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Entry into a Material Definitive Agreement

On October 28, 2019, Celsion Corporation (the "Company"), reported that it entered into a common stock purchase agreement (the "Purchase Agreement") with Aspire Capital Fund, LLC, an Illinois limited liability company ("Aspire Capital") which provides that, upon the terms and subject to the conditions and limitations set forth therein, Aspire Capital is committed to purchase up to an aggregate of $10.0 million of shares of the Company’s common stock over the 24-month term of the Purchase Agreement (Filing, 8-K, Celsion, OCT 28, 2019, View Source [SID1234549921]). Concurrently with entering into the Purchase Agreement, the Company also entered into a registration rights agreement with Aspire Capital (the "Registration Rights Agreement"), in which the Company agreed to file one or more registration statements, as permissible and necessary to register under the Securities Act of 1933, as amended (the "Securities Act"), registering the sale of the shares of the Company’s common stock that have been and may be issued to Aspire Capital under the Purchase Agreement.

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Under the Purchase Agreement, after the Securities and Exchange Commission (the "SEC") has declared effective the registration statement referred to above, on any trading day selected by the Company, the Company has the right, in its sole discretion, to present Aspire Capital with a purchase notice (each, a "Purchase Notice"), directing Aspire Capital (as principal) to purchase up to 100,000 shares of the Company’s common stock per business day, up to $10.0 million of the Company’s common stock in the aggregate at a per share price (the "Purchase Price") equal to the lesser of:

the lowest sale price of the Company’s common stock on the purchase date; or
the arithmetic average of the three (3) lowest closing sale prices for the Company’s common stock during the ten (10) consecutive trading days ending on the trading day immediately preceding the purchase date.

In addition, on any date on which the Company submits a Purchase Notice to Aspire Capital in an amount of 100,000 shares, the Company also has the right, in its sole discretion, to present Aspire Capital with a volume-weighted average price purchase notice (each, a "VWAP Purchase Notice") directing Aspire Capital to purchase an amount of stock equal to up to 30% of the aggregate shares of the Company’s common stock traded on its principal market on the next trading day (the "VWAP Purchase Date"), subject to a maximum number of shares the Company may determine. The purchase price per share pursuant to such VWAP Purchase Notice is generally 97% of the volume-weighted average price for the Company’s common stock traded on its principal market on the VWAP Purchase Date.

The Purchase Price will be adjusted for any reorganization, recapitalization, non-cash dividend, stock split, or other similar transaction occurring during the period(s) used to compute the Purchase Price. The Company may deliver multiple Purchase Notices and VWAP Purchase Notices to Aspire Capital from time to time during the term of the Purchase Agreement, so long as the most recent purchase has been completed.

The Purchase Agreement provides that the Company and Aspire Capital shall not effect any sales under the Purchase Agreement on any purchase date where the closing sale price of the Company’s common stock is less than $0.25. There are no trading volume requirements or restrictions under the Purchase Agreement, and the Company will control the timing and amount of sales of the Company’s common stock to Aspire Capital. Aspire Capital has no right to require any sales by the Company, but is obligated to make purchases from the Company as directed by the Company in accordance with the Purchase Agreement. There are no limitations on use of proceeds, financial or business covenants, restrictions on future fundings, rights of first refusal, participation rights, penalties or liquidated damages in the Purchase Agreement. In consideration for entering into the Purchase Agreement, concurrently with the execution of the Purchase Agreement, the Company issued to Aspire Capital 100,000 shares of the Company’s common stock (the "Commitment Shares"). The Purchase Agreement may be terminated by the Company at any time, at its discretion, without any cost to the Company. Aspire Capital has agreed that neither it nor any of its agents, representatives and affiliates shall engage in any direct or indirect short-selling or hedging of the Company’s common stock during any time prior to the termination of the Purchase Agreement. Any proceeds from the Company receives under the Purchase Agreement are expected to be used for working capital and general corporate purposes.

The foregoing is a summary description of certain terms of the Purchase Agreement and the Registration Rights Agreement and, by its nature, is incomplete. Copies of the Purchase Agreement and Registration Rights Agreement are filed herewith as Exhibits 10.1 and 4.1, respectively, to this Current Report on Form 8-K and are incorporated herein by reference. All readers are encouraged to read the entire text of the Purchase Agreement and the Registration Rights Agreement.

