FDA Approves ERBITUX(R) (cetuximab) as First-Line Treatment in KRAS Mutation-Negative (Wild-Type) Epidermal Growth Factor Receptor (EGFR)-Expressing Metastatic Colorectal Cancer in Combination with FOLFIRI (Irinotecan, 5-Fluorouracil, Leucovorin)

NEW YORK & INDIANAPOLIS--(BUSINESS WIRE)-- Eli Lilly and Company (NYSE: LLY) and Bristol-Myers Squibb Company (NYSE: BMY) today announced that ERBITUX® (cetuximab) in combination with the chemotherapy regimen FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) has been granted full approval by the U.S. Food and Drug Administration (FDA) for the first-line treatment of patients with KRAS mutation-negative (commonly known as KRAS wild-type), epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer (mCRC) as determined by FDA-approved tests for this use. ERBITUX is not indicated for the treatment of KRAS mutation-positive colorectal cancer. Concurrently, the FDA also approved the first KRAS companion diagnostic test, the therascreen® KRAS diagnostic kit developed by QIAGEN.

"Cancer is a heterogeneous disease and we have learned that not all patients with mCRC should be viewed as the same," said Brian Daniels, senior vice president, Global Development and Medical Affairs, Bristol-Myers Squibb. "Today's approval demonstrates our ability to bring diverse cancer therapies to market that address the needs of patients with KRAS mutation-negative (wild-type) mCRC."

The new indication is based on data from the CRYSTAL (Cetuximab combined with iRinotecan in first-line therapY for metaSTatic colorectAL cancer) trial, a Phase 3 open-label, randomized, multicenter study conducted outside the U.S. that used European Union (EU)-approved cetuximab as the clinical trial material. ERBITUX provides approximately 22 percent higher exposure relative to the EU-approved cetuximab; these pharmacokinetic data, together with the results of this trial and other clinical trial data, establish the efficacy of ERBITUX at the recommended dose in combination with FOLFIRI for first-line KRAS mutation-negative (wild-type) EGFR-expressing mCRC.

With today's approval, ERBITUX is now the first and only FDA-approved therapy for a specific subset of mCRC patients, targeting those with KRAS mutation-negative (wild-type) tumors. This is based on the positive CRYSTAL study with progression-free survival (PFS) as the primary endpoint in the all randomized patient population treated with EU-approved cetuximab plus FOLFIRI (the CRYSTAL regimen) versus FOLFIRI alone.

The Full Prescribing Information for ERBITUX includes a Boxed WARNING regarding infusion reactions. Serious infusion reactions occurred with the administration of ERBITUX in approximately 3 percent of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. Healthcare providers should immediately interrupt and permanently discontinue ERBITUX infusion for serious infusion reactions.

Please see Important Safety Information including Boxed WARNINGS on pages 6-10.

Among the all randomized patient population, a statistically significant improvement in PFS was observed for the EU-approved cetuximab plus FOLFIRI arm compared with the FOLFIRI-alone arm (median PFS 8.9 vs. 8.1 months, HR 0.85 [95% CI, 0.74-0.99], p-value=0.0358). Additionally, the median overall survival (OS) in each arm was 19.6 months (95% CI, 18-21) and 18.5 months (95% CI, 17-20), respectively (HR= 0.88; 95% CI, 0.78-1.0), which was not significantly different. The objective response rate (ORR) in each arm was 46% (95% CI, 42-50) and 38% (95% CI, 34-42), respectively.

In the post-hoc analysis of the KRAS subgroups, the median PFS of the KRAS mutation-negative (wild-type) patients treated with EU-approved cetuximab plus FOLFIRI (n=320) or FOLFIRI alone (n=356) was 9.5 months (95% CI, 8.9-11.1) and 8.1 months (95% CI, 7.4-9.2), respectively (HR= 0.70; 95% CI, 0.57-0.86). The median OS in each arm was 23.5 months (95% CI, 21-26) and 19.5 months (95% CI, 17-21), respectively (HR= 0.80; 95% CI, 0.67-0.94). The ORR in each arm was 57% (95% CI, 51-62) and 39% (95% CI, 34-44), respectively.

There is no evidence of effectiveness in the subgroup of patients with KRAS mutation-positive tumors. The median PFS of the KRAS mutation-positive patients treated with EU-approved cetuximab (n=216) or FOLFIRI alone (n=187) was 7.5 months (95% CI, 6.7-8.7) versus 8.2 months (95% CI, 7.4-9.2), respectively (HR= 1.13; 95% CI, 0.88-1.46). The median OS in each arm was 16.0 months (95% CI, 15-18) versus 16.7 months (95% CI, 15-19), respectively (HR=1.04; 95% CI, 0.84-1.29). The ORR in each arm was 31% (95% CI, 25-38) and 35% (95% CI, 28-43), respectively.

