On June 28, 2019 Replimune Group Inc. (NASDAQ: REPL), a biotechnology company developing oncolytic immuno-gene therapies derived from its Immulytic platform, reported financial results for its fourth fiscal quarter and year ended March 31, 2019, and provided an update on its business (Press release, Replimune, JUN 28, 2019, View Source [SID1234537335]).

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"This past fiscal year has been incredibly productive for Replimune, with the advancement of several important clinical programs and a successful IPO that provides us with a solid financial foundation to continue to develop our portfolio of therapies," said Robert Coffin, Ph.D., co-founder, President and CEO of Replimune. "We are continuing to make significant strides as we work towards delivering on the promise of our oncolytic immuno-gene therapies. Importantly, we expect to initiate our randomized controlled registration-directed Phase 2 clinical trial in cutaneous squamous cell carcinoma (CSCC) in the near term, and to advance our second product candidate into the clinic with the initiation of a Phase 1 trial of RP2 later this year. The Phase 2 part of our clinical trial of RP1 in combination with nivolumab in four solid tumor types has also initiated, and we expect to be sharing the first set of clinical data from the Phase 1 part of the clinical trial in the fourth quarter of 2019."

Recent Business Highlights and Upcoming Events

RP1 – Initiated the Phase 2 part of the Phase 1/2 clinical trial of RP1 in combination with nivolumab. In the Phase 2 part of the clinical trial, RP1 in combination with nivolumab is being tested in four 30-patient cohorts of patients with melanoma, non-melanoma skin cancers (NMSC), metastatic bladder cancer and microsatellite instability-high (MSI-H) tumors. Enrollment in the United States and the United Kingdom is now open in the melanoma, NMSC and bladder cancer cohorts, and enrollment in the MSI-H cohort will open as soon as a protocol-required MSI-H patient is evaluable from Phase 1. The patients enrolled into the melanoma cohort will either be treatment naïve or have received one prior systemic therapy, including anti-PD1 and/or anti-CTLA-4 therapy, and the patients enrolled into the other three cohorts will all be naïve to anti-PD1 therapy. Efficacy and biomarker data will be evaluated within each tumor-type cohort.
RP1 – Data from the Phase 1 part of the Phase 1/2 clinical trial of RP1 alone and in combination with nivolumab is expected to be reported at a medical conference in the fourth quarter of 2019. The Phase 1 part of this ongoing clinical trial tested single-agent RP1 by direct injection into a single superficial or nodal tumor and by imaging-guided injection into a single visceral tumor in patients with advanced heavily pre-treated cancers who have failed available therapy, with the goal of defining the recommended Phase 2 dose. Following determination of the recommended Phase 2 dose, an expansion group of advanced cancer patients, who have failed available therapy, then received RP1 at the recommended Phase 2 dose in combination with nivolumab at standard clinical doses. This clinical trial is being conducted under a clinical trial supply agreement with Bristol Myers Squibb (BMS) for the supply of nivolumab.
RP1 – Opening of the Phase 2 clinical trial of RP1 in combination with cemiplimab is expected in the near term. The registration directed randomized controlled Phase 2 clinical trial will enroll approximately 240 patients with CSCC, comparing treatment with cemiplimab alone to treatment with cemiplimab in combination with RP1, under the Company’s collaboration with Regeneron. Cemiplimab is Regeneron’s anti-PD1 therapy that was approved by the U.S. Food and Drug Administration (FDA) for the treatment of locally recurrent and metastatic CSCC.
RP 2 – Phase 1 clinical trial of RP2 as a single agent and in combination with nivolumab anti-PD1 therapy anticipated to initiate in the third quarter of 2019.RP2 is a further armed oncolytic immuno-gene therapy that, in addition to expressing GALV-GP-R- and GM-CSF, also expresses a genetically encoded anti-CTLA-4 antibody intended to block the inhibition of the initiation of immune response caused by CTLA-4. RP2 is intended to be used primarily in combination with anti-PD1 or anti-PD-L1 therapy. Because of the need to address questions from regulatory authorities regarding certain Chemistry, Manufacturing, and Controls aspects of RP2, this clinical trial is expected to initiate one quarter later than originally anticipated. As with the clinical trial with RP1 in combination with nivolumab, this clinical trial will be conducted under a clinical trial supply agreement with BMS for the supply of nivolumab.
RP3 – Phase 1 clinical trial of RP3 as a single agent and in combination with anti-PD1 therapy to initiate in 2020.RP3 is a further armed oncolytic immuno-gene therapy which expresses two immune co-stimulatory activating ligands in addition to the GALV-GP R- fusogenic protein and anti-CTLA-4. Following the assessment of a number of co-stimulatory pathways, which, like anti-CTLA-4, are expected to be primarily active at the site and time of anti-tumor immune response initiation, the selected immune co-stimulatory pathway activating proteins are CD40L and 4-1BBL. CD40L activates CD40, resulting in the broad activation of both innate and adaptive immunity, and 4-1BBL activates 4-1BB (CD137) to promote the expansion of cellular and memory immune responses.
Presented posters at ASCO (Free ASCO Whitepaper) and AACR (Free AACR Whitepaper). At the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, Replimune presented a "trials in progress" poster on the Company’s Phase 1/2 clinical trial of RP1 alone and in combination with nivolumab. A poster describing preclinical data relating to Replimune’s Immulytic platform and entitled "Development & characterization of a new oncolytic immunotherapy platform based on herpes simplex virus type 1" was presented at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) annual meeting in March 2019. Both posters are available on the Company’s website.
Build out of Replimune’s manufacturing facility to support late-stage development and commercialization is on track and expected to be operational in the first half of 2020. In July 2018, Replimune signed a lease for a 63,000-square-foot facility in Framingham, MA where the Company intends to establish world-class multi-product manufacturing capabilities for its Immulytic product candidates. The capacity of this facility is expected to be sufficient to support full commercialization of the Company’s product candidates. The facility is expected to be operational in the first half of 2020.
Financial Highlights

