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Lilly’s CYRAMZA® (ramucirumab) Receives Fourth FDA Approval

On April 24, 2015 Eli Lilly has received its fourth U.S. Food and Drug Administration (FDA) approval for CYRAMZA (ramucirumab) (Press release, Eli Lilly, APR 24, 2015, View Source [SID:1234503179]). CYRAMZA (ramucirumab injection 10 mg/mL solution) is now also indicated in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil) chemotherapy for the treatment of patients with metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.

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"CYRAMZA now has approvals in advanced or metastatic forms of three of the world’s most common and deadly cancers – gastric, non-small cell lung, and colorectal – with four FDA approvals received in just over a year," said Sue Mahony, Ph.D., senior vice president and president, Lilly Oncology. "This progress is encouraging and supports our ongoing development program for CYRAMZA. Achieving today’s milestone is another example of Lilly’s commitment to people living with gastrointestinal cancers."

Dr. Mahony added, "We are also pleased with the efficient and collaborative reviews we had with the FDA on these submissions." While granted a standard review, this application for CYRAMZA in mCRC was reviewed and approved in approximately nine weeks following its submission to the FDA. All three supplemental applications for CYRAMZA received FDA approval within six months from the time of submission.

The approval is based on the Phase III trial known as RAISE, which compared CYRAMZA plus FOLFIRI to placebo plus FOLFIRI in people with mCRC who had disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. Efficacy endpoints in the trial included the major efficacy outcome measure of overall survival (OS) and the supportive efficacy outcome measure of progression-free survival (PFS). The labeling for CYRAMZA contains Boxed Warnings for: hemorrhage, including severe and sometimes fatal events; gastrointestinal (GI) perforation, a potentially fatal event; and impaired wound healing. CYRAMZA should be permanently discontinued in patients who experience severe bleeding or a GI perforation. CYRAMZA should be withheld prior to surgery and discontinued if a patient develops wound healing complications. See the Important Safety Information at the end of this press release and the Prescribing Information.

For patients receiving CYRAMZA treatment, Lilly is committed to offering patient assistance programs. Patients, physicians, pharmacists, or other healthcare professionals with additional questions about CYRAMZA should contact The Lilly Answers Center at 1-800-LillyRx (1-800-545-5979) or visit www.lilly.com. Healthcare professionals may also find additional product information on CYRAMZA at www.CYRAMZA.com.

About CYRAMZA (ramucirumab)
In the U.S., CYRAMZA (ramucirumab) is approved for use as a single agent or in combination with paclitaxel (a type of chemotherapy) as a treatment for people with advanced or metastatic gastric (stomach) or gastroesophageal junction (GEJ) adenocarcinoma whose cancer has progressed on or after prior fluoropyrimidine- or platinum-containing chemotherapy. It is also approved in combination with docetaxel (a type of chemotherapy) as a treatment for people with metastatic non-small cell lung cancer (NSCLC) whose cancer has progressed on or after platinum-based chemotherapy. Additionally, it is approved with FOLFIRI (a type of chemotherapy) as a therapy for people with metastatic colorectal cancer (mCRC) whose cancer has progressed on or after therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.

CYRAMZA is an antiangiogenic therapy. It is a vascular endothelial growth factor (VEGF) Receptor 2 antagonist that specifically binds and blocks activation of VEGF Receptor 2 by blocking the binding of VEGF receptor ligands VEGF-A, VEGF-C, and VEGF-D. CYRAMZA inhibited angiogenesis in an in vivo animal model.

ImmunoGen, Inc. Reports Third Quarter Fiscal Year 2015 Financial Results

On April 24, 2015 ImmunoGen, Inc. (Nasdaq: IMGN), a biotechnology company that develops novel anticancer therapeutics using its ADC technology, today reported financial results for the three-month period ended March 31, 2015 – the third quarter of the Company’s 2015 fiscal year. ImmunoGen also provided an update on its product pipeline and financial guidance (Press release, ImmunoGen, APR 24, 2015, View Source [SID1234503177]).

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"We are executing against our product development plan and recently strengthened our financial resources to support these programs," commented Daniel Junius, President and CEO. "The clinical findings with mirvetuximab soravtansine to date are encouraging, and we look forward to their presentation at ASCO (Free ASCO Whitepaper) next month. Based on these data and the medical need, we are expanding the compound’s clinical program and implementing preparations to support an accelerated development pathway."

