On June 24, 2021 Incyte (Nasdaq:INCY) reported the outcome of a meeting of the Oncologic Drugs Advisory Committee (ODAC) of the U.S. Food and Drug Administration (FDA), which reviewed the Biologics License Application (BLA) for retifanlimab, an intravenous PD-1 inhibitor, as a potential treatment for adult patients with locally advanced or metastatic squamous cell carcinoma of the anal canal (SCAC) who have progressed on, or who are intolerant of, platinum-based chemotherapy (Press release, Incyte, JUN 24, 2021, View Source [SID1234584314]). The Committee voted 13-4 that a regulatory decision on retifanlimab for the treatment of advanced or metastatic SCAC should be deferred until further data are available from clinical trial POD1UM-303, a confirmatory trial in platinum-naïve advanced SCAC that is currently underway.

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The ODAC provides the FDA with independent opinions and recommendations from outside experts on marketed and investigational medicines for use in the treatment of cancer. The FDA considers the advice of the ODAC in its review but is not bound to follow its recommendations.

"While we are disappointed by the outcome of today’s ODAC vote, we will continue to work closely with the FDA as it completes its review of the BLA for retifanlimab," said Lance Leopold, M.D., Group Vice President, Immuno-Oncology Clinical Development, Incyte. "Patients with advanced SCAC who have progressed after first-line platinum-based chemotherapy currently have no FDA-approved treatments available to them and face an extremely poor prognosis. We continue to believe that retifanlimab can provide an additional, much-needed option for these patients based on the favorable benefit/risk shown in our trial."

The BLA for retifanlimab is based on data from the Phase 2 POD1UM-202 trial evaluating retifanlimab in 94 previously treated patients with locally advanced or metastatic SCAC who have progressed on, or are intolerant of, platinum-based chemotherapy. The FDA previously granted retifanlimab Orphan Drug Designation for the treatment of anal cancer, along with Priority Review, and set the Prescription Drug User Fee Act (PDUFA) target action date for retifanlimab as July 25, 2021.

SCAC is almost always associated with human papillomavirus (HPV) and HIV infections and accounts for nearly 3% of digestive system cancers.1 Patients with metastatic SCAC have a poor 5-year survival, and there are no FDA-approved treatments for patients who have progressed after first-line chemotherapy.2

About POD1UM-202

POD1UM-202 (NCT03597295) is an open-label, single-arm, multicenter, Phase 2 study evaluating retifanlimab in 94 patients with locally advanced or metastatic squamous cell carcinoma of the anal canal (SCAC) who have progressed on, or were ineligible for or intolerant of, platinum-based chemotherapy. Retifanlimab 500mg is administered as an intravenous infusion every 4 weeks for up to 2 years.

The primary endpoint was overall response rate (ORR) as determined by independent central review using RECIST v1.1. Secondary endpoints included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS); safety and pharmacokinetics.

For more information about the study, please visit View Source

About POD1UM

The POD1UM (PD1 Clinical Program in Multiple Malignancies) clinical trial program for retifanlimab includes Phase 1, 2 and 3 studies for patients with solid tumors both as monotherapy and in combination with Incyte’s early development portfolio. Additional indications in late-stage development include platinum-naïve squamous cell carcinoma of the anal canal (SCAC), microsatellite instability-high endometrial cancer, Merkel cell carcinoma and non-small cell lung cancer.

About Retifanlimab

Retifanlimab (formerly INCMGA0012), an investigational intravenous PD-1 inhibitor, is currently under evaluation in Phase 1, 2 and 3 studies for patients with solid tumors both as monotherapy and in combination with Incyte’s early development portfolio. Additional indications in late-stage development include platinum-naïve squamous cell carcinoma of the anal canal (SCAC), microsatellite instability-high endometrial cancer, Merkel cell carcinoma and non-small cell lung cancer.

Retifanlimab has been granted Orphan Drug Designation by the U.S. Food and Drug Administration for the treatment of anal cancer. A Marketing Authorization Application for retifanlimab is also under review by the European Medicines Agency.