The issuance of the Commitment Shares and all other shares of common stock that may be issued from time to time to Aspire Capital under the Purchase Agreement is exempt from registration under the Securities Act, pursuant to the exemption for transactions by an issuer not involving any public offering under Section 4(a)(2) of the Securities Act.

MIRATI THERAPEUTICS PRESENTS FIRST CLINICAL DATA OF PHASE 1/2 TRIAL OF MRTX849 AT THE 2019 AACR-NCI-EORTC INTERNATIONAL CONFERENCE ON MOLECULAR TARGETS AND CANCER THERAPEUTICS

On October 28, 2019 Mirati Therapeutics, Inc. (NASDAQ: MRTX), a clinical-stage targeted oncology company, reported the first clinical results from its Phase I/2 trial evaluating MRTX849, an investigational KRAS G12C inhibitor, in patients with solid tumors expressing KRAS G12C mutations (Press release, Mirati, OCT 28, 2019, View Source [SID1234549920]). MRTX849 demonstrated clinical activity, including objective responses, in patients with non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). While the maximum tolerated dose (MTD) has not yet been established, dose expansion is underway, and the trial continues to enroll patients. These data were presented in an oral presentation at the 2019 AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) in Boston.

"Patients whose tumors carry the KRAS G12C mutation have a poor prognosis, are resistant to standard of care treatment and have no available targeted therapeutic options," said Charles M. Baum, M.D., Ph.D., President and Chief Executive Officer, Mirati Therapeutics. "Early efficacy and safety data from this Phase 1/2 trial demonstrate the potential of a potent and effective KRAS therapy. We look forward to investigating MRTX849 in patients with a variety of KRAS G12C mutated cancers and bringing the hope of a targeted therapy to them."

The ongoing Phase 1/2, first-in-human, open-label multicenter trial has enrolled 17 patients, including 10 patients with NSCLC, 4 patients with CRC, and 3 patients with other tumor types. Five dose cohorts have been evaluated: 150 mg, 300 mg, 600 mg, and 1200 mg, taken orally once daily, and 600 mg, taken orally twice daily. The trial enrolled single patient dose escalation cohorts in an accelerated titration design. Trial objectives include evaluation of safety, tolerability, pharmacodynamics (PD), pharmacokinetics (PK) and tumor response evaluated using RECIST v1.1 criteria.

As of the data cut-off date of October 11, 2019, 12 patients across all dose levels were evaluable for response with at least one radiographic scan.

At the highest dose (600 mg BID), three of five (3/5) evaluable patients with NSCLC and one of two (1/2) evaluable patients with CRC achieved a partial response (PR); the remaining patients experienced stable disease (SD).

Across all dose levels, three of six (3/6) patients with NSCLC and one of four (1/4) patients with CRC achieved a PR. Two responding patients (1 NSCLC and 1 CRC) achieved confirmed PRs, both with continuing tumor shrinkage following their first scan. The other two patients with PRs (both NSCLC) remain on study but have not yet had confirmatory scans.

Clinical PK data demonstrated that the dose of 600 mg BID results in drug levels that meet or exceed those likely to lead to full inhibition of KRAS G12C signaling.

Treatment duration across all dose levels ranged from 6.7- 38.6 weeks for patients with NSCLC and 9.9-30.1 weeks for patients with CRC as of the data cut-off.

Treatment-related adverse events (AEs) were primarily grade 1 events. One patient experienced a dose-limiting toxicity (DLT) at the 1200 mg QD dose (capsule burden intolerance [12 capsules]) and one patient experienced a DLT at the 600 mg BID dose (grade 3/4 isolated amylase/lipase increase). The MTD has not yet been established and further dose escalation may be explored. Enrollment into dose expansion at the 600 mg BID dose is underway.

"There are currently no effective targeted therapies for patients with KRAS-mutant cancers," said Pasi A. Jänne, M.D., Ph.D., Director of The Lowe Center for Thoracic Oncology at the Dana Farber Cancer Institute and MRTX849-001 investigator. "KRAS mutations are the most common oncogenic alteration in all of human cancers, and as such, finding a therapeutic approach for this subset of cancers would have tremendous clinical impact for cancer patients."