Mr. Junius continued, "We are also expanding the development program for our CD37-targeting ADC, IMGN529, to include assessment in combination with rituximab for non-Hodgkin lymphoma as well as evaluation as a single agent for diffuse large B-cell lymphoma and chronic lymphocytic leukemia. Updates on other hematology programs include that we are developing our plans for the CD19-targeting ADC, coltuximab ravtansine, for B-cell malignancies that we recently regained from Sanofi, we remain on track for IND submission later this year with IMGN779 for acute myeloid leukemia, and Biotest continues to make important progress with their CD138-targeting ADC for multiple myeloma and certain solid tumors."

Pipeline Updates

Mirvetuximab soravtansine, a potential new therapy for many cases of ovarian cancer as well as for endometrial cancer and other solid tumors that highly express folate receptor α (FRα); wholly owned by ImmunoGen.

This ADC now has received orphan designation in ovarian cancer in the EU as well as in the US.
Initial findings with mirvetuximab soravtansine – used as a single agent – to treat FRα-positive platinum-resistant ovarian cancer will be presented at the 2015 ASCO (Free ASCO Whitepaper) Annual Meeting. The data are from a disease-specific Phase 1 cohort. ImmunoGen plans to initiate a Phase 2 trial in this indication by the end of 2015 that could potentially support an accelerated registration pathway.
ImmunoGen also plans to initiate in 2H2015 assessment of mirvetuximab soravtansine used in combination regimens for ovarian cancer.
Assessment of mirvetuximab soravtansine for the treatment of FRα-positive relapsed/ refractory (R/R) endometrial cancer is ongoing. ImmunoGen is preparing to also assess it for FRα-positive R/R non-small cell lung cancer.
In addition to the every three week dosing schedule being used in the disease-specific testing underway, dose-finding with a weekly dosing regimen is advancing. The findings to date also have been accepted for presentation at ASCO (Free ASCO Whitepaper).

IMGN529, a potential new treatment for B-cell malignancies; wholly owned by ImmunoGen.

Once the recommended Phase 2 dose is established, ImmunoGen plans to evaluate it specifically for the treatment of R/R diffuse large B-cell lymphomas (DLBCL) and chronic lymphocytic leukemia.
Preclinical findings with IMGN529 used with rituximab (Rituxan) will be reported at the International Conference on Malignant Lymphoma in Lugano in June 2015. ImmunoGen is planning to initiate a clinical trial to assess the combination.
The next IMGN529 clinical data presentation(s) are targeted for the ASH (Free ASH Whitepaper) annual meeting in December.

Indatuximab ravtansine (BT-062), a CD138-targeting ADC for multiple myeloma and certain solid tumors; wholly owned by Biotest; ImmunoGen holds rights to opt-in with Biotest on joint US development and commercialization.

Phase 2 trial ongoing in multiple myeloma; Phase 1 trial ongoing in triple-negative breast cancer and metastatic urinary bladder cancer.

Coltuximab ravtansine (SAR3419), a potential therapy for DLBCL and other B-cell malignancies; demonstrated encouraging activity in the treatment of R/R DLBCL in STARLYTE Phase 2 trial presented at ASCO (Free ASCO Whitepaper) 2014 and selected for Best of ASCO (Free ASCO Whitepaper).

ImmunoGen recently regained the rights to this promising ADC from Sanofi.

IMGN779, CD33-targeting ADC utilizing one of ImmunoGen’s DNA-acting payload agents; a potential treatment for acute myeloid leukemia and myelodysplastic syndrome; wholly owned by ImmunoGen.

Remains on track for IND submission in 2H2015.

IMGN289, EGFR-targeting ADC, wholly owned by ImmunoGen.

The Company has stopped Phase 1 testing and returned the program to research.

Genentech/Roche’s ado-trastuzumab emtansine (Kadcyla), which uses ImmunoGen’s ADC technology.

Approved in the US, Europe, and other geographies based on the results from the EMILIA Phase 3 trial; in development by Roche for a number of indications, with data from the MARIANNE Phase 3 trial to be presented at ASCO (Free ASCO Whitepaper).
ImmunoGen recently reported a monetization transaction pertaining to the royalties earned on Kadcyla sales.

Financial Results

For the Company’s quarter ended March 31, 2015 (3QFY2015), ImmunoGen reported a net loss of $21.6 million, or $0.25 per basic and diluted share, compared to a net loss of $37.5 million, or $0.44 per basic and diluted share, for the same quarter last year (3QFY2014).

