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FDA Oncologic Drugs Advisory Committee Votes in Favor of Daiichi Sankyo’s Pexidartinib for the Treatment of Select Patients with TGCT, a Rare, Debilitating Tumor

On May 14, 2019 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported that the U.S. Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC) voted (Vote: 12 yes, 3 no, zero abstained) that the demonstrated benefit of pexidartinib outweighs the risks in the treatment of adult patients with symptomatic TGCT, which is associated with severe morbidity or functional limitations, and which is not amenable to improvement with surgery (Press release, Daiichi Sankyo, MAY 14, 2019, View Source [SID1234536292]).

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"Today’s vote in favor of pexidartinib marks a significant step toward delivering the first approved systemic therapy for select TGCT patients whose disease is not amenable to improvement with surgery," said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo. "Some people living with TGCT experience debilitating symptoms and need innovative treatment options. We believe that pexidartinib has the potential to help address this need by offering carefully selected TGCT patients an important treatment advancement, and we look forward to working with the FDA as it completes its review of our application."

The New Drug Application (NDA) for pexidartinib is currently under Priority Review in the U.S., and the FDA is expected to decide whether to approve the application by the PDUFA date of August 3, 2019. The FDA will consider today’s vote as it reviews the NDA, although it is not obligated to follow the Committee’s recommendation. The NDA submission is based on the results of the pivotal phase 3 ENLIVEN study of oral pexidartinib, the first placebo-controlled study of a systemic investigational therapy in patients with TGCT.

The ENLIVEN study met its primary endpoint of tumor response rate by RECIST, which was 39 percent in pexidartinib-treated patients and zero percent for placebo-treated patients at week 25 (p <0.0001). In the ENLIVEN study, hepatic toxicities were more frequent with pexidartinib versus placebo (aspartate aminotransferase [AST] or alanine aminotransferase [ALT] ≥3X the upper limit of normal [ULN]: 33 percent, total bilirubin ≥2X ULN: 5 percent, N=61). In the randomized Part 1 of the study, eight (13%) patients discontinued pexidartinib due to adverse events (AEs); one discontinuation was due to hypertension and seven were due to liver-related AEs occurring within the first two months of treatment. Of the liver-related AEs, three were serious nonfatal AEs with increased bilirubin, one lasting ~7 months. In non-TGCT development studies using pexidartinib, two severe liver toxicity cases (one required liver transplant, one was associated with death) were observed.

About TGCT (PVNS/GCT-TS)
Tenosynovial giant cell tumor (TGCT), also referred to as pigmented villonodular synovitis (PVNS) or giant cell tumor of the tendon sheath (GCT-TS), is a rare, non-malignant tumor that can be locally aggressive. TGCT affects the synovium-lined joints, bursae, and tendon sheaths, resulting in swelling, pain, stiffness and reduced mobility in the affected joint or limb.[1],[2],[3]

While the exact incidence of TGCT is not known, it is estimated that the incidence of TGCT is 11 to 50 cases per million person-years, based on studies from three countries.[4],[5],[6] TGCT is subcategorized into two types: localized, which is more common and accounts for 90 percent of cases, and diffuse, which accounts for 10 percent of cases.5,6 The current standard of care for TGCT is surgical resection.1,2 However, in patients with a recurrent, difficult to treat, or diffuse form where the tumor can wrap around bone, tendons, ligaments and other parts of the joint, it is more difficult to remove or might not be amenable to improvement with surgery due to the risk of morbidity and potential recurrence. Additional surgeries for more severe cases can lead to significant joint damage, debilitating functional impairments, and reduced quality of life and amputation may be considered.[7],[8],[9]

Recurrence rates for localized TGCT are estimated to be up to 15 percent following complete resection.2,[10],[11],[12] Diffuse TGCT recurrence rates are estimated to be about 20 percent to 50 percent following complete resection.3,10,[13] TGCT affects all age groups; the diffuse type on average occurs most often in people below the age of 40 and the localized type typically occurs in people between 30 and 50 years old.1,4,5,6

About Pexidartinib
Pexidartinib is an investigational, novel, oral small molecule that potently inhibits CSF1R (colony stimulating factor-1 receptor), which is a primary growth driver of abnormal cells in the synovium that cause TGCT. Pexidartinib also inhibits c-kit and FLT3-ITD. Pexidartinib was discovered by Plexxikon Inc., the small molecule structure-guided R&D center of Daiichi Sankyo.