In addition, data demonstrating the efficacy of MRTX849 in preclinical studies were published simultaneously with the oral presentations at AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper), in Cancer Discovery, a journal of the American Association of Cancer Researchers (AACR) (Free AACR Whitepaper). "The KRAS G12C Inhibitor, MRTX849, Provides Insight Toward Therapeutic Susceptibility of KRAS Mutant Cancers in Mouse Models and Patients," by lead author Jill Hallin, Principal Scientist at Mirati and corresponding author James G. Christensen, Ph.D. Executive Vice President and Chief Scientific Officer at Mirati, describes the challenging research path leading to a novel therapy that directly targets KRAS. Cancer Discovery publishes high-impact, peer-reviewed articles describing major advances in research and clinical trials.

About MRTX849

MRTX849 is an investigational, orally-available small molecule that is designed to potently and selectively inhibit a form of KRAS which harbors a substitution mutation (G12C). KRAS G12C mutations are present in approximately 14% of NSCLC adenocarcinoma patients, 4% of colorectal cancer patients, and subsets of other types of cancer. Tumors characterized by KRAS G12C mutations are commonly associated with poor prognosis and resistance to therapy, and patients with these mutations have few treatment options. MRTX849 is being evaluated in a Phase 1/2 trial treating patients with molecularly-identified, KRAS G12C-positive advanced solid tumors.

APX3330 Phase I oncology trial presented at AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Meeting

On October 28, 2019 Apexian Pharmaceuticals, Inc., a clinical stage drug development company focused on advancing APX3330 for the treatment of diseases mediated by the APE1/Ref-1 protein, reported additional data on their Phase 1 study using APX3330 in patients with advanced solid tumors (Press release, Apexian Pharmaceuticals, OCT 28, 2019, View Source [SID1234549919]). Results of the trial were presented as a talk in the "Spotlight on Proffered Papers: Emerging Data from Phase I Trials of New Molecular Entities" session on Sunday, October 27.

An additional presentation followed in a poster session. The presentations occurred at the American Association for Cancer Research (AACR) (Free AACR Whitepaper)-National Cancer Institute-European Organization for Research and Treatment of Cancer (AACR-NCI-EORTC) (Free AACR-NCI-EORTC Whitepaper) annual international meeting in Boston, MA. The presentation titled "A phase I study targeting the APE1/Ref-1 DNA repair-redox signaling protein with the APX3330 inhibitor" was presented by Dr. Mark R. Kelley, Chief Scientific Officer of Apexian and Professor of Pediatrics, Indiana University Simon Cancer Center.

"As we continue development of APX3330 for cancer and other indications, we are very pleased to have been selected to present our phase I trial findings in a platform talk and poster presentation" said Dr. Mark Kelley, Chief Scientific Officer of Apexian. "APX3330 is an oral drug and we observed a strong safety profile, recommended phase 2 dose, predicted PK and target engagement of APX3330 on APE1/Ref-1 using transcriptome and proteomic analysis of tumors".

Dr. Richard Messmann, Chief Medical Officer of Apexian added, "The APE1/Ref-1 protein plays a critical role in mediating a variety of diseases. Our phase I data have now confirmed that APX3330 targets the APE1 protein as expected. These findings pave the way toward confirming the utility of APX3330 in treating diseases as diverse as cancer, diabetic retinopathy, and inflammatory bowel disease, all mediated by the APE1/Ref-1 protein."

Zymeworks Announces Phase 1 Data for ZW25 in Combination with Chemotherapy in Advanced Gastroesophageal Adenocarcinoma at AACR-NCI-EORTC International Conference

On October 28, 2019 Zymeworks Inc. (NYSE: ZYME), a clinical-stage biopharmaceutical company developing multifunctional therapeutics, reported the first data from its Phase 1 study evaluating novel bispecific antibody ZW25 in combination with chemotherapy in HER2-expressing gastroesophageal adenocarcinoma (GEA) in a poster presentation at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper), taking place October 26 – 30 in Boston (Press release, Zymeworks, OCT 28, 2019, View Source [SID1234549918]).

"Today we report the promising anti-tumor activity of ZW25 in combination with chemotherapy for people with HER2-expressing GEA," said Diana Hausman, M.D., Chief Medical Officer at Zymeworks. "These results compare favorably with current standard of care treatments for patients who have progressed after first-line therapies, including trastuzumab and chemotherapy. The data further support the prioritization of our ongoing Phase 2 trial of ZW25 plus chemotherapy as a first-line treatment for GEA and our goal of establishing ZW25 as the new best-in-class therapy for people with HER2-expressing cancers."

The FDA has granted Fast Track designation to ZW25 for first-line HER2-positive GEA in combination with standard of care chemotherapy, and a Phase 2 trial evaluating combination treatment in this setting is actively enrolling patients (NCT03929666).

"The patients in this Phase 1 study have a difficult-to-treat, advanced stage of cancer, which has progressed despite multiple prior therapies," said Funda Meric-Bernstam, M.D., Professor and Chair of the Department of Investigational Cancer Therapeutics, Medical Director of the Institute for Personalized Cancer Therapy at The University of Texas MD Anderson Cancer Center. "The preliminary activity and tolerability of ZW25 combination treatment with paclitaxel or capecitabine brings hope to these patients and warrants further investigation in a first-line setting."

Clinical Data Presented Today

Safety and Efficacy of ZW25, a HER2-Targeted Bispecific Antibody in Combination with Chemotherapy in Patients with Locally Advanced and/or Metastatic HER2-Expressing Gastroesophageal Cancer (Abstract# B001, Poster Presentation on Monday, October 28 at 12:30 pm ET)

The results from part three of an ongoing Phase 1 study present the safety and efficacy of ZW25, at the recommended dose of 20 mg/kg every other week, in combination with paclitaxel or capecitabine as a treatment for 14 patients with heavily pretreated HER2-expressing GEA. Patients received a median of 2.5 prior systemic therapies, and 93% had progressed following trastuzumab treatment.

Nine of 14 patients were response-evaluable. Overall, the majority of patients experienced a decrease in their target lesions with a disease control rate of 78%, comprising five (56%) partial responses and two (22%) stable disease. These responses were observed in both low and high HER2-expressing GEA. At the time of the data cut-off, four of the five partial responses had been confirmed, and five (56%) response-evaluable patients were still on study.

The overall safety profile of ZW25 plus chemotherapy was similar to that seen with chemotherapy alone. The most common treatment-related adverse events (TRAE) occurring in two or more patients were primarily Grade 1 or 2 and manageable with symptomatic treatment. Of the TRAE occurring in two or more patients, Grade 3 or higher events attributed to ZW25 and/or chemotherapy were fatigue and neutropenia (2 patients each) and stomatitis, peripheral neuropathy, and hypokalaemia (1 patient each). Five patients had chemotherapy dose reductions due to TRAEs, but no patients needed ZW25 dose reductions due to adverse events.

About the Phase 1 Clinical Trial

Zymeworks’ Phase 1 study has three parts. From part one of the study (the dose-escalation phase), the recommended single-agent dose was determined to be 20 mg/kg once every two weeks or 10 mg/kg weekly. In the second part of the study (the cohort expansion phase), additional patients are being enrolled to further assess ZW25’s single-agent tolerability and anti-tumor activity against a variety of cancer types in different settings. The third part of the study (the combination phase) is underway and evaluating ZW25 in combination with selected chemotherapy agents in patients with HER2 high or lower HER2 expression levels.

About ZW25

ZW25 is being evaluated in Phase 1 and Phase 2 clinical trials across North America and South Korea. It is a bispecific antibody, based on Zymeworks’ Azymetric platform, that can simultaneously bind two distinct locations on HER2, known as biparatopic binding. This unique design results in multiple mechanisms of action including dual HER2 signal blockade, increased binding and removal of HER2 protein from the cell surface, and potent effector function leading to encouraging anti-tumor activity in patients. Zymeworks is developing ZW25 as a HER2-targeted treatment option for patients with any solid tumor that expresses HER2. The FDA has granted Fast Track designation to ZW25 for first-line gastroesophageal adenocarcinoma in combination with standard of care chemotherapy and Orphan Drug designation to ZW25 for the treatment of both gastric and ovarian cancers.

European Commission Approves BAVENCIO® (avelumab) Plus Axitinib Combination for First-Line Treatment of Patients With Advanced Renal Cell Carcinoma

On October 28, 2019 Merck KGaA, Darmstadt, Germany, which operates its biopharmaceutical business as EMD Serono in the US and Canada, and Pfizer Inc. (NYSE: PFE) reported that the European Commission (EC) has approved BAVENCIO (avelumab) in combination with axitinib for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC) (Press release, Pfizer, OCT 28, 2019, View Source [SID1234549916]). The approval was based on positive interim results from the Phase III JAVELIN Renal 101 study, which demonstrated that BAVENCIO in combination with axitinib significantly lowered risk of disease progression or death by 31% (HR: 0.69 [95% CI: 0.574–0.825; p<0.0001]) and nearly doubled objective response rate (ORR; 52.5% [95% CI: 47.7-57.2] vs. 27.3% [95% CI: 23.2-31.6]) compared with sunitinib in patients with advanced RCC regardless of PD-L1 status. The study included patients across International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic risk groups. Improvement in progression-free survival (PFS) was observed across pre-specified subgroups in patients receiving the treatment combination.1 Merck KGaA, Darmstadt, Germany, and Pfizer have a global strategic alliance to jointly develop and commercialize BAVENCIO.

"There is a high incidence of kidney cancer in Europe, and for the most common type, renal cell carcinoma, we continue to need additional treatment options, particularly for patients with advanced disease, where outcomes are poorest," said Professor James Larkin, Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust and Professor at the Institute of Cancer Research (ICR). "We’ve seen a demonstrated efficacy benefit and safety and tolerability profile for avelumab in combination with axitinib across all prognostic risk groups in patients with advanced renal cell carcinoma, so today’s approval in Europe brings an important option that can help healthcare professionals optimize treatment strategies across risk stratification."

In 2018, an estimated 136,500 new cases of kidney cancer were diagnosed in Europe, and approximately 54,700 people died from the disease.2 Many patients living with advanced RCC do not go on to receive additional treatment after first-line therapy,3,4for reasons that may include poor performance status or adverse events from their initial treatment.3,5,6 The five-year survival rate for patients with advanced RCC is approximately 12%.7

"This first European approval of an anti-PD-L1 as part of a combination treatment for advanced renal cell carcinoma builds on our commitment to bringing innovative treatment options to patients with hard-to-treat cancers through our extensive JAVELIN clinical trial program," said Rehan Verjee, Global Head of Innovative Medicine Franchises for the Biopharma business of Merck KGaA, Darmstadt, Germany. "RCC is the most common form of kidney cancer, accounting for 90% of diagnoses. We are now working to make BAVENCIO in combination with axitinib available for patients with advanced renal cell carcinoma as quickly as possible."

"The European Commission approval of BAVENCIO in combination with axitinib has the potential to bring even more patients with advanced renal cell carcinoma a new first-line treatment, and it allows us to continue to deliver on our more than decade-long passion to do more for patients with kidney cancer," said Andy Schmeltz, Global President, Pfizer Oncology. "We thank all of the researchers, doctors, advocates, patients and their families who helped get us here today, and we will continue in our fight against this advanced cancer."

The EC’s decision follows the U.S. Food and Drug Administration (FDA) approval of BAVENCIO in combination with axitinib for the first-line treatment of patients with advanced RCC in May 2019. A supplemental application for BAVENCIO in combination with axitinib in unresectable or metastatic RCC was submitted in Japan in January 2019.

Additionally, with this approval, the posology section of the Summary of Product Characteristics for BAVENCIO has been updated. The recommended dose of BAVENCIO as monotherapy is 800 mg administered intravenously over 60 minutes every 2 weeks. Administration of BAVENCIO should continue according to the recommended schedule until disease progression or unacceptable toxicity. The recommended dose of BAVENCIO in combination with axitinib is 800 mg administered intravenously over 60 minutes every 2 weeks and axitinib 5 mg orally taken twice daily (12 hours apart) with or without food until disease progression or unacceptable toxicity.1

Data from JAVELIN Renal 101 Study Supporting Approval
This approval was based on interim data from the Phase III JAVELIN Renal 101 study, a randomized, multicenter, open-label study of BAVENCIO in combination with axitinib in 886 patients with untreated advanced or metastatic RCC with a clear cell component. The study included patients across risk groups (International Metastatic Renal Cell Carcinoma Database Consortium [IMDC]: 21% favorable, 62% intermediate and 16% poor; Memorial Sloan Kettering Cancer Center [MSKCC]: 22% favorable, 65% intermediate and 11% poor). The primary efficacy endpoints were progression-free survival (PFS) as assessed by a Blinded Independent Central Review (BICR) using RECIST v1.1 and overall survival (OS) in the first-line treatment of patients with advanced RCC who have PD-L1-positive tumors (PD L1 expression level 1%). PFS based on BICR assessment per RECIST v1.1 and OS irrespective of PD L1 expression, objective response (OR), time to response (TTR), duration of response (DOR) and safety are included as secondary endpoints. The study is continuing for OS.

In the analysis, BAVENCIO in combination with axitinib significantly improved median PFS compared with sunitinib by more than five months in patients irrespective of PD-L1 expression (13.3 months [95% CI: 11.1–15.3] vs. 8.0 months [95% CI: 6.7–9.8]). With a median follow-up for OS of 19 months, data for the trial’s other endpoint of OS were immature, with 27% of deaths, and the trial is continuing as planned. The hazard ratio for OS in patients treated with BAVENCIO in combination with axitinib compared with sunitinib was 0.80 (95% CI: 0.616, 1.027) at the interim analysis.

The most common adverse reactions were diarrhea (62.8%), hypertension (49.3%), fatigue (42.9%), nausea (33.5%), dysphonia (32.7%), decreased appetite (26.0%), hypothyroidism (25.2%), cough (23.7%), headache (21.3%), dyspnea (20.9%), and arthralgia (20.9%).

About the JAVELIN Clinical Development Program
The clinical development program for avelumab, known as JAVELIN, involves at least 30 clinical programs and more than 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.8-10 In November 2014, Merck KGaA, Darmstadt, Germany, and Pfizer announced a strategic alliance to co-develop and co-commercialize BAVENCIO.

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

In the US, the FDA granted accelerated approval for BAVENCIO for the treatment of (i) adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (mMCC) and (ii) patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy, or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. These indications are approved under accelerated approval based on tumor response rate and duration of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

Avelumab is currently approved for patients with MCC in 50 countries globally, with the majority of these approvals in a broad indication that is not limited to a specific line of treatment.

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 axitinib 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 axitinib 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 axitinib, 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 axitinib: 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 axitinib 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 axitinib for Grade 3-4 cardiovascular events. MACE occurred in 7% of patients with advanced RCC treated with BAVENCIO in combination with axitinib 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.

The most common adverse reactions (all grades, ≥ 20%) in patients with metastatic Merkel cell carcinoma (MCC) were fatigue (50%), musculoskeletal pain (32%), diarrhea (23%), nausea (22%), infusion-related reaction (22%), rash (22%), decreased appetite (20%), and peripheral edema (20%).

Selected treatment-emergent laboratory abnormalities (all grades, ≥ 20%) in patients with metastatic MCC were lymphopenia (49%), anemia (35%), increased aspartate aminotransferase (34%), thrombocytopenia (27%), and increased alanine aminotransferase (20%).

The most common adverse reactions (all grades, ≥ 20%) in patients with locally advanced or metastatic urothelial carcinoma (UC) were fatigue (41%), infusion-related reaction (30%), musculoskeletal pain (25%), nausea (24%), decreased appetite/hypophagia (21%), and urinary tract infection (21%).

Selected laboratory abnormalities (Grades 3-4, ≥ 3%) in patients with locally advanced or metastatic UC were hyponatremia (16%), increased gamma-glutamyltransferase (12%), lymphopenia (11%), hyperglycemia (9%), increased alkaline phosphatase (7%), anemia (6%), increased lipase (6%), hyperkalemia (3%), and increased aspartate aminotransferase (3%).

Fatal adverse reactions occurred in 1.8% of patients with advanced renal cell carcinoma (RCC) receiving BAVENCIO in combination with axitinib. 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 axtinib (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 axitinib (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%).

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

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

Arterial and venous thrombotic events have been observed with axitinib 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 axitinib. Axitinib 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 axitinib dose.

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

Gastrointestinal perforation and fistula, including death, have occurred with axitinib. 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 axitinib. Monitor thyroid function before initiation of, and periodically throughout, treatment.

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

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

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

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

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

Axitinib 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 axitinib plasma concentrations and should be avoided.

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

Please see full Prescribing Information for axitinib.

ADVERSE REACTIONS (BAVENCIO + AXITINIB)
Fatal adverse reactions occurred in 1.8% of patients with advanced renal cell carcinoma (RCC) receiving BAVENCIO in combination with axitinib. 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 axitinib (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 RCCreceiving BAVENCIO in combination with axitinib (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%).