In 2017, Incyte entered into an exclusive collaboration and license agreement with MacroGenics, Inc. for global rights to retifanlimab. In 2019, Incyte and Zai Lab announced a collaboration and license agreement for the development and commercialization of retifanlimab in Greater China.

On June 24, 2021 Transgene (Paris:TNG) (Euronext Paris: TNG), a biotech company that designs and develops virus-based immunotherapeutics against cancer, reported that a first patient has been enrolled in a randomized, controlled Phase II study evaluating the combination of TG4001 with avelumab versus avelumab monotherapy in patients with HPV16-positive anogenital tumors (NCT: 03260023) (Press release, Transgene, JUN 24, 2021, View Source [SID1234584330]).

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TG4001 IS AN INVESTIGATIONAL THERAPEUTIC VACCINE TARGETING HPV-POSITIVE TUMORS, including cervical, anal, and other anogenital cancers. It is based on a Vaccinia vector (MVA), which is engineered to express HPV16 E6 and E7 antigens and interleukin 2 (IL-2). TG4001 is designed to alert the immune system specifically to cells presenting these HPV antigens (that can be found on HPV-related tumors) and to induce a specific cellular immune response against these cancer cells.

Based on promising data obtained in the Phase Ib/II part of the trial, Transgene is progressing the development of TG4001 in combination with avelumab, through a randomized Phase II trial and an extended collaboration with the alliance of Merck KGaA, Darmstadt, Germany, and Pfizer, which is supplying avelumab.

PHASE II TRIAL AIMS TO SHOW THE SUPERIORITY OF TG4001 + AVELUMAB OVER AVELUMAB MONOTHERAPY

The randomized Phase II trial is focusing on patients with recurrent or metastatic HPV16-positive anogenital cancer, including cervical, vulvar, vaginal, penile, and anal cancer, without liver metastases. In the Phase Ib/II part of the study, very encouraging clinical outcome was observed in patients without liver metastases [1,2].

Patients will be randomized to either receive the combination regimen of the therapeutic vaccine TG4001 and avelumab or avelumab alone. The trial will be enrolling patients in the USA and in Europe (France and Spain).

The primary endpoint of the trial is progression-free survival (PFS) according to RECIST 1.1. Secondary endpoints include objective response rate (ORR), disease control rate (DCR), overall survival (OS) and a series of immunological parameters.

An interim analysis will be performed after the enrollment of approximately 50 patients. Transgene expects to communicate interim analysis data around the end of 2022.

Dr. Maud Brandely, MD, PhD, Chief Medical Officer of Transgene, added: "We are confident that the combination regimen of TG4001 and avelumab has the potential to deliver improved progression-free survival for patients with advanced/recurrent HPV16-positive anogenital cancer without liver metastases. This confidence is based on the very encouraging results from the initial Phase Ib/II study, which showed important clinical benefits in this patient population in terms of response rate and progression-free survival. This earlier study part also showed that patients had vaccine-induced reactive T cells against E6, E7 or both. This randomized trial has been designed to further demonstrate that the addition of TG4001 to an immune checkpoint inhibitor can improve the clinical outcome for patients with HPV16-positive anogenital cancer without liver metastases. We are looking forward to announcing the interim results from this expanded study which could be a key milestone in bringing TG4001 to patients in need of improved treatment options."

About the trial
The multi-center, open label, randomized Phase II trial (NCT03260023) is designed to compare the efficacy of the combination of TG4001 and avelumab versus avelumab alone in patients with HPV16-positive anogenital cancers who have disease progression after a maximum of one line of systemic treatment for recurrent/metastatic disease, or who are not eligible for first-line chemotherapy.

Prof. Christophe Le Tourneau, M.D., PhD, Head of the Department of Drug Development and Innovation (D3i) at the Curie Institute, is the Principal Investigator of the study. The trial is being conducted in collaboration with Merck KGaA, Darmstadt, Germany, and Pfizer Inc. (NYSE: PFE), which are providing avelumab for the trial. Avelumab is co-developed and co-commercialized by Merck KGaA, Darmstadt, Germany and Pfizer Inc. Transgene will continue to be the sponsor of the trial and conduct the trial.