Pexidartinib is currently under regulatory review with the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT), which is associated with severe morbidity or functional limitations, and which is not amenable to improvement with surgery. In addition to Priority Review designation, pexidartinib has been granted Breakthrough Therapy designation for the treatment of patients with pigmented villonodular synovitis (PVNS) or giant cell tumor of the tendon sheath (GCT-TS), where surgical resection may result in potentially worsening functional limitation or severe morbidity, and Orphan Drug designation for PVNS/GCT-TS by the FDA. Pexidartinib also has received Orphan Drug designation from the European Commission for the treatment of TGCT. Pexidartinib is an investigational compound that has not been approved for any indication in any country. Safety and efficacy have not been established.

About Daiichi Sankyo Cancer Enterprise
The mission of Daiichi Sankyo Cancer Enterprise is to leverage our world-class, innovative science and push beyond traditional thinking to create meaningful treatments for patients with cancer. We are dedicated to transforming science into value for patients, and this sense of obligation informs everything we do. Anchored by three pillars including our investigational Antibody Drug Conjugate Franchise, Acute Myeloid Leukemia Franchise and Breakthrough Science, we aim to deliver seven distinct new molecular entities over eight years during 2018 to 2025. Our powerful research engines include two laboratories for biologic/immuno-oncology and small molecules in Japan, and Plexxikon Inc., our small molecule structure-guided R&D center in Berkeley, CA. Compounds in pivotal stage development include: [fam-] trastuzumab deruxtecan, an antibody drug conjugate (ADC) for HER2 expressing breast, gastric and other cancers; quizartinib, an oral selective FLT3 inhibitor, for newly-diagnosed and relapsed/refractory FLT3-ITD acute myeloid leukemia (AML); and pexidartinib, an oral CSF1R inhibitor, for tenosynovial giant cell tumor (TGCT). For more information, please visit: www.DSCancerEnterprise.com.

Phio Pharmaceuticals Reports First Quarter 2019 Financial Results and Corporate Highlights

On May 14, 2019 Phio Pharmaceuticals Corp. (NASDAQ: PHIO), a biotechnology company developing the next generation of immuno-oncology therapeutics based on its proprietary self-delivering RNAi (sd-rxRNA) therapeutic platform, reported its financial results for the first quarter ended March 31, 2019 and provided a business update (Press release, Phio Pharmaceuticals, MAY 14, 2019, View Source [SID1234536286]).

"Our financial results during the first quarter of the year continue to remain consistent and in line with our projections for 2019. With an approximate $2 million quarterly cash burn expected to continue for the remainder of the year, the Company expects to have funding into the second half of 2020 while also providing us with the ability to significantly advance and expand our pipeline projects. In parallel with progressing our lead pipeline products, we have expanded our collaborations to include a collaboration with Glycostem Therapeutics and have increased our data output supporting the broad applicability of our self-delivering RNAi platform in various immune cell types and immuno-oncology applications, such as adoptive cell therapy and direct intra-tumoral use of our products," said Dr. Gerrit Dispersyn, President and CEO of Phio Pharmaceuticals Corp. "By bringing new talent on board and implementing improved R&D processes, we look forward to further accelerating our R&D efforts within the financial expectations and projected cash runway."

Quarter in Review and Recent Corporate Updates

Leadership:
Appointed Gerrit Dispersyn, Dr. Med. Sc. as the Company’s President and Chief Executive Officer. Dr. Dispersyn succeeded Geert Cauwenbergh, Dr. Med. Sc., who retired as CEO of the Company and remains as a member of the Company’s Board of Directors.
Appointed John A. Barrett, Ph.D. as the Company’s Chief Development Officer. Dr. Barrett joins Phio from Ziopharm Oncology, Inc. where he served as the company’s Vice President of R&D and Translational Medicine. He has accumulated over 25 years of experience working in research and development and is an expert in developing cell-based immuno-oncology therapies. Dr. Barrett will lead the development and execution of the Company’s preclinical and clinical strategy for our product candidates.
Entered into a research collaboration with Glycostem Therapeutics BV to explore the potential synergies of using our sd-rxRNA in combination with Glycostem’s proprietary Natural Killer-cell (NK-cell) generation technology (oNKord). The goal of the collaboration is to develop cellular immunotherapies for cancer treatment with enhanced efficacy and/or safety, resulting in further improvement of Glycostem’s cellular immunotherapies for the treatment of cancer patients.
Presented a poster titled "Feasibility and efficacy using self-delivering RNAi against TGFB1 to reduce TME immunosuppression" at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2019.
Data from the poster demonstrated that an sd-rxRNA targeting TGFB1 was efficiently taken up by cancer and immune cells resulting in downregulation of target gene expression. The data further showed that intra-tumoral injection of sd-rxRNA targeting TGFB1 can reduce the immunosuppressive tumor microenvironment and potentially boost immune effector cell activity. Future clinical development activities will explore the possible synergistic effects of this approach in combination with adoptive cell therapy or other oncology therapies.
On May 14, 2019, the Nasdaq Stock Market provided written notice and granted the Company an additional 180 calendar days, or until November 11, 2019, to regain compliance with the minimum bid price requirements set forth in the Nasdaq listing rules. The written notice has no effect on the listing of the Company’s common stock at this time.
Select Financial Results

Cash Position

At March 31, 2019, the Company had cash of $12.7 million as compared with $14.9 million at December 31, 2018. The Company expects its cash to provide funding into the second half of 2020.