Replimune reported a net loss of $6.6 million for the fiscal fourth quarter, ended March 31, 2019, and a net loss of $30.8 million for the fiscal year ended March 31, 2019, as compared to a net loss of $7.1 million and net loss of $19.7 million for the comparable periods in the prior fiscal year, respectively. The increase in net losses for both periods were primarily due to an increase in research and development expenses and administrative costs associated with our operations.

Research and development expenses were $5.4 million for the fiscal fourth quarter of 2019, and $22.2 million for the year ended March 31, 2019, as compared to $4.5 million and $13.5 million for the comparable periods in the prior fiscal year, respectively. The increase in research and development expenses was primarily driven by additional costs related to Replimune’s preclinical and clinical development activities for its pipeline, as well as increased salary and related benefits costs due to the increase in employee headcount from 44 on March 31, 2018 to 67 on March 31, 2019.

General and administrative expenses were $2.4 million for the fiscal fourth quarter of 2019, and $8.8 million for the year ended March 31, 2019, as compared to $2.5 million and $5.7 million for the comparable periods in the prior fiscal year, respectively. The increase in general and administrative expenses was primarily due to the increase in employee headcount and the impact of stock-based compensation in 2019.

Replimune ended the fiscal year with $134.8 million in cash and cash equivalents and short-term investments, compared with $141.8 million as of December 31, 2018 and $61.6 million as of March 31, 2018. The year-on-year increase reflects net proceeds received of $103.3 million (net of deferred offering costs of $9.9 million) in connection with the Company’s IPO in July 2018.

Based on its current operating plan, Replimune expects that its current cash and cash equivalents and short-term investments will enable it to fund its operating expenses and capital expenditure requirements into the second half of calendar 2021.

