Institut de Cancérologie Gustave Roussy, Villejuif, FRANCE, ²Przychodnia Lekarska Komed, Konin, POLAND, ³Sheba Medical Center, Ramat, ISRAEL, ⁴Centrum Onkologii Instytut im. Marii Sklodowskiej-Curie, Warsaw, POLAND, ⁵Poznan University for Medical Sciences, Med-Polonia, Poznan, POLAND, ⁶Moscow City Oncology Hospital # 62, Moscow, RUSSIAN FEDERATION, ⁷Cancer Research Center, Moscow, RUSSIAN FEDERATION, ⁸Universität Zürich, Zurich, SWITZERLAND, ⁹CHU de Reims - Hôpital Robert Debré, Reims, FRANCE, ¹⁰CHRU de Lille - Hôpital Claude Huriez, Lille, FRANCE, ¹¹Istituto Oncologico Veneto, Padua, ITALY, ¹²Swissmed Centrum Zdrowia S.A., Gdansk, POLAND, ¹³VFN a 1LF.UK, Prague, CZECH REPUBLIC, ¹⁴Universitaetsklinikum Schleswig-Holstein, Kiel, GERMANY,¹⁵GlaxoSmithKline Oncology Research & Development, Collegeville, PA, USA, ¹⁶University Hospital Essen, Essen, GERMANY

Aim: BRAFi (D) and MEKi (T) each demonstrated superior progression-free survival (PFS) vs. chemotherapy in pts with BRAF V600E/K mutation-positive metastatic melanoma (MM). However, the emergence of disease resistance and development of cutaneous squamous cell carcinoma (cuSCC) are associated with BRAF inhibition. Simultaneous inhibition of BRAF and MEK mitigated these effects as shown in the Phase I/II study of D+T combination therapy vs. D monotherapy (NCT01072175) and the Phase III study of D+T combination therapy vs. D monotherapy (NCT01584648), with an improvement in overall response rate (ORR), PFS and reduced frequency of cuSCC. This Phase III study (NCT01597908) was conducted to establish superiority of D+T combination over V with respect to overall survival (OS) in pts with BRAF V600E/K mutation-positive MM.

Methods: Pts were randomised 1:1 to receive D (150 mg twice daily [BID]) and T (2 mg once daily) vs. V monotherapy (960 mg BID) as first-line therapy. Eligible pts were ≥ 18 years old and had an ECOG performance status ≤ 1, with histologically confirmed, unresectable stage IIIC or IV, BRAF V600E/K mutation-positive MM. The primary endpoint was OS; secondary endpoints were PFS, ORR, duration of response, and safety. Crossover was prohibited. A pre-specified interim OS analysis was performed when 77% (222/288) of the total number of expected deaths, required for the protocol-specified final analysis, were observed; the study could be stopped for efficacy if the one-sided P value was < 0.0107.

Results: From June 2012 to Oct 2013, 704 pts were randomised (352 to each arm). IDMC recommended stopping study based on an interim analysis which demonstrated an OS benefit that crossed the pre-specified efficacy stopping boundary for D+T combination. Rates of adverse events were generally similar for both arms and consistent with data from previous trials. Full efficacy and safety results will be presented at the meeting.

Conclusions: D+T demonstrated a significant improvement in OS compared with V in pts with BRAF V600E/K mutation-positive MM.

Disclosure: C. Robert: has received fees for Advisory Board participation from Bristol-Meyers Squibb, Roche, Merck, GlaxoSmithKline, Novartis and Amgen; P. Rutkowski: receives personal fees Novartis, Pfizer, GSK, and Roche, in addition to travel grants and fees for participation in speakers bureau and Advisory Boards from GSK and Novartis; R. Dummer: received grants and personal fees from GSK, Roche, Novartis, MSD and BMS.
L. Mortier: received personal fees from GSK; V. Chiarion-Sileni: receiving compensation for Advisory Board participation GlaxoSmithKline, Bristol-Meyers Squibb and Roche; A. Hauschild: Consult, Hon and Trial funding: Amgen,BMS,Celgene,Eisai,GSK,MelaSciences,Merck Serono,MSD/Merck,Novartis,Oncosec,Roche
P. Sun, S. Rubin and J. Legos: is an employee of GlaxoSmithKline and owns stock in the company; W. Crist: is an employee of GlaxoSmithKline; S.M. Little: is an employee and owns stock in GSK; D. Schadendorf: received personal fees, other support, and non-financial support from GlaxoSmithKline, Roche, Novartis, Amgen, Bristol-Meyers Squibb and MSD/Merck, and grants from MSD/Merck. All other authors have declared no conflicts of interest.

Keywords: dabrafanib, melanoma, trametinib, vemurafenib