Research and Development Expenses

Research and development expenses for the quarter ended March 31, 2019 were $1.1 million as compared with $1.4 million for the quarter ended March 31, 2018. The decrease was primarily due to a reduction in headcount and the payroll-related expenses, as well as the completion of the Company’s drug manufacture of RXI-762 in the prior year period.

General and Administrative Expenses

General and administrative expenses for the quarter ended March 31, 2019 were $1.1 million as compared with $0.9 million for the quarter ended March 31, 2018. The increase was primarily due to an increase in stock-based compensation expense related to the restricted stock issued to the Company’s former Chief Executive Officer in lieu of cash compensation.

Net Loss

Net loss for the quarter ended March 31, 2019 was $2.1 million, compared with $2.2 million for the quarter ended March 31, 2018. The decrease was primarily due to changes in operating expenses, as discussed above

Daiichi Sankyo Announces Outcome of FDA Oncologic Drugs Advisory Committee Meeting to Review FLT3 Inhibitor Quizartinib for the Treatment of Patients with Relapsed/Refractory FLT3-ITD AML

On May 14, 2019 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported the outcome of the U.S. Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC) to discuss the company’s New Drug Application (NDA) for quizartinib for the treatment of adults with relapsed/refractory FLT3-ITD acute myeloid leukemia (AML) (Press release, Daiichi Sankyo, MAY 14, 2019, https://www.prnewswire.com/news-releases/daiichi-sankyo-announces-outcome-of-fda-oncologic-drugs-advisory-committee-meeting-to-review-flt3-inhibitor-quizartinib-for-the-treatment-of-patients-with-relapsedrefractory-flt3-itd-aml-300850274.html [SID1234536285]).

Three committee members voted yes and 8 committee members voted no when asked if the results from the pivotal phase 3 QuANTUM-R study demonstrated that treatment with quizartinib provides a benefit that outweighs the safety risks for patients with relapsed/refractory FLT3-ITD AML.

"While we are disappointed by the outcome of today’s ODAC vote, we will work closely with the FDA as it completes the review of our submission," said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo. "Patients with relapsed/refractory FLT3-ITD AML are facing a very aggressive disease with poor prognosis, and we continue to believe that quizartinib could offer an important additional treatment option that specifically targets FLT3-ITD, a driver mutation in AML."

The FDA is not bound by the recommendations of the advisory committee. The NDA for quizartinib is currently under Priority Review in the U.S., and the FDA is expected to make a decision on approval by the Prescription Drug User Fee Act (PDUFA) date of August 25, 2019. The NDA submission of quizartinib is based on the results of the pivotal phase 3 QuANTUM-R study, which was the first randomized phase 3 study to show that a FLT3 inhibitor prolonged overall survival as an oral, single agent compared to chemotherapy in patients with relapsed/refractory FLT3-ITD AML.

In the quizartinib QuANTUM-R study, the median treatment duration with quizartinib was 4 cycles of 28 days each versus 1 cycle in the salvage chemotherapy arm. Incidence of treatment-emergent adverse events was comparable between patients who received single agent quizartinib and those who received salvage chemotherapy. The most common adverse drug reactions (>30 percent, any Grade) in patients treated with quizartinib included infections, bleeding, nausea, asthenic conditions, pyrexia, febrile neutropenia, and vomiting, and the most common Grade ≥ 3 adverse drug reactions (>20 percent) were infection and febrile neutropenia. The most common laboratory adverse reactions (incidence >50 percent) were decreased white blood cell count, decreased lymphocyte count, decreased hemoglobin, decreased neutrophil count, and decreased platelet count. QTcF >500 msec occurred in 8 patients (3.3 percent) and 2 out of 241 patients discontinued quizartinib due to QTcF prolongation. There were no reported events of Grade 4 QTcF prolongation (Torsades de Pointes, sudden death or cardiac arrest) in the quizartinib arm. The safety profile observed in QuANTUM-R appears consistent with that observed at similar doses in the quizartinib clinical development program.