On June 28, 2019 Sorrento Therapeutics, Inc. (Nasdaq: SRNE, "Sorrento"), a clinical stage, antibody-centric biopharmaceutical company developing new therapies to turn malignant cancers into manageable and possibly curable diseases, reported the pricing of its public offering of 8,333,334 shares of its common stock, Series A warrants to purchase up to an aggregate of 8,333,334 shares of its common stock, Series B warrants to purchase up to an aggregate of 8,333,334 shares of its common stock and Series C warrants to purchase up to an aggregate of 8,333,334 shares of its common stock, at a price to the public of $3.00 per share and accompanying Series A, Series B and Series C warrant (Press release, Sorrento Therapeutics, JUN 28, 2019, View Source [SID1234537336]). The Series A warrants will be exercisable commencing six months from the date of issuance, will expire on the 10-year anniversary of the date of issuance and will have an exercise price of $3.75 per share, subject to certain adjustments. The Series B warrants will be exercisable commencing on the date of issuance, will expire on the date that is nine months from the date of issuance and will have an exercise price of $3.00 per share, subject to certain adjustments. The Series C warrants will be exercisable six months from the date of issuance and only to the extent and in proportion to a holder of the Series C warrants exercising its corresponding Series B warrants, will expire on the 10-year anniversary of the date of issuance and will have an exercise price of $3.75 per share, subject to certain adjustments. Gross proceeds, before deducting underwriting discounts and commissions and estimated offering expenses, are expected to be approximately $25.0 million. Sorrento currently intends to use the net proceeds from the offering for the continued clinical development of its RTX, CEA CAR-T and CD38 CAR-T programs and general research and development, working capital and general corporate purposes. In addition, Sorrento has granted the underwriters a 30-day option to purchase up to 1,250,000 additional shares of its common stock and/or 1,250,000 warrant combinations, which consists of 1,250,000 Series A warrants, 1,250,000 Series B warrants and 1,250,000 Series C warrants. The offering is expected to close on or about July 2 2019, subject to satisfaction of customary closing conditions.

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JMP Securities and H.C. Wainwright & Co. are acting as joint book-running managers for the offering.

The public offering is being made pursuant to a shelf registration statement on Form S-3 (File No. 333-221443) previously filed with the Securities and Exchange Commission (the "SEC") on November 9, 2017, amended on December 1, 2017 and declared effective by the SEC on December 6, 2017. The securities may be offered only by means of a prospectus. A preliminary prospectus supplement and the accompanying prospectus relating to and describing the terms of the offering have been filed with the SEC and are available on the SEC’s website at www.sec.gov. Copies of the final prospectus supplement and the accompanying prospectus relating to the offering, when available, may be obtained from JMP Securities LLC, 600 Montgomery Street, Suite 1100, San Francisco, California 94111, Attention: Prospectus Department, by calling (415) 835-8985 or by e-mail at [email protected] or H.C. Wainwright & Co., LLC, 430 Park Avenue, 3rd Floor, New York, NY 10022, by calling (646) 975-6996 or by e-mail at [email protected].

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

On June 28, 2019 Athenex, Inc. (Nasdaq: ATNX), a global biopharmaceutical company dedicated to the discovery, development and commercialization of novel therapies for the treatment of cancer, reported that the Company has strategically expanded its presence in Europe and Latin America to grow its global clinical research and development capacity (Press release, Athenex, JUN 28, 2019, View Source;p=RssLanding&cat=news&id=2402595 [SID1234537323]). The Company believes these initiatives have the potential to enhance Athenex’s capacity to conduct global clinical studies and support its regional marketing decision process. They are part of the Company’s strategy to build on its current strong presence in U.S. and Asia, and help maximize the global potential of its pipeline.

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Athenex’s oncology-focused pipeline currently has nine clinical candidates, including two drug candidates in Phase III development. In line with the Company’s goal to expand its capability and bandwidth to optimize global development and commercialization of its pipeline products, Athenex has been evaluating operational opportunities in Europe and Latin America.

As part of Athenex’s strategy to establish operations in Europe, the second largest healthcare market in the world, the Company has formed a subsidiary in the United Kingdom and established offices in Manchester. The Company is currently conducting clinical studies in the United Kingdom and intends to continue expanding its research and development capabilities in the region.

In Latin America, Athenex recently entered into a definitive agreement to acquire certain assets of CIDAL Limited in exchange for shares of Athenex common stock, subject to customary closing conditions. CIDAL is a contract research organization with headquarters in Guatemala and operations in various countries in Latin America. CIDAL has provided important CRO services and support to Athenex, including for its Phase III study of oral paclitaxel and encequidar for metastatic breast cancer. The asset purchase is expected to strengthen Athenex’s clinical research and operations capabilities and support the Company’s clinical development worldwide.