"Both response rates and overall survival in KRAS wild-type patients treated with the CRYSTAL regimen are important when considering the treatment options for patients with first-line mCRC," said Eric Van Cutsem, MD, PhD, professor of medicine and digestive oncology, University Hospital Gasthuisberg, Leuven, Belgium, and lead investigator of the pivotal trial.

Selected adverse events of any grade from the CRYSTAL trial occurring in at least 10 percent of patients receiving EU-approved cetuximab in combination with FOLFIRI versus FOLFIRI alone were: acne-like rash (86% vs. 13%, respectively), diarrhea (66% vs. 60%), neutropenia (49% vs. 42%), rash (44% vs. 4%), stomatitis (31% vs. 19%), anorexia (30% vs. 23%), pyrexia (26% vs. 14%), dermatitis acneiform (26% vs. < 1%), dry skin (22% vs. 4%), acne (14% vs. 0), paronychia (20% vs. < 1%), palmar-plantar erythrodysesthesia syndrome (19% vs. 4%), skin fissures (19% vs. 1%), conjunctivitis (18% vs. 3%), dyspepsia (16% vs. 9%), weight decreased (15% vs. 9%), pruritis (14% vs. 3%), and infusion-related reaction (14% vs. < 1%). U.S.-licensed ERBITUX provides approximately 22 percent higher exposure relative to the EU-approved cetuximab. The data provided above are consistent in incidence and severity of adverse reactions with those seen for ERBITUX in this indication. The tolerability of the recommended dose is supported by safety data from additional studies of ERBITUX.

"The totality of the data from CRYSTAL, along with data from other ERBITUX trials, provide compelling and consistent evidence of the benefit of ERBITUX in the treatment of KRAS mutation negative (wild-type) EGFR-expressing mCRC," said Richard Gaynor, MD, vice president, Product Development and Medical Affairs, Oncology, Eli Lilly and Company.

KRAS: The Biomarker in mCRC to Help Identify Appropriate Patients for ERBITUX Therapy

Data from the landmark CRYSTAL study, along with other cetuximab studies, demonstrate the importance of testing for KRAS status at diagnosis of mCRC to identify appropriate patients for ERBITUX therapy.

Both the National Comprehensive Cancer Network® (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines®, Category 2A)* and the American Society of Clinical Oncology (ASCO) recommend KRAS gene testing in colorectal cancer patients at diagnosis of metastatic disease.

"Research results have consistently demonstrated that KRAS is an important biomarker in mCRC, underscoring the need for all patients with this disease to undergo testing for KRAS status at initial diagnosis," said John Mendelsohn, MD, The University of Texas MD Anderson Cancer Center. "The field of biomarker-driven cancer therapy has come a long way since my colleagues and I began our research on EGF receptor inhibition with this monoclonal antibody in 1980. It is gratifying to see such progress being made, and I am honored to have been involved in the success of ERBITUX."

NCCN Guidelines recommend ERBITUX (cetuximab) for first-line as a treatment option in combination with FOLFIRI for patients with advanced or metastatic KRAS wild-type mCRC (Category 2A).*

Since its first approval in 2004, approximately 139,814 patients have received ERBITUX therapy in the U.S. alone.

About CRYSTAL

The approval is based on a Phase 3 randomized, open-label multicenter study of patients with mCRC, which was sponsored by Merck KGaA, Darmstadt, Germany. Patients were randomized (1:1) to receive either EU-approved cetuximab with FOLFIRI (the CRYSTAL regimen) or FOLFIRI alone as first-line treatment (n=1,217). The primary endpoint was PFS in all randomized patients. Secondary endpoints were overall survival and response rate. CRYSTAL was conducted outside the U.S. using EU-approved cetuximab as the clinical trial material. ERBITUX provides approximately 22 percent higher exposure relative to the EU-approved cetuximab; these pharmacokinetic data, together with the results of this trial and other clinical trial data, establish the efficacy of ERBITUX at the recommended dose in combination with FOLFIRI for first-line KRAS mutation-negative (wild-type) EGFR-expressing mCRC.

Study treatment continued until disease progression or unacceptable toxicity occurred. Eighty-five percent of patients required no dose reduction (minimum cetuximab dose level greater than or equal to 225 mg/m2) and received the full treatment regimen.