About FLT3-ITD AML
AML is an aggressive blood and bone marrow cancer that causes uncontrolled growth and accumulation of malignant white blood cells that fail to function normally and interfere with the production of normal blood cells.1 In the U.S. this year, it is estimated that there will be more than 19,000 new diagnoses of AML and more than 10,000 deaths from AML.2 The five-year survival rate of AML reported from 2007 to 2013 was approximately 27 percent, which was the lowest of all leukemias.1

FLT3 gene mutations are one of the most common genetic abnormalities in AML.3 FLT3-ITD is the most common FLT3 mutation, affecting approximately one in four patients with AML.4,5,6,7 FLT3-ITD is a driver mutation that presents with high leukemic burden and has poor prognosis and a significant impact on disease management for patients with AML.5,8 Patients with FLT3-ITD AML have a worse overall prognosis, including an increased incidence of relapse, an increased risk of death following relapse and a higher likelihood of relapse following hematopoietic stem cell transplantation as compared to those without this mutation.9,10

About Quizartinib
Quizartinib, the lead investigational agent in the AML Franchise of the Daiichi Sankyo Cancer Enterprise, is an oral selective type II FLT3 inhibitor currently under regulatory review with the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA) and the Japan Ministry of Health, Labour and Welfare (MHLW) for the treatment of adult patients with relapsed/refractory AML which is FLT3-ITD positive. Quizartinib has been granted Priority Review and Breakthrough Therapy designation for the treatment of adult patients with relapsed/refractory FLT3-ITD AML, and Fast Track designation for the treatment of relapsed/refractory AML by the FDA. Quizartinib also has been granted Orphan Drug designation by both the FDA and the European Commission (EC) for the treatment of AML and by the Japan MHLW for the treatment of FLT3-mutated AML.

Quizartinib is also in phase 3 development in combination with standard chemotherapy in newly-diagnosed FLT3-ITD AML (QuANTUM-First) in the U.S., EU and Japan; phase 1/2 development for pediatric and young adult relapsed/refractory FLT3-ITD AML in North America and the EU; and phase 1 development in combination with an investigational MDM2 inhibitor, milademetan, for relapsed/refractory FLT3-ITD AML and newly-diagnosed FLT3-ITD AML unfit for intensive chemotherapy in the U.S. and Japan.

Quizartinib and milademetan are investigational agents that have not been approved for any indication in any country. Safety and efficacy have not been established.

Milestone Pharmaceuticals Announces Full Exercise of Underwriters’ Option to Purchase Additional Shares in Its Initial Public Offering

On May 14, 2019 Milestone Pharmaceuticals Inc. (Nasdaq: MIST), a Phase 3 clinical-stage biopharmaceutical company dedicated to developing and commercializing etripamil for the treatment of cardiovascular indications, reported that the underwriters for its initial public offering of common shares have fully exercised their option to purchase an additional 825,000 common shares at the public offering price of $15.00 per share (Press release, Milestone Pharmaceuticals, MAY 14, 2019, View Source [SID1234536284]). The gross proceeds to Milestone from the exercise of the option, are expected to be approximately $12.4 million, bringing the total gross proceeds of Milestone’s initial public offering to approximately $94.9 million before deducting underwriting discounts, commissions and offering expenses. All of the common shares were offered by Milestone. The closing of the option exercise is expected to occur on May 15, 2019, subject to satisfaction of customary closing conditions.

Milestone’s common shares are listed on the Nasdaq Global Select Market under the ticker symbol "MIST."

Jefferies LLC, Cowen and Company, LLC, and Piper Jaffray & Co. served as joint book-running managers for the offering. Oppenheimer & Co. Inc. served as lead manager for the offering.

The shares were offered by Milestone pursuant to registration statements that were declared effective by the U.S. Securities and Exchange Commission ("SEC") on May 8, 2019. A prospectus relating to and describing the terms of the offering has been filed with the SEC and is available on the SEC’s website at www.sec.gov.

The offering of these shares was made only by means of a prospectus. Copies of the final prospectus relating to this offering may be obtained from Jefferies LLC, Attention: Equity Syndicate Prospectus Department, 520 Madison Avenue, 2nd Floor, New York, NY 10022, or by telephone at (877) 821-7388, or by e-mail at [email protected], or from Cowen and Company, LLC, c/o Broadridge Financial Solutions, 1155 Long Island Avenue, Edgewood, NY 11717, Attention: Prospectus Department, by telephone at 631-592-5973 or by email at [email protected], or from Piper Jaffray & Co., Attention: Prospectus Department, 800 Nicollet Mall, J12S03, Minneapolis, MN 55402, by telephone at (800) 747-3924 or by email at [email protected].

This press release shall not constitute an offer to sell or the solicitation of an offer to buy, nor shall there be any sale of Milestone’s common shares in any jurisdiction in which such offer, solicitation or sale would be unlawful prior to the registration or qualification under the securities laws of such state or jurisdiction.

