Novartis announces US collaboration to co-promote Lenvima® in combination with everolimus for advanced renal cell carcinoma (RCC)

EAST HANOVER, N.J., June 2, 2016 /PRNewswire/ -- Novartis Pharmaceuticals Corporation today announced an agreement with Eisai Inc. to collaborate on commercial and certain medical affairs activities in the United States (US) to co-promote Lenvima* (lenvatinib) capsules used in combination with everolimus for the treatment of patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy. Everolimus is marketed by Novartis as Afinitor^®** tablets. The collaboration follows the US Food and Drug Administration (FDA) approval last month of Lenvima in combination with everolimus for this indication, the only VEGF-mTOR inhibitor regimen approved in the US for patients with advanced RCC. Lenvima was granted Breakthrough Therapy designation by the FDA for this indication.

Under the terms of the collaboration agreement, Novartis and Eisai will promote the availability of this combination regimen to appropriate healthcare professionals nationwide, and participate in certain joint medical affairs activities to facilitate appropriate medical use of and medical education regarding the combination. Each company will continue to book sales of its respective product. 

"The goal of this collaboration is to inform physicians that they have a new breakthrough treatment option that simultaneously blocks two key pathways in advanced renal cell carcinoma," said Bruno Strigini, President of Novartis Oncology. "Novartis Oncology's long experience in RCC coupled with Eisai's equal commitment to cancer patients offers a combination of expertise we believe will be a positive force for the RCC community."

RCC is the most common type of kidney cancer in adults, and accounts for 90% of malignant kidney tumors¹. In 2016, nearly 63,000 people will be diagnosed with RCC in the US². Roughly one-third of patients with RCC has metastatic, or advanced, cancer at the time of diagnosis, meaning that the cancer has spread to other parts of the body³. Two primary molecular pathways involved in the progression of advanced RCC are the mammalian target of rapamycin (mTOR) pathway and the vascular endothelial growth factor (VEGF) pathway⁴; everolimus inhibits the mTOR pathway and Lenvima targets the VEGF pathway. A key treatment goal in aRCC is to block the growth of the tumor for as long as possible.

The combination treatment was approved by the FDA on May 13, 2016, based on results of Study 205, Eisai's Phase II registration trial. Study 205 was a multicenter, randomized trial in 153 patients with unresectable advanced or metastatic RCC who were previously treated with an anti-angiogenic therapy and randomized 1:1:1 to receive a combination of 18 mg Lenvima plus 5 mg everolimus, Lenvima only (24 mg once a day) or everolimus only (10 mg once a day) administered orally in continuous 28-day cycles until disease progression or unacceptable toxicity⁵. The primary efficacy endpoint of this study was investigator-assessed progression free survival (PFS), or time from randomization until disease progression or death⁵. Other endpoints of the study included objective response rate (ORR), overall survival (OS) and safety⁵.

The median PFS in patients treated with Lenvima and everolimus (n=51) was 14.6 months (95% confidence interval [CI]: 5.9–20.1) compared with 5.5 months (95% CI: 3.5–7.1) for those treated with everolimus alone (n=50) (hazard ratio [HR] 0.37; 95% CI: 0.22–0.62)⁵. The combination regimen resulted in a 63% reduction in risk of disease progression or death compared with everolimus alone. The ORR with the combination was 37% (95% CI: 24–52; 35% partial response + 2% complete response) compared to 6% (all partial response, 95% CI: 1–17) with everolimus alone. The OS with the combination was 25.5 months (95% CI: 16.4–32.1) versus 15.4 months for everolimus alone (95% CI: 11.8–20.6), HR 0.67 (95% CI: 0.42–1.08)⁵.

The most common adverse reactions observed in study patients treated with Lenvima and everolimus (greater than 30%) were, in order of decreasing frequency, diarrhea, fatigue, arthralgia/myalgia, decreased appetite, vomiting, nausea, stomatitis/oral inflammation, hypertension, peripheral edema, cough, abdominal pain, dyspnea, rash, weight decreased, hemorrhagic events and proteinuria. The most common serious adverse reactions (greater than or equal to 5%) were renal failure (11%), dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%) and dyspnea (5%)⁵.