"These initiatives represent an important step in our ongoing strategic efforts to expand our clinical research and operations for global development, with the potential for increased clinical research efficiencies and cost-effectiveness" said Dr. Johnson Lau, Chairman and Chief Executive Officer of Athenex. "Our office in Manchester will enable us to evaluate the best strategy for Europe, an important market for Athenex. We have been engaging with many experienced pharma/biotech specialists who are already contributing to our research programs and look forward to working more closely with these talents. We are also delighted to extend our operations in Latin America through CIDAL, which we believe will increase our bandwidth for clinical research and regulatory development. We believe having a stronger presence in these territories will position us well to evaluate new R&D and commercialization opportunities in Europe and Latin America."

On June 28, 2019 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of Tecentriq (atezolizumab) plus chemotherapy (Abraxane; nab-paclitaxel) for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) whose tumours have PD-L1 expression (≥ 1%) and who have not received prior chemotherapy for metastatic disease (Press release, Hoffmann-La Roche, JUN 28, 2019, View Source [SID1234537324]).

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"This CHMP recommendation marks a breakthrough in the treatment of triple-negative breast cancer, an aggressive type of breast cancer with high unmet medical need," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "With today’s announcement, we hope that people living with PD-L1-positive metastatic triple-negative breast cancer in Europe will soon have a new treatment option with the Tecentriq combination."

The CHMP recommendation is based on data from the Phase III IMpassion130 study, which demonstrated that Tecentriq plus nab-paclitaxel significantly reduced the risk of disease worsening or death (progression-free survival; PFS) by 38% compared with nab-paclitaxel alone (median PFS=7.5 vs 5 months; HR=0.62, 95% CI: 0.49–0.78, p<0.0001) in people who were tested positive for PD-L1 expression on tumour-infiltrating immune cells (IC). The Tecentriq combination showed a clinically meaningful overall survival (OS) improvement of seven months vs nab-paclitaxel alone in the PD-L1-positive population (median OS=25.0 vs 18.0 months; HR=0.71, 95% CI: 0.54–0.93). OS results in the PD-L1-positive population were not formally tested due to the hierarchical design of the study, as statistical significance was not met for OS in the intention-to-treat (ITT) population (median OS=21.0 vs 18.7 months; HR=0.86, 95% CI: 0.72–1.02, p=0.078). The study will continue until the next planned analysis.

The assessment of PD-L1 on tumour-infiltrating immune cells is essential for identifying the TNBC patients benefiting from this Tecentriq combination. PD-L1 expression status in the IMpassion130 study was assessed by the VENTANA PD-L1 (SP142) assay.

Safety in the Tecentriq plus nab-paclitaxel arm appeared consistent with the known safety profiles of the individual study medicines or underlying disease, and no new safety signals were identified with the combination. Serious adverse events (SAEs) were reported in 23% of people receiving Tecentriq plus nab-paclitaxel, compared with 18% of people receiving chemotherapy alone. Grade 3–4 AEs were reported in 49% of people receiving Tecentriq plus nab-paclitaxel, compared with 42% of people receiving chemotherapy alone.

Currently, Roche has seven ongoing Phase III studies investigating Tecentriq in TNBC, including early and advanced stages of the disease.

About the IMpassion130 study
IMpassion130 is a Phase III, multicentre, randomised, double-blind study evaluating the efficacy, safety and pharmacokinetics of Tecentriq plus nab-paclitaxel compared with placebo plus nab-paclitaxel in people with unresectable locally advanced or metastatic TNBC who have not received prior systemic therapy for metastatic breast cancer. The study enrolled 902 people who were randomised equally (1:1) The co-primary endpoints are PFS per investigator assessment (RECIST 1.1) in the ITT population and in the PD-L1-positive population, and OS in the ITT population and in the PD-L1-positive population. Performing a test for statistical significance for OS in the PD-L1-positive population is dependent upon OS results from all randomised patients. PD-L1 expression status was assessed by the VENTANA PD-L1 (SP142) Assay. Secondary endpoints include objective response rate and duration of response.