FDA Approves BAVENCIO® (avelumab) Plus INLYTA® (axitinib) Combination for Patients with Advanced Renal Cell Carcinoma

On May 14, 2019 EMD Serono, the biopharmaceutical business of Merck KGaA, Darmstadt, Germany in the US and Canada, and Pfizer Inc. (NYSE: PFE) reported that the US Food and Drug Administration (FDA) has approved BAVENCIO (avelumab) in combination with INLYTA (axitinib) for the first-line treatment of patients with advanced renal cell carcinoma (RCC) (Press release, EMD Serono, MAY 14, 2019, View Source [SID1234536283]). This is the first FDA approval for an anti-PD-L1 therapy as part of a combination regimen for patients with advanced RCC. The approval of BAVENCIO in combination with INLYTA was based on positive results from the Phase III JAVELIN Renal 101 study (NCT02684006), in which the combination significantly improved median progression-free survival (PFS) compared with sunitinib by more than five months in the intent-to-treat (ITT) patient population (HR: 0.69 [95% CI: 0.56–0.84]; 2-sided p-value=0.0002; median PFS for BAVENCIO in combination with INLYTA: 13.8 months [95% CI: 11.1-NE]; sunitinib: 8.4 months [95% CI: 6.9-11.1]). The ITT population included patients regardless of PD-L1 expression and across IMDC (International Metastatic Renal Cell Carcinoma Database) prognostic risk groups (favorable 21%, intermediate 62% and poor 16%).1

"As we look to continue to improve outcomes for people with advanced RCC, new treatment approaches have the potential to benefit patients," said Robert J. Motzer, M.D., Jack and Dorothy Byrne Chair in Clinical Oncology, Memorial Sloan Kettering Cancer Center, New York, US, and principal investigator for JAVELIN Renal 101. "With today’s FDA approval of avelumab in combination with axitinib, we can now offer patients with advanced RCC a first-line treatment option that combines a PD-L1 immunotherapy with a well-known VEGFR TKI to provide a significant reduction in the risk of disease progression or death and doubling of the response rate compared with sunitinib."

RCC is a type of cancer where PD-L1 expression may contribute to inhibition of the immune response against the tumor.2 It is also a highly vascular tumor, in which vascular endothelial growth factor (VEGF) plays a key role.3

"A kidney cancer diagnosis is life-changing for both patients and their loved ones, and having a treatment strategy for their disease quickly becomes a priority," said Dena Battle, President, KCCure. "The approval of new treatments such as BAVENCIO in combination with INLYTA gives patients with advanced RCC much-needed options."

There is a significant unmet need for first-line treatments that delay progression and have an acceptable safety profile. Approximately 20% to 30% of patients are first diagnosed with RCC at the advanced stage, and 30% of patients treated for an earlier stage go on to develop metastases.4,5 About half of patients living with advanced RCC do not go on to receive additional treatment after first-line therapy,6,7 for reasons that may include poor performance status or adverse events from their initial treatment.6,8,9

"Today’s approval of BAVENCIO in combination with INLYTA builds on Pfizer’s long heritage in bringing innovation to the RCC community with the hopes of making a significant and meaningful impact on the lives of patients," said Andy Schmeltz, Global President, Pfizer Oncology. "For more than 12 years, Pfizer has led the field in its commitment to developing new treatments for patients with advanced kidney cancer."

"With today’s FDA approval of BAVENCIO in combination with INLYTA, we feel privileged that we can offer patients with first-line advanced renal cell carcinoma a new treatment option," said Rehan Verjee, President, EMD Serono, and Global Head of Innovative Medicine Franchises, Merck KGaA, Darmstadt, Germany.

In JAVELIN Renal 101, the objective response rate (ORR) was doubled in the ITT population with BAVENCIO in combination with INLYTA versus sunitinib (51.4% [95% CI: 46.6-56.1] vs. 25.7% [95% CI: 21.7-30.0]). With a median overall survival (OS) follow-up of 19 months, data for the trial’s other primary endpoint of OS were immature, with 27% of deaths in the ITT population, and the trial is continuing as planned. The most common adverse reactions (≥20%) were diarrhea, fatigue, hypertension, musculoskeletal pain, nausea, mucositis, palmar-plantar erythrodysesthesia, dysphonia, decreased appetite, hypothyroidism, rash, hepatotoxicity, cough, dyspnea, abdominal pain and headache. Serious adverse reactions occurred in 35% of patients receiving BAVENCIO in combination with INLYTA. The incidence of major adverse cardiovascular events (MACE) was higher with BAVENCIO in combination with INLYTA versus sunitinib.1 Findings from the study have been published in The New England Journal of Medicine.10

The European Medicines Agency (EMA) validated the Type II variation application for BAVENCIO in combination with INLYTA in advanced RCC in March 2019, and a supplemental application for BAVENCIO in combination with INLYTA in unresectable or metastatic RCC was submitted in Japan in January 2019.