Eisai Inc. is the US pharmaceutical subsidiary of Eisai Co., Ltd., headquartered in Japan.

About Afinitor
Afinitor is a prescription medicine used to treat adults with advanced kidney cancer (renal cell carcinoma or RCC) when certain other medicines have not worked. Data on the use of Afinitor in combination with Lenvima are not included in the Full Prescribing Information for Afinitor.

Important Safety Information
Patients should not take Afinitor if they are allergic to Afinitor or to any of its ingredients. Patients should tell their health care provider before taking Afinitor if they are allergic to sirolimus (Rapamune^®†) or temsirolimus (Torisel^®‡).

Afinitor can cause serious side effects, including lung or breathing problems, infections, and kidney failure, which can even lead to death. If patients experience these side effects, they may need to stop taking Afinitor for a while or use a lower dose. Patients should follow their health care provider's instructions.

In some patients, lung or breathing problems may be severe and can even lead to death. Patients should tell their health care provider right away if they have any of these symptoms: new or worsening cough, shortness of breath, chest pain, difficulty breathing, or wheezing.

Afinitor may make patients more likely to develop an infection, such as pneumonia, or a bacterial, fungal, or viral infection. Viral infections may include reactivation of hepatitis B in people who have had hepatitis B in the past. In some people these infections may be severe and can even lead to death. Patients may need to be treated as soon as possible. Patients should tell their health care provider right away if they have a temperature of 100.5˚F or above, chills, or do not feel well. Symptoms of hepatitis B or infection may include the following: fever, chills, skin rash, joint pain and inflammation, tiredness, loss of appetite, nausea, pale stools or dark urine, yellowing of the skin, or pain in the upper right side of the stomach.

Patients who take an angiotensin-converting enzyme (ACE) inhibitor medicine during treatment with Afinitor are at a possible increased risk for a type of allergic reaction called angioedema. Patients should get medical help right away if they have trouble breathing or develop swelling of the tongue, mouth, or throat during treatment with Afinitor.

Afinitor may cause kidney failure. In some people this may be severe and can even lead to death. Patients should have tests to check their kidney function before and during their treatment with Afinitor.

Afinitor can cause incisions to heal slowly or not heal well. Patients should tell their health care provider if their incision is red, warm, or painful; if they have blood, fluid, or pus in their incision; or if their incision opens up or is swollen.

Common side effects include mouth ulcers. Afinitor can cause mouth ulcers and sores. Other common side effects include infections, feeling weak or tired, nausea and vomiting, skin problems, headache, weight loss, loss of appetite, cough, diarrhea, fever, swelling of the hands, arms, legs, feet, face, or other parts of the body, joint pain, abnormal taste, stomach-area (abdomen) pain, nose bleeds, increased blood cholesterol and sugar levels, decreased blood phosphate levels, low red and white blood cells, and the absence of menstrual periods (menstruation).

Please see full Prescribing Information for Afinitor available at Afinitor.com.

About Lenvima
Lenvima (lenvatinib) is a kinase inhibitor that is indicated for:

• Differentiated Thyroid Cancer (DTC): single agent for patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory DTC.
• Renal Cell Carcinoma (RCC): in combination with everolimus for patients with advanced RCC following one prior anti-angiogenic therapy.

Lenvatinib, discovered and developed by Eisai, is a receptor tyrosine kinase (RTK) inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1-3. Lenvatinib also inhibits other RTKs that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1-4; the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. The combination of lenvatinib and everolimus showed increased anti-angiogenic and anti-tumor activity as demonstrated by decreased human endothelial cell proliferation, tube formation, and VEGF signaling in vitro and tumor volume in mouse xenograft models of human renal cell cancer greater than each drug alone.