About triple-negative breast cancer
Breast cancer is the most common cancer among women, with more than 2 million diagnosed worldwide each year.1 TNBC represents 15% of all breast cancers and is more common in women under the age of 50, compared with other forms of breast cancer.2,3,4 It is defined by the lack of expression and/or amplification of the targetable receptors for oestrogen, progesterone and HER2 amplification.5 Patients with metastatic TNBC generally experience rapid progression and shorter OS, compared with other subtypes of breast cancer.3

About Roche in breast cancer
Roche has been advancing breast cancer research for more than 30 years with the goal of helping as many people with the disease as possible. Our medicines, along with companion diagnostic tests, have contributed to bringing breakthrough innovations in HER2-positive breast cancer. As our understanding of breast cancer biology rapidly improves, we are working to identify new biomarkers and approaches to treatment for all forms of early and advanced breast cancer, including triple-negative and hormone receptor-positive.

Our targeted medicines Herceptin, Perjeta and Kadcyla are continuing to transform the treatment of early and advanced HER2-positive breast cancer and, through our Tecentriq and ipatasertib clinical programmes, we hope to bring new treatment combinations to people with breast cancer, ultimately improving outcomes.

About Tecentriq
Tecentriq is a monoclonal antibody designed to bind with a protein called PD-L1, which is expressed on tumour cells and tumour-infiltrating immune cells, blocking its interactions with both PD-1 and B7.1 receptors. By inhibiting PD-L1, Tecentriq may enable the activation of T cells. Tecentriq is a cancer immunotherapy (CIT) that has the potential to be used as a foundational combination partner with other immunotherapies, targeted medicines and various chemotherapies across a broad range of cancers. The development of Tecentriq and its clinical programme is based on our greater understanding of how the immune system interacts with tumours and how harnessing a person’s immune system combats cancer more effectively.

Tecentriq is approved in the US, EU and/or countries around the world, either alone or in combination with targeted therapies and/or chemotherapies in various forms of non-small cell and small cell lung cancer, certain types of metastatic urothelial cancer, and in PD-L1-positive triple-negative breast cancer.

About Roche in cancer immunotherapy
For more than 50 years, Roche has been developing medicines with the goal to redefine treatment in oncology. Today, we’re investing more than ever in our effort to bring innovative treatment options that help a person’s own immune system fight cancer.

By applying our seminal research in immune tumour profiling within the framework of the Roche-devised cancer immunity cycle, we are accelerating and expanding the transformative benefits with Tecentriq to a greater number of people living with cancer. Our cancer immunotherapy development programme takes a comprehensive approach in pursuing the goal of restoring cancer immunity to improve outcomes for patients.

To learn more about the Roche approach to cancer immunotherapy please follow this link: View Source

On June 28, 2019 Pfizer Inc. (NYSE:PFE) reported the United States (U.S.) Food and Drug Administration(FDA) has approved ZIRABEV (bevacizumab-bvzr), a biosimilar to Avastin (bevacizumab),1 for the treatment of five types of cancer: metastatic colorectal cancer; unresectable, locally advanced, recurrent or metastatic non-squamous non-small cell lung cancer (NSCLC); recurrent glioblastoma; metastatic renal cell carcinoma (RCC); and persistent, recurrent or metastatic cervical cancer (Press release, Pfizer, JUN 28, 2019, View Source [SID1234537325]).2

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"Biosimilars like ZIRABEV can help increase access to impactful therapies, driving market competition that may ultimately lower costs and help address the diverse needs of patients living with cancer," said Andy Schmeltz, Global President, Pfizer Oncology. "We are proud to add ZIRABEV to our growing oncology portfolio for U.S. patients living with a wide variety of tumor types."

The FDA approval was based on review of a comprehensive data package which demonstrated biosimilarity of ZIRABEV to the reference product. This includes results from the REFLECTIONS B7391003 clinical comparative study, which showed clinical equivalence and found no clinically meaningful differences between ZIRABEV and the reference product in patients with advanced non-squamous NSCLC.3

"ZIRABEV represents a welcome addition to the treatment armamentarium in its approved indications, potentially providing physicians with a medicine that has a similar safety profile and efficacy as the reference product," said Dr. Niels Reinmuth, Department of Thoracic Oncology, Asklepios Lung Clinic, Munich-Gauting, Germany and lead author of the REFLECTIONS B7391003 study.4 "The FDA’s approval of ZIRABEV may provide an important new option for the treatment of multiple forms of cancer."