Patients will receive TG4001 at the dose of 5×107 plaque-forming units (pfu), subcutaneously (SC), weekly for 6 weeks, every 2 weeks up to six months, and every 12 weeks thereafter, in combination with avelumab or avelumab alone at 800 mg, intravenously (IV) every two weeks, until disease progression. The primary endpoint of the trial is progression-free survival (PFS) according to RECIST 1.1. Secondary endpoints include objective response rate (ORR), disease control rate (DCR), overall survival (OS) and other immunological parameters. The trial could enroll approximately 150 patients until the final analysis.

Patients with liver metastases will be followed in an ancillary arm and will not be included in the primary analyses.

***

About the data presented at SITC (Free SITC Whitepaper) 2020 and ESMO (Free ESMO Whitepaper) IO 2020 [1,2]
The results from the Phase Ib/II parts of the trial combining TG4001 with avelumab in HPV16-positive recurrent and/or metastatic malignancies were presented at SITC (Free SITC Whitepaper) 2020 [1] and ESMO (Free ESMO Whitepaper) IO 2020[2].

The combination of TG4001 and avelumab demonstrated anti-tumor activity (23.5% ORR) in patients with previously treated recurrent and/or metastatic HPV-related cancers (including patients with oropharyngeal cancers and anogenital cancers). Presence of liver metastases had a profound impact on the outcome in terms of ORR and PFS. In patients without liver metastases, an ORR of 34.8% and a median PFS of 5.6 months were achieved. The treatment induced HPV-specific T-cell responses and was associated with increased levels of immune cell infiltration in the tumors and expression of genes associated with activation of the immune system.

About TG4001
TG4001 is an investigational therapeutic vaccine based on a non-propagative, highly attenuated Vaccinia vector (MVA), which is engineered to express HPV16 antigens (E6 & E7) and an adjuvant (IL-2). TG4001 is designed to have a two-pronged antiviral approach: to alert the immune system specifically to cells presenting the HPV16 E6 and E7 antigens, that can be found in HPV16-related tumors, and to further stimulate the infection-clearing activity of the immune system through interleukin 2 (IL-2). TG4001 has been administered to more than 300 individuals, demonstrating good safety and promising efficacy results [1, 2]. Its mechanism of action and good safety profile make TG4001 an excellent candidate for combinations with other therapies in HPV-mediated solid tumors.

On June 24, 2021 SkylineDx reported to invest in research and development in the field of Squamous Cell Carcinoma (SCC), as part of a Dutch consortium including the Erasmus MC Cancer Institute, University Medical Center Rotterdam (EMC) (Press release, SkylineDx, JUN 24, 2021, View Source [SID1234584346]). The collaboration focuses on the discovery and validation of a model that identifies the SCC patient at high risk of developing metastasis. These high-risk patients would benefit from an intensive surveillance program to closely monitor the progress of their disease. The second objective is to enrich the model by adding genomic information to identify the most aggressive tumors among high-risk patients. Those patients may benefit from more aggressive or adjuvant treatment to reduce their risk of metastasis. This collaboration has a unique starting point because the researchers have extensive experience and will work with the unique infrastructure of large national routinely collected health care datasets of metastatic SCC patients.

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Squamous Cell Carcinoma is the second most common form of skin cancer and is diagnosed approximately 1.8 million times per year in the United States [2]. Exact number of people who develop or die from SCC is unknown as this cancer is not well-tracked globally and notably understudied. In general, 95% of patients have a good prognosis and will not develop SCC-related metastasis.

"Unfortunately, we lack predictive models that can differentiate these patients with a good prognosis from the patients at high risk of developing metastasis. Consequently, in current clinical practice, the entire patient population receives an intensive 5-year follow-up regime, putting an unnecessary burden on both patients and the healthcare system", comments Dr. Marlies Wakkee, Dermatologist at EMC. "This consortium is a strong collaborative effort between different experts from a scientific and a business perspective to develop and translate the scientific project to clinical practice. Through the support of this investment, we have the opportunity to truly improve the diagnostic, treatment and follow-up pathways of patients with this type of skin cancer".

"There is a huge medical unmet need affecting millions of Squamous Cell Carcinoma patients globally each year. I am confident that together with EMC, we can develop the prediction models into actionable molecular tests, ready for clinical use", concludes Dharminder Chahal, CEO SkylineDx. "After several research and study initiatives in melanoma, we now continue to expand our scope and add value as a company in a broader field of skin cancer".

On June 24, 2021 Takara Bio Inc. reported that it has entered into a License and Supply Agreement with BioNTech Cell & Gene Therapies GmbH ("BioNTech"), a BioNTech SE company (www.BioNTech.de), Germany, under which Takara Bio grants BioNTech a commercial license to use applicable patents relating to RetroNectin (Press release, Lifescience Newswire, JUN 24, 2021, View Source [SID1234584381]). Under this agreement, Takara Bio provides BioNTech with reliable supplies of RetroNectin.

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The patented technologies licensed to BioNTech are based on Takara Bio’s proprietary RetroNectin method, which includes a technology enabling highly efficient gene transduction to cells by retrovirus/lentivirus vector and expansion of T-cells with high efficiency. With such advantages, RetroNectin method is one of the mostly used standard protocols utilized for "Engineered T-cell Therapy", which includes promising TCR and CAR gene therapies recently raising higher expectations.

Under the agreement signed with Takara Bio, BioNTech is allowed to use RetroNectin for production of its cell & gene therapy products, therapies in which a patient’s T cells are genetically engineered to express a CAR for the treatment of multiple solid tumors.

Takara Bio is promoting supply of RetroNectin to clinical development of Engineered T-cell Therapy actively pursued worldwide in recent years, and expects higher sales growth in the future.

On June 24, 2021 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a commercial-stage pharmaceutical company pioneering novel cancer therapies, reported the expansion of its royalty agreement with entities managed by HealthCare Royalty Management, LLC (HCR) for up to $100 million in new financing to support the ongoing development and commercialization of XPOVIO (selinexor), the Company’s first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound, and for the clinical development of Karyopharm’s other programs, including eltanexor (Press release, Karyopharm, JUN 24, 2021, View Source [SID1234584315]). XPOVIO is currently marketed in the U.S. for multiple hematologic malignancy indications and has received conditional marketing authorization by the European Commission for patients with heavily pretreated multiple myeloma. Eltanexor is currently being investigated for the treatment of patients with refractory myelodysplastic syndrome.

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Under the terms of the amended agreement, Karyopharm received $60 million and is eligible to receive two additional $20 million payments subject to certain prespecified future development and commercial milestones. HCR will receive tiered royalty payments based on worldwide net revenues of XPOVIO and any other future products. This expanded agreement follows a previous investment of $75 million that HCR made in Karyopharm in September 2019.

Karyopharm expects that the $60 million received from HCR under this expanded royalty agreement, combined with its existing cash, cash equivalents and investments, and the cash expected to be generated from product sales, will be sufficient to fund its operations into the middle of 2023.

"We are thrilled to expand our relationship with HCR and this additional non-dilutive financing provides Karyopharm with immediate and substantial capital to support the ongoing commercialization and clinical development of XPOVIO and our other products in future cancer indications, including in a variety of high unmet need solid tumor settings," said Richard Paulson, MBA, President and Chief Executive Officer of Karyopharm. "As we continue to make progress on our commercialization efforts, we are delighted to have the support and confidence of HCR to further expand our clinical development efforts on behalf of patients across the globe."

Clarke Futch, Chairman and Chief Executive Officer of HCR stated: "Based on the strong relationship we have built with the Karyopharm team over the past few years and our increasing confidence in the long-term potential for XPOVIO, we are delighted to broaden our investment in Karyopharm and further support the expansion of XPOVIO, including into solid tumors."