Important Safety Information

Warnings and Precautions

• In DTC, hypertension was reported in 73% of patients on Lenvima vs 16% with placebo (44% vs 4% grade ≥3). In RCC, hypertension was reported in 42% of patients on Lenvima + everolimus vs 10% with everolimus alone (13% vs 2% grade 3). Blood pressure should be controlled prior to treatment and monitored throughout. Withhold dose for grade 3 hypertension despite optimal antihypertensive therapy; resume at reduced dose when controlled at grade ≤2. Discontinue for life-threatening hypertension
• In DTC, cardiac dysfunction was reported in 7% of patients on Lenvima vs 2% with placebo (2% vs 0% grade ≥3). In RCC, cardiac dysfunction was reported in 10% of patients on Lenvima + everolimus vs 6% with everolimus alone (3% vs 2% grade 3). Monitor for signs/symptoms of cardiac decompensation. Withhold for grade 3 cardiac dysfunction. Resume at reduced dose or discontinue based on severity and persistence of cardiac dysfunction. Discontinue for grade 4 cardiac dysfunction
• In DTC, arterial thromboembolic events were reported in 5% of patients on Lenvima vs 2% with placebo (3% vs 1% grade ≥3). In RCC, arterial thromboembolic events were reported in 2% of patients on Lenvima + everolimus vs 6% with everolimus alone (2% vs 4% grade ≥3). Discontinue following an arterial thrombotic event. The safety of resuming Lenvima after an arterial thromboembolic event has not been established, and Lenvima has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months
• Across clinical studies in which 1,160 patients received Lenvima monotherapy, hepatic failure (including fatal events) was reported in 3 patients and acute hepatitis in 1 patient. In DTC, ALT and AST increases (grade ≥3) occurred in 4% and 5% of patients on Lenvima, respectively, vs 0% with placebo. In RCC, ALT and AST increases (grade ≥3) occurred in 3% of patients on Lenvima + everolimus vs 2% and 0% with everolimus alone, respectively. Monitor liver function before initiation, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Withhold dose for liver impairment grade ≥3 until resolved to grade 0, 1, or baseline. Resume at reduced dose or discontinue based on severity/persistence of hepatotoxicity. Discontinue for hepatic failure
• In DTC, proteinuria was reported in 34% of patients on Lenvima vs 3% with placebo (11% vs 0% grade 3). In RCC, proteinuria was reported in 31% of patients on Lenvima + everolimus vs 14% with everolimus alone (8% vs 2% grade 3). Monitor for proteinuria before and during treatment. Withhold dose for proteinuria ≥2 g/24 h. Resume at reduced dose when proteinuria is <2 g/24 h. Discontinue for nephrotic syndrome
• In RCC, diarrhea was reported in 81% of patients on Lenvima + everolimus vs 34% with everolimus alone (19% vs 2% grade ≥3). Initiate prompt medical management for the development of diarrhea. Monitor for dehydration. Withhold dose for diarrhea grade ≥3. Resume at a reduced dose when diarrhea resolves to grade 1 or baseline. Discontinue for grade 4 diarrhea despite medical management
• In DTC, events of renal impairment were reported in 14% of patients on Lenvima vs 2% with placebo (3% vs 1% grade ≥3). In RCC, events of renal impairment were reported in 18% of patients on Lenvima + everolimus vs 12% with everolimus alone (10% vs 2% grade ≥3). Withhold Lenvima for grade 3 or 4 renal failure/impairment. Resume at reduced dose or discontinue, depending on severity/persistence of renal impairment. Active management of diarrhea and any other gastrointestinal (GI) symptoms should be initiated for grade 1 events
• In DTC, events of GI perforation or fistula were reported in 2% of patients on Lenvima vs 0.8% with placebo. In RCC, events of GI perforation, abscess, or fistula (grade ≥3) were reported in 2% of patients on Lenvima + everolimus vs 0% with everolimus alone. Discontinue in patients who develop GI perforation or life-threatening fistula
• In DTC, QT/QTc interval prolongation was reported in 9% of patients on Lenvima vs 2% with placebo (2% vs 0% >500 ms). In RCC, QTc interval increases >60 ms were reported in 11% of patients on Lenvima + everolimus (6% >500 ms) vs 0% with everolimus alone. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or patients taking drugs known to prolong the QT interval. Monitor and correct electrolyte abnormalities in all patients. Withhold dose for QTc interval prolongation >500 ms. Resume at reduced dose when QTc prolongation resolves to baseline
• In DTC, hypocalcemia (grade ≥3) was reported in 9% of patients on Lenvima vs 2% with placebo. In RCC, hypocalcemia (grade ≥3) was reported in 6% of patients on Lenvima + everolimus vs 2% with everolimus alone. Monitor blood calcium levels at least monthly and replace calcium as necessary. Interrupt and adjust Lenvima as necessary
• Across clinical studies in which 1,160 patients received Lenvima monotherapy, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 4 patients. Withhold Lenvima for RPLS until fully resolved. Resume at reduced dose or discontinue based on the severity and persistence of neurologic symptoms
• In DTC, hemorrhagic events occurred in 35% of patients on Lenvima vs 18% with placebo (2% vs 3% grade ≥3). The most frequently reported hemorrhagic event was epistaxis (11% grade 1, 1% grade 2). Discontinuation due to hemorrhagic events occurred in 1% of patients on Lenvima. There was 1 fatal intracranial hemorrhage case among 16 patients who received Lenvima and had central nervous system metastases at baseline. In RCC, hemorrhagic events occurred in 34% of patients on Lenvima + everolimus vs 26% with everolimus alone (8% vs 2% grade ≥3). The most frequently reported hemorrhagic event was epistaxis (23% for Lenvima + everolimus vs 24% with everolimus alone). There was 1 fatal cerebral hemorrhage case. Discontinuation due to hemorrhagic events occurred in 3% of patients on Lenvima + everolimus. Consider the risk of severe or fatal hemorrhage associated with tumor invasion/infiltration of major blood vessels (eg, carotid artery). Withhold dose for grade 3 hemorrhage. Resume at reduced dose or discontinue based on severity/persistence of hemorrhage. Discontinue for grade 4 hemorrhage
• In DTC patients with normal baseline thyroid-stimulating hormone (TSH), elevation of TSH level above 0.5 mU/L was observed postbaseline in 57% of patients on Lenvima vs 14% with placebo. In RCC, grade 1 or 2 hypothyroidism occurred in 24% of patients on Lenvima + everolimus vs 2% with everolimus alone. In RCC patients with normal or low TSH at baseline, elevation of TSH was observed postbaseline in 60% of patients on Lenvima + everolimus vs 3% with everolimus alone. Monitor thyroid function prior to treatment initiation and monthly thereafter. Treat hypothyroidism according to standard medical practice to maintain a euthyroid state
• Lenvima can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with Lenvima and for at least 2 weeks following completion of therapy