The alliance is committed to providing patient access and reimbursement support through its CoverOne program to patients who have been prescribed BAVENCIO. This program provides a spectrum of patient access and reimbursement support services intended to help US patients prescribed BAVENCIO receive appropriate access. CoverOne may be reached by phone at 844-8COVER1 (844-826-8371) or online at www.CoverOne.com.

Pfizer is committed to ensuring that patients who are prescribed INLYTA have access to this innovative therapy. Patients in the US have access to Pfizer Oncology Together, which offers personalized support and financial assistance resources to help patients access their prescribed Pfizer Oncology medications. For more information, please call 1-877-744-5675 or visit PfizerOncologyTogether.com.

In an effort to streamline the patient enrollment process, EMD Serono and Pfizer have partnered to create a single enrollment form for the BAVENCIO and INLYTA combination for patients with advanced RCC that can be processed through both CoverOne and Pfizer Oncology Together. Each program will independently conduct the access and reimbursement activities for the product for which it is responsible.

About Renal Cell Carcinoma
In 2019, an estimated 73,820 new cases of kidney cancer will be diagnosed in the US, and approximately 14,770 people will die from the disease.11 RCC is the most common form of kidney cancer, accounting for about 2% to 3% of all cancers in adults.12,13 Approximately 20% to 30% of patients with kidney cancer are first diagnosed at the advanced stage.4 The five-year survival rate for patients with metastatic RCC is approximately 12%.14

About the JAVELIN Renal 101 study
The Phase III JAVELIN Renal 101 study is a randomized (1:1), multicenter, open-label study of BAVENCIO in combination with INLYTA in 886 patients with untreated advanced RCC regardless of tumor PD-L1 expression [intent-to-treat (ITT) population]. Patients with autoimmune disease or conditions requiring systemic immunosuppression were excluded. The major efficacy outcome measures were PFS as assessed by a Blinded Independent Central Review (BICR) using RECIST v1.1 and OS in patients with PD-L1-positive tumors using a clinical trial assay (PD-L1 expression level ≥1%). If PFS was statistically significant in patients with PD-L1-positive tumors, it was then tested in the ITT population. The hazard ratio for PFS in patients with PD-L1-positive tumors was HR 0.61 (95% CI: 0.48, 0.79). PFS and OS in the ITT population, overall response and safety are included as secondary endpoints. The study is continuing for OS.

About the JAVELIN Clinical Development Program
The clinical development program for avelumab, known as JAVELIN, involves at least 30 clinical programs and about 10,000 patients evaluated across more than 15 different tumor types. In addition to RCC, these tumor types include gastric/gastro-esophageal junction cancer, head and neck cancer, Merkel cell carcinoma, non-small cell lung cancer, and urothelial carcinoma.

About BAVENCIO (avelumab)
BAVENCIO is a human anti-programmed death ligand-1 (PD-L1) antibody. BAVENCIO has been shown in preclinical models to engage both the adaptive and innate immune functions. By blocking the interaction of PD-L1 with PD-1 receptors, BAVENCIO has been shown to release the suppression of the T cell-mediated antitumor immune response in preclinical models.15-17 BAVENCIO has also been shown to induce NK cell-mediated direct tumor cell lysis via antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro.17-19 In November 2014, EMD Serono and Pfizer announced a strategic alliance to co-develop and co-commercialize BAVENCIO.

BAVENCIO Approved Indication in the US
BAVENCIO (avelumab) in combination with INLYTA (axitinib) is indicated in the US for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

BAVENCIO Important Safety Information from the US FDA-Approved Label
BAVENCIO can cause immune-mediated pneumonitis, including fatal cases. Monitor patients for signs and symptoms of pneumonitis, and evaluate suspected cases with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold BAVENCIO for moderate (Grade 2) and permanently discontinue for severe (Grade 3), life-threatening (Grade 4), or recurrent moderate (Grade 2) pneumonitis. Pneumonitis occurred in 1.2% of patients, including one (0.1%) patient with Grade 5, one (0.1%) with Grade 4, and five (0.3%) with Grade 3.

BAVENCIO can cause hepatotoxicity and immune-mediated hepatitis, including fatal cases. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater hepatitis. Withhold BAVENCIO for moderate (Grade 2) immune-mediated hepatitis until resolution and permanently discontinue for severe (Grade 3) or life-threatening (Grade 4) immune-mediated hepatitis. Immune-mediated hepatitis occurred with BAVENCIO as a single agent in 0.9% of patients, including two (0.1%) patients with Grade 5, and 11 (0.6%) with Grade 3.