Biosimilars have been a significant catalyst for change for the healthcare industry over the last decade, with the potential to create a more sustainable healthcare system. With more than 10 years of global in-market experience and six approved biosimilar products in the U.S., Pfizer is proud to be a leader and at the forefront of this vital healthcare segment. ZIRABEV is Pfizer’s second oncology monoclonal antibody (mAb) biosimilar to be approved by the FDA, following the FDA approval of TRAZIMERA (trastuzumab-qyyp) in March 2019.5 ZIRABEV was also approved for use in the European Union (EU) in February 2019 for the treatment of metastatic carcinoma of the colon or rectum, metastatic breast cancer, unresectable advanced, metastatic or recurrent NSCLC, advanced and/or metastatic RCC and persistent, recurrent or metastatic carcinoma of the cervix.6

About ZIRABEV (bevacizumab-bvzr)

ZIRABEV is a mAb biosimilar of the reference product, Avastin, which works by inhibiting the formation of new blood cells (angiogenesis) by specifically recognizing and binding to vascular endothelial growth factor (VEGF) protein. As part of the REFLECTIONS clinical trial program, ZIRABEV has been studied in nearly 400 patients to date.3,7,8,9

ZIRABEV IMPORTANT SAFETY INFORMATION

Warnings and Precautions

Gastrointestinal Perforations and Fistulae. Serious and sometimes fatal gastrointestinal perforation occurred at a higher incidence in patients receiving bevacizumab products compared to patients receiving chemotherapy. Non-GI fistulae (
Surgery and Wound Healing Complications. The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in bevacizumab-treated patients. Withhold for at least 28 days prior to elective surgery. Do not administer for at least 28 days following surgery and until the wound is fully healed. Discontinue in patients who develop wound healing complications that require medical intervention or necrotizing fasciitis
Hemorrhage. Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding occurred up to 5-fold more frequently in patients receiving bevacizumab. In clinical studies, the incidence of grade ≥3 hemorrhagic events among patients receiving bevacizumab ranged from 0.4% to 7%. Do not administer ZIRABEV to patients with serious hemorrhage or a recent history of hemoptysis (≥1/2 tsp of red blood). Discontinue ZIRABEV in patients who develop grade 3–4 hemorrhage
Additional serious and sometimes fatal adverse events with increased incidence in the bevacizumab-treated arm vs chemotherapy arm included:
Arterial thromboembolic events (grade ≥3, 5%, highest in patients with GBM). Discontinue in patients who develop a severe ATE.
Renal injury and proteinuria. Monitor proteinuria during ZIRABEV therapy. Patients with a 2+ or greater urine dipstick reading should undergo 24-hour urine collection. Withhold for proteinuria >2 grams per 24 hours and resume when less than 2 grams per 24 hours. Discontinue in patients who develop nephrotic syndrome
Grade 3–4 proteinuria ranged from 0.7% to 7% in clinical studies
Nephrotic syndrome (
Additional serious adverse events with increased incidence in the bevacizumab-treated arm vs chemotherapy arm included:
Venous thromboembolism (grade ≥3, 11% seen in Study GOG-0240). Discontinue ZIRABEV in patients with a Grade 4 VTE, including pulmonary embolism
Hypertension (grade 3–4, 5%–18%). Monitor blood pressure during treatment and, for ZIRABEV associated hypertension, continue monitoring after discontinuation. Withhold for severe hypertension. Discontinue for hypertensive crisis or hypertensive encephalopathy
Posterior reversible encephalopathy syndrome (PRES) (
Congestive heart failure (CHF) (1%). Discontinue ZIRABEV in patients who develop CHF
Infusion-related reactions with the first dose of bevacizumab occurred in
Inform females of reproductive potential of the risk of ovarian failure prior to initiating treatment with ZIRABEV
Pregnancy Warning