About Metastatic Colorectal Cancer (mCRC)

In 2012, 143,460 new cases of colorectal cancer (CRC) are estimated to occur, and an estimated 51,690 deaths from CRC are expected to occur, accounting for 9 percent of all projected cancer deaths. Colorectal cancer is a cancer that develops in the colon or the rectum, which are both parts of the gastrointestinal system. Metastatic colorectal cancer (mCRC) occurs when the disease has spread to at least one distant organ and tissues, such as the liver, lungs, lining of the abdomen or ovaries. One out of five CRC patients is diagnosed with metastatic disease. The five-year survival rate for patients with mCRC is 12 percent.

"For colorectal cancer patients who are diagnosed at the late stage, it is devastating," said Andrew Spiegel, chief executive officer, Colon Cancer Alliance. "Knowing their KRAS status at the time of diagnosis provides patients, physicians, and their families with a new understanding in how to best manage their care."

About ERBITUX® (cetuximab)

ERBITUX (cetuximab) is a monoclonal antibody (IgG1 Mab) designed to inhibit the function of a molecular structure expressed on the surface of normal and tumor cells called the epidermal growth factor receptor (EGFR, HER1, c-ErbB-1). In vitro assays and in vivo animal studies have shown that binding of cetuximab to the EGFR blocks phosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth induction of apoptosis (cell death), and decreased matrix metalloproteinase and vascular endothelial growth factor production. Signal transduction through the EGFR results in activation of KRAS wild-type protein. However, in cells with activating KRAS somatic mutations, the mutant KRAS protein is continuously active and appears independent of EGFR regulation. In vitro, cetuximab can mediate antibody-dependent cellular cytotoxicity (ADCC) against certain human tumor types. In vitro assays and in vivo animal studies have shown that cetuximab inhibits the growth and survival of tumor cells that express the EGFR. No anti-tumor effects of cetuximab were observed in human tumor xenografts lacking EGFR expression.

INDICATIONS

Head and Neck Cancer

Colorectal Cancer

ERBITUX is indicated for the treatment of KRAS mutation-negative (wild-type) epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer (mCRC) as determined by FDA-approved tests for this use

Limitation of Use: ERBITUX is not indicated for treatment of KRAS mutation-positive colorectal cancer

IMPORTANT SAFETY INFORMATION INCLUDING BOXED WARNINGS

Infusion Reactions

Cardiopulmonary Arrest

Pulmonary Toxicity

Dermatologic Toxicities

ERBITUX Plus Radiation Therapy and Cisplatin

Electrolyte Depletion

Late Radiation Toxicities

Pregnancy and Nursing

Adverse Events

Please see Important Safety Information and U.S. Full Prescribing Information including Boxed WARNINGS.

About ERBITUX Patient Programs

Bristol-Myers Squibb and Eli Lilly and Company are committed to supporting patient access to ERBITUX and have put in place a number of programs to help patients and providers. Destination Access™, which is a Reimbursement Support Program, helps patient access by providing benefits investigation support, prior authorization assistance, appeals assistance and patient assistance. More information about our patient assistance program can be obtained by calling 1-800-861-0048.

In addition to Destination Access, The ERBITUX PATIENT SUPPORT PROGRAM has been developed to provide patients and healthcare providers with information and helpful resources on dermatological reactions associated with ERBITUX and guidance on how to manage them. For additional information, visit www.erbitux.com.

About Eli Lilly and Company

Lilly, a leading innovation-driven corporation, is developing a growing portfolio of pharmaceutical products by applying the latest research from its own worldwide laboratories and from collaborations with eminent scientific organizations. Headquartered in Indianapolis, Ind., Lilly provides answers — through medicines and information — for some of the world's most urgent medical needs. Additional information about Lilly is available at www.lilly.com.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol-Myers Squibb, visit www.bms.com, or follow us on Twitter at http://twitter.com/bmsnews.

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding product development. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. Among other risks, there can be no guarantee that additional indications will be approved, or if approved, that they will be commercially successful. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's and Lilly's businesses, particularly those identified in the cautionary statement and risk factors discussion in Bristol-Myers Squibb's and Lilly's Annual Reports on Form 10-K for the year ended December 31, 2011, in their Quarterly Reports on Form 10-Q and their Current Reports on Form 8-K. Neither Bristol-Myers Squibb nor Lilly undertakes any obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.

* Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for Colon Cancer V3.2012. © 2012 National Comprehensive Cancer Network, Inc. All rights reserved. Accessed May 9, 2012. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES™, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. Category 2A: The recommendation is based on lower-level evidence and there is uniform NCCN consensus that the intervention is appropriate.

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Source: Bristol-Myers Squibb

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