BAVENCIO in combination with INLYTA can cause hepatotoxicity with higher than expected frequencies of Grade 3 and 4 alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation. Consider more frequent monitoring of liver enzymes as compared to when the drugs are used as monotherapy. Withhold BAVENCIO and INLYTA for moderate (Grade 2) hepatotoxicity and permanently discontinue the combination for severe or life-threatening (Grade 3 or 4) hepatotoxicity. Administer corticosteroids as needed. In patients treated with BAVENCIO in combination with INLYTA, Grades 3 and 4 increased ALT and AST occurred in 9% and 7% of patients, respectively, and immune-mediated hepatitis occurred in 7% of patients, including 4.9% with Grade 3 or 4.

BAVENCIO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold BAVENCIO until resolution for moderate or severe (Grade 2 or 3) colitis until resolution. Permanently discontinue for life-threatening (Grade 4) or recurrent (Grade 3) colitis upon reinitiation of BAVENCIO. Immune-mediated colitis occurred in 1.5% of patients, including seven (0.4%) with Grade 3.

BAVENCIO can cause immune-mediated endocrinopathies, including adrenal insufficiency, thyroid disorders, and type 1 diabetes mellitus.

Monitor patients for signs and symptoms of adrenal insufficiency during and after treatment, and administer corticosteroids as appropriate. Withhold BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency. Adrenal insufficiency was reported in 0.5% of patients, including one (0.1%) with Grade 3.

Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation. Manage hypothyroidism with hormone replacement therapy and hyperthyroidism with medical management. Withhold BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) thyroid disorders. Thyroid disorders, including hypothyroidism, hyperthyroidism, and thyroiditis, were reported in 6% of patients, including three (0.2%) with Grade 3.

Type 1 diabetes mellitus including diabetic ketoacidosis: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Withhold BAVENCIO and administer antihyperglycemics or insulin in patients with severe or life-threatening (Grade ≥3) hyperglycemia, and resume treatment when metabolic control is achieved. Type 1 diabetes mellitus without an alternative etiology occurred in 0.1% of patients, including two cases of Grade 3 hyperglycemia.

BAVENCIO can cause immune-mediated nephritis and renal dysfunction. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater nephritis. Withhold BAVENCIO for moderate (Grade 2) or severe (Grade 3) nephritis until resolution to Grade 1 or lower. Permanently discontinue BAVENCIO for life-threatening (Grade 4) nephritis. Immune-mediated nephritis occurred in 0.1% of patients.

BAVENCIO can result in other severe and fatal immune-mediated adverse reactions involving any organ system during treatment or after treatment discontinuation. For suspected immune-mediated adverse reactions, evaluate to confirm or rule out an immune-mediated adverse reaction and to exclude other causes. Depending on the severity of the adverse reaction, withhold or permanently discontinue BAVENCIO, administer high-dose corticosteroids, and initiate hormone replacement therapy, if appropriate. Resume BAVENCIO when the immune-mediated adverse reaction remains at Grade 1 or lower following a corticosteroid taper. Permanently discontinue BAVENCIO for any severe (Grade 3) immune-mediated adverse reaction that recurs and for any life-threatening (Grade 4) immune-mediated adverse reaction. The following clinically significant immune-mediated adverse reactions occurred in less than 1% of 1738 patients treated with BAVENCIO as a single agent or in 489 patients who received BAVENCIO in combination with INLYTA: myocarditis including fatal cases, pancreatitis including fatal cases, myositis, psoriasis, arthritis, exfoliative dermatitis, erythema multiforme, pemphigoid, hypopituitarism, uveitis, Guillain-Barré syndrome, and systemic inflammatory response.

BAVENCIO can cause severe or life-threatening infusion-related reactions. Premedicate patients with an antihistamine and acetaminophen prior to the first 4 infusions and for subsequent infusions based upon clinical judgment and presence/severity of prior infusion reactions. Monitor patients for signs and symptoms of infusion-related reactions, including pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Interrupt or slow the rate of infusion for mild (Grade 1) or moderate (Grade 2) infusion-related reactions. Permanently discontinue BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Infusion-related reactions occurred in 25% of patients, including three (0.2%) patients with Grade 4 and nine (0.5%) with Grade 3.

BAVENCIO in combination with INLYTA can cause major adverse cardiovascular events (MACE) including severe and fatal events. Consider baseline and periodic evaluations of left ventricular ejection fraction. Monitor for signs and symptoms of cardiovascular events. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue BAVENCIO and INLYTA for Grade 3-4 cardiovascular events. MACE occurred in 7% of patients with advanced RCC treated with BAVENCIO in combination with INLYTA compared to 3.4% treated with sunitinib. These events included death due to cardiac events (1.4%), Grade 3-4 myocardial infarction (2.8%), and Grade 3-4 congestive heart failure (1.8%).

BAVENCIO can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to a fetus including the risk of fetal death. Advise females of childbearing potential to use effective contraception during treatment with BAVENCIO and for at least 1 month after the last dose of BAVENCIO. It is not known whether BAVENCIO is excreted in human milk. Advise a lactating woman not to breastfeed during treatment and for at least 1 month after the last dose of BAVENCIO due to the potential for serious adverse reactions in breastfed infants.

Please see full US Prescribing Information and Medication Guide available at View Source

INLYTA Important Safety Information from the US FDA-Approved Label
Hypertension including hypertensive crisis has been observed with INLYTA. Blood pressure should be well controlled prior to initiating INLYTA. Monitor for hypertension and treat as needed. For persistent hypertension, despite use of antihypertensive medications, reduce the dose. Discontinue INLYTA if hypertension is severe and persistent despite use of antihypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis.

Arterial and venous thrombotic events have been observed with INLYTA and can be fatal. Use with caution in patients who are at increased risk or who have a history of these events.

Hemorrhagic events, including fatal events, have been reported with INLYTA. INLYTA has not been studied in patients with evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose.

Cardiac failure has been observed with INLYTA and can be fatal. Monitor for signs or symptoms of cardiac failure throughout treatment with INLYTA. Management of cardiac failure may require permanent discontinuation of INLYTA.

Gastrointestinal perforation and fistula, including death, have occurred with INLYTA. Use with caution in patients at risk for gastrointestinal perforation or fistula. Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment.

Hypothyroidism requiring thyroid hormone replacement has been reported with INLYTA. Monitor thyroid function before initiation of, and periodically throughout, treatment.

No formal studies of the effect of INLYTA on wound healing have been conducted. Stop INLYTA at least 24 hours prior to scheduled surgery.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been observed with INLYTA. If signs or symptoms occur, permanently discontinue treatment.

Proteinuria has been observed with INLYTA. Monitor for proteinuria before initiation of, and periodically throughout, treatment with INLYTA. For moderate to severe proteinuria, reduce the dose or temporarily interrupt treatment.

Liver enzyme elevation has been observed during treatment with INLYTA. Monitor ALT, AST, and bilirubin before initiation of, and periodically throughout, treatment.

For patients with moderate hepatic impairment, the starting dose should be decreased. INLYTA has not been studied in patients with severe hepatic impairment.

INLYTA can cause fetal harm. Advise patients of the potential risk to the fetus and to use effective contraception during treatment.

Avoid strong CYP3A4/5 inhibitors. If unavoidable, reduce the dose. Grapefruit or grapefruit juice may also increase INLYTA plasma concentrations and should be avoided.

Avoid strong CYP3A4/5 inducers and, if possible, avoid moderate CYP3A4/5 inducers.

For more information and full Prescribing Information, visit www.INLYTA.com.

ADVERSE REACTIONS (BAVENCIO + INLYTA)
Fatal adverse reactions occurred in 1.8% of patients with advanced renal cell carcinoma (RCC) receiving BAVENCIO in combination with INLYTA. These included sudden cardiac death (1.2%), stroke (0.2%), myocarditis (0.2%), and necrotizing pancreatitis (0.2%).

The most common adverse reactions (all grades, ≥20%) in patients with advanced RCC receiving BAVENCIO in combination with INLYTA (vs sunitinib) were diarrhea (62% vs 48%), fatigue (53% vs 54%), hypertension (50% vs 36%), musculoskeletal pain (40% vs 33%), nausea (34% vs 39%), mucositis (34% vs 35%), palmar-plantar erythrodysesthesia (33% vs 34%), dysphonia (31% vs 3.2%), decreased appetite (26% vs 29%), hypothyroidism (25% vs 14%), rash (25% vs 16%), hepatotoxicity (24% vs 18%), cough (23% vs 19%), dyspnea (23% vs 16%), abdominal pain (22% vs 19%), and headache (21% vs 16%).

Selected laboratory abnormalities (all grades, ≥20%) worsening from baseline in patients with advanced RCC receiving BAVENCIO in combination with INLYTA (vs sunitinib) were blood triglycerides increased (71% vs 48%), blood creatinine increased (62% vs 68%), blood cholesterol increased (57% vs 22%), alanine aminotransferase increased (ALT) (50% vs 46%), aspartate aminotransferase increased (AST) (47% vs 57%), blood sodium decreased (38% vs 37%), lipase increased (37% vs 25%), blood potassium increased (35% vs 28%), platelet count decreased (27% vs 80%), blood bilirubin increased (21% vs 23%), and hemoglobin decreased (21% vs 65%).