Adverse Reactions

• In DTC, the most common adverse reactions observed in Lenvima-treated patients vs placebo-treated patients were hypertension (73% vs 16%), fatigue (67% vs 35%), diarrhea (67% vs 17%), arthralgia/myalgia (62% vs 28%), decreased appetite (54% vs 18%), weight decrease (51% vs 15%), nausea (47% vs 25%), stomatitis (41% vs 8%), headache (38% vs 11%), vomiting (36% vs 15%), proteinuria (34% vs 3%), palmar-plantar erythrodysesthesia syndrome (32% vs 1%), abdominal pain (31% vs 11%), and dysphonia (31% vs 5%)
• In DTC, adverse reactions led to dose reductions in 68% of patients receiving Lenvima and in 5% of patients receiving placebo; 18% of patients discontinued Lenvima and 5% discontinued placebo for adverse reactions. The most common adverse reactions (≥10%) resulting in dose reductions of Lenvima were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (≥1%) resulting in discontinuation of Lenvima were hypertension (1%) and asthenia (1%)
• In RCC, the most common adverse reactions observed in patients treated with Lenvima + everolimus vs everolimus alone were diarrhea (81% vs 34%), fatigue (73% vs 40%), arthralgia/myalgia (55% vs 32%), decreased appetite (53% vs 18%), vomiting (48% vs 12%), nausea (45% vs 16%), stomatitis/oral inflammation (44% vs 50%), hypertension/increased blood pressure (42% vs 10%), peripheral edema (42% vs 20%), cough (37% vs 30%), abdominal pain (37% vs 8%), dyspnea/exertional dyspnea (35% vs 28%), rash (35% vs 40%), weight decreased (34% vs 8%), hemorrhagic events (32% vs 26%), and proteinuria/urine protein present (31% vs 14%)
• In RCC, adverse reactions led to dose reductions or interruption in 89% of patients receiving Lenvima + everolimus and in 54% of patients receiving everolimus. The most common adverse reactions (≥5%) resulting in dose reductions in the Lenvima + everolimus–treated group were diarrhea (21%), fatigue (8%), thrombocytopenia (6%), vomiting (6%), nausea (5%), and proteinuria (5%). Treatment discontinuation due to an adverse reaction occurred in 29% of patients in the Lenvima + everolimus–treated group and in 12% of patients in the everolimus-treated group

Use in Specific Populations

• Because of the potential for serious adverse reactions in nursing infants, advise women to discontinue breastfeeding during treatment
• Lenvima may result in reduced fertility in females of reproductive potential and may result in damage to male reproductive tissues, leading to reduced fertility of unknown duration

For full Prescribing Information, visit Lenvima.com.  

Disclaimer
The foregoing release contains forward-looking statements that can be identified by words such as "commitment," "Breakthrough Therapy," "will," "goal," "breakthrough treatment," or similar terms, or by express or implied discussions regarding potential new indications or labeling for Afinitor alone or in combination with Lenvima (lenvatinib), or regarding potential future revenues from Afinitor alone or in combination with Lenvima. You should not place undue reliance on these statements. Such forward-looking statements are based on the current beliefs and expectations of management regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that Afinitor alone or in combination with Lenvima will be submitted or approved for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that Afinitor alone or in combination with Lenvima will be commercially successful in the future. In particular, management's expectations regarding Afinitor alone or in combination with Lenvima could be affected by, among other things, the uncertainties inherent in research and development, including unexpected clinical trial results and additional analysis of existing clinical data; unexpected regulatory actions or delays or government regulation generally; the company's ability to obtain or maintain proprietary intellectual property protection; general economic and industry conditions; global trends toward health care cost containment, including ongoing pricing pressures; unexpected safety, quality or manufacturing issues, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

About Novartis
Novartis Pharmaceuticals Corporation researches, develops, manufactures and markets innovative medicines aimed at improving patients' lives. We offer a broad range of medicines for cancer, cardiovascular disease, endocrine disease, inflammatory disease, infectious disease, neurological disease, organ transplantation, psychiatric disease, respiratory disease and skin conditions. The company's mission is to improve people's lives by pioneering novel healthcare solutions.

Located in East Hanover, New Jersey, Novartis Pharmaceuticals Corporation is an affiliate of Novartis AG, which provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, eye care and cost-saving generic pharmaceuticals. Novartis is the only global company with leading positions in these areas. In 2015, the Group achieved net sales of USD 49.4 billion, while R&D throughout the Group amounted to approximately USD 8.9 billion (USD 8.7 billion excluding impairment and amortization charges). Novartis Group companies employ approximately 118,000 full-time-equivalent associates. Novartis products are available in more than 180 countries around the world. For more information, please visit http://www.novartis.com.

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References

1. American Cancer Society. Kidney Cancer (adult) - Renal Cell Carcinoma. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003107-pdf.pdf Accessed June 2016.
2. American Cancer Society. Kidney Cancer Statistics. Available at http://www.cancer.org/cancer/kidneycancer/detailedguide/kidney-cancer-adult-key-statistics. Accessed June 2016.
3. National Cancer Institute SEER Fact Sheet. Kidney and Renal Pelvis Cancer. Available at: http://seer.cancer.gov/statfacts/html/kidrp.html. Accessed June 2016.
4. Hainsworth, et al. Phase II Trial of Bevacizumab and Everolimus in Patients With Advanced Renal Cell Carcinoma. Journal of Clinical Oncology. 2010; 28(13): 2131-2136.
5. Lenvima (levantinib) Prescribing Information. Woodcliff Lake, New Jersey, USA: Eisai, Inc. May 2016.

*Lenvima is a registered trademark of Eisai R&D Management Co., Ltd. licensed to Eisai Inc. 
**Afinitor is a registered trademark of Novartis AG or its affiliates.
^†Rapamune is a registered trademark of Wyeth Pharmaceuticals Inc.
^‡Torisel is a registered trademark of Wyeth Pharmaceuticals Inc. 

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