Based on the mechanism of action and animal studies, bevacizumab products may cause fetal harm
Advise female patients that bevacizumab products may cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy
Advise females of reproductive potential to use effective contraception during treatment with ZIRABEV and for 6 months after the last dose of ZIRABEV
Advise nursing women that breastfeeding is not recommended during treatment with ZIRABEV and for 6 months following their last dose of treatment
Bevacizumab products may impair fertility
Most Common Adverse Events

Across studies, the most common adverse reactions observed in bevacizumab patients at a rate >10% were:
Epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, exfoliative dermatitis
Across all studies, bevacizumab was discontinued in 8% to 22% of patients because of adverse reactions
Indication-Specific Adverse Events

In first-line metastatic colorectal cancer (MCRC), the most common grade 3–4 events in Study 2107, which occurred at a (≥2%) higher incidence in the bevacizumab plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%)
In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the bevacizumab plus FOLFOX4 vs FOLFOX4 groups, were fatigue (19% vs 13%), diarrhea (18% vs 13%), sensory neuropathy (17% vs 9%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), hypertension (9% vs 2%), abdominal pain (8% vs 5%), hemorrhage (5% vs 1%), other neurological (5% vs 3%), ileus (4% vs 1%), and headache (3% vs 0%). These data are likely to underestimate the true adverse event rates due to the reporting mechanisms used in this study
In non–small cell lung cancer (NSCLC), grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a (≥2%) higher incidence in bevacizumab-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thromboembolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%)
In recurrent glioblastoma (rGBM) Study EORTC 26101, 22% of patients discontinued treatment in the bevacizumab with lomustine arm due to adverse reactions compared with 10% of patients in the lomustine arm. In patients receiving bevacizumab with lomustine, the adverse reaction profile was similar to that observed in other approved indications
In metastatic renal cell carcinoma (mRCC), the most common grade 3–5 adverse events in Study BO17705, occurring at a (≥2%) higher incidence in bevacizumab-treated patients vs controls, were fatigue (13% vs 8%), asthenia (10% vs 7%), proteinuria (7% vs 0%), hypertension (6% vs 1%, including hypertension and hypertensive crisis), and hemorrhage (3% vs 0.3%, including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, hemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma)
In persistent, recurrent, or metastatic cervical cancer, grade 3 or 4 adverse reactions in Study GOG-0240, occurring at a higher incidence (≥2%) in 218 patients receiving bevacizumab plus chemotherapy compared to 222 patients receiving chemotherapy alone, were abdominal pain (12% vs 10%), diarrhea (6% vs 3%), anal fistula (4% vs 0%), proctalgia (3% vs 0%), urinary tract infection (8% vs 6%), cellulitis (3% vs 0.5%), fatigue (14% vs 10%), hypertension (11% vs 0.5%), thrombosis (8% vs 3%), hypokalemia (7% vs 4%), hyponatremia (4% vs 1%), dehydration (4% vs 0.5%), neutropenia (8% vs 4%), lymphopenia (6% vs 3%), back pain (6% vs 3%), and pelvic pain (6% vs 1%)
INDICATIONS

Metastatic Colorectal Cancer

ZIRABEV, in combination with intravenous fluorouracil-based chemotherapy, is indicated for the first- or second-line treatment of patients with metastatic colorectal cancer (mCRC).

ZIRABEV, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with mCRC who have progressed on a first-line bevacizumab product-containing regimen.

Limitation of Use: ZIRABEV is not indicated for adjuvant treatment of colon cancer.

First-Line Non-Squamous Non-Small Cell Lung Cancer

ZIRABEV, in combination with carboplatin and paclitaxel, is indicated for the first line treatment of patients with unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer (NSCLC).

Recurrent Glioblastoma

ZIRABEV is indicated for the treatment of recurrent glioblastoma (GBM) in adults.

Metastatic Renal Cell Carcinoma

ZIRABEV, in combination with interferon alfa, is indicated for the treatment of metastatic renal cell carcinoma (mRCC).

Persistent, Recurrent, or Metastatic Cervical Cancer

ZIRABEV, in combination with paclitaxel and cisplatin or paclitaxel and topotecan, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer.