Results From Phase 3 Trial Show Vectibix® (Panitumumab) Improves Overall Survival In Chemorefractory Wild-Type KRAS Metastatic Colorectal Cancer Versus Best Supportive Care

On June 18, 2015 Amgen reported that a Phase 3 study evaluating Vectibix (panitumumab) and best supportive care (BSC) met its primary endpoint, demonstrating a statistically significant improvement in overall survival (OS) in patients with chemorefractory wild-type KRAS (exon 2) metastatic colorectal cancer (mCRC) compared to those patients treated with BSC alone (Press release, Amgen, JUN 18, 2015, View Source [SID:1234505462]).

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The Vectibix treatment arm further showed statistical significance for all key secondary endpoints including OS in patients with wild-type RAS (absence of mutations in exons 2, 3 and 4 of KRAS and NRAS) mCRC.

In the Vectibix treatment arm, the observed adverse events were consistent with the known Vectibix safety profile.

Full results will be submitted to a future medical congress and for publication.

"Amgen has been at the forefront of researching personalized approaches to treating cancer, and the Vectibix clinical program continues to underscore the importance of identifying options for patients based on their cancer’s genetic makeup," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "These positive overall survival results for Vectibix reinforce the importance of KRAS and RAS biomarkers in making treatment decisions in metastatic colorectal cancer."

Colorectal cancer is the third most common cancer worldwide, with approximately 1.2 million cases occuring globally each year.1,2 In the U.S., colorectal cancer is the second leading cause of cancer-related deaths, with an estimated 132,700 new cases diagnosed in 2015.3,4 In Europe, colorectal cancer is the second most common cancer, with approximately 470,000 new cases each year.5

About Study ‘0007 (NCT01412957)
This Phase 3 global, multicenter, randomized, open-label study was designed to evaluate the survival benefit of Vectibix and best supportive care (BSC) compared to BSC alone in patients with chemorefractory wild-type KRAS (exon 2) metastatic colorectal cancer (mCRC). The primary endpoint was overall survival (OS). Key secondary endpoints included progression-free survival (PFS) in patients with wild-type KRAS mCRC, as well as OS and PFS in patients with wild-type RAS (absence of mutations in exons 2, 3 and 4 of KRAS and NRAS) mCRC.

Patients were randomized 1:1 to receive 6 mg/kg of Vectibix every 14 days and BSC, or BSC alone (as defined by the investigator).

About Vectibix (panitumumab)
Vectibix is the first fully human anti-EGFR antibody approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic colorectal cancer (mCRC). Vectibix was approved in the U.S. in September 2006 as a monotherapy for the treatment of patients with EGFR-expressing mCRC after disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy.

In May 2014, the FDA approved Vectibix for use in combination with FOLFOX, as first-line treatment in patients with wild-type KRAS (exon 2) mCRC. With this approval, Vectibix became the first-and-only biologic therapy indicated for use with FOLFOX, one of the most commonly used chemotherapy regimens, in the first-line treatment of mCRC for patients with wild-type KRAS mCRC.

Important U.S. Product Information
Vectibix is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use:

As first-line therapy in combination with FOLFOX
As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy
Limitation of Use: Vectibix is not indicated for the treatment of patients with RAS-mutant mCRC or for whom RAS mutation status is unknown.

WARNING: DERMATOLOGIC TOXICITY
Dermatologic Toxicity: Dermatologic toxicities occurred in 90 percent of patients and were severe (NCI-CTC grade 3 or higher) in 15% of patients receiving Vectibix monotherapy.

In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures.

Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (e.g., Stevens-Johnson syndrome or toxic epidermal necrolysis). Withhold or discontinue Vectibix for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications. Dose modifications for Vectibix. concerning dermatologic toxicity are provided in the product labeling.

Vectibix is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereafter is referred to as "RAS".

Retrospective subset analyses across several randomized clinical trials were conducted to investigate the role of RAS mutations on the clinical effects of anti-EGFR-directed monoclonal antibodies (panitumumab or cetuximab). Anti-EGFR antibodies in patients with tumors containing RAS mutations resulted in exposing those patients to anti-EGFR related adverse reactions without clinical benefit from these agents.

Additionally, in Study 3, 272 patients with RAS-mutant mCRC tumors received Vectibix. in combination with FOLFOX and 276 patients received FOLFOX alone. In an exploratory subgroup analysis, OS was shorter (HR = 1.21, 95% CI 1.01-1.45) in patients with RAS-mutant mCRC who received Vectibix and FOLFOX versus FOLFOX alone.

Progressively decreasing serum magnesium levels leading to severe (Grade 3-4) hypomagnesemia occurred in up to 7% (in Study 2) of patients across clinical trials. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix treatment, periodically during Vectibix treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate.

In Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grade 3-4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix administration. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions.

Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix in combination with chemotherapy.

Fatal and non-fatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix therapy. Discontinue Vectibix therapy if ILD is confirmed.

In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix versus the risk of pulmonary complications must be carefully considered.

Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix.

Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix for acute or worsening keratitis.

In an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3–5 (87% vs 72%) adverse reactions. NCI-CTC grade 3–4 adverse reactions occurring at a higher rate in Vectibix-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%; primarily occurring in patients with diarrhea), hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0).

NCI-CTC grade 3–5 pulmonary embolism occurred at a higher rate in Vectibix-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix-treated patients.

As a result of the toxicities experienced, patients randomized to Vectibix, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study, compared with those randomized to bevacizumab and chemotherapy.

Advise patients of the need for adequate contraception in both males and females while receiving Vectibix and for 6 months after the last dose of Vectibix therapy. Vectibix may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women.

Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, it should not be resumed earlier than 2 months following the last dose of Vectibix.

Women who become pregnant during Vectibix treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Women who are nursing during Vectibix treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

In Study 1, the most common adverse reactions (> 20%) with Vectibix were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. The most common (> 5%) serious adverse reactions in the Vectibix arm were general physical health deterioration and intestinal obstruction.

In Study 3, the most commonly reported adverse reactions (> 20%) in patients with wild-type KRAS mCRC receiving Vectibix (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) were diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin. Serious adverse reactions (> 2% difference between treatment arms) in Vectibix-treated patients with wild-type KRAS mCRC were diarrhea and dehydration.

To see the Vectibix Prescribing Information, including Boxed Warning visit www.vectibix.com.

In the EU, Vectibix is currently indicated for the treatment of adult patients with wild-type RAS mCRC:

in first-line in combination with FOLFOX and FOLFIRI.
in second-line in combination with FOLFIRI for patients who have received first-line fluoropyrimidine-based chemotherapy (excluding irinotecan).
as monotherapy after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.

FORMA THERAPEUTICS ACHIEVES CLINICAL CANDIDATE LICENSING MILESTONE FOR AN EPIGENETIC COMPOUND IN STRATEGIC ALLIANCE WITH CELGENE CORPORATION

On June 17, 2015 FORMA Therapeutics reported that they have successfully met a preclinical development candidate milestone in their strategic collaboration agreement with Celgene Corporation, announced in April 2014, under which FORMA and Celgene will discover, develop and commercialize drug candidates (Press release, Forma Therapeutics, JUN 17, 2015, View Source [SID:1234509340]).

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This collaboration enables Celgene to evaluate named clinical candidate profiles and elect to license development and commercialization rights in a stepwise manner, upon FORMA’s successful completion of defined preclinical activities. Celgene has obtained an exclusive EU license for a defined clinical program and related compounds, in exchange for an undisclosed payment to FORMA. Under the terms of the collaboration agreement, FORMA will advance this program through Phase 1, and Celgene will be responsible thereafter for all further global clinical development for each licensed candidate. Phase 1 studies will begin in the second half of 2015.

Paolo Paoletti, M.D., Research and Development Committee Chair for FORMA’s Board of Directors added, "FORMA’s highly differentiated clinical candidate in the exciting area of epigenetics will be advanced for both solid and liquid tumors which may improve the lives of patients worldwide. The joint collaboration with Celgene and their steadfast commitment to oncology provides FORMA with a unique opportunity to advance an innovative pipeline of novel therapies."

FORMA THERAPEUTICS ANNOUNCES ACHIEVEMENT OF MULTIPLE COLLABORATION MILESTONES WITH BOEHRINGER INGELHEIM FOR MODULATING PROTEIN-PROTEIN INTERACTIONS

On June 17, 2015 FORMA Therapeutics reported the achievement of several discovery milestones in their alliance with Boehringer Ingelheim (BI) for the discovery of novel drug candidates against protein-protein interactions (PPI) for the treatment of cancer. Financial milestones payable to FORMA for this achievement have not been disclosed (Press release, Forma Therapeutics, JUN 17, 2015, View Source [SID:1234509337]).

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"FORMA’s continued successes within the BI partnership, an agreement originally announced in January 2012 and with milestones achieved in 2014, underscore our ability to make tractable progress in the challenging area of protein-protein interactions," said Steven Tregay, Ph.D., President and CEO, FORMA Therapeutics. "Investment in creative and talented individuals, as well as fully exploiting various technology platforms, has provided FORMA with keen insights into three-dimensional protein structure and druggable binding pockets. We are quite pleased to have contributed to BI’s drug discovery pipeline by identifying a panel of novel scaffolds across multiple targets."

BioInvent progresses collaboration with leading U.S. biotechnology company

On June 17, 2015 BioInvent International (OMXS: BINV) announces that its partnership with a leading U.S. biotechnology company advances to next phase (Press release, BioInvent, JUN 17, 2015, http://www.bioinvent.com/media-centre/press-releases/release/?ReleaseID=838A03317B4A0E87 [SID:1234506546]). The collaboration aims to discover novel therapeutic antibodies to be incorporated into the U.S. company’s CAR-T programs.

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The unnamed biotech company signed earlier this year a license to get access to BioInvent’s unique ability to discover antibodies with the antibody library n-CoDeR. The first of up to three targets covered by the agreement has now been identified and the work to develop appropriate antibodies can thus be initiated.

Under the license agreement BioInvent may receive revenue in the form of potential clinical milestone payments and royalties on future sales of any product developed as a result of the collaboration. In addition, BioInvent is in the early phase of the collaboration entitled to limited compensation for the work to identify antibodies against the first target.

"We are excited to start the identification of appropriate antibodies using our unique technology platform. We are delighted to be partnering with one of the world’s most innovative biotechnology companies on a project of such potential significance." stated Michael Oredsson, CEO of BioInvent.

This kind of agreement allow us to further strengthen BioInvent’s prominent position within the immuno-oncology field and to use our n-CoDeR library in new clinical applications. At the same time it contributes to offset costs relating to our internal development of innovative antibody-based cancer drugs", concluded Michael Oredsson.

CAR-Ts are T cells that have been removed from the body and attached through genetic engineering to an antibody fragment that recognizes a specific tumor protein. The result is a cancer immunotherapy drug with the killing power of a greatly enhanced T cell, combined with the tumor-targeting ability of an antibody.

Seattle Genetics Announces Multiple ADCETRIS® (Brentuximab Vedotin) Data Presentations at the International Conference on Malignant Lymphoma

On June 17, 2015 Seattle Genetics reported several ADCETRIS (brentuximab vedotin) data presentations at the 13th International Conference on Malignant Lymphoma (ICML) being held June 17 to 19, 2015, in Lugano, Switzerland (Press release, Seattle Genetics, JUN 17, 2015, View Source;p=RssLanding&cat=news&id=2060135 [SID:1234505449]). ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, which is expressed in classical Hodgkin lymphoma (HL), systemic anaplastic large cell lymphoma (sALCL) and several other types of non-Hodgkin lymphoma (NHL). Seven oral presentations and one poster at ICML demonstrate the breadth of the clinical development program for ADCETRIS. Data include an additional analysis of the phase 3 AETHERA clinical trial showing that up to 16 cycles (approximately one year) of ADCETRIS consolidation therapy following autologous stem cell transplant (ASCT) significantly extended progression-free survival (PFS) versus placebo for those patients with primary-refractory HL. In addition, data from several corporate and investigator-sponsored trials with ADCETRIS showed activity in a variety of HL and NHL treatment settings. ADCETRIS is currently approved by the U.S. Food and Drug Administration (FDA) for relapsed HL and sALCL and was granted conditional marketing authorization by the European Commission for relapsed or refractory HL and sALCL.

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"Since the initial FDA approval of ADCETRIS in 2011 for the treatment of relapsed HL and sALCL, it has been approved in more than 55 countries, and our clinical development program has expanded to include more than 30 corporate and investigator-sponsored clinical trials in CD30-expressing malignancies," said Clay B. Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. "The ADCETRIS data presented at ICML support our broad development plans for ADCETRIS. In the near-term, we anticipate an FDA decision on its use in the AETHERA setting as a post-transplant consolidation therapy, and, ultimately, our goal is to move even earlier into the treatment paradigm and redefine frontline treatment of HL with the addition of ADCETRIS."

Analysis of primary-refractory Hodgkin lymphoma patients in a randomized, placebo-controlled study of brentuximab vedotin consolidation after autologous stem cell transplant (Seattle Genetics and Takeda; Abstract #120, oral presentation Friday, June 19, 2015, at 11:50 a.m. CEST)

Data were reported from an additional analysis of the phase 3 AETHERA clinical trial evaluating PFS by investigator in patients who were refractory to frontline treatment. Previously published data suggest primary-refractory HL patients have poor outcomes following ASCT, as demonstrated by the historical two-year PFS and three-year overall survival rates of less than 40 percent and 50 percent, respectively. Of the 329 patients enrolled in the AETHERA trial, 60 percent (196 patients) were primary-refractory to frontline treatment.

Results of the analysis demonstrated:

Two-year PFS rates per investigator among primary-refractory patients on the ADCETRIS and placebo arms were 60 percent and 42 percent, respectively, consistent with the primary analysis in the full intent-to-treat population.

Subgroup analyses of patients by disease characteristics as well as number of risk factors showed that PFS was improved broadly across subgroups, including patients with B-symptoms, extranodal involvement and those who received more than two systemic anticancer treatments pre-ASCT.

Adverse events in primary-refractory patients who received ADCETRIS were consistent with the known safety profile.

Additional AETHERA data were included in a poster presentation reporting the frequency of healthcare resource utilization (HRU) among patients on the two treatment arms of the trial. Preliminary reports suggest a trend toward lower HRU in patients treated with ADCETRIS compared with placebo.

ADCETRIS is currently not approved for use in the AETHERA treatment setting. Based on the positive results from the AETHERA trial, a supplemental Biologics License Application (BLA) for ADCETRIS in the post-ASCT consolidation treatment of HL patients at high risk of relapse or progression was accepted for filing by the FDA. The FDA granted Priority Review for the application and the Prescription Drug User Fee Act (PDUFA) target action date is August 18, 2015.

Additional ADCETRIS corporate and investigator presentations are included below and full abstracts can be found in the ICML Educational and Abstract Book accessed on the ICML website at www.lymphcon.ch.

Wednesday, June 17, 2015

Healthcare utilization in the AETHERA trial: phase 3 study of brentuximab vedotin in patients at increased risk of residual Hodgkin lymphoma post ASCT (Seattle Genetics and Takeda; Abstract #177, poster presentation)

Thursday, June 18, 2015

Brentuximab vedotin plus AVD for non-bulky limited stage classical Hodgkin lymphoma: A phase 2 trial (Investigator-sponsored; Abstract #087, oral presentation at 5:15 p.m. CEST)

Preliminary efficacy and safety of brentuximab vedotin and AVD chemotherapy followed by involved-site radiotherapy in early stage, unfavorable risk Hodgkin lymphoma (Investigator-sponsored; Abstract #088, oral presentation at 5:25 p.m. CEST)

Sequential brentuximab vedotin and AVD for older Hodgkin lymphoma patients: Initial results from a phase 2 multicenter study (Investigator-sponsored; Abstract #089, oral presentation at 5:35 p.m. CEST)

A phase 1 study of brentuximab vedotin (Bv) and bendamustine (B) in patients with relapsed or refractory Hodgkin lymphoma (HL) and anaplastic large T-Cell lymphoma (ALCL) (Investigator-sponsored; Abstract #090, oral presentation at 5:45 p.m. CEST)

Brentuximab vedotin demonstrates antitumor activity in CD30+ DLBCL (Seattle Genetics; Abstract #091, oral presentation at 5:55 p.m. CEST)

Updated results of a phase 2 trial of brentuximab vedotin combined with RCHOP in frontline treatment of pts with high-intermediate/high-risk DLBCL (Seattle Genetics; Abstract #092, oral presentation at 6:05 p.m. CEST)

ADCETRIS is not currently approved for use in frontline HL, in combination with bendamustine for relapsed or refractory HL and sALCL, or in DLBCL.

About ADCETRIS

ADCETRIS is being evaluated broadly in more than 30 ongoing clinical trials, including four phase 3 studies, in earlier lines of its approved HL and sALCL indications as well as in many additional types of CD30-positive malignancies, including cutaneous T-cell lymphoma, B-cell lymphomas and mature T-cell lymphomas.

ADCETRIS (brentuximab vedotin) is an ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.

ADCETRIS for intravenous injection received accelerated approval from the FDA and approval with conditions from Health Canada for two indications: (1) the treatment of patients with HL after failure of ASCT or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates, and (2) the treatment of patients with sALCL after failure of at least one prior multi-agent chemotherapy regimen. The indications for ADCETRIS are approved under accelerated approval based on overall response rate. An improvement in patient-reported outcomes or survival has not been established. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

ADCETRIS was granted conditional marketing authorization by the European Commission in October 2012 for two indications: (1) for the treatment of adult patients with relapsed or refractory CD30-positive HL following ASCT, or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, and (2) the treatment of adult patients with relapsed or refractory sALCL. ADCETRIS has received marketing authorization by regulatory authorities in more than 55 countries. See important safety information below.

Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda will be solely responsible for development costs.