Revenues for 3QFY2015 were $11.4 million, compared to $6.9 million for 3QFY2014. They include $5.1 million of license and milestone fees, principally from a $5 million cash milestone payment earned from Novartis with the initiation of Phase 1 testing of its product candidate, LOP628. They also include $5.1 million of royalty payments received from Roche in March 2015 for sales of Kadcyla during the three-month period ended December 31, 2014. The royalty transaction recently announced impacts royalties earned on Kadcyla sales starting January 1, 2015. Revenues for 3QFY2015 also include $0.7 million of clinical materials revenue and $0.5 million of research and development support fees. The level of research support and the number of batches of clinical materials produced and released to partners varies on a quarter-to-quarter basis.

Operating expenses in 3QFY2015 were $32.7 million, compared to $44.3 million in 3QFY2014, and consist of research and development expenses of $25.7 million and general and administrative expenses of $7.0 million. The prior year period included a $12.8 million non-cash charge recorded to research and development expense related to a collaboration agreement executed with CytomX.

ImmunoGen had approximately $111.8 million in cash and cash equivalents as of March 31, 2015, – inclusive of a $20 million upfront payment received from Takeda – compared with $142.3 million as of June 30, 2014. Cash used in operations was $27.4 million in the first nine months of FY2015 and capital expenditures were $4.5 million.

Financial Guidance for Fiscal Year 2015

ImmunoGen has updated its guidance for its fiscal year ending June 30, 2015. The Company’s guidance for its net loss is unchanged, and expected to be between $60 million and $65 million. Expected revenues are now projected to be between $85 million and $95 million, compared with previous guidance of between $100 million and $105 million, due to changes in the expected timing of partner milestone events. Expected operating expenses are now projected to be between $145 million and $150 million, compared with previous guidance of between $160 million and $165 million.

ImmunoGen now projects cash and cash equivalents at June 30, 2015 to be between $265 million and $275 million, compared to previous guidance of $75 million to $85 million. This change principally reflects the Kadcyla royalty monetization transaction announced in March 2015. The Company’s guidance for cash used in operations and capital expenditures remains unchanged from that issued on January 2015. These are projected to be between $55 million and $60 million and between $7 million and $9 million, respectively.

The U. S. Food and Drug Administration approved CYRAMZA® (ramucirumab) for use in combination with FOLFIRI for the treatment of patients with metastatic colorectal cancer (mCRC) whose disease has progressed on a first line bevacizumab-, oxaliplatin- and fluoropyrimidine-containing regimen

On April 24, 2015, the U. S. Food and Drug Administration approved ramucirumab (CYRAMZA, Eli Lilly and Company) for use in combination with FOLFIRI for the treatment of patients with metastatic colorectal cancer (mCRC) whose disease has progressed on a first line bevacizumab-, oxaliplatin- and fluoropyrimidine-containing regimen (Press release, Eli Lilly, APR 24, 2015, View Source [SID:1234503178]). Ramucirumab is a recombinant human monoclonal IgG1 antibody that binds to the human vascular endothelial growth factor- receptor 2 (VEGF-R2), preventing the interaction of VEGF-R2 to its ligands.

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This approval is based on the results of a randomized, double-blind, multinational trial enrolling patients with mCRC that progressed during or within 6 months of discontinuation of bevacizumab-, oxaliplatin- and fluoropyrimidine-based combination chemotherapy.

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The clinical trial accrued 1072 patients who were randomly allocated (1:1) to receive FOLFIRI plus placebo or FOLFIRI plus ramucirumab (N=536 per arm). Treatment cycles on both arms were repeated every 2 weeks and ramucirumab was administered at a dose of 8 mg/kg by intravenous infusion every two weeks. Ramucirumab was continued until disease progression or unacceptable toxicity.

The primary efficacy endpoint was overall survival (OS). Treatment assignment was stratified by geographic region (North America vs. Europe vs. other regions), KRAS status (wild-type vs. mutant) and time to progression for the beginning of first-line treatment (< 6 months vs. greater than or equal to 6 months).

The median age of the study population was 62 years, 57% were men, and 99% had an ECOG performance status of 0 or 1. A statistically significant OS improvement was observed in patients receiving FOLFIRI plus ramucirumab compared to those receiving FOLFIRI plus placebo [HR 0.85 (95% CI: 0.73, 0.98), p=0.023, stratified log-rank test]. Median OS was 13.3 and 11.7 months for patients on the FOLFIRI plus ramucirumab and FOLFIRI plus placebo arms, respectively. PFS was also significantly improved in patients who received ramucirumab in combination with FOLFIRI [HR 0.79 (95% CI: 0.70, 0.90), p<0.001]. Median PFS was 5.7 and 4.5 months, respectively.

In general, the safety data was consistent with the known safety profile established in previously approved indications. However, thyroid dysfunction (hypothyroidism) was reported in 2.6% of patients based on thyroid monitoring in patients with mCRC.

The recommended dose and schedule in patients receiving ramucirumab in combination with FOLFIRI after progression on a first-line bevacizumab containing regimen is 8 mg/kg administered every 2 weeks as a 60-minute IV infusion.

Full prescribing information is available at:
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Bristol-Myers Squibb Receives Positive CHMP Opinion in the European Union for Opdivo (nivolumab) for the Treatment of Advanced Melanoma in Both First-Line and Previously Treated Patients

On April 24, 2015 Bristol-Myers Squibb reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending that Opdivo (nivolumab), a PD-1 immune checkpoint inhibitor, be granted approval for use in both first-line and previously treated patients with advanced (unresectable or metastatic) melanoma (Press release, Bristol-Myers Squibb, APR 24, 2015, View Source [SID:1234503174]). This is the first positive opinion given by the CHMP for a PD-1 immune checkpoint inhibitor, and it will now be reviewed by the European Commission, which has the authority to approve medicines for the European Union (EU).

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The EMA granted Bristol-Myers Squibb accelerated assessment of Opdivo based on current regulations that fulfills its guidance about "medicinal products of major interest from the point of view of public health and in particular from the view point of therapeutic innovation."

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"We are pleased with today’s CHMP positive opinion, as it is a step closer to us bringing this important medicine for those advanced melanoma patients in Europe in need of new options," said Michael Giordano, senior vice president, Head of Development, Oncology. "Our vision is to transform how we approach cancer – from clinical practice to improved patient outcomes. We continue to expand the breadth and depth of our immuno-oncology portfolio across the continuum of melanoma and multiple other cancers, to provide more patients with the potential opportunity for long-term survival."

Positive Opinion based on CheckMate -066, -037

The CHMP positive opinion is based on data from two Phase III studies (CheckMate -066 and -037), demonstrating the efficacy and safety of Opdivo in advanced melanoma patients with important unmet needs. CheckMate -066, a Phase III randomized double-blind study, comparing Opdivo to the chemotherapy dacarbazine (DTIC) in patients with treatment-naïve advanced melanoma, is the first Phase III trial of an investigational PD-1 immune checkpoint inhibitor to demonstrate an overall survival benefit in advanced melanoma, as well as a higher objective response rate. A second study, CheckMate -037, is a Phase III randomized, controlled open-label study of Opdivo versus investigator’s choice chemotherapy in patients with advanced melanoma who were previously treated with Yervoy (ipilimumab), which showed improvement in objective response rates. These data are supported by a Phase Ib study (Study -003) in relapsed advanced or metastatic melanoma, which demonstrated the first characterization of Opdivo benefit/risk in advanced melanoma. There was consistent Opdivo dosing of 3 mg/kg every two weeks across all three trials.

About Opdivo

Bristol-Myers Squibb has a broad, global development program to study Opdivo in multiple tumor types consisting of more than 50 trials – as monotherapy or in combination with other therapies – in which more than 7,000 patients have been enrolled worldwide.

Opdivo became the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world on July 4, 2014 when Ono Pharmaceutical Co. announced that it received manufacturing and marketing approval in Japan for the treatment of patients with unresectable melanoma. In the U.S., the U.S. Food and Drug Administration (FDA) granted its first approval for Opdivo for the treatment of patients with unresectable or metastatic melanoma and disease progression following Yervoy (ipilimumab) and, if BRAF V600 mutation positive, a BRAF inhibitor. On March 5, 2015, Opdivo recently received its second FDA approval for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.

About Advanced Melanoma

Melanoma is a form of skin cancer characterized by the uncontrolled growth of pigment-producing cells (melanocytes) located in the skin. Metastatic melanoma is the deadliest form of the disease, and occurs when cancer spreads beyond the surface of the skin to the other organs, such as the lymph nodes, lungs, brain or other areas of the body. The incidence of melanoma has been increasing for at least 30 years. In 2012, an estimated 232,130 melanoma cases were diagnosed globally. Melanoma is mostly curable when treated in its early stages. However, in its late stages, the average survival rate has historically been just six months with a one-year mortality rate of 75%, making it one of the most aggressive forms of cancer.

Bayer Submits Marketing Authorization for Radium-223 Dichloride to Treat Prostate Cancer with Bone Metastases in Japan (for specialized target groups only)

On April 24, 2015 Bayer reported Bayer HealthCare has submitted an application for marketing authorization to the Ministry of Health, Labour and Welfare (MHLW) in Japan for radium-223 dichloride (radium-223) solution for injection for the treatment of prostate cancer patients with bone metastases (Press release, Bayer, APR 24, 2015, View Source [SID:1234503173]).

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"The number of patients suffering from prostate cancer has steadily increased in Japan over the past years, and for patients with advanced disease, there are limited options," said Dr. Joerg Moeller, Member of the Bayer HealthCare Executive Committee and Head of Global Development. "With its specific mode of action and the proven clinical benefit, radium-223 reflects our commitment to developing innovative cancer treatments for patients for whom only limited therapy options are available today."

The regulatory submission is based on data from the pivotal Phase III ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) trial as well as data from additional trials to evaluate the safety and efficacy of radium-223 in Japanese patients. At the interim analysis of the ALSYMPCA trial, radium-223 significantly improved overall survival (OS) [HR=0.695 (95% CI 0.552-0.875), p=0.00185]. Median OS was 14.0 months with radium-223 plus best standard of care vs. 11.2 months with placebo plus best standard of care. Additionally, at the interim analysis there was a delay in the time to first symptomatic skeletal event (SSE) for patients treated with radium-223 vs. placebo. An updated analysis conducted after the study was unblinded showed a further improvement in OS for patients treated with radium-223 vs. placebo, with a median OS of 14.9 months vs. 11.3 months [HR=0.695 (95% CI 0.581-0.832)].

The most common adverse reactions (occurring at a rate of 10% or greater) in patients receiving radium-223 in the ALSYMPCA trial were nausea, diarrhea, vomiting and peripheral edema. The most common hematologic laboratory abnormalities (occurring at a rate of 10% or greater) were anemia, lymphocytopenia, leukopenia, thrombocytopenia and neutropenia.

About the ALSYMPCA Trial
The ALSYMPCA trial was a Phase III, randomized, double-blind, placebo-controlled international study of radium-223 with best standard of care vs. placebo with best standard of care in symptomatic castration-resistant prostate cancer (CRPC) patients with bone metastases. The trial enrolled 921 patients in more than 100 centers in 19 countries. The study treatment consisted of up to six intravenous injections of radium-223 or placebo each separated by an interval of four weeks.

The primary endpoint of the study was OS. A key secondary endpoint was time to first SSE, as defined as external beam radiation therapy (EBRT) to relieve skeletal symptoms, new symptomatic pathologic bone fracture, occurrence of spinal cord compression or tumor-related orthopedic surgical intervention.

About Castration-Resistant Prostate Cancer (CRPC) and Bone Metastases
Prostate cancer is the second most commonly diagnosed malignancy in men worldwide. In 2012, an estimated 1,111,000 men were diagnosed with prostate cancer and 307,000 died from the disease worldwide. In Japan, an estimated 47,000 men were affected with prostate cancer and 12,000 died from the disease in 2013. Prostate cancer is the fifth leading cause of death from cancer in men worldwide, and the sixth leading cause of death from cancer in Japanese men.

CRPC is an advanced form of prostate cancer. A majority of men with CRPC have symptomatic bone metastases resulting in pain, skeletal events such as fractures or spinal cord compression, and/or reduced survival. In fact, bone metastases lead to an increased risk of morbidity and death in patients with CRPC.

About Radium-223 Dichloride
Radium-223 dichloride (radium-223) is a therapeutic alpha particle-emitting pharmaceutical with an anti-tumor effect on bone metastases. Radium-223 mimics calcium and selectively targets bone, specifically areas of bone metastases, by forming complexes with the bone mineral hydroxyapatite. The high linear energy transfer of alpha emitters leads to a high frequency of double-strand DNA breaks in adjacent tumor cells, resulting in a potent cytotoxic effect. The alpha particle range from radium-223 is less than 100 micrometers, which minimizes damage to the surrounding normal tissue.

Radium-223 has been approved under the brand name Xofigo in more than 40 countries worldwide, including the U.